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Colorectal Regimens v4.3 NWLCN 16Dec10

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Colorectal Regimens v4.3 NWLCN 16Dec10 Powered By Docstoc
					COLORECTAL REGIMENS
Section by: Dr Pippa Riddle, Dr Suzy Cleator , Dr Harpreet Wasan, Dr Charles Lowdell,
Dr Riz Ahmed, , Professor Robert Leonard, Professor Hani Gabra.
Section last updated: 19th July 2010               Section last corrected 16thDecember2010
Approved by GI Oncology Lead Clinician:                          Professor H Gabra Date
Approved by NWLCN Colorectal Tumour Group:                      Mr P Dawson        Date
Review date: June 2011

INDEX                                                                                     Page

COLORECTAL CANCER
Chemotherapy alone (No radiotherapy)
1.  5Fluorouracil Single Agent +/- Folinic Acid
    a.    MAYO           5FU 425/FA 20 5 day                             CTIS 739            3
                         5FU 370/FA 20 5 day                             CTIS 659            3
    b.    Degramont                                                      CTIS 734/CVAD       5
                                                                         CTIS 1219/NS        5
       c.      Lokich/5FU-300 contin                                     CTIS 221            7
       d.      5FU 370/FA 20 weekly                                      CTIS 239            8
               5FU 425/FA 20 weekly                                      CTIS 1217           8

2.     Oral Fluoropyrimidine Single Agent
       a.     Capecitabine 2500/day 14 day (DeGramont substitute)        CTIS 810             9
       b.     Tegafur with uracil (Uftoral)                              CTIS 1215           12

3.     Irinotecan chemotherapy
       a.     IrMdG Irinotecan-Degramont                                 CTIS 751/CVAD       13
                                                                         CTIS 1220/NS        13
       b.      Irinotecan-Capecitabine                                   CTIS                15
       c.      Irinotecan Single Agent                                   CTIS 195            19

4.     Oxaliplatin Chemotherapy
       a.     OxMdG       Oxaliplatin-Degramont                          CTIS 327/CVAD       20
                                                                         CTIS 1216/NS        20
       b.      Cape-Ox         Oxaliplatin-Capecitabine                  CTIS                24
               Ox-Ralt         Oxaliplatin-Raltitrexed (see page 32)

5.     Mitomycin Chemotherapy
       a.    MitoC-5FU.Contin                                            CTIS 195            26
       b.    MitoC-Capecitabine                                          CTIS                28

6.     Raltitrexed (Tomudex)
       a.      Raltitrexed Single Agent                                  CTIS 736            30
       b.      Raltitrexed-Oxaliplatin                                   CTIS                32




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                                                                                       Page
7.     Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibodies
       General advice on prophylaxis against skin reactions                              33

8.     Cetuximab (Erbitux)                                                               33
       NHS
       a.     Cetuximab-OxMdG              Cetuximab-Oxaliplatin-Degramont               33
       b.     Cetuximab-IrMdG              Cetuximab-Irinotecan-Degramont                38
       Additional Private Care
       c.     Cetuximab Single Agent                                                     40
       d.     Cetuximab-CapeOx             Cetuximab-Oxaliplatin-Capecitabine            41

9.     Bevacizumab (Avastin) ALL REGIMENS ADDITIONAL PRIVATE CARE
       a.    Bevacizumab-OxMdG      Bevacizumab-Oxaliplatin-Degramont                    43
       b.    Bevacizumab-Cape-Ox    Bevacizumab-Oxaliplatin-Capecitabine                 47
       c.    Bevacizumab-IrMdG      Bevacizumab-Irinotecan-Degramont                     48
       d.    Bevacizumab-Cape       Bevacizumab-Capecitabine                             49

10.    Panitumumab (Vectibix) Additonal Private Care
       a.    Panitumumab Single Agent                                                    50

11.    Embolisation (Additional Private Care)
       a.    SIR-spheres embolisation                                                    52


COLORECTAL CANCER
Chemo radiation regimens

Chemo-Radiation Dose Modifications                                                       55

12.    5Fluorouracil Single Agent + Radiotherapy
       a.    Bossett Regimen 5FU 350/FA 20 + RT                       CTIS 282, 283      56

13.    Capecitabine + Radiotherapy
       a.   Capecitabine-1650 + RT                                    CTIS 1028          57


ANAL CANCER
Chemo-radiation Regimens
14.  Mitomycin/5FU + RT                                                                  58
     UKCCR Regimen local disease                       via CVAD       wk 1CTIS 742       58
                                                                      wk 5 CTIS 738      58
                                                       Via NS         wk 1 CTIS 708      58
                                                                      wk5 CTIS 709       58
Chemotherapy Alone
15.  Cisplatin-5FU. CISP-60-5FU 4 day                                 CTIS 1364          59
                                                                      CVAD 1218/NS       59

16.    Docetaxel Single Agent (Additional Private Care)                                  61

17.    Capecitabine Dose Tables                                                          63
       WHO Performance status                                                            66
       Cockcroft Gault formula                                                           66

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COLORECTAL REGIMENS
Section by: Dr Pippa Riddle, Dr Suzy Cleator , Dr Harpreet Wasan, Dr Charles Lowdell,
Dr Riz Ahmed, , Professor Robert Leonard, Professor Hani Gabra.
Section last updated: 19th July 2010                 Last corrected: 16th December 2010
Approved by GI Oncology Lead Clinician:                     July 2010
Approved by NWLCN Colorectal Tumour Group:                  July 2010
Review date: June 2011

CHEMOTHERAPY ALONE (No radiotherapy)

1.     5-Fluorouracil Single Agent Regimens +/- Folinic Acid
       Folinic acid refers to the mixed racemix D and L isomers.
       Calcium levofolinate refers to L folinic acid isomers only.

MAYO Adaptations:
1a. 5FU425/FA20 5day (CTIS: 739) or 5FU 370/FA20 5day (CTIS: 659)
    Folinic Acid          20mg/m2            IV bolus                                   Days 1 to 5
    5 Fluorouracil        dose determined by age see below
    Dose under 70 years   425mg/m2           IV bolus                                   Days 1 to 5
    and ECOG 1
    Dose over 70 years    370mg/m2           IV bolus                                   Days 1 to 5
    and/or ECOG 2

       Interval between cycles:    Repeat every 28 days
       Number of cycles:           Colon cancer
                                   Neoadjuvant                        up to 6 cycles/6 months
                                   Adjuvant                           up to 6 cycles/6 months
                                   Metastatic/local recurrence        up to 6 cycles/6 months
       Tests before starting course of chemo:           FBC, U&Es, LFTs, tumour markers CEA,
                                                        CA19-9
       Tests to OK/Confirm each cycle of chemo:         FBC, U&Es, LFTs
       Supportive drugs with each cycle:                Low risk antiemetics
                                                        Chlorhexidine mouthwash 10mls QDS
                                                        Loperamide 2-4mg QDS PRN
       Patient information:                Chemotherapy treatment booklet (local information)
                                           Your chemotherapy record (NWLCN red book)
                                           BACUP information sheet
       Additional information:
              Administration notes:
              Suck ice cubes or ice lollies 5 minutes before and for 30 minutes after injection (if
              tolerated) of 5FU may reduce the incidence of stomatitis.
       Dose Modifications: See MAYO table Lower GI page 4-5
       References: J. Clin Oncol 1997 15:246-50. O’Connell et al
                     Ann. Oncol 1998 9 (5):535-41. Borner MM
                     J. Clin Oncol 1989 7(10):1407-18 (425mg)
                     J. Clin Oncol 1991;9:449-52 (ice chips)




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Table: MAYO (Ref. QUASAR protocol UKCCCR 1998)
Radical treatment only: For combination of Haematological/non Haematological toxicity
 Wait until FULL recovery ie. neutrophils 1.5 x109/L and platelets 100 x109/L and/or any
   persistent mucositis and diarrhoea have resolved.
 If resolved within 2 weeks restart chemo using dose modifications below.
 If FULL recovery takes more than 2 weeks discuss with consultant.

Haematological                                     Non Haematological Toxicity
Toxicity                                     On day of chemo or during previous cycle
                                                      (Diarrhoea or mucositis)
Neutrophils           Platelets                                CTC Grade
x109/L                x109/L         0-1                  2                    3                  4
≥ 1.5   And              ≥100 Full dose            Full dose          Delay until            Do not give
                                                                      recovery to toxicity
                                                                      ≤grade 2 then give
                                                                      50% dose
                                                                      reduction
≥1.0-1.5* And/or            50-99 Delay until      Delay until        Delay until full       Do not give
                                  haematological   haematological     haematological
Discuss with consultant as in     recovery then    recovery then      and non-
some cases may go ahead with
neutrophils 1.0 to 1.5 provided   give full dose   give 20% dose      haematological
platelets ≥100                                     reduction          recovery to toxicity
                                                                      grade ≤2 then
                                                                      give 50% dose
                                                                      reduction
0.5-0.99         Or     25-49 Delay until full     Delay until        Delay until full       Do not give
                              haematological       haematological     haematological
                              recovery then        recovery then      and non-
                              give 20% dose        give 30% dose      haematological
                              reduction            reduction          recovery to toxicity
                                                                      ≤ grade 2 then
                                                                      give 50% dose
                                                                      reduction
<0.5             Or     <25     Delay until        Delay until        Delay until full       Do not give
                                haematological     haematological     haematological
                                recovery then      recovery then      and non-
                                give 50% dose      give 50% dose      haematological
                                reduction          reduction          recovery to toxicity
                                                                      ≤ grade 2 then
                                                                      give 50% dose
                                                                      reduction

Do not dose reduce Folinic Acid




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 Side-Effect: MAYO                         Dose Modification     (Source:Quasar/FOCUS trials)
 Haematology                               See above
 Renal function GFR ≤ 30mls/min            Unclear guidance. Discuss with consultant
 Hepatic function                          Unclear guidance. Discuss with consultant
 Stomatitis                                Routine mouthcare with chlorhexidine. Ensure ice chips
                                           are being used during administration of 5FU.
                                           If still a problem reduce dose according to table above
 Diarrhoea                                 Give loperamide 2-4mg oral QDS PRN (max 16mg/day)
                                           or codeine phosphate 30-60mg oral QDS PRN.
                                           If still a problem reduce dose according to table above
 Hand-Foot Syndrome                        Reduce dose according to table page 4

                                           Phase III randomised controlled trials show no benefit for
                                           pyridoxine for prevention or treatment of 5FU induced hand
                                           foot syndrome. Pyridoxine is not recommended.
 DPD Deficiency (Focus)                    1-3% of patients have markedly exaggerated 5FU toxicity
                                           due to reduced 5FU catabolism. Discuss with consultant.
 Cardiotoxicity (Focus)                    Uncommon. 5FU may provoke angina or MI in patients
                                           with ischaemic heart disease. Seek specialist opinion on
                                           upgraded anti-anginal medication and consider dose
                                           reduction or alternative non 5FU treatment.
 Neurotoxicity (Focus)                     Uncommon – Cerebellar
                                           Consider alternative non 5FU treatment


1b.    DeGramont Regimen:
       May 2005: Where possible DeGramont regimens should be standardised to the “Modified”
       version either via CVAD/Infusor or via peripheral line/litre infusion bags (unless dictated
       otherwise by clinical trials).

       DeGramont – Modified (MdG via CVAD CTIS: 734, MdG via N/S CTIS: 1219)
       Folinic Acid            350mg           IV over 2 hours          Day 1
                                       2
       5 Fluorouracil          400mg/m         IV bolus                 Day 1
       5 Fluorouracil         2800mg/m2        IV over 46 hours         Days 1 to 2

       Interval between cycles:   Repeat every 14 days
       Number of cycles:          Colon cancer:
                                  Neoadjuvant:       Duration depends on response and future
                                                     plans generally 3-4 cycles
                                  Adjuvant:          12 cycles/6 months
                                  Metastatic
                                  Locally/advanced: 6-12 cycles/3-6 months
                                                     Depends on response (tumour markers/CT
                                                     scans). Review as directed by
                                                     markers/clinical assessment. Beyond 12
                                                     cycles at consultant’s directions only.
       Tests before starting course of chemo:        FBC, U&Es, LFTs, tumour markers
                                                     CEA, CA19-9
       Tests to OK/Confirm each cycle of chemo:      FBC, U&Es, LFTs
       Supportive drugs with each cycle:             Low risk antiemetics

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                                                               Chlorhexidine mouthwash 10mls QDS.
                                                               Loperamide 2-4mg QDS PRN (max
                                                               16mg/24hrs)
       Patient information:                      Chemotherapy treatment booklet (local information)
                                                 Your chemotherapy record (NWLCN red book)
                                                 BACUP information sheet on Degramont
                                                 Written information on mechanical pump (if via CVAD)
       Additional information:
              Administration notes:
              5FU: If 5FU administered using an ambulatory infusion pump via a central venous
              access device (CVAD) refer to relevant protocol for care of CVAD. Joint care with
              the community nursing services should be arranged in advance to support the
              patient and to assist with disconnecting the chemotherapy and flushing the CVAD.
              Written community nursing referral should be completed and the patient should be
              discharged with a home spillage kit, sharps container and a small supply of
              equipment to flush the line and dress the entry site of the CVAD.
       Dose modifications: See DeGramont Modified table below
       References: J. Clin Oncol 1997;15:808-15 De Gramont et al
                     J. Clin Oncol 1998;16:301-308 Meta Analysis Group in Cancer
                     Annals Oncology 1998;9(Suppl 4):47 (modified)

Table: DeGramont – Modified
NB. Palliative patients will require greater dose reductions than stated below based on individual
patient parameters. Discuss with consultant.
  Side-Effect: MdG                                    Dose Modification (Source: Focus (CR08) Trial/2000)
  Haematology (CR08)
  Neutrophils                        Platelets
  x109/L                              x109/L
  1.5         and                   100             Full dose
  <1.5         or                     <100            Delay until recovery.
                                                      Only treat when WBC/neutrophils and platelets are
                                                      above these limits
                                                      If more than 1 delay, or one delay of 2 weeks
                                                      occurs then restart with:
                                                      5FU: 20% dose reduction (bolus and infusion).
                                                      Continue with this reduced dose unless further
                                                      toxicity occurs.
                                                      If further delays for myelotoxicity occur despite the
                                                      20% dose reduction, discuss with consultant
  Renal function GFR ≤ 30mls/min                      Unclear guidance. Discuss with consultant
  Hepatic function                                    Unclear guidance. Discuss with consultant
  Stomatitis (Focus)                                  If mouth ulcers occur despite routine chlorhexidine
                                                      mouthwash:
                                                      5FU: 20% dose reduction (bolus and infusion).
                                                      Continue with this reduced dose unless further
                                                      toxicity occurs.
  Diarrhoea (Focus)                                   Between cycles – treat symptomatically
                                                      loperamide 2-4mg QDS PRN and/or codeine
                                                      phosphate 30-60mg QDS PRN
                                                      Not resolved by next cycle: Delay 1 week/until
                                                      recovered
                                                      If diarrhoea still a problem
                                                       Despite symptomatic treatment
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  Side-Effect: MdG                            Dose Modification (Source: Focus (CR08) Trial/2000)
                                               Or more than one delay is required
                                              Then dose reduce 5FU: 20% dose reduction
                                              (bolus and infusion). Continue with this reduced
                                              dose unless further toxicity occurs.
  Hand-Foot Syndrome (Focus/Focus 2)
                                 Grade 2 Dose reduce.
                                          5FU: 20% dose reduction (bolus and infusion) for
                                          subsequent cycles.

                                              Phase III randomised controlled trials show no benefit
                                              from pyridoxine for prevention or treatment of 5FU
                                              induced hand foot syndrome. Pyridoxine is not
                                              recommended.
  DPD Deficiency (Focus)                      1-3% of patients have markedly exaggerated 5FU
                                              toxicity due to reduced 5FU catabolism. Discuss
                                              with consultant.
  Cardiotoxicity (Focus)                      Uncommon. 5FU may provoke angina or MI in
                                              patients with ischaemic heart disease. Seek
                                              specialist opinion on upgraded anti-anginal
                                              medication and consider dose reduction or
                                              alternative non 5FU treatment.
  Neurotoxicity (Focus)                       Uncommon – Cerebellar
                                              Consider alternative non 5FU treatment


1c.    Lokich/5FU-300 Contin (CTIS: 221)
       5-Fluorouracil         300mg/m2/day            IV continuous infusion for 12 weeks

       Continuous infusion for 12 weeks , 1 cycle = 3 weeks. Repeat tests every 21 days

       Interval between cycles:   Continuous infusion for 12 to 24 weeks (4 to 8 cycles of 21
                                  days)
       Number of cycles:          Colon cancer
                                  Neoadjuvant: depends on response
                                  and future plans                   12 weeks generally
                                  Adjuvant:                          12-24 weeks
                                  Metastatic/locally advanced:       12-24 weeks depends on
                                                                     response (tumour markers/CT
                                                                     scans). Review as directed by
                                                                     markers/clinical assessment.
                                                                     Beyond 24 weeks at
                                                                     consultant’s direction only.
       Tests before starting course of chemo:          FBC, U&Es, LFTs, tumour markers
                                                       CEA,CA19-9
       Tests to OK/Confirm each cycle of chemo:        FBC, U&Es, LFTs
       Supportive drugs with each cycle:               Low risk antiemetics.
                                                       Chlorhexidine mouthwash 10mls QDS.
                                                       Loperamide 2-4mg QDS PRN (max 16mg/
                                                       24hrs)
       Patient information:              Chemotherapy treatment booklet (local information)
                                         Your chemotherapy record (NWLCN red book)
                                         BACUP information sheet
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                                             Written information on mechanical pump (if via CVAD)
       Additional information:
              Administration notes:    See Colorectal page 6
       Dose modifications:       Table Lokich below
       References: J. Clin Oncol 1989;7:425-32. Lokich et al
                     NEJM 1994;331:502-7. O’Connell et al.

Table: Lokich
NB. Palliative patients will require greater dose reductions than stated below based on individual
patient parameters. Discuss with consultant.
  Side-effect: Lokich                           Dose Modification (Source: CR06 Trial)
  Haematology
  WBC           <1.5 x 109/L                    Interrupt infusion for 1 week (or until recovery
  OR                                            Resume with
  Platelets     <75 x 109/L                     5FU: reduce dose by 50mg/m2/ day
  Renal function GFR ≤ 30mls/min                Unclear guidance. Discuss with consultant
  Hepatic function                              Unclear guidance. Discuss with consultant
  Stomatitis (CR06)                             Routine mouthcare with chlorhexidine.
                                                If still a problem: stop chemo until recovery then
                                                Restart with 5FU: Reduce by 50mg/m2/day
  Diarrhoea    (CR06)                           Give loperamide 2-4mg QDS or codeine phosphate
                                                30-60mg QDS
                                                If still a problem: stop chemo until recovery then:
                                                Restart with 5FU: Reduce by 50mg/m2/day
  Hand/Foot Syndrome
                                      Grade 2 Stop chemo until recovery then: Restart with 5FU:
                                               Reduce by 50mg/m2/day.

                                                Phase III randomised controlled trials show no benefit
                                                from pyridoxine for prevention or treatment of 5FU
                                                induced hand foot syndrome. Pyridoxine is not
                                                recommended.
  DPD Deficiency                                1-3% of patients have markedly exaggerated 5FU
                                                toxicity due to reduced 5FU catabolism. Discuss
                                                with consultant.
  Cardiotoxicity                                Uncommon. 5FU may provoke angina or MI in
                                                patients with ischaemic heart disease. Seek
                                                specialist opinion on upgraded anti-anginal
                                                medication and consider dose reduction or
                                                alternative non 5FU treatment.
  Neurotoxicity                                 Uncommon – Cerebellar
                                                Consider alternative non 5FU treatment


1d.    5FU370/FA20 weekly (CTIS: 239 ) or 5FU425/FA20 weekly (CTIS: 1217)
       Folinic Acid           20mg/m2            IV bolus                                       Day 1
       5 Fluorouracil         dose determined by age see below
       Dose under 70 years    425mg/m2           IV bolus                                       Day 1
       and ECOG 1
       Dose over 70 years     370mg/m2           IV bolus                                       Day 1
       and/or ECOG 2


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       Use standard MAYO (Colorectal page 1) in preference to this regimen ie. only use this
       regimen if unable to tolerate MAYO or infusional 5-FU (DeGramont). This regimen is used
       in exceptional circumstances eg. in severe renal failure.

       Interval between cycles: Repeat every 7 days
       Number of cycles:          Colon cancer: Adjuvant:          30 weeks
       Tests before starting course of chemo:        FBC, U&Es, LFTs, tumour markers
                                                     CEA,CA19-9
       Tests to OK/Confirm each cycle of chemo:      FBC, U&Es, LFTs
       Supportive drugs with each cycle:             Low risk antiemetics
                                                     Chlorhexidine mouthwash 10mls QDS
                                                     Loperamide 2-4mg QDS PRN (max
                                                     16mg/24hrs)
       Patient information:              Chemotherapy treatment booklet (local information)
                                         Your chemotherapy record (NWLCN red book)
                                         BACUP information sheet
       Additional information:
              Administration notes:
              See notes for 5FU425/FA20 5day on Colorectal page 3
       Dose Modifications: Table MAYO Colorectal page 4-5
       Reference: QUASAR


2.     Oral Fluoropyrimidine Single Agent Regimens
       Capecitabine is not licensed as a substitute for 5Fluorouracil in all 5FU regimens/clinical
       circumstances. Capecitabine should only be substituted for infusional 5FU regimens where
       there is local New Drugs Panel approval.

2a.    Capecitabine 2500 (Degramont substitute) (CAPE 2500-14 day (CTIS: 810)
       Capecitabine            1250mg/m2          BD Oral                    Days 1 to 14
                               ie. 2500mg/m2/day after food with water
                               See dose table page 61-63
                               Consider 25% dose reduction in patients over 70 years

       Interval between cycles:        Repeat every 21 days
       Number of cycles:               Metastatic colorectal cancer 1st line only
                                       approved by NICE:                   Up to 8 cycles/6 months
                                                                           Depends on response (tumour
                                                                           markers and CT scans).
                                       Adjuvant following Duke’s C
                                       colon cancer:                              8 cycles/6 months
                                       Where there is local approval for
                                       capecitabine substitution for 5FU/Degramont

                                  Adjuvant following surgery of
                                  high risk Duke’s B                     8 cycles/6 months
                                  ie. where there are additional adverse
                                  characteristics such as vascular
                                  invasion, bowel perforation, or
                                  adverse histological features.
       Tests before starting course of chemo:          FBC, U&Es, LFTs, Crcl (calculated). If
                                                       <50mls/min do EDTA, tumour markers
                                                       CEA, C19-9

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       Tests to OK/Confirm each cycle of chemo:           FBC, U&Es, LFTs, Crcl. Redo EDTA if
                                                          rising creatinine
       Supportive drugs with each cycle:                  Low risk antiemetics
       Patient information:               Chemotherapy treatment booklet (local information)
                                          Your chemotherapy record (NWLCN red book)
                                          BACUP information sheet
                                          Capecitabine patient diary
                                          Patient must receive nurse capecitabine counselling; see
                                          below
       Additional information:
              Unknown: effects on fertility.
              Administration notes:
              Patients must receive specific capecitabine counselling prior to treatment from a
              capecitabine trained nurse/pharmacist as per local policy. Patients must be given
              written and verbal information on capecitabine including how to take the tablets,
              when to stop (ie. In the event of toxicity and after 14 days), and whom to contact
              when side effects occur. Written information should be sent to the patient’s GP.
              Capecitabine tablets should be taken with water 30 minutes after food and
              approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin
              and therefore patients on these drugs must have their blood levels monitored more
              regularly. Capecitabine is contraindicated with allopurinol.
       Dose modifications: See Table below
       Reference: J. Clin Oncol 2001 19:2282-92. Hoff et al

Table: Capecitabine – colorectal
NB. Palliative patients will require greater dose reductions than below based on individual patient
parameters. Discuss with consultant.
Side-effects: Capecitabine                  Dose Modifications (Focus 2/SPC)
Haematology
Neutrophils                    Platelets
x 109/L                        x 109/L
1.5        and                100         Full dose. Only treat if neutrophils and platelets are above
                                            these levels.
<1.5             or            <100         Delay 1 week or until recovery.

       If >1 delay or 1 delay  2 weeks Capecitabine: 20% dose reduction. Continue at this lower
                                        dose for subsequent cycles unless further toxicity occurs.

                           Further delays    If further delay(s) for myelotoxicity occur despite 20%
                                            dose reduction, discuss with consultant
Renal function (SCOT Trial)
Crcl                        50mls/min      Full dose
                          30-49mls/min      Capecitabine 25% dose reduction.
                            <30mls/min      Do not give. Discuss with consultant. Consider 5FU.
Hepatic function
Bilirubin         Either AST or ALT
≤3 x ULN      and      ≤2.5 x ULN           Full dose
>3 x ULN      or        >2.5 x ULN          Capecitabine withhold until recovery then discuss with
                                            consultant
Diarrhoea
                                 Grade 1 Loperamide 2-4mg QDS PRN. Maximum 16mg/24 hours.
                                 Grade 2 As Grade 1 plus stop capecitabine until recovery then
                                          reduce dose according to SPC table overleaf
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Side-effects: Capecitabine                 Dose Modifications (Focus 2/SPC)
Stomatitis (SPC)
                                  Grade 1 Commence sucralfate 1g/5mls mouthwash QDS
                                 Grade 2 Stop capecitabine until recovery
                                          Commence sucralfate 1g/5mls mouthwash QDS, reduce
                                          dose according to SPC table below
Hand-Foot Syndrome
                                  Grade 1 Stop capecitabine until recovery. Once recovered restart
                                          with full dose
                                 Grade 2 Stop capecitabine until recovery. Once recovered, reduce
                                          dose according to SPC table below

                                           Phase III randomised controlled trials show no benefit from
                                           pyridoxine for prevention or treatment of 5FU induced hand foot
                                           syndrome. Pyridoxine is not recommended.
DPD Deficiency                             1-3% of patients have markedly exaggerated capecitabine
                                           toxicity due to reduced capecitabine catabolism. Discuss
                                           with consultant.
Cardiotoxicity                             Uncommon. Capecitabine may provoke angina or MI in
                                           patients with ischaemic heart disease. Seek specialist
                                           opinion on upgraded anti-anginal medication and consider
                                           dose reduction or alternative non-capecitabine treatment.
Neurotoxicity                              Uncommon – Cerebellar
                                           Consider alternative non-capecitabine treatment

Capecitabine Non haematological toxicity (SPC)
NCIC                  During course of treatment               Dose adjustment for next cycle
Grade
Grade 1               Continue treatment                       Capecitabine full dose
Grade 2
1st appearance        Interrupt capecitabine until resolved    All drugs full dose
                      to grade 0-1
2nd appearance        Interrupt capecitabine until resolved    Capecitabine 25% dose reduction.
                      to grade 0-1
3rd appearance        Interrupt capecitabine until resolved    Capecitabine 50% dose reduction.
                      to grade 0-1
4th appearance        Discontinue capecitabine                 Stop treatment
                      permanently
Grade 3
1st appearance        Interrupt capecitabine until resolved    Capecitabine 25% dose reduction
                      to grade 0 to 1
2nd appearance        Interrupt capecitabine until resolved    Capecitabine 50% dose reduction
                      to grade 0 to 1
3rd appearance        Discontinue capecitabine treatment       Do not give
                      permanently
Grade 4
1st appearance        Discontinue permanently.
                      If consultant considers it is in best
                      interest of patient to continue:         Under direction of consultant
                      interrupt capecitabine until resolved    Capecitabine 50% dose reduction
                      to grade 0 to 1

77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                       Colorectal Page 11 of 66
2b.    Tegafur with Uracil (Uftoral) (CTIS: 1215)
       Uftoral                   324mg/m2                  TDS                              Days 1 to 28
       Calcium folinate          30mg                      TDS                              Days 1 to 28
       (Folinic acid)

       NB. ie. Uftoral 972mg/m2/day = tegafur 300mg/m2/day plus uracil 672mg/m2/day.
       Each Uftoral capsule 324mg contains Tegafur 100mg and Uracil 224mg

Table: Uftoral capsules dose (SPC)
 Surface area                                        Uftoral capsules/day
        m2
 < 1.17               3 capsules/day:      1 capsule TDS
 1.17-1.49            4 capsules/day:      2 capsules in the morning, 1 capsule midday and evening
 1.50-1.83            5 capsules/day:      2 capsules morning and midday, 1 capsule in the evening
 > 1.83               6 capsules/day:      2 capsules TDS

       Interval between cycles: Repeat every 35 days
       Number of cycles:            6 cycles
       Tests before starting course of chemo:             FBC, U&Es, LFTs, tumour markers CEA,
                                                          C19-9, Crcl (calculated)
       Tests to OK/Confirm each cycle of chemo:           FBC, U&Es, LFTs, Crcl (calculated)
       Supportive drugs with each cycle:                  Low risk antiemetics
       Patient information:                Chemotherapy treatment booklet (local information)
                                           Your chemotherapy record (NWLCN red book)
                                           BACUP information sheet
                                           Uftoral patient diary
                                           Patient must receive nurse uftoral counselling; see below
       Additional information:
              Administration notes:
              Patient must receive specific uftoral counselling prior to treatment from a trained
              nurse/pharmacist. Patients must be given written and verbal information on uftoral
              including how to take the tablets, when to stop (ie. In the event of toxicity and after
              28 days), and whom to contact when side effects occur. Written information should
              be sent to the patient’s GP. Uftoral taken with separate calcium folinate tablets in 3
              divided doses. Uftoral capsules should be taken one hour before or one hour after
              food. Uftoral interacts with warfarin and phenytoin and therefore patients on these
              drugs must have their blood levels monitored more regularly. Dose of calcium
              folinate does not alter in the case of uftoral dose reduction.
       Dose modifications: See Uftoral table below. NB. Do not dose reduce Folinic Acid
       Reference: eMC 2005

Table: Uftoral: Do not dose reduce calcium folinate when uftoral dose is reduced.
Side-effect: Uftoral                            Dose Modification (SPC)
Haematology
Neutrophils                    Platelets
x109/L                         x109/L
1.5         and               100             Full dose
<1.5         or                <100             Stop therapy until counts above these limits. Once
                                                recovered dose according to grade.
                                                grade 2: Full dose
                                                grade 3: Decrease dose by 1 capsule/day in all
                                                subsequent treatment.

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Side-effect: Uftoral                        Dose Modification (SPC)

Renal                                       SPC states the effect of renal impairment has not been
                                            assessed. Discuss with consultant
Hepatic                                     SPC states the effect of hepatic impairment has not
                                            been assessed. Discuss with consultant
Non-haematological toxicities eg.
Stomatitis, Diarrhoea
                              Grade 0-1 Full dose
                                Grade 2 Stop chemo until recovered to  grade 1 then full dose.
                              Grade 3-4 Stop chemo until recovered to  grade 1 then restart
                                        with dose reduction: Decrease subsequent doses by 1
                                        capsule/day for all future treatment
DPD Deficiency                          1-3% of patients have markedly exaggerated uftoral
                                        toxicity due to reduced uftoral catabolism. Discuss with
                                        consultant.
Cardiotoxicity                          Uncommon. Uftoral may provoke angina or MI in
                                        patients with ischaemic heart disease. Seek specialist
                                        opinion on upgraded anti-anginal medication and
                                        consider dose reduction or alternative non uftoral
                                        treatment.
Neurotoxicity                           Uncommon – Cerebellar
                                        Consider alternative non uftoral treatment


3.      Irinotecan Chemotherapy
3a.     MdG plus Irinotecan (IrMdG via CVAD CTIS: 751, IrMdG via N/S CTIS: 1220)
        Atropine                250mcg            SC                        Day 1
        Irinotecan              180mg/m2          IV over 30 mins           Day 1
        Folinic Acid            350mg             IV over 2 hours           Day 1
        5-Fluorouracil          400mg/m2          IV bolus                  Day 1
                                         2
        5-Fluorouracil          2400mg/m          IV over 46 hours          Day 1 to 2

        Interval between cycles: Repeat every 14 days
        Number of cycles:          Colorectal cancer 1st line metastatic:   12 cycles
        Tests before starting course of chemo:         FBC, U&Es, LFTs, tumour markers
                                                       CEA,CA19-9, Crcl (calculated).
                                                       Performance status: PS 0 or 1: proceed
                                                       PS 2: caution, PS3: Do not give
                                                       Caution in patients with previous history of
                                                       diarrhoea or abdominal pelvic disease.
        Tests to OK/Confirm each cycle of chemo:       FBC, U&Es, LFTs
        Supportive drugs with each cycle:              5HT3 antiemetics as per local protocol
                                                       Chlorhexidine mouthwash 10mls QDS
                                                       Atropine as above to prevent acute
                                                       cholinergic syndrome (diarrhoea,
                                                       sweating, salivation, bradycardia).
                                                       Loperamide if necessary see table below
                                                       Ciprofloxacin if necessary see table below
        Patient information:              Chemotherapy treatment booklet (local information)
                                          Your chemotherapy record (NWLCN red book)
                                          BACUP information sheet
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                                                 Irinotecan patient information on diarrhoea
                                                 Loperamide will be prescribed to be used when directed
                                                 See table below for high doses with irinotecan
                                                 Written information on mechanical pump (if via CVAD)
         Additional information:
                Administration notes:
                Irinotecan:
                Give patient information on loperamide for diarrhoea. Patient must contact hospital if
                diarrhoea continues for longer than 48 hours or if they are also experiencing vomiting
                and fever.
                5FU:          See MdG Colorectal page 6
         Dose modifications: Table: DeGram-Irino page 14
         Reference: Lancet 2000 355:1014-7. Douillard JY et al

Table: DeGram-Irino
  Side-Effect: Ir-MdG                             Dose Modification (Source: Focus Trial/SPC)
  Haematological                                  Myelotoxicity more common than with degramont alone
  Neutrophils                      Platelets
  x109/L                           x109/L
  1.5         and                    100        Full dose

  <1.5              or                <100        Delay 1 week and recheck FBC. Only give when
                                                  neutrophils and platelets are above these limits.

  If neutropenia grade 4, febrile                 Irinotecan:               20% dose reduction
  neutropenia, thrombocytopenia grade             5FU (bolus and infusion): 20% dose reduction
  4 or leucopenia grade 4 occurs (SPC
  July 02) or if more than 1 delay or 1           If further delays occur for myelotoxicity despite 20%
  delay greater than 2 weeks                      reduction, discuss with consultant
  Renal function
  Crcl                          ≤50mls/min        Unclear guidance. Discuss with consultant
  Hepatic Function (SPC)                          Irinotecan and metabolites cleared by biliary excretion.
                                                  Delayed clearance in cholestasis.
  Bilirubin                             ALP
  <1.5 x ULN             and     ≤5.0 x ULN       Full dose all drugs

  1.5-3.0 x ULN          or      >5.0 x ULN Irinotecan: 50% dose reduction
                                            5-Fluorouracil: Full dose

  >3 x ULN               and               Any    Irinotecan: Do not give
                                                  5-Fluorouracil: 50% dose reduction
  Stomatitis (Focus)                              Routine mouth care with chlorhexidine mouthwash. If
                                                  mouth ulcers occur despite this, dose reduce
                                                  5FU: 20% dose reduction (bolus and infusion) for all
                                                  subsequent cycles
  Diarrhoea
  Immediate diarrhoea (within first 24            Incidence of immediate diarrhoea is low due to use of
  hours)                                          atropine premed.

                                                  If acute diarrhoea/cholinergic syndrome occurs
                                                  administer another dose of atropine 250mcg SC stat.


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  Side-Effect: Ir-MdG                          Dose Modification (Source: Focus Trial/SPC)

  Delayed diarrhoea occurring more
  than 24 hours after irinotecan and at
  any time before next cycle:
                          Initial treatment Irinotecan induced delayed diarrhoea should be treated
                                            early with high dose loperamide, 4mg after first loose
                                            stool then 2mg every 2 hours until 12 hours after last
                                            loose stool (up to 24mg/day for a maximum of 48 hours
                                            because or risk of paralytic ileus).

                            Lasts >24 hours If diarrhoea lasts > 24 hours add Ciprofloxacin PO
                                            500mg BD.

                            Lasts >48 hours If diarrhoea lasts > 48 hours or patient reports
                                            symptoms of dehydration, admit acutely for rehydration
                                            and further management.

                                   Grade 3-4 After an episode of severe diarrhoea (grade 3/4), delay
                                             until full recovery then resume at
                                             Irinotecan:                  20% dose reduction
                                             5FU (bolus & infusion) :     20% dose reduction.

              Unresolved by next cycle If diarrhoea from previous cycle (even if not severe) not
                                       resolved by next cycle due - delay 1 week.
  Hand-Foot Syndrome
                             Grade 2 5FU: 20% dose reduction (bolus and infusion)
                                       Irinotecan: full dose.

                                               Phase III randomised controlled trials show no benefit from
                                               pyridoxine for prevention or treatment of 5FU induced hand
                                               foot syndrome. Pyridoxine is not recommended.
  DPD Deficiency (Focus)                       1-3% of patients have markedly exaggerated 5FU
                                               toxicity due to reduced 5FU catabolism. Discuss with
                                               consultant
  Cardiotoxicity (Focus)                       Uncommon. 5FU may provoke angina attack or MI in
                                               patients with ischaemic heart disease. Seek specialist
                                               opinion on upgraded anti-anginal medication and
                                               consider dose reduction or alternative non 5FU
                                               treatment.
  Neurotoxicity (Focus)                        Uncommon – Cerebellar
                                               Consider alternative Non 5FU treatment

3b.    Irinotecan-Capecitabine
       Atropine                250mcg            SC                         Day 1
                                        2
       Irinotecan              200mg/m           IV over 30 mins            Day 1
       Capecitabine            800mg/m2          Oral twice a day           Day 1 to 14
                               1600mg/m2/day     with water after food
                               Consider 25% dose reduction in over 70 years

       Interval between cycles:        Repeat every 21 days
       Number of cycles:               Colorectal cancer 1st line metastatic where              8 cycles
                                       there is local approval for capecitabine
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                                    substitution of 5FU
       Tests before starting course of chemo:             FBC, U&Es, LFTs, tumour markers CEA,
                                                          CA19-9, Crcl calculated. Do EDTA if <
                                                          50mls/min.
                                                          Performance status:
                                                          PS 0 or 1:    proceed
                                                          PS 2:         caution
                                                          PS 3:         do not give
                                                          Caution in patients with previous history of
                                                          diarrhoea or abdominal pelvic disease.
       Tests to OK/Confirm each cycle of chemo:           FBC, U&Es, LFTs, Crcl calculated. Do/redo
                                                          EDTA if rising creatinine
       Supportive drugs with each cycle:                  5HT3 antiemetics as per local protocol.
                                                          Atropine to prevent acute cholinergic
                                                          reactions
                                                          Loperamide if necessary see table below
                                                          Ciprofloxacin if necessary see table below
       Patient information:                Chemotherapy treatment booklet (local information)
                                           Your chemotherapy record (NWLCN red book)
                                           BACUP information sheet
                                           Capecitabine patient diary
                                           Patient must receive nurse capecitabine counselling
                                           Irinotecan information booklet on diarrhoea
                                           Loperamide will be prescribed to be used when directed
                                           See table for high dose loperamide with irinotecan
       Additional information:
              Administration notes:
              Irinotecan:
              Give patient information on loperamide to treat irinotecan induced diarrhoea. Patient
              must contact hospital if diarrhoea continues for longer than 48hours or if they are
              also experiencing vomiting and fever. Atropine should be administered
              subcutaneously as a pre medication to avoid acute cholinergic syndrome.
              Capecitabine:
              Patients must receive specific capecitabine counselling prior to treatment from a
              capecitabine trained nurse/pharmacist as per local policy. Patients must be given
              written and verbal information on capecitabine including how to take the tablets,
              when to stop (ie. In the event of toxicity and after 14 days), and whom to contact
              when side effects occur. Written information should be sent to the patient’s GP.
              Capecitabine tablets should be taken with water 30 minutes after food and
              approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin
              and therefore patients on these drugs must have their blood levels monitored more
              regularly. Capecitabine is contraindicated with allopurinol.
       Dose modifications:
       Reference:

Table: Irinotecan-Capecitabine
Side effect: Irino-Cape                     Dose modifications:
Haematology
Neutrophils                    Platelets
x109/L                         x109/L
≥1.5         and               ≥100         Full dose. Only treat if neutrophils and platelets are
                                            above these levels.


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Side effect: Irino-Cape                                Dose modifications:
<1.5         or                   <100                 Delay for 1 week or until recovery.

If more than 1 delay or 1 delay greater                Irinotecan:          20% dose reduction
than 2 weeks, Neutropenia grade 4,                     Capecitabine:        20% dose reduction
Febrile neutropenia, or                                If further delays occur for myelotoxicity despite 20%
Leucopenia grade 4 (SPC 2002)                          dose reduction discuss with consultant

Renal function (SCOT Trial)
CrCl
                                         ≥50ml/min Full dose
                                       30-49ml/min Capecitabine:       25% dose reduction
                                                   Irinotecan:         discuss with consultant
                                        <30mls/min Do not give. Discuss with consultant
Hepatic function                                            Irinotecan                Capecitabine

Bilirubin                     Either   AST or ALT
<1.5 x ULN         and                 ≤2.5 x ULN      Full dose                       Full dose

<1.5 x ULN         and           2.5-5.0 x ULN         Full dose                       Withhold until recovered
                                                                                       then discuss with
                                                                                       consultant

1.5-3.0 x ULN and                      ≤2.5 x ULN Irinotecan 50% dose                  Full dose
                                                  reduction

1.5-3.0 x ULN        and         2.5-5.0 x ULN Irinotecan 50% dose                     Withhold until recovered
                                               reduction                               then discuss with
                                                                                       consultant

1.5-3.0 x ULN         or               >5.0 x ULN Irinotecan 50% dose                  Withhold until recovered
                                                  reduction                            then discuss with
                                                                                       consultant

>3.0 x ULN           and                    Any        Do not give                     Withhold until recovered
                                                                                       then discuss with
                                                                                       consultant
Diarrhoea
Capecitabine induced diarrhoea
                                          Grade 1 Loperamide 2-4mg QDS PRN up to 16mg/24hours.
                                         ≥Grade 2 As grade 1 plus stop capecitabine until recovery then
                                                  reduce dose according to SPC table on page 11.

Irinotecan immediate onset diarrhoea                   Incidence of immediate diarrhoea is low due to use of
within first 24 hours                                  atropine premed. If acute diarrhoea/cholinergic
                                                       syndrome occurs, administer another dose of atropine
                                                       250mcg SC stat.
Irinotecan Induced Delayed Diarrhoea
Occurring more than 24 hours after irinotecan and at
any time before next cycle      Initial treatment      Irinotecan induced delayed diarrhoea should be treated
                                                       early with high dose loperamide, 4mg after first loose
                                                       stool then 2mg every 2 hours until 12 hours after last
                                                       loose stool (up to 24mg/day for a maximum of 48 hours
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Side effect: Irino-Cape                       Dose modifications:
                                              because of paralytic ileus).

                            Lasts >24 hours If diarrhoea lasts > 24 hours add Ciprofloxacin PO
                                            500mg BD.

                            Lasts >48 hours If diarrhoea lasts > 48 hours or patient reports
                                            symptoms of dehydration, admit acutely for rehydration
                                            and further management.

                                   Grade 3-4 After an episode of severe diarrhoea (grade 3/4), delay
                                             until full recovery then resume at
                                             Irinotecan:                  20% dose reduction
                                             5FU (bolus & infusion) :     20% dose reduction.

                   Unresolved by next cycle If diarrhoea from previous cycle (even if not severe) not
                                            resolved by next cycle due - delay 1 week.
Stomatitis (SPC)
                                     Grade 1 Commence sucralfate 1g/5mls mouthwash QDS

                                    ≥Grade 2 Stop capecitabine until recovery
                                             Commence sucralfate 1g/5mls mouthwash QDS,
                                             reduce dose according to SPC table below
                                             Irinotecan full dose
Hand-Foot Syndrome
                                     Grade 1 Stop capecitabine until recovery.
                                             Discuss with consultant if irinotecan should continue.
                                             Once recovered restart capecitabine next cycle with full
                                             dose.

                                    ≥Grade 2 Stop chemotherapy until recovery.
                                             Once recovered reduce capecitabine dose according to
                                             table on colorectal page 10
                                             Irinotecan full dose

                                              Phase III randomised controlled trials show no benefit from
                                              pyridoxine for prevention or treatment of 5FU induced hand foot
                                              syndrome. Pyridoxine is not recommended
DPD Deficiency                                1-3% of patients have markedly exaggerated
                                              capecitabine toxicity due to reduced capecitabine
                                              catabolism. Discuss with consultant.
Cardiotoxicity                                Uncommon. Capecitabine may provoke angina or MI in
                                              patients with ischaemic heart disease. Seek specialist
                                              opinion on upgraded anti-anginal medication and
                                              consider dose reduction or alternative non-capecitabine
                                              treatment.
Neurotoxicity                                 Uncommon – Cerebellar
                                              Consider alternative non-capecitabine treatment




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3c.     Irinotecan Single Agent (CTIS: 691)
        Atropine                      250mcg               SC Stat pre irinotecan    Day 1
        Irinotecan                    *350mg/m2            IV over 90 mins           Day 1
                                       2
        * Reduce dose to 300mg/m for patients > 70 years, or at any age if performance
            status =2
            Caution in patients with previous history of diarrhoea or abdominal-pelvic disease

        Interval between cycles: Repeat every 21 days
        Number of cycles:          Colorectal cancer 2nd line metastatic:  6 cycles
        Tests before starting course of chemo:         FBC, U&Es, LFTs, tumour markers CEA,
                                                       CA19-9, Crcl (calculated)
                                                       Performance status PS 0 or 1: proceed
                                                       PS 2: Caution, PS3: Do not give
        Tests to OK/Confirm each cycle of chemo :      FBC, U&Es, LFTs, Crcl (calculated)

        Supportive drugs with each cycle:                       5HT3 antiemetics as per local protocol.
                                                                Atropine as above to prevent acute
                                                                cholinergic symptoms (diarrhoea, sweating,
                                                                salivation, bradycardia).
                                                                Loperamide if necessary see table below
                                                                Ciprofloxacin if necessary see table below
        Patient information:                      Chemotherapy treatment booklet (local information)
                                                  Your chemotherapy record (NWLCN red book)
                                                  BACUP information sheet
                                                  Irinotecan information booklet on diarrhoea
                                                  Loperamide will be prescribed to be used when directed
                                                  See table for high dose loperamide with irinotecan
        Additional information:
               Administration notes:
               Give patient information on loperamide to treat irinotecan induced diarrhoea. Patient
               must contact hospital if diarrhoea continues for longer than 48hours or if they are
               also experiencing vomiting and fever. Atropine should be administered
               subcutaneously as a pre medication to avoid acute cholinergic syndrome.
        Dose modifications:        See Table below
        Reference: Lancet 1998;352:1413-18. Cunningham et al
                      Lancet 1998;352:11407-1412 Rougier et al

Table: Irinotecan alone
 Side-effect: Irinotecan alone                     Dose Modification     (Source: Focus Trial/SPC)
 Haematology
 Neutrophils                  Platelets
    9
 x10 /L                         x109/L
 1.5         and                 100             Full dose all drugs

 <1.5             or                       <100    Delay 1 week until recovery. Only treat above these
                                                   levels

 If neutropenia grade 4, febrile           Irinotecan:  20% dose reduction
 neutropenia, thrombocytopenia grade 4 If further delays occur for myelotoxicity despite 20%
 or leucopenia grade 4 occurs (SPC January dose reduction. Discuss with consultant
 02) or if more than 1 delay or 1 delay
 greater than 2 weeks

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 Side-effect: Irinotecan alone                          Dose Modification      (Source: Focus Trial/SPC)
 Renal function
 Crcl                      ≤50mls/min                   Unclear guidance. Discuss with consultant
 Hepatic Function (SPC)                                 Irinotecan and metabolites cleared by biliary excretion.
                                                        Delayed clearance in cholestasis.
 Bilirubin                                 AST
 <1.5 x ULN                and       <5.0 x ULN         Full dose

 1.5-3.0 x ULN             or         >5.0 x ULN Irinotecan: 50% dose reduction

 > 3.0 x ULN           and       Any                    Irinotecan: omit
 Diarrhoea
 Irinotecan Immediate Onset Diarrhoea                   Incidence of immediate diarrhoea low due to use of
 within first 24 hours                                  atropine premed. If acute diarrhoea/cholinergic
                                                        syndrome occurs administer another dose of atropine
                                                        250mcg SC Stat.

 Irinotecan Induced Delayed Diarrhoea
 occurring more than 24 hours after irinotecan and at
 any time before next cycle:    Initial treatment       Irinotecan induced delayed diarrhoea should be treated
                                                        early with high dose loperamide 4mg after first loose
                                                        stool then 2mg every 2 hours until 12 hours after last
                                                        loose stool (up to 24mg/day for a maximum 48 hours
                                                        because of risk of paralytic ileus).

                                Lasts >24 hours If diarrhoea lasts > 24 hours add Ciprofloxacin 500mg
                                                BD PO.

                                Lasts >48 hours If diarrhoea lasts > 48 hours or patient reports
                                                symptoms of dehydration, admit acutely for rehydration
                                                and further management.

                                       Grade 3-4 After an episode of severe diarrhoea (grade 3 / 4),
                                                 delay until full recovery then resume at
                                                 Irinotecan:           20% dose reduction
                                                 5FU :                 20% dose reduction (bolus &
                                                 infusion)

                   Unresolved by next cycle If diarrhoea from previous cycle (even if not severe) not
                                            resolved by next cycle due – delay 1 week.


4.      Oxaliplatin Chemotherapy
4a.     OxMdG DeGramont – Modified plus Oxaliplatin (OxMdG via CVAD CTIS: 327, OxMdG
        via N/S, CTIS: 1216)
        Folinic Acid         350mg              IV over 2 hours        Day 1
                                     2
        Oxaliplatin          85mg/m             IV over 2 hours        Day 1
        5-Fluorouracil       400mg/m2           IV bolus               Day 1
                                       2
        5-Fluorouracil       2400mg/m           IV over 46 hours       Day 1 to 2

        Interval between cycles:            Repeat every 14 days

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        Number of cycles:           Colorectal cancer
                                    Adjuvant Duke’s C if ineligible for trials: 12 cycles
                                    Metastatic 1st or 2nd line:                 6-12 cycles
        Tests before starting course of chemo:            FBC, U&Es, LFTs, tumour markers
                                                          CEA, CA19-9, Crcl (calculated)
        Tests to OK/Confirm each cycle of chemo:          FBC, U&Es, LFTs, Crcl (calculated)
        Supportive drugs with each cycle:                 5HT3 antiemetics as per local protocol
                                                          Chlorhexidine mouthwash 10mls QDS.
                                                          Loperamide 2-4mg QDS, PRN (max
                                                          16mg/day)
        Patient information:                Chemotherapy treatment booklet (local information)
                                            Your chemotherapy record (NWLCN red book)
                                            BACUP information sheet
                                            Written information on mechanical pump (if via CVAD)
        Additional information:
               Administration notes:
               Oxaliplatin
               Oxaliplatin is incompatible with normal saline, therefore, the venous access device
               and administration sets should be flushed with 5% glucose. Folinic acid in 5%
               glucose is administered at the same time as the oxaliplatin. Patients should be
               advised to keep warm as exposure to cold post oxaliplatin infusion may aggravate
               symptoms of peripheral neuropathy and laryngopharyngeal dysthesia. In the event
               of laryngopharyngeal symptoms during an oxaliplatin infusion, reassure the patient
               that the symptoms are likely to resolve. This must not be confused with an allergic
               response which requires emergency intervention. The patient who suffers from
               laryngopharyngeal spasm may be re-challenged with oxaliplatin at a slower infusion
               rate of up to 6 hours. On occasions pain may be experienced in the infusion arm, if
               so, slow infusion rate to a maximum 6 hours. Consider CVAD if problematic.
               5FU: See MdG Colorectal page 5
               If 5FU administered using an ambulatory infusion pump via a central venous access
               device (CVAD), refer to relevant protocol for care of CVAD. Joint care with the
               community nursing services should be arranged in advance to support the patient
               and assist with disconnecting the chemotherapy and flushing the CVAD. Written
               community nursing referral should be completed and the patient should be
               discharged with a home spillage kit, sharps container and a small supply of
               equipment to flush the line and dress the entry site of the CVAD.
        Dose modifications: Table: OxMdG below
        Reference: J. Clin Onc 2000;18:2938-47. DeGramont et al

Table: OxMdG
 Side-effect: OxMdG                        Dose Modification (Source: Focus Trial/SPC/Coin Trial)
 Haematology (Coin)                        Myelotoxicity more frequent (30%) with OxMdG than with
                                           MdG.
 Neutrophils            Platelets
 x109/L                 x109/L
 1.5        and        75                Full dose all drugs

 <1.5           or     <75                 Delay 1 week then recheck FBC. Only give if neutrophils
                                           and platelets above these limits. Lower limit for platelets
                                           is due to possible mild thrombocytopenia after a number
                                           of cycles of OxMdG.



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 Side-effect: OxMdG                        Dose Modification (Source: Focus Trial/SPC/Coin Trial)
 If more than 1 delay or 1 delay 2        Wait for full recovery then:
 weeks:                                    Oxaliplatin: Full dose
                                           5FU: Omit bolus dose but give full dose infusion.
                                           Continue without bolus dose on subsequent cycles.

                                           If further delays for myelotoxicity occur despite omitting
                                           bolus 5FU discuss with consultant.

 Neutrophils <1.0x109/L at any time        Oxaliplatin: 25% dose reduction in addition to any 5FU
 (SPC)                                     reduction above

 Renal Function (Coin)                     Oxaliplatin – Not nephrotoxic but is renally cleared.
 Crcl
                          30mls/min Full dose all drugs
                          <30mls/min Oxaliplatin           Omit
                                     5-FU:                 Discuss with consultant 25% dose
                                                           reduction (bolus and infusion)
 Hepatic Function (Coin)             NB. Significantly impaired hepatic function may be a sign
                                     of disease progression ie. review treatment.
                                     Oxaliplatin not principally cleared by liver but is evidence
                                     of delayed clearance in patients with marked hepatic
                                     dysfunction.
 AST/ALT >5 x ULN                    Withhold 5FU until recovery
 Bilirubin > 3 x ULN (>51micromol/l) Oxaliplatin: 50% dose reduction
                                     5-Fluorouracil: 50% dose reduction (bolus and infusion)
 Neurotoxicity                       Oxaliplatin : peripheral sensory symptoms
                                     5FU : uncommon and cerebellar. Consider other chemo
                                     regimen
 Paraesthesia of hands and feet
 Dysaesthesia in throat (often
 precipitated by cold)

 Symptoms lasts few hours to a few         No treatment or dose reduction required.
 days after oxaliplatin administration

 Acute laryngopharyngeal                   Administer next oxaliplatin over 6 hours (SPC).
 dysaesthesia during or within the
 hours following the oxaliplatin 2
 hour infusion

 Symptoms last longer than 7 days          Reduce oxaliplatin dose from 85mg/m2 to 65mg/m2
 and are troublesome                       (metastatic setting) or 75mg/m2 (adjuvant) (SPC).

 If paraesthesia without functional        Reduce oxaliplatin from 85mg/m2 to 65mg/m2 (metastatic
 impairment persists until the next        setting) or 75mg/m2 (adjuvant) (SPC)
 cycle

 If paraesthesia with functional           Omit oxaliplatin, give DeGramont alone until fully
 impairment persist until the next         resolved. Resumption of oxaliplatin may be considered
 cycle                                     once fully resolved. Check dose with consultant (SPC).



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 Side-effect: OxMdG                        Dose Modification (Source: Focus Trial/SPC/Coin Trial)
 Persistent peripheral sensory             Localised moderate paraesthesias or paraesthesias that
 neuropathy                                may interfere with functional activities can persist for up to
                                           3 years following treatment cessation in the adjuvant
                                           setting.
 Stomatitis (Coin)                         If mouth ulcers occur despite chlorhexidine mouthcare
                                           delay until recovery to grade 1 or less then
                                           5FU: 20% dose reduction (bolus and infusion).

                                       If further toxicity occurs despite above reductions then:
                                       5FU:            40% dose reduction (bolus and
                                                       infusion)
                                       Oxaliplatin: 20% dose reduction
 Diarrhoea              Between cycles Between cycles - treat symptomatically loperamide 2-4mg
 (Coin)                                QDS and/or codeine phosphate 30-60mg QDS as
                                       required

            Not resolved by next cycle Not resolved by next cycle: Delay 1 week/until resolved

                             Unresolved If problematic despite symptomatic treatment or more
                                        than 1 delay give
                                        5FU:          20% dose reduction (bolus and infusion)
                                        Oxaliplatin : 20% dose reduction

                                           If further toxicity occurs despite above dose reduction
                                           then
                                           5FU:            20% dose reduction (bolus and infusion)
                                           Oxaliplatin: further 20% dose reduction

 If Grade 4 diarrhoea, neutrophils         Delay until recovered then reduce oxaliplatin from
 <1.0 and platelets <50 (SPC)              85mg/m2 to 65mg/m2 (metastatic) or to 75mg/m2
                                           (adjuvant) plus
                                           5FU: 20% dose reduction bolus and infusion
 Hand-Foot Syndrome
                                Grade 2 5FU: 20% dose reduction (bolus and infusion)

                                           Phase III randomised controlled trials show no benefit from pyridoxine
                                           for prevention or treatment of 5FU induced hand foot syndrome.
                                           Pyridoxine is not recommended
 DPD Deficiency (FOCUS)                    1-3% of patients have markedly exaggerated 5FU toxicity
                                           due to reduced 5FU Catabolism.
                                           Discuss with consultant
 Cardiotoxicity (FOCUS)                    Uncommon. 5FU may provoke angina attack or MI in
                                           ischaemic heart disease. Seek specialist opinion on
                                           upgraded anti-anginal medication and consider dose
                                           reduction or alternative non 5FU treatment.




77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                           Colorectal Page 23 of 66
 Side-effect: OxMdG                        Dose Modification (Source: Focus Trial/SPC/Coin Trial)
 Allergic reactions to oxaliplatin         Grade 1 and 2
 Approximately 9.1% (SPC) incidence        If acute hypersensitivity occurs:
 of acute hypersensitivity to               Discontinue infusion
 oxaliplatin.                               Treat with IV corticosteroids and antihistamine
                                            After full recovery continue with 5FU/FA alone
 During administration patient may          Rechallenge at consultant’s discretion with: (COIN)
 develop rash, fever, swollen              Dexamethasone 4mg orally every 6 hours starting 24
 mouth/tongue hyper or hypotension         hours pre chemo
 etc.                                      Dexamethasone 8mg IV 30 minutes pre chemo
 This rarely develops to full blown        Chlorphenamine 10mg IV bolus dose 30 mins pre chemo
 anaphylaxis even with repeated            Ranitidine 50mg IV bolus dose 30mins pre chemo
 treatment                                 Continue dexamethasone, chlorphenamine and ranitidine
                                           for 24-48 hours after oxaliplatin
                                           Grade 3 and 4
                                           Treat for full anaphylaxis. DO NOT GIVE further
                                           oxaliplatin

4b.    Oxaliplatin-Capecitabine (Cape-Ox)
       Oxaliplatin        130mg/m2                 IV over 2 hours            Day 1
       Capecitabine       1000mg/m2                Orally twice a day         Day 1 to 14
                          ie 2000mg/m2/day         after a meal with water
                          Consider 25% dose reduction in patients over 70 years
                          See dose table page 62-66

       Interval between cycles:     Repeat every 21 days
       Number of cycles:            Adjuvant Dukes C:             8 cycles
                                    Where there is local approval for capecitabine substitution 5FU
       Tests before starting course of chemo:             FBC, U&Es, LFTs, CrCl (calculated). If
                                                          <50mls/min do EDTA, tumour markers
                                                          CEA, C19-9
       Tests to OK/Confirm each cycle of chemo:           FBC, U&Es, LFTs, CrCl. Redo EDTA if
                                                          rising creatinine
       Supportive drugs with each cycle:                  5HT3 antiemetics as per local protocol
       Patient information:               Chemotherapy treatment booklet (local information)
                                          Your chemotherapy record (NWLCN red book)
                                          BACUP information sheet
                                          Capecitabine patient diary
                                          Patient must receive nurse capecitabine counselling;
       Additional information:
              Administration notes:
              Oxaliplatin: See Colorectal page 21
              Capecitabine:
              Patients must receive specific capecitabine counselling prior to treatment from a
              capecitabine trained nurse/pharmacist as per local policy. Patients must be given
              written and verbal information on capecitabine including how to take the tablets,
              when to stop (ie. In the event of toxicity and after 14 days), and whom to contact
              when side effects occur. Written information should be sent to the patient’s GP.
              Capecitabine tablets should be taken with water 30 minutes after food and
              approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin
              and therefore patients on these drugs must have their blood levels monitored more
              regularly. Capecitabine is contraindicated with allopurinol.
       References: J.Clin Onc 2008 26:5910-5917
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      Dose modifications:
Table Oxaliplatin-Capecitabine
Side effect: Cape-Ox                       Dose modification:
Haematology (REAL 2)                             Oxaliplatin                        Capecitabine
Neutrophils          Platelets
    9
x 10 /L              x 109/L
1.0         and        75                Full dose                        Full dose

0.5-0.9        or              50-74       Delay oxaliplatin until          Stop capecitabine until
                                           recovery then restart with       recovery then full dose
                                           oxaliplatin 100mg/m2

< 0.5          or              25-49       Delay oxaliplatin until          Stop capecitabine until
                                           recovery then restart with       recovery then full dose
                                           oxaliplatin 100mg/m2

Any            and             <25         Delay oxaliplatin until          Stop capecitabine until
                                           recovery then restart with       recovery then full dose
                                           oxaliplatin 100mg/m2

Neutropenic fever OR                       Reduce to oxaliplatin            Full dose on subsequent
Grade 3 infection/fever with               100mg/m2 on subsequent           cycles
neutropenia (ANC <1) at any time           cycles

Grade 4 infection/fever with               Reduce to oxaliplatin            Full dose on subsequent
neutropenia (ANC <1) at any time           100mg/m2 on subsequent           cycles
                                           cycles

If more than 1 delay or 1 delay >2         Maintain oxaliplatin dose        Capecitabine: 20% dose
weeks                                      reduction                        reduction.
                                                                            Continue this dose for
                                                                            subsequent cycles unless
                                                                            further toxicity occurs.
                                                                            If further delays occur
                                                                            despite 20% dose
                                                                            reduction discuss with
                                                                            consultant.
Hepatic function (SPC/Real 2)
Bilirubin      Either AST or ALT
≤1.5 x ULN and         ≤2.5 x ULN          Full dose                        Full dose
1.5-3.0 x ULN and      2.5 x ULN          Discuss with consultant          Full dose
>3.0 x ULN and         >2.5 x ULN          Discuss with consultant          Stop capecitabine
                                                                            Discuss with consultant
Renal function (SCOT Trial)
                                ≥50mls/min Full dose                        Full dose
                              30-49mls/min Full dose                        25% dose reduction
                                <30mls/min Do not give EOX                  Do not give

Cardiotoxicity (REAL 2)                    Any patient who develops unexplained cardiac failure
Unexplained cardiac failure                while on treatment should undergo evaluation of cardiac
                                           function with a MUGA scan or echocardiogram. If left
                                           ventricular function is less than the lower limit of normal
                                           range then epirubicin should be omitted.
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Side effect: Cape-Ox                        Dose modification:
Stomatitis (SPC/REAL 2)
                                  Grade 1 Commence sucralfate, mouthwash 1g/5mls QDS
                                          Full dose all drugs
                                Grade 2 As Grade 1 and stop capecitabine until recovery, then
                                          restart with dose according to SPC table page 11
                        Recurrent Grade 3 As Grade 2 but if Grade 3 / 4 stomatitis recurs despite
                                          appropriate capecitabine dose reduction then reduce
                                          oxaliplatin doses to 100mg/m2 in subsequent cycles
Diarrhoea (REAL 2/SPC)
                          Grade 1 Full dose all drugs
                          Grade 2 Stop capecitabine, start codeine phosphate 30-60mg
                                   oral QDS.
                                   If diarrhoea resolves within 2 days restart all drugs full
                                   dose.
                                   If diarrhoea persists, wait until recovery then restart
                Recurrent ≥Grade 3 Capecitabine: dose reduction as per SPC table page 11
                                   As for Grade 2 but if grade 3 / 4 diarrhoea recurs despite
                                   appropriate capecitabine dose reduction then reduce
                                   oxaliplatin dose to 100mg/m2 in subsequent cycles
Hand-Foot Syndrome (SPC)
                           Grade 1 Stop capecitabine until recovery. Once recovered –
                                   restart full dose all drugs
                          Grade 2 Stop capecitabine until recovery. Once recovered,
                                   restart chemo with dose according to SPC table page 11

                                            Phase III randomised controlled trials show no benefit from
                                            pyridoxine for prevention or treatment of 5FU induced hand
                                            foot syndrome. Pyridoxine is not recommended.
Neurotoxicity (REAL 2)
Cold related dysaethesia
                       Lasting 1-7 days Full dose
                        Lasting >7 days Full dose
              Persistent between cycles Oxaliplatin: withhold until recovery then restart
                                                     oxaliplatin at 100mg/m2
                                                     If recurs despite dose reduction, omit
                                                     oxaliplatin in subsequent cycles. Discuss
                                                     carboplatin substitution with consultant.


5.     Mitomycin Regimens
5a.    Mitomycin-5FU Contin (CTIS: 195)
       Mitomycin              7mg/m2 (max14mg) IV bolus                    Day 1
                                        2
       5-Fluorouracil         300mg/m /day     IV continuous infusion for 42 days

       Interval between cycles:   Repeat every 42 days
       Number of cycles:          Colorectal metastatic relapse: Maximum 4 cycles (total
                                  mitomycin dose 28mg/m2, max 56mg)
       Tests before starting course of chemo:         FBC (including manual film haemolysis
                                                      screen), U&Es, LFTs, tumour markers CEA,
                                                      CA19-9, Crcl (calculated)

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       Tests to OK/Confirm each cycle of chemo:        FBC (including manual film haemolysis
                                                       screen), U&Es, LFTs
                                                       Do not give mitomycin C unless
                                                        Creatinine within normal range
                                                        Bilirubin <30 micromol/L
                                                        WBC 3.0 x 109/L
                                                        Neutrophils 1.5 x 109/L
                                                        Platelets 100 x 109/L
                                                        No red blood cell fragmentation seen in
                                                          blood film
       Supportive drugs with each cycle:               Low risk antiemetics.
                                                       Chlorhexidine mouthwash 10mls QDS.
                                                       Loperamide 2-4mg QDS PRN (max
                                                       16mg/day)
       Patient information:              Chemotherapy treatment booklet (local information)
                                         Your chemotherapy record (NWLCN red book)
                                         BACUP information sheet
                                         Written information on mechanical pump (if via CVAD)
       Additional information:
              Administration notes:
              Mitomycin: Mitomycin is a vesicant, administer in line with the NWLCN
              administration policy.
              5Fluorouracil:       See MdG Colorectal page 6
       Dose modifications:         Table Mito-5FU Contin below
       Reference: Annals Oncology 1997;8:995-1001 Ross P et al

Table: Mito-5FU Contin
Side effect: Mito-5FU Contin                  Dose Modification (FOCUS)
Haematology
Neutrophils                Platelets
   9
x10 /L                       x109/L
1.5            and            100           Full dose
<1.5            or             <100           Delay mitomycin 1 week (but continue 5FU)
                                              If still not recovered after 1 week, delay mitomycin
                                              further 5 weeks.
If Grade 3-4 neutropenic fever occurs         Stop 5FU until recovery. Resume chemo with 5FU
                                              alone ie. omit any further mitomycin C.
Renal
Creatinine                          >ULN      Do not give mitomycin
Hepatic
Bilirubin                   >30micromol/L Do not give mitomycin
Stomatitis
                                    Grade 1 Sucralfate suspension 10mls QDS as mouthwash
                                    Grade 2 If occurs despite above
                                            Interrupt 5FU infusion until resolved. Then
                                            5FU: Dose reduce by 50mg/m2/day
                                   Grade 3 Interrupt 5FU infusion until resolved. Then
                                            5FU: Dose reduce by 100mg/m2/day
Diarrhoea
                                    Grade 1 Loperamide 2-4mg QDS PRN max 16mg/24 hours
                                            Or
                                            Codeine phosphate 30-60mg QDS PRN
                                    Grade 2 If occurs despite above, interrupt 5FU infusion until
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Side effect: Mito-5FU Contin                Dose Modification (FOCUS)
                                            resolved then:
                                            5FU: dose reduce by 50mg/m2/day
                                   Grade 3 Interrupt 5FU infusion until resolved then:
                                            5FU: dose reduce by 100mg/m2/day
Hand Foot Syndrome
                                   Grade 2 Stop 5FU until recovered then:
                                            5FU: dose reduce by 50mg/m2/day

                                              Phase III randomised controlled trials show no benefit from
                                              pyridoxine for prevention or treatment of 5FU induced hand
                                              foot syndrome. Pyridoxine is not recommended.
Haemolytic Uraemic Syndrome (HUS)             Do not give mitomycin unless
Extremely rare with this dose of               Serum creatinine within normal range
mitomycin.                                     Bilirubin <30 micromol/L
Usually fatal if it does occur                 WBC >3.0 x 109/L
                                               Neutrophils 1.5 x 109/L
                                               Platelets 100 x 109/L
                                               No red blood fragmentation seen in blood film

                                              If early HUS suspected: Stop mitomycin permanently
HUS suspected eg. red blood cell              Treat with prednisolone 40mg OD x 7 days
fragmentation


5b.    Mitomycin C-Capecitabine
       Mitomycin        7mg/m2 (max 14mg)        IV bolus                   Day 1
       Capecitabine     1250mg/m2                Orally twice a day         Days 1 to 14
                                          2
                        ie. total 2500mg/m /day  with water after a meal    and 22 to 35
                        See dose table page 59-61
                        Consider 25% dose reduction in patients over 70 years

       Interval between cycles:        Repeat every 42 days
       Number of cycles:               Colorectal metastatic relapse where
                                       there is local approval for
                                       capecitabine substitution of 5FU:       Maximum 4 cycles
                                                                               (total mitomycin dose
                                                                               28mg/m2, max 56mg)
       Tests before starting course of chemo:              FBC (including manual film haemolysis
                                                           screen), U&Es, LFTs, tumour markers,
                                                           CEA, CA19-9, Crcl (calculated) if
                                                           <50mls/min do EDTA
       Tests to OK/Confirm each cycle of chemo:            FBC (including manual film haemolysis
                                                           screen), U&Es, LFTs
                                                           Do not give mitomycin C unless
                                                            Creatinine within normal range
                                                            Bilirubin <30 micromol/L
                                                            WBC 3.0 x 109/L
                                                            Neutrophils 1.5 x 109/L
                                                            Platelets 100 x 109/L
                                                            No red blood cell fragmentation seen in
                                                              blood film
       Supportive drugs with each cycle:                   Low risk antiemetics.
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        Patient information:                    Chemotherapy treatment booklet (local information)
                                                Your chemotherapy record (NWLCN red book)
                                                BACUP information sheet
                                                Capecitabine patient diary
                                                Patient must receive nurse capecitabine counselling
      Additional information:
             Administration notes:
             Mitomycin:
             Mitomycin is a vesicant and should be administered with the NWLCN administration
             policy.
             Capecitabine:
             Patients must receive specific capecitabine counselling prior to treatment from a
             capecitabine trained nurse/pharmacist as per local policy. Patients must be given
             written and verbal information on capecitabine including how to take the tablets,
             when to stop (ie. In the event of toxicity and after 14 days), and whom to contact
             when side effects occur. Written information should be sent to the patient’s GP.
             Capecitabine tablets should be taken with water 30 minutes after food and
             approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin
             and therefore patients on these drugs must have their blood levels monitored more
             regularly. Capecitabine is contraindicated with allopurinol.
      Dose modifications: table Mito-C-Cape page 29
      Reference: B.J.Cancer. 2005;93:510-514. Chong G et al.
Table: Mito-Capecitabine
Side effect: Mito-Capecitabine                  Dose Modification
Haematology
Neutrophils                Platelets
x109/L                       x109/L
1.5           and             100             Full dose. Only treat if WBC, neutrophils and platelets
                                                are above these levels
<1.5                   or               <100    Delay all chemotherapy 1 week (or until recovery)
                                                If still not recovered after 1 week, delay mitomycin
                                                further 5 weeks.
                                                If > 1 delay or 1 delay ≥2 weeks give capecitabine 20%
                                                dose reduction on all future cycles. If further delays
                                                occur despite dose reduction discuss with consultant.

If Grade 3-4 neutropenic fever occurs           Stop chemotherapy until recovery. Resume chemo with
                                                capecitabine alone ie. omit any further mitomycin C.
Renal   (Scot trial)

Crcl                            50mls/min   Full dose all drugs
                                30-49mls/min Omit mitomycin. Capecitabine 25% dose reduction.
                                  <30mls/min Do not give. Discuss with consultant
Hepatic
Bilirubin                      >30micromol/L Do not give mitomycin

Bilirubin                   Either AST or ALT
3 x ULN          and        2.5 x ULN         Full dose capecitabine
>3 x ULN          or          >2.5 x ULN        Do not give chemo. Discuss with consultant
Stomatitis
                                     Grade 1 Sucralfate suspension 1g/5ml mouthwash QDS
                                    ≥Grade 2 As grade 1 and stop capecitabine until recovery then
                                             reduce dose according to SPC table on page 11
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Side effect: Mito-Capecitabine       Dose Modification
Diarrhoea
                             Grade 1 Loperamide 2-4mg QDS PRN max 16mg/24 hours
                                     Or codeine phosphate 30-60mg QDS PRN
                             Grade 2 As grade 1 and stop capecitabine until recovery then
                                     reduce dose according to SPC table on page 11
Hand Foot Syndrome           Grade 1 Stop capecitabine until recovery. Once recovered
                                     restart capecitabine with full dose.
                            ≥Grade 2 Stop capecitabine until recovery. Once recovered
                                     reduce capecitabine dose according to SPC table on
                                     page 10

                                           Phase III randomised controlled trials show no benefit from
                                           pyridoxine for prevention or treatment of 5FU induced hand
                                           foot syndrome. Pyridoxine is not recommended.

Haemolytic Uraemic Syndrome (HUS)          Do not give mitomycin unless
Extremely rare with this dose of            Serum creatinine within normal range
mitomycin.                                  Bilirubin <30 micromol/L
Usually fatal if it does occur              WBC >3.0 x 109/L
                                            Neutrophils 1.5 x 109/L
                                            Platelets 100 x 109/L
                                            No red blood fragmentation seen in blood film

HUS suspected eg. red blood cell           If early HUS suspected: Stop mitomycin permanently
fragmentation                              Treat with prednisolone 40mg OD x 7 days
DPD Deficiency                             1-3% of patients have markedly exaggerated
                                           5FU/capecitabine toxicity due to reduced
                                           5FU/capecitabine catabolism. Discuss with consultant.
Cardiotoxicity                             Uncommon. 5FU/capecitabine may provoke angina or
                                           MI in patients with ischaemic heart disease. Seek
                                           specialist opinion on upgraded anti-anginal medication
                                           and consider dose reduction or alternative non
                                           5FU/capecitabine treatment.



6.     Raltitrexed Regimens
6a.    Raltitrexed-3 (single Agent) (CTIS: 736)
       Raltitrexed         3mg/m2             IV over 15 minutes                         Day 1

       Interval between cycles:  Repeat every 21 days
       Number of cycles:         Palliative chemotherapy for advanced colorectal cancer
                                 intolerant of 5Fluorouracil ie. develop angina or have
                                 poorly controlled angina or recent myocardial infarct.
                                 Under direction of Consultant.            6 cycles
       Tests before starting chemo:                   FBC, U&E, LFTs, Crcl calculated. Do
                                                      EDTA if <65mls/min
       Tests to OK/Confirm each cycle of chemo:       FBC, U&E, LFTs, Crcl calculated, redo
                                                      EDTA if rising creatinine
       Supportive drugs with each cycle:              Low risk antiemetics
                                                      Chlorhexidine mouthwash 10mls QDS
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                                                          Loperamide 2-4mg QDS (max 16mg/day)
                                                          PRN or codeine phosphate 30-60mg QDS
                                                          PRN
        Patient Information:            Chemotherapy treatment booklet (local information)
                                        Your chemotherapy record (NWLCN red book)
                                        BACUP Information Sheet on Raltitrexed
        Additional information:
        Dose modifications:
        Reference: European J. Cancer. 1995;31: Cunningham et al

Table Raltitrexed (adapted from CR06)
For combination haematological/non haematological toxicity
    Wait until full recovery ie. neutrophils >2.0 x 109/L and platelets ≥100 x 109/L and/or any
      persistent mucositis and diarrhoea have resolved
    If resolved within 2 weeks restart using dose modifications below
    If FULL recovery takes more than 2 weeks discuss with consultant.

Haematological                                        Non haematological toxicity
Toxicity                                       on day of chemo and during previous cycle
                                                           (eg. diarrhoea or mucositis)
Neutrophils           Platelets
x109/L                x109/L                                     CTC Grade
                                         0-1                 2                       3                4
≥ 2.0       And           ≥100    Full dose          Raltitrexed          Delay until non-       Do not give
                                                     25% dose             haematological
                                                     reduction            toxicity recovery to
                                                                          ≤grade 2 then give
                                                                          Raltitrexed 50%
                                                                          dose reduction
≥1.0-1.9* And             50-99   Delay until        Delay until          Delay until full       Do not give
                                  haematological     haematological       haematological
* Discuss with consultant as in   recovery then      recovery then        and non-
some cases may go ahead with
neutrophils 1.0-1.9 provided      give full dose     give raltitrexed     haematological
platelets ≥100                                       25% dose             recovery to toxicity
                                                     reduction            ≤grade 2 then
                                                                          give raltitrexed
                                                                          50% dose
                                                                          reduction
0.5-0.99      Or          25-49 Delay until          Delay until          Delay until full       Do not give
                                haematological       haematological       haematological
                                recovery then        recovery then        and non-
                                give raltitrexed     give raltitrexed     haematological
                                25% dose             25% dose             recovery to toxicity
                                reduction            reduction            ≤grade 2 then give
                                                                          raltitrexed 50%
                                                                          dose reduction
<0.5         Or           <25     Delay until        Delay until          Do not give            Do not give
                                  haematological     haematological
                                  recovery then      recovery then
                                  give raltitrexed   give raltitrexed
                                  50% dose           50% dose
                                  reduction          reduction


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Side effect: Raltitrexed                   Dose modification:
Mucositis/diarrhoea                        See above for dose modifications.
                                           If severe mucositis associated with myelosuppression
                                           occurs patient should be vigorously supported with early
                                           hospitalisation for IV fluids, antiemetics, anti-diarrhoeals
                                           and antibiotics
Renal function (CR06)
Crcl                          ≥65mls/min Full dose 3mg/m2 every 21 days
                             25-65mls/min 1.5mg/m2 every 28 days
                              < 25mls/min Do not give
Liver function
Raised transaminases                       Discuss with consultant
                                           CR06 trial states “asyptomatic transient rises in liver
                                           transaminases are common, maximal in cycles 2 and 3,
                                           then tends to resolve with continued treatment”.


6b.    Raltitrexed/Oxalplatin (TOMOX)
       For additional Private Care unless local NDP approved/PCT agreement to fund
       Raltitrexed          3mg/m2              IV over 15 minutes            Day 1
                                     2
       Oxaliplatin*         130mg/m             IV over 2 hours               Day 1

       *Some papers used oxaliplatin 100mg/m2

       Interval between cycles:  Repeat every 21 days
       Number of cycles:         Subject to local approval in combination for patients
                                 Intolerant of 5Fluorouracil ie. develop angina or have
                                 poorly controlled angina or recent myocardial infarct.
                                 Under direction of Consultant.                         6 cycles
       Tests before starting chemo:                   FBC, U&E, LFTs, Crcl calculated. Do
                                                      EDTA if <65mls/min, tumour markers CEA,
                                                      CA19-9
       Tests to OK/Confirm each cycle of chemo:       FBC, U&E, LFTs, Crcl calculated, redo
                                                      EDTA if rising creatinine
       Supportive drugs with each cycle:              5HT3 antiemetics as per local protocol
                                                      Chlorhexidine mouthwash 10mls QDS
                                                      Loperamide 2-4mg QDS (max 16mg/day)
                                                      PRN or codeine phosphate 30-60mg QDS
                                                      PRN
       Patient Information:      Chemotherapy treatment booklet (local information)
                                 Your chemotherapy record (NWLCN red book)
                                 BACUP Information Sheet on Raltitrexed
       Additional information:   Oxaliplatin see page 21
                                 Raltitrexed see page 31
       Dose modifications:       Oxaliplatin see page 24
                                 Raltitrexed see page 32
       Reference:




77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                       Colorectal Page 32 of 66
7.     Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibodies

       EGFR Related Skin Reactions
       General advice:

       Sun:            Advise patient to avoid sun and use sun-block
       Dry skin:       Use oil for washing instead of soap
                       Avoid hot water for baths/shower
                       Emollient creams help
                       Topical corticosteroid creams NOT recommended
                       Fissures may occur in dry skin and topical dressings eg. hydrocolloid
                       dressings as advisee by dermatologist are helpful
       Pruritis:       Consider oral antihistamines

       Nail toxicity: Seek Dermatological advice
                      Daily salt baths and local antiseptic/astringent ointments have been found to
                      be helpful.
                      Anti-inflammatory drugs may help to ease the pain

8.     Cetuximab (Erbitux)
       Funding for Cetuximab is only available on the NHS for NICE approved indications (see I
       ndividual regimens Cetuximab-OX-MdG and Cetuximab-Irino-MdG).
       Cetuximab is licensed for the treatment of patients with epidermal growth factor receptor
       (EGFR) expressing KRAS wild type metastatic colorectal cancer:
           In combination with chemotherapy
           As a single agent in patients who have failed oxaliplatin and irinotecan based
              therapy and who are intolerant of irinotecan.

       Kras testing is available from:
              Molecular Diagnostics
              Wales Gene Park
              2nd Floor Neuadd Merionnydd
              East Park
              Cardiff
              CF14 4YS
              Contact: saunderscm@cardiff.ac.uk
       Request form must be completed including patient consent.

8a.    Cetuximab-Oxaliplatin-5Fluorouracil (Cetuximab-OxMdG)

       Week 1
       Loading dose: Cetuximab/OxMdG (Cetuximab CTIS: 1019, OxMdG CTIS: 327)
       Chlorphenamine          10mg             IV    bolus dose       Day 1
       Dexamethasone           8mg              IV    bolus dose       Day 1
       Paracetamol             1g               Oral once              Day 1
       Ranitidine              150mg            Oral once              Day 1
                                       2
       Cetuximab               400mg/m          IV    over 2 hours     Once only on
                                                                       Day 1 of week 1
       Minimum 1 hour later
       Folinic Acid            350mg            IV    over 2 hours     Day 1
       Oxaliplatin             85mg/m2          IV    over 2 hours     Day 1
                                       2
       5Fluorouracil           400mg/m          IV    bolus            Day 1
       5Fluorouracil           2400mg/m2        IV    over 46 hours    Day 1
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       Week 2
       Maintenance dose Cetuximab: (CTIS: 1020)
       Chlorphenamine          10mg             IV           bolus dose                Day 1
       Dexamethasone           8mg              IV           bolus dose                Day 1
       Paracetamol             1g               Oral         once                      Day 1
       Ranitidine              150mg            Oral         once                      Day 1
       Cetuximab               250mg/m2         IV           over 1 hour*              Once only on
                                                                                       Day 1 of week 2
       Week 3 onwards
       Cetuximab/OxMdG (Cetuximab CTIS: 1020, OxMdG CTIS: 327)
       Chlorphenamine        10mg              IV   bolus dose                         Day 1 and 8
       Dexamethasone         8mg               IV   bolus dose                         Day 1 and 8
       Paracetamol           1g                Oral once                               Day 1 and 8
       Ranitidine            150mg             Oral once                               Day 1 and 8
                                     2
       Cetuximab             250mg/m           IV   over 1 hour*                       Day 1 and 8

       Minimum 1 hour later
       Folinic Acid                    350mg          IV     over 2 hours              Day 1
       Oxaliplatin                     85mg/m2        IV     over 2 hours              Day 1
       5Fluorouracil                   400mg/m2       IV     bolus                     Day 1
       5Fluorouracil                   2400mg/m2      IV     over 46 hours             Day 1

       * Cetuximab maintenance dose infused over 1 hour if patient has tolerated loading dose
       week 1. NB Do not exceed infusion rate 10mg/min

       Interval between cycles:        Week 1    loading dose cetuximab 400mg/m2 plus OxMdG
                                                 once only week 1
                                  Week 2         Maintenance cetuximab 250mg/m2 once only week
                                                 2
                                  Week 3         Cetuximab 250mg/m2          Day 1 and 8
                                  onwards        OxMdG                       Day 1
                                                 Repeat every 14 days
       Number of cycles:          Maximum 16 weeks in line with NICE for 1st line metastatic
                                  colorectal cancer only when all of the following
                                  criteria are met:
                                       The primary colorectal tumour has been resected or is
                                          potentially operable
                                       The metastatic disease is confined to the liver and is
                                          unresectable
                                       The patient is fit enough to undergo surgery to resect the
                                          primary colorectal tumour and to undergo liver surgery if
                                          the metastases become resectable after treatment with
                                          Cetuximab
                                       The manufacturer rebates 16% of the amount of
                                          cetuximab used on a per patient basis
                                  Additional Private Care outside of NICE. Do not continue past
                                  progression
       Tests before starting course of chemo:           FBC, U&Es, LFTs, Mg and Ca for 8 weeks
                                                        after last dose , CrCl (calculated), tumour
                                                        markers, CEA, CA19-9,
       Tests to OK/confirm each cycle of chemo:         FBC, U&Es, Mg, Ca, LFTs
       Supportive drugs with each cycle:                OxMdG
                                                        5HT3 antiemetics as local protocol
                                                        Chlorhexidine mouthwash 10mls QDS
77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                    Colorectal Page 34 of 66
                                                                Loperamide 2-4mg QDS PRN (Max
                                                                16mg/day)
                                                                Cetuximab
                                                                Chlorphenamine, dexamethasone,
                                                                paracetamol and ranitidine as above to
                                                                prevent infusion related reactions
       Patient information:                       Chemotherapy treatment booklet (local information)
                                                  Your chemotherapy record book (NWLCN Red Book)
                                                  BACUP sheets
                                                  General advice on EGFR related skin reactions
                                                  Written information on mechanical pump (if via CVAD)
       Additional information:
       Chemotherapy must be administered at least 1 hour after end of cetuximab infusion.
              Oxaliplatin:         See OxMdG colorectal page 21
              5Fluorouracil:       See OxMdG colorectal page 21
              Cetuximab:           See cetuximab colorectal page 41
       Dose modifications:
              NB: OxMdG and cetuximab may be delayed and/or dose modified independently of
              each other.
              Treatment with either cetuximab or chemotherapy may be delayed due to toxicity.
              If treatment with cetuximab is delayed because of cetuximab toxicity, the 14 day
              rhythm of chemotherapy is retained.
              If chemotherapy is delayed because of toxic effects of the chemotherapy, the 7 day
              rhythm of cetuximab is retained.
              For this reason OxMdG and Cetuximab are prescribed separately on CTIS.
              OxMdG – see dose modifications colorectal page 21
              Cetuximab – see dose modifications colorectal page xxx

Table: Cetuximab
Side-effect: Cetuximab                       Dose modification (Coin/Crystal/SPC)
Allergic/Hypersensitivity Reaction Crystal
trial)                        CTC Grade
                                   Grade 1 Decrease cetuximab infusion rate by 50% and monitor
                                          o
             Transient rash/drug fever <38 C closely for any worsening.
                                             The total infusion time for cetuximab should not exceed
                                             240minutes.

                                     Grade 2 Stop cetuximab infusion contact doctor.
                                     o
            Urticaria, drug fever ≥ 38 C and/or
                                             Administer bronchodilators, oxygen etc as medically
                 asymptomatic bronchospasm
                                             indicated.
                                             Once allergic/hypersensitivity reaction has resolved or
                                             decreased to grade 1 in severity, resume cetuximab
                                             infusion with 50% reduction in rate of infusion and
                                             monitor closely for any worsening.

                        Grade 3 or Grade 4 Stop cetuximab infusion immediately and disconnect
      Grade 3: Symptomatic bronchospasm, infusion tubing from the patient.
 requiring parenteral medication with or without Administer adrenaline/epinephrine, bronchodilators,
     urticaria, hypersensitivity-related oedema,
                                   angio-oedema
                                                 antihistamines, glucorticoids, intravenous fluids,
                                                 vasopressor agents, oxygen as medically indicated.

                                     Grade 4 Grade 4: Anaphylaxis DO NOT rechallenge with
                                             cetuximab
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Side-effect: Cetuximab                          Dose modification (Coin/Crystal/SPC)

      Recurrent allergic/hypersensitivity If a patient has a second allergic/hypersensitivity
                        reactions (Crystal) reaction on the slower infusion rate, stop the cetuximab
                                            infusion and treat reaction but DO NOT rechallenge with
                                            cetuximab.

Skin Toxicity

General Information (SPC)
Skin reactions may develop in more than 80% of patients and mainly present as acne-like rash
and/or less frequently as pruritus, dry skin, desquamation or nail disorders (eg. paronychia).
Approximately 15% of skin reactions are severe including single cases of skin necrosis. The
majority of skin reactions develop within the first 3 weeks of therapy. They generally resolve,
without sequelae over time following cessation of treatment if the recommended adjustments in
dose are followed.
Skin lesions induced by cetuximab may predispose patients to suprainfections (eg. S Aureus)
which may lead to subsequent complications eg. cellulitis, erysipelas or potentially with fatal
outcome, staphylococcal scalded skin syndrome or sepsis.

Nail Toxicity (COIN B)
Nail toxicity occurs in 8% of patients with cetuximab characterised by paronychial inflammation
with associated swelling of the lateral skin folds of toes and fingers, especially big toes and thumb
which may be painful. This may persist for up to 12 weeks after cessation of cetuximab.

General Advice (COIN B)
Sun                                             Advise patient to avoid sun and use sun-block

Pruritis                                        Consider oral antihistamine

Dry skin                                        Use oil for washing instead of soap
(may contribute to pruritis)                    Avoid hot water for baths/shower
                                                Emollient creams help
                                                Topical corticosteroid creams NOT recommended
                                                Fissures may occur in dry skin and topical dressings eg.
                                                hydrocolloid dressings as advised by dermatologist are
                                                helpful

Nail toxicities                                 Seek Dermatological advice
                                                Daily salt baths and local antiseptic/astringent ointments
                                                have been found to be helpful.
                                                Anti-inflammatory drugs may help to ease the pain

Skin Toxicity (COIN B)
NCI-CTC
             Grade 1 acneform eruption Full dose cetuximab. Consider topical antibiotics eg.
                                       metronidazole but caution as some users report
                                       increased irritation.

              Grade 2 acneform eruption Full dose cetuximab. Consider systemic antibiotics eg.
     (Rash on up to 50% of body surface area)
                                        second generation tetracyclines such as doxycycline
                                        100mg oral daily and refer to dermatologist.

77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                          Colorectal Page 36 of 66
Side-effect: Cetuximab                Dose modification (Coin/Crystal/SPC)
          Grade ≥ 3 acneform eruption
         (Rash on ≥50% of body surface area)
                            1st Appearance Start doxycycline 100mg oral once a day and refer to
                                           dermatologist. Interrupt cetuximab therapy until reaction
                                           has resolved to grade 2 or less then restart cetuximab
                                           without any change in dose ie. 250mg/m 2 maintenance.
                                           If reaction does not resolve to ≤grade 2, discontinue
                                           cetuximab.

                           2nd Appearance Interrupt cetuximab therapy until reaction has resolved
                                          to grade 2 or less then restart with reduced dose
                                          cetuximab: 200mg/m2 maintenance.
                                          If reaction does not resolve to ≤grade 2, discontinue
                                          cetuximab.

                            3rd Appearance Interrupt cetuximab therapy until reaction has resolved
                                           to grade 2 or less then restart with reduced dose
                                           cetuximab ie. 150mg/m2 maintenance.
                                           If reaction does not resolve to ≤grade 2, discontinue
                                           cetuximab.

                      4th Appearance (SPC) Discontinue cetuximab permanently

  Reactions do NOT resolve to grade 2 Discontinue cetuximab permanently

                 More than 2 consecutive
            infusions are withheld (Crystal). Discontinue cetuximab permanently


Nail problems                                       Refer to dermatologist (see general advice page 41)

Electrolyte Disturbances (SPC)                      Correct electrolyte depletions as appropriate

                                 Magnesium Progressively decreasing serum magnesium levels
                          (up to 65% of patients)
                                            occur frequently and may lead to severe
                                 <0.6mmol/L hypomagnesaemia which may last up to 8 weeks after
                                            the last dose. Hypomagnesaemia is reversible following
                                            discontinuation of cetuximab.
                                            Correct by intravenous supplementation if <0.6mmol/L.

                             Hypokalaemia May develop as a consequence of diarrhoea

                            Hypocalcaemia May occur. In combination with platinum-based
                                          chemotherapy, the frequency of severe hypocalcaemia
                                          may be increased

Haematology
Haemoglobin                    <9g/dl               SPC states cetuximab has not been studied in patients
Leucocyctes                    <3.0 x 109/L         with one or more of the parameters opposite.
Neutrophils                    <1.5 x 109/L         However, clinical trials (COIN, COIN B, Crystal) did not
Platelets                      <100 x 109/L         always delay/interrupt cetuximab if haematological
                                                    parameters were low and concomitant chemotherapy
                                                    was delayed. Discuss continuing with consultant.
77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                             Colorectal Page 37 of 66
Side-effect: Cetuximab                       Dose modification (Coin/Crystal/SPC)
Renal Function
Serum creatinine       >1.5 x ULN            SPC states only patients with adequate renal function
                                             have been investigated to date.
                                             Discuss with consultant if serum creatinine > 1.5 x ULN
Hepatic Function
Transaminase                   > 5 x ULN     SPC states only patients with adequate hepatic function
and/or                                       have been investigated to date.
Bilirubin                      > 1.5 x ULN   Discuss with consultant if parameters opposite occur.


8b.    Cetuximab-Irinotecan-5Fluorouracil (Cetuximab-IrMdG)
       Week 1
       Loading dose: Cetuximab/IrMdG (Cetuximab CTIS: 1019, IrMdG CTIS: 751)
       Chlorphenamine           10mg              IV    bolus dose        Day 1
       Dexamethasone            8mg               IV    bolus dose        Day 1
       Paracetamol              1g                Oral once               Day 1
       Ranitidine               150mg             Oral once               Day 1
                                        2
       Cetuximab                400mg/m           IV    over 2 hours      Once only
                                                                          Day 1 of week 1
       Minimum 1 hour later
       Atropine                 250mcg            SC                      Day 1
                                        2
       Irinotecan               180mg/m           IV    over 30 mins      Day 1
       Folinic Acid             350mg             IV    over 2 hours      Day 1
       5Fluorouracil            400mg/m2          IV    bolus             Day 1
                                          2
       5Fluorouracil            2400mg/m          IV    over 46 hours     Day 1

       Week 2:
       Cetuximab maintenance (CTIS: 1020)
       Chlorphenamine          10mg                       IV      bolus dose                Day 1
       Dexamethasone           8mg                        IV      bolus dose                Day 1
       Paracetamol             1g                         Oral    once                      Day 1
       Ranitidine              150mg                      Oral    once                      Day 1
       Cetuximab               250mg/m2                   IV      over 1 hour*              Day 1

       Week 3 onwards:
       Cetuximab/IrMdG (Cetuximab CTIS: 1020, IrMdG CTIS: 751)
       Chlorphenamine          10mg              IV    bolus dose                           Day 1 and 8
       Dexamethasone           8mg               IV    bolus dose                           Day 1 and 8
       Paracetamol             1g                Oral once                                  Day 1 and 8
       Ranitidine              150mg             Oral once                                  Day 1 and 8
       Cetuximab               250mg/m2          IV    over 1 hour*                         Day 1 and 8

       Minimum 1 hour later
       Atropine                        250mcg             SC                                Day 1
       Irinotecan                      180mg/m2           IV      over 30 mins              Day 1
       Folinic Acid                    350mg              IV      over 2 hours              Day 1
       5Fluorouracil                   400mg/m2           IV      bolus                     Day 1
       5Fluorouracil                   2400mg/m2          IV      over 46 hours             Day 1

       *Cetuximab maintenance dose (week 2 onwards) infused over 1 hour if patient has
       tolerated loading dose week one. NB. Do not exceed infusion rate 10mg/min.

77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                         Colorectal Page 38 of 66
       Interval between cycles:        Week 1    loading dose cetuximab 400mg/m2 plus IrMdG
                                                 once only in week one
                                  Week 2         Maintenance cetuximab 250mg/m2 once only in
                                                 week two
                                  Week 3         Cetuximab 250mg/m2           Day 1 and 8
                                  onwards        IrMdG                        Day 1
                                                 Repeat every 14 days
       Number of cycles:             Maximum 16 weeks in line with NICE for 1st line metastatic
                                     colorectal cancer only when all of the following criteria are
                                     met.
                                      The primary colorectal tumour has been resected or is
                                         potentially operable
                                       The metastatic disease is confined to the liver and is
                                         unresectable
                                       The patient is fit enough to undergo surgery to resect the
                                         primary colorectal tumour and to undergo liver surgery if
                                         the metastases become resectable after treatment with
                                         Cetuximab
                                       The patient is unable to tolerate or has contraindications
                                         to oxaliplatin.
                                      Use outside of NICE is Additional Private Care
                                      Do not give past progression
       Tests before starting course of chemo:            FBC, U&Es, LFTs, Mg and Ca for 8 weeks
                                                         after last dose, tumour markers,
                                                         CEA, CA19-9
                                                         Performance status:
                                                         PS 0 or 1:     Proceed
                                                         PS 2:          Caution
                                                         PS 3:          Do not give
                                                         Caution in patients with previous history of
                                                         diarrhoea or abdominal pelvic disease
       Tests to OK/confirm each cycle of chemo:          FBC, U&Es, Mg and Ca for 8 weeks after
                                                         last dose, LFTs
       Supportive drugs with each cycle:                 IrMdG
                                                         5HT3 antiemetics as local protocol
                                                         Chlorhexidine mouthwash 10mls QDS
                                                         Atropine as above to prevent acute
                                                         cholinergic syndrome (diarrhoea, sweating,
                                                         salivation, bradycardia.
                                                         Loperamide if necessary: see dose
                                                         modification table.
                                                         Ciprofloxacin if necessary: see dose
                                                         modification table.
                                                         Cetuximab
                                                         Chlorphenamine, dexamethasone,
                                                         paracetamol and ranitidine as above to
                                                         prevent infusion related reactions
       Patient information:              Chemotherapy treatment booklet (local information)
                                         Your chemotherapy record book (NWLCN Red Book)
                                         BACUP sheets
                                         General advice on EGFR related skin reactions
                                         Written information on mechanical pump (if via CVAD)
       Additional information:
       Chemotherapy must be administered at least one hour after end of cetuximab infusion
77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                     Colorectal Page 39 of 66
            Cetuximab:           See Colorectal page 42
            IrMdG:               See Colorectal page 14
       Dose modifications:
            NB: IrMdG and cetuximab may be delayed and/or dose modified independently of
            each other.
            Treatment with either cetuximab or chemotherapy may be delayed due to toxicity.
            If treatment with cetuximab is delayed because of cetuximab toxicity, the 14 day
            rhythm of chemotherapy is retained.
            If chemotherapy is delayed because of toxic effects of the chemotherapy, the 7 day
            rhythm of cetuximab is retained.
            For this reason OxMdG and Cetuximab are prescribed separately on CTIS.
            Cetuximab: see colorectal page 42
            IrMdG:         see colorectal page 14

8c.    Cetuximab Monotherapy/Single Agent
       For additional Private Care unless local NDP approved/PCT agreement to fund
       Week 1
       Loading dose Cetuximab (CTIS: 1019)
       Chlorphenamine             10mg                IV    bolus dose        Day 1
       Dexamethasone              8mg                 IV    bolus dose        Day 1
       Paracetamol                1g                  Oral once               Day 1
       Ranitidine                 150mg               Oral once               Day 1
       Cetuximab                  400mg/m2            IV    over 2 hours      Once only
                                                                              Day 1
       Week 2 onwards
       Maintenance dose Cetuximab (CTIS: 1020)
       Chlorphenamine             10mg                IV    bolus dose        Day 1
       Dexamethasone              8mg                 IV    bolus dose        Day 1
       Paracetamol                1g                  Oral once               Day 1
       Ranitidine                 150mg               Oral once               Day 1
                                            2
       Cetuximab                  250mg/m             IV    over 1 hour*      Day 1

       * Over 1 hour if patient has tolerated loading dose
       NB. Infusion rate must NOT exceed 10mg/min

       Interval between cycles:   Loading dose cetuximab 400mg/m2 ONCE only week one
                                  followed 7 days later by cetuximab 250mg/m2 repeated every 7
                                  days thereafter.
       Indication:                Licensed for patients with epidermal growth factor receptor
                                  (EGFR) expressing KRAS wild type metastatic colorectal
                                  cancer.
                                  Licensed as single agent in metastataic colorectal cancer
                                  patients who have failed oxaliplatin and irinotecan based
                                  therapy and who are intolerant to irinotecan.
       Number of cycles:          Continue until progression of underlying disease. Do not
                                  continue past progression.
       Tests before staring course of chemo:           FBC, U&E, Mg, Ca, LFTs
       Tests to OK/confirm each cycle of chemo:        FBC, U&E, Mg and Ca for 8 weeks after the
                                                       last dose, LFTs
       Supportive drugs with each cycle:       Chlorphenamine, dexamethasone, paracetamol
                                               and ranitidine to prevent infusion related reactions
       Patient information:              Chemotherapy treatment booklet (local information
                                         Your chemotherapy record (NWLCN red book)
                                         BACUP information sheet
77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                     Colorectal Page 40 of 66
                                             General advice on EGFR related skin reactions
       Additional information:
              Administration notes: (SPC)
              Cetuximab:
              Close monitoring is required during and for at least 1 hour after the end of the
              infusion. Availability of resuscitation equipment must be ensured.
              Patients must receive premedication with antihistamine and corticosteroid prior to
              every cetuximab infusion.
              The first cetuximab infusion is infused over 2 hours. If well tolerated then
              subsequent infusions may be administered over 1 hour. If the patient experiences
              mild/moderate infusion related reactions consult the doctor as the infusion rate must
              be decreased. The maximum rate of infusion must not exceed 10mg/min.
              If cetuximab is administered in combination with other chemotherapy, the
              chemotherapy must be administered at least 1 hour after the end of the cetuximab
              infusion.
       Dose modifications: See table page xx

8d.    Cetuximab-Capecitabine-Oxaliplatin Cetux-Reduced dose CapeOx
       For Additional Private Care unless local NDP approved/PCT agreement to fund
       NB. Capecitabine reduced starting dose in CapeOx plus cetuximab due to increased
       toxicity of capecitabine-cetuximab combination

       Week 1
       Loading dose Cetuximab/Reduced Dose CapeOx                  (Cetuximab CTIS: 1019,
                                                                   Reduced dose CapeOx CTIS: )
       Chlorphenamine                  10mg               IV       bolus dose        Day 1
       Dexamethasone                   8mg                IV       bolus dose        Day 1
       Paracetamol                     1g                 Oral     once              Day 1
       Ranitidine                      150mg              Oral     once              Day 1
       Cetuximab                       400mg/m2           IV       over 2 hours      Once only on
                                                                                     Day 1 of week 1
       Minimum 1 hour later
       Oxaliplatin                     130mg/m2          IV     over 2 hours                Day 1
       Capecitabine                    850mg/m2          Oral twice a day                   Day 1 to 14
                                       ie. 1700mg/m2/day with water after food              (28 doses
                                                                                            starting evening
                                                                                            of day 1)
       Week 2 and 3
       Maintenance dose Cetuximab: (CTIS: 1020)
       Chlorphenamine          10mg             IV                 bolus dose               Day 1
       Dexamethasone           8mg              IV                 bolus dose               Day 1
       Paracetamol             1g               Oral               once                     Day 1
       Ranitidine              150mg            Oral               once                     Day 1
                                       2
       Cetuximab               250mg/m          IV                 over 1 hour*             Once only on
                                                                                            Day 1 of week 2
       Week 4 onwards
       Cetuximab/Reduced dose CapeOx                (Cetuximab CTIS: 1020,
                                                    Reduced dose CapeOx CTIS: )
       Chlorphenamine                  10mg               IV    bolus dose      Day 1, 8 and 15
       Dexamethasone                   8mg                IV    bolus dose      Day 1, 8 and 15
       Paracetamol                     1g                 Oral once             Day 1, 8 and 15
       Ranitidine                      150mg              Oral once             Day 1, 8 and 15
       Cetuximab                       250mg/m2           IV    over 1 hour     Day 1, 8 and 15

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       Minimum 1 hour later
       Oxaliplatin                     130mg/m2          IV     over 2 hours              Day 1
       Capecitabine                    850mg/m2          Oral twice a day                 Day 1 to 14
                                       ie. 1700mg/m2/day with water after food            (28 doses
                                                                                          starting evening
                                                                                          of day 1)

       Cetuximab maintenance dose (week 2 onwards) infused over 1 hour if patient has tolerated
       loading dose week 1. NB Do not exceed infusion rate 10mg/min

       Interval between cycles:        Week 1    loading dose cetuximab 400mg/m2 plus reduced
                                                 dose CapeOx once only week 1
                                   Week 2        Maintenance cetuximab 250mg/m2 once week 2
                                   Week 3        Maintenance cetuximab 250mg/m2 once week 3
                                   Week 4        Cetuximab 250mg/m2          Day 1, 8 and 15
                                   onwards       Reduced dose CapeOx         Day 1
                                                 Repeat every 21 days
       Number of cycles:           Additional Private Care
                                   12 cycles            ie. 24 weekly cetuximab doses (including
                                                        loading dose) and 12 cycles Modified
                                                        CapeOx.
                                   Do not continue past progression
       Tests before starting course of chemo:           FBC, U&Es, LFTs, Mg, Ca, tumour markers,
                                                        CEA, CA19-9, CrCl (calculated) if
                                                        <50mls/min do EDTA
       Tests to OK/confirm each cycle of chemo:         FBC, U&Es, Mg, and Ca for 8 weeks after
                                                        last dose, LFTs, CrCl (calculated). Redo
                                                        EDTA if rising creatinine.
       Supportive drugs with each cycle:                Reduced Dose CapeOx
                                                        5HT3 antiemetics as local protocol
                                                        Cetuximab
                                                        Chlorphenamine, dexamethasone,
                                                        paracetamol and ranitidine as above to
                                                        prevent infusion related reactions
       Patient information:               Chemotherapy treatment booklet (local information)
                                          Your chemotherapy record book (NWLCN Red Book)
                                          BACUP sheets
                                          Capecitabine patient diary
                                          Patient must receive nurse capecitabine counselling
                                          General advice on EGFR related skin reactions
       Additional information:
       Chemotherapy must be administered at least 1 hour after end of cetuximab infusion.
              Cetuximab:           See colorectal page 42
              CapeOx:              See colorectal page 21, 24
       Dose modifications:
              NB: Reduced dose-CapeOx and cetuximab may be delayed and/or dose modified
              independently of each other.
              Treatment with either cetuximab or chemotherapy may be delayed due to toxicity.
              If treatment with cetuximab is delayed because of cetuximab toxicity, the 21 day
              rhythm of chemotherapy is retained.
              If chemotherapy is delayed because of toxic effects of the chemotherapy, the 7 day
              rhythm of cetuximab is retained.
              For this reason Reduced dose-CapeOx and Cetuximab maintenance are prescribed
              separately on CTIS.
77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                       Colorectal Page 42 of 66
             Cape-Ox   dose modifications see colorectal page 24
             Cetuximab dose modifications see colorectal page 42
       Reference: BJC 2009 100:251-258. Adams RA et al


9.     Bevacizumab (Avastin)
       Funding for Bevacizumab is not currently (June 2010) available on the NHS.
       Bevacizumab is licensed in combination with fluoropyrimidine based chemotherapy for the
       treatment of patients with metastatic carcinoma of the colon or rectum.

9a.    Bevacizumab-Oxaliplatin-5Fluorouracil (Bev-OxMdG)
       (Bevacizumab CTIS: OxMdG CTIS: 327)
       For additional Private Care unless NDP approved/PCT agreement to fund
       Bevacizumab                5mg/kg            IV    over 90 mins*                     Day 1
       Folinic acid               350mg             IV    over 2 hours                      Day 1
                                          2
       Oxaliplatin                85mg/m            IV    over 2 hours                      Day 1
       5Fluorouracil              400mg/m2          IV    bolus                             Day 1
                                            2
       5Fluorouracil              2400mg/m          IV    over 46 hours                     Day 1

       *First infusion of bevacizumab should be infused over 90 minutes. If this first infusion is
       well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute
       infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.

       Interval between cycles:        Repeat every 14 days
       Number of cycles:               Metastatic carcinoma of
                                       colon or rectum:       Duration depends on response.
                                                              3-6 months is standard if responding,
                                                              Longer treatment must be discussed
                                                              with consultant.
                                                              Do not continue past progression
       Tests before starting course of chemo:          FBC, U&Es, LFTs, tumour markers, CEA,
                                                       CA19-9, CrCl (calculated), INR.
                                                       Blood pressure, dipstick for proteinuria
                                                       Do not administer bevacizumab within 28
                                                       days of surgery, see Colorectal page 37
                                                       See SPC for other cautions with
                                                       bevacizumab eg. gastro intestinal
                                                       perforations, wound healing, hypertension,
                                                       proteinurIa, thromboembolism,
                                                       haemorrhage, CNS metastases, congestive
                                                       heart failure.
       Tests to OK/confirm each cycle of chemo:        FBC, U&Es, LFTs, BP, dipstick proteinuria,
                                                       Crcl calculated
       Supportive drugs with each cycle:        5HT3 antiemetics as local protocol
                                                Chlorhexidine mouthwash 10mls QDS
                                                Loperamide 2-4mg QDS PRN (Max 16mg/day)
       Patient information:              Chemotherapy treatment booklet (local information)
                                         Your chemotherapy record book (NWLCN Red Book)
                                         BACUP sheets
                                         Written information on mechanical pump (if via CVAD)
                                         General advice on EGFR related skin reactions
       Additional information:
              Administration notes:
              Bevacizumab:
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             Bevacizumab should be administered diluted with normal saline.
             Do NOT mix bevacizumab with any other fluids. Where other fluids follow
             bevacizumab infusion, flush first with normal saline then flush with the other fluid.
             Bevacizumab first infusion is administered over 90 minutes. If this first infusion is
             well tolerated, the second infusion may be administered over 60 minutes. If the 60
             minute infusion is well tolerated all subsequent infusions may be administered over
             30 minutes. See dose modifications table for action if dose not tolerated.
             Oxaliplatin - see colorectal page 21
             5Flourouracil – see colorectal page 21
       Dose modifications/cautions:
             Bevacizumab dose reduction for adverse events is not recommended (SPC). If
             indicated, bevacizumab therapy should either be permanently discontinued or
             temporarily suspended until toxicity resolves. Chemotherapy alone may continue if
             bevacizumab toxicity/side effects dictate that bevacizumab should be withheld.
             OxMdG:         Dose modifications see colorectal page 21
       Reference:

Table: Bevacizumab
Side effect: Bevacizumab              Dose modification (SPC)
All toxicities graded according to CTCAE v3.0 guidelines
Thrombosis/Embolism

Venous thromboembolic event
Grade 3 or incidentally discovered         Hold bevacizumab for 2 weeks. Bevacizumab may be
pulmonary embolus (first occurrence)       resumed after initiation of therapeutic-dose
                                           anticoagulant therapy as soon as all of the following
                                           criteria are met:

                                            The patient must be on a stable dose of
                                              anticoagulant and, if on an oral coumarin-derivative,
                                              have an INR within the target range (usually between
                                              2 and 3) prior to restarting bevacizumab.
Symptomatic Grade 4 venous                 Permanently discontinue bevacizumab
thromboembolic event (first
occurrence)
                                           Permanently discontinue bevacizumab if patient
Arterial thromboembolic event – any        develops any grade of arterial thromboembolic event.
grade
Haemorrhage
Grade 1 and 2                              No schedule modifications
Grade 3 or 4 (first occurrence)            Discontinue bevacizumab and institute appropriate
                                           treatment
Proteinuria
First occurrence of proteinuria:
                            1+ (dipstick) Administer bevacizumab as scheduled. NO additional
                                          evaluation is required.
                  2+, 3+ and 4+ dipstick Administer bevacizumab as scheduled and collect 24-
                                          hour urine to determine the total protein within 3 days
                                          prior to the next scheduled dose.
                                          If
                                           24-hour proteinuria ≤2g:
                                              Administer bevacizumab as scheduled
                                           24-hour proteinuria >2g:
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Side effect: Bevacizumab                    Dose modification (SPC)
                                              Bevacizumab treatment should be withheld pending
                                              next 24 hour total protein.
                                                 If
                                               Repeat 24 hour urine protein ≤2g:
                                                 Administer bevacizumab as schedule. 24-hour
                                                 protein should be further monitored prior to each
                                                 administration of bevacizumab until it has
                                                 decreased to ≤1g/24 hour.
                                               Repeat 24-hour urine protein > 2g:
                                                 Bevacizumab dose should be withheld until 24-
                                                 hour protein has decreased to ≤2g. 24-hour
                                                 protein should be further monitored prior to each
                                                 administration of bevacizumab until it has
                                                 decreased to ≤1g/24 hour.

Second and subsequent occurrence of
≥2+ proteinuria (dipstick)
                           2+ (dipstick) Administer bevacizumab as scheduled. NO additional
                                         evaluation is required.

                      3+ and 4+ (dipstick): Administer bevacizumab as scheduled and collect 24-
                                            hour urine to determine the total protein within 3 days
                                            prior to the next scheduled dose is required:
                                            If
                                             24-hour proteinuria ≤2g: Administer bevacizumab as
                                                scheduled
                                             24-hour proteinuria >2g: Bevacizumab treatment
                                                should be withheld pending next 24 hour total
                                                protein.
                                                    If
                                                 Repeat 24 hour urine protein ≤2g:
                                                    Administer bevacizumab as schedule. 24-hour
                                                    protein should be further monitored prior to each
                                                    administration of bevacizumab until it has
                                                    decreased to ≤1g/24 hour.
                                                 Repeat 24-hour urine protein > 2g:
                                                    Bevacizumab dose should be withheld until 24-
                                                    hour protein has decreased to ≤2g. 24-hour
                                                    protein should be further monitored prior to each
                                                    administration of bevacizumab until it has
                                                    decreased to ≤1g/24 hour.
Nephrotic Syndrome                          Discontinue bevacizumab treatment
Grade 4
Gastro-intestinal perforation
Gastro-intestinal perforation or            Discontinue bevacizumab permanently and institute
dehiscence                                  appropriate treatment
Wound healing complications
Prevention of wound healing                 Bevacizumab therapy should not be initiated for at least
complications                               28 days following major surgery or until the surgical
                                            wound is fully healed. Bevacizumab therapy should be
                                            withheld for at least 28 days before elective surgery.
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Side effect: Bevacizumab                          Dose modification (SPC)

Wound healing complications                       In patients who experience wound healing complications
                                                  during bevacizumab treatment, bevacizumab should be
                                                  withheld until the wound is fully healed.
Fistula or intra-abdominal abscess
Fistula or intra-abdominal abscess                Patients who develop a fistula or intra-abdominal
                                                  abscess should discontinue bevacizumab
Hypertension
Patients should be monitored for development of, or worsening hypertension by frequent blood
pressure measurement. BP measurement should be taken after the patient has been in a resting
position for ≥5 minutes. Repeated measurement of BP for verification should be taken of the initial
reading is ≥140mmHg systolic and/or ≥90mmHg diastolic blood pressure
Grade 1 Hypertension                    Continue with bevacizumab
Asymptomatic, transient (<24hr) increase
>20mmHg (diastolic) or to >150/100mmHg if
previously within normal limits.

Grade 2 Hypertension                              Monotherapy of antihypertensive may be indicated.
Recurrent or persistent (>24hrs) increase by      Withhold bevacizumab. Once BP controlled to
20mmHg (diastolic) or to >150/100mmHg if          <150/100mmHg patient may restart bevacizumab.
previously within normal limits

Grade 3 Hypertension                              Withhold bevacizumab for persistent or symptomatic
Requiring more than one anti-hypertensive or
more intensive therapy than previously.           hypertension, until BP controlled.
                                                  If hypertension is not controlled with medication
                                                  permanently discontinue bevacizumab.

Grade 4 Hypertension                              Stop bevacizumab permanently.
Life threatening consequence eg.
hypertensive crisis
Infusion-related or allergic reactions
Infusion related reactions
eg. fever, chills, headaches, nausea.
Allergic reactions
eg. fever, rash, urticaria, bronchospasm

                                       ≤ Grade 2 If infusion related reactions occur with any infusion:
                                                 Administer the next dose with premedication over the
                                                 same time period (ie. do not reduce infusion time for
                                                 next dose).

                                                  If next dose with premedication is well tolerated, then the
                                                  subsequent infusion time may be reduced by 30 minutes
                                                  (+/- 10mins) provided premedication is still used ie. 90
                                                  minute infusion reduced to 60 minutes.

                                                  If infusion related reactions occur with the reduced
                                                  infusion time with premedication then all subsequent
                                                  doses must be administered over the previous longer
                                                  infusion time with premedication.

                                                  eg. if infusion related reactions occur with a 60 minute infusion all
                                                  subsequent doses should be administered over 90 minutes (+/-
                                                  15mins) with premedication.
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Side effect: Bevacizumab                      Dose modification (SPC)

                                              eg. if infusion related reactions occur with 30 minute infusion, all
                                              subsequent doses should be administered over 60 minutes (+/-
                                              10mins) with premedication

                                    Grade 3 Stop bevacizumab infusion. DO NOT restart on that
                                            day.
                                            Discuss with consultant to decide if bevacizumab should
                                            be permanently discontinued or reinstituted with
                                            premedication over 90 minutes (+/- 15mins). If the
                                            reaction occurred at the 90 minute rate, initially
                                            challenge at a slower rate and gradually increase to 90
                                            minutes. When bevacizumab reinstituted, the patient
                                            should be monitored for a duration comparable to
                                            duration of previous reaction,.

                                    Grade 4 If suspected anaphylactic reactions during bevacizumab
                                            infusion STOP bevacizumab infusion, institute usual
                                            medical response to reaction, consider application of
                                            tourniquet proximal to the injection site to slow systemic
                                            absorption of bevacizumab (do not obstruct arterial flow
                                            in the limb)

       Reference:

9b.    Bevacizumab-Oxaliplatin-Capecitabine (Bev-CapeOx; Bev-Xelox)
       For additional Private Care unless local NDP approved/PCT agreement to fund
       Bevacizumab          7.5mg/kg            IV    over 90 minutes*        Day 1
                            (max 1012mg)**
       Oxaliplatin          130mg/m2            IV    over 2 hours            Day 1
       Capecitabine         1000mg/m2           Oral twice a day              Day 1 to 14
                                         2
                            Ie.2000mg/m /day          with water after food   (28 doses)
                                                                              starting evening
                                                                              of Day 1

       * First bevacizumab dose is administered over 90 minutes, if this first infusion is well
       tolerated, the second infusion may be administered over 60 minutes. If the 60 minute
       infusion is well tolerated all subsequent infusions may be administered over 30 minutes.
       ** Maximum doses from AVANT study.

       Interval between cycles:        Repeat every 21 days
       Number of cycles:               Metastatic carcinoma of
                                       colon or rectum:    Up to 12 cycles
                                                           Do not continue past progression
       Tests before course of chemo:                FBC, U&Es, LFTs, tumour markers, CEA,
                                                    CA19-9, Crcl calculated. EDTA if
                                                    ≤50mls/min. BP, dipstick proteinuria.
       Tests to OK/confirm each cycle of chemo:     FBC, U&Es, LFTs, Crcl calculated, BP,
                                                    dipstick proteinuria.
       Supportive drugs with each cycle:      Cape-Ox
                                              5HT3 antiemetics as local protocol
                                              Chlorhexidine mouthwash 10mls QDS
                                              Bevacizumab; none
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       Patient information:                  Chemotherapy treatment booklet (local information)
                                             Your chemotherapy record book (NWLCN Red Book)
                                             BACUP sheets
                                             Capecitabine patient diary
                                             Patient must receive nurse capecitabine counselling
                                             General advice on EGFR related skin reactions.
       Additional information:
              Administration:
              Bevacizumab:             see Colorectal page 35
              Oxaliplatin:             see Colorectal page 12
              Capecitabine:            see Colorectal page 24
       Dose modification:
              Bevacizumab:             see Colorectal page 35
              CapeOx:                  see Colorectal page 24
       Reference:

9c.    Bevacizumab-Irinotecan-MdG (Bev-IrMdG) (Bev CTIS:            IrMdG CTIS: 751)
       For additional Private Care unless local NDP approved/PCT agreement to fund
       Bevacizumab                5mg/kg              IV    over 90mins*       Day 1
                                  (max 675mg)**
       Atropine                   250mcg              SC    stat               Day 1
                                            2
       Irinotecan                 180mg/m             IV    over 30mins        Day 1
       Folinic Acid               350mg               IV    over 2 hours       Day 1
                                            2
       5Fluorouracil              400mg/m             IV    bolus              Day 1
       5Fluorouracil              2400mg/m2           IV    over 46 hours      Day 1

       * First bevacizumab dose is administered over 90 minutes, if this first infusion is well
       tolerated, the second infusion may be administered over 60 minutes. If the 60 minute
       infusion is well tolerated all subsequent infusions may be administered over 30 minutes.
       ** Maximum doses from AVANT study.

       Interval between cycles:        Repeat every 14 days
       Number of cycles:               Metastatic carcinoma of
                                       colon or rectum:          Up to 12 cycles
                                                                 Do not continue past progression
       Tests before course of chemo:                      FBC, U&Es, LFTs, Crcl calculated. BP,
                                                          dipstick proteinuria, tumour markers, CEA,
                                                          CA19-9
       Tests to OK/confirm each cycle of chemo:           FBC, U&Es, LFTs, Crcl calculated, BP,
                                                          dipstick proteinuria
       Supportive drugs with each cycle:            IrMdG
                                                    5HT3 antiemetics as local protocol
                                                    Atropine as above to prevent acute cholinergic
                                                    syndrome from irinotecan
                                                    Chlorhexidine mouthwash 10mls QDS
                                                    Bevacizumab
                                                    None
       Patient information:                  Chemotherapy treatment booklet (local information)
                                             Your chemotherapy record book (NWLCN Red Book)
                                             BACUP sheets
                                             General advice on EGFR related skin reactions
                                             Written information on mechanical pump (if via CVAD)
       Additional information:
              Administration:
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            Bevacizumab:               see Colorectal page 35
            Irinotecan/MdG:            see Colorectal page 14
       Dose modification:
            Bevacizumab:               see Colorectal page 35
            Irinotecan/MdG:            see Colorectal page 14

9d.    Bevacizumab-Capecitabine (Bev-CapeOx; Bev-Xelox)
       For additional Private Care unless local NDP approved/PCT agreement to fund
       Bevacizumab          7.5mg/kg            IV     over 90 minutes*       Day 1
                            (max 1012mg)**
       Capecitabine         *1250mg/m2          Oral twice a day              Day 1 to 14
                            Ie.2500mg/m2/day           with water after food  (28 doses)
                                                                              starting evening
                                                                              of Day 1
             Capecitabine starting dose;
             *If     GFR ≥ 51ml/min             <70 years    full dose
                                                ≥ 70 years 1000mg/m2
                     GFR 30-50ml/min            <70 years    1000mg/m2
                                                ≥ 70 years 750mg/m2

       * First bevacizumab dose is administered over 90 minutes, if this first infusion is well
       tolerated, the second infusion may be administered over 60 minutes. If the 60 minute
       infusion is well tolerated all subsequent infusions may be administered over 30 minutes.
       ** Maximum doses from AVANT study.

       Interval between cycles:        Repeat every 21 days
       Number of cycles:               Metastatic carcinoma of
                                       colon or rectum:          Up to 8 cycles (24 weeks)
                                                                 Do not continue past progression
       Tests before course of chemo:                      FBC, U&Es, LFTs, tumour markers, CEA,
                                                          CA19-9, Crcl calculated. EDTA if
                                                          ≤50mls/min. BP, dipstick proteinuria.
       Tests to OK/confirm each cycle of chemo:           FBC, U&Es, LFTs, Crcl calculated, BP,
                                                          dipstick proteinuria.
       Supportive drugs with each cycle:            Cape
                                                    Antiemetics as local protocol
                                                    Chlorhexidine mouthwash 10mls QDS
                                                    Bevacizumab
                                                    None
       Patient information:                  Chemotherapy treatment booklet (local information)
                                             Your chemotherapy record book (NWLCN Red Book)
                                             BACUP sheets
                                             Capecitabine patient diary
                                             Patient must receive nurse capecitabine counselling
                                             General advice on EGFR related skin reactions.
       Additional information:
              Administration:
              Bevacizumab:             see Colorectal page 35
              Capecitabine:            see Colorectal page 24
       Dose modification:
              Bevacizumab:             see Colorectal page 35
              Capecitabine:            see Colorectal page 9
       Reference:

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10.    Panitumumab
       Funding for panitumumab is not currently (June 2010) available on the NHS
       Panitumumab is licensed as monotherapy for the treatment of patients with EGFR
       expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure
       of fluoropyrimidine-oxaliplatin and irinotecan containing chemotherapy regimens.

       Panitumumab Single Agent
       For additional Private Care unless local NDP approved/PCT agreement to fund
       Panitumumab                6mg/kg        IV    over 1 hour*              Day 1
                                                      Using low protein binding
                                                      0.2 or 0.22 micrometer
                                                      inline filter

       *Panitumumab doses higher than 1000mg should be infused over 90 minutes (SPC)

       Interval between cycles:                  Repeat every 14 days
       Number of cycles:                         Duration depends on response.
                                                 3-6 months is standard if responding, Longer
                                                 treatment must be discussed with consultant.
                                                 Do not continue past progression
       Tests before starting course of chemo:             FBC, U&Es, Mg, Ca, LFTs, tumour markers
                                                          CEA, CA19-9
       Tests to OK/confirm each cycle of chemo:           FBC, U&Es, Mg and Ca for up to 8
                                                          weeks after completion of treatment, LFTs
       Supportive drugs with each cycle:         None
       Patient information:               Chemotherapy treatment booklet (local information)
                                          Your chemotherapy record book (NWLCN Red Book)
                                          BACUP sheet
                                          Information on EGFR related skin reactions
       Additional information:
       Panitumumab doses must be diluted in sodium chloride 0.9%, maximum concentration
       10mg/ml. Do not use any other fluid. Flush with normal saline before and after dose.
       Panitumumab must be administered as an intravenous infusion via an infusion pump, via a
       low protein binding 0.2 or 0.22 micron in line filter over approximately 60 minutes.
       Diluted solutions should be mixed by gentle inversion. DO NOT SHAKE.
       The final concentration should not exceed panitumumab 10mg/ml. Doses over 1000mg
       should be diluted to 150mls and infused over 90 minutes.
       Dose modifications:

Table: Panitumumab
Side effect: Panitumumab                   Dose modification: (SPC)
Haematology
White blood cells ≥ 3.0 x 109/L            Full dose
and/or                                     Below these parameters discuss with consultant
Neutrophils ≥ 2.0 x 109/L
and/or
Platelets ≥ 100 x 109/L
Renal Function
                            ≥ 60mls/min    Full dose
                                           Panitumumab has not been studied in patients with
                                           renal impairment.
                                           Below 60mls/min discuss with consultant

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Side effect: Panitumumab                     Dose modification: (SPC)
Hepatic Function                             Panitumumab has not been studied in patients with
                                             hepatic impairment. Discuss with consultant.
Dermatological Reactions:
NCI-CTC           Grade 1 (if tolerable) Full dose
                  Grade 2 (if tolerable) Full dose

                                  ≥ Grade 3 Withhold panitumumab until reaction has resolved to
               Or Grade 1 / 2 if intolerable ≤ grade 2 then restart with panitumumab 50% dose
                                             reduction.

                  If reaction does not recur If reactions do not recur with 50% dose reduction, then
                                             escalate the dose of panitumumab in 25% increments
                                             until the recommended dose is reached.

                    Reactions not resolved If reactions do not resolve to ≤ grade 2 after withholding
                                           one or two doses of panitumumab, then panitumumab
                                           should be discontinued permanently.

                     If reaction recurs after If reactions recur (after withholding treatment and
                             dose reduction restarting with 50% dose reduction) then panitumumab
                                              should be discontinued permanently.

               If reaction is intolerable Panitumumab should be discontinued permanently
             even with dose reduction
Pulmonary complications                   See SPC

Electrolyte Disturbances (Piccolo trial)     Correct electrolyte disturbances as they occur.
                                             Hypomagnesaemia (and accompanying
                                             hypocalcaemia) may occur up to 8 weeks after
                                             completion of treatment.
                                             Serum magnesium <0.6mmol/L correct by intravenous
                                             supplementation.




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11.    Radio-Embolisation SIR Spheres plus OxMdG
       Radioembolisation (RE) is a technique that has been developed to target multiple sites of disease within the
       liver as a form of bracytherapy. SIR-Spheres (Sirtex Medical Ltd, Sydney, Australia) contain the pure β-
       emitter, yttrium-90, labelled to resin microspheres with a mean diameter of approximately 32 μm. The
       physical half-life of yttrium-90 is 64.1 hours.

       In a single out-patient procedure involving trans-femoral catheterisation and fluoroscopic guidance,
       approximately 40 to 80 million microspheres are injected into the arterial supply of the liver. Hepatic
       metastases from colorectal cancer derive approximately 90% of their blood flow from the arterial vasculature
       rather than the portal venous system, and this characteristic ensures that the microspheres become lodged in
       the malignant microvasculature.

       Sine RE delivers high doses of ionising radiation to the tumour compartment whilst maintaining radiation
       exposure of the normal liver to a tolerable level, it can be regarded as a form of brachytherapy. It has also
       been termed selective internal radiotherapy (SIRT).

11a.   Radio Embolisation: Recruit to trials whenever possible
       For additional Private Care unless local NDP approved/PCT agreement to fund
       SIR – Spheres microspheres plus OxMdG
       Summary: Cycle 1                  Full dose OxMdG
                     Cycle 2             Radio embolisation plus reduced dose OxMdG
                     Cycle 3             Reduced dose OxMdG
                     Cycle 4             Reduced dose OxMdG
                     Cycle 5 to 12       Full dose OxMdG

       Cycle 1 (Full dose OxMdG)
       Folinic acid                     350mg                    IV over 2 hours                           Day 1
       Oxaliplatin                      85mg/m2                  IV over 2 hours                           Day 1
       5Fluorouracil                    400mg/m2                 IV bolus dose                             Day 1
       5Fluorouracil                    2400mg/m2                IV over 46hours                           Day 1

       Cycle 2 only (Radio embolism plus reduced dose OxMdG)
       Folinic acid                 350mg                   IV over 2 hours                                Day 1
                                              2
       Oxaliplatin                  60mg/m                  IV over 2 hours                                Day 1
       5Fluorouracil                400mg/m2                IV bolus dose                                  Day 1
                                                  2
       5Fluorouracil                2400mg/m                IV over 46hours                                Day 1
       Radio-embolism using SIR-spheres microspheres                                                       Day 3
       (yttrium-90)                 Consult manufacturers users manual for dose
                                    Dose calculated based on BSA, % tumour
                                    involvement and “percentage lung shunting”

       Cycles 3 and 4 (Reduced dose OxMdG)
       Folinic acid               350mg                          IV over 2 hours                           Day 1
       Oxaliplatin                60mg/m2                        IV over 2 hours                           Day 1
       5Fluorouracil              400mg/m2                       IV bolus dose                             Day 1
       5Fluorouracil              2400mg/m2                      IV over 16hours                           Day 1

       Cycle 5 to 12
       As cycle 1

       Interval between cycles:         Repeat every 14 days as detailed above
       Number of cycles:                Only for loco-regional treatment of HCC confined to liver.
                                        Hepatocellular carcinoma with
                                        Childs Pugh A or possible good B               12 cycles
                                                                                       (ie. one radio-
                                                                                       embolisation)
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      Tests before starting course of chemo: FBC, U&Es, LFTs, Crcl (calculated).
                            Preliminary arteriogram of liver (within 32 days of RE) to determine
                              vascular anatomy of the liver (to provide “road map” of arterial
                              supply of liver to plan delivery of SIR-spheres – see User manual
                            “Break through” macro-aggregated albumin (MAA) nuclear scan
                              within 32 days of RE (to calculate percentage of SIR-spheres that
                              will pass through the liver and lodge in lungs due to arteriovenous
                              shunts. Dose must be adjusted to limit y99 damage to lung – see
                              SIR-spheresUser manual.
                            Contrast enhanced helical CT scan to calculate % tumour
                              involvement (needed to calculate SIR-sphere dose see SIR-sphere
                              users manual)
      Tests to OK/confirm each cycle of chemo:          FBC, U&Es, LFTs, Crcl (calculated).
      Supportive drugs with each cycle:                 5HT3 antiemetics as per local protocol.
                                                        NB. In cycle 2 continue 5HT3 antiemetics to
                                                        cover day of RE as a minimum
                                                        Chlorhexidine mouthwash 10mls QDS
                                                        Loperamide 2-4mg QDS PRN (max
                                                        16mg/day)
                                                        Proton pump inhibitor from day of diagnostic
                                                        hepatic arteriogram for minimum 8 weeks.
                                                        Fluids only 3 hours before RE
                                                        Prophylactic antibiotics 1 hour before
                                                        procedure according to local policy
                                                        Prophylactic narcotic analgesia for RE
                                                        procedure.
                                                        Minor opioids (dihydrocodeine) usually
                                                        sufficient but major opioids (eg pethidine)
                                                        may be required within first 24 hours of RE.
                                                        Prophylactic antibiotics post procedure
                                                        according to local policy.
      Patient Information:               Chemotherapy treatment booklet (local information)
                                         Your chemotherapy record (NWLCN red book)
                                         BACUP information sheet(s)
                                         SIR-Sphere patient information
                                         Written information on mechanical pump (if via CVAD)
      Additional information:            OxMdG see colorectal page 21
      Dose modification:
Table: SIR-Spheres
Side-effect                                Dose Modification (FOXFIRE TRIAL)
Fever                                      Most patients (up to 80%) develop a mild fever that lasts
                                           several days following RE administration but which does
                                           not require treatment

Abdominal Pain                             RE is followed by abdominal pain in approximately 50%
                                           of patients. This can vary from minor discomfort (grade
                                           1) through to grade 3. In almost all cases it is self
                                           limiting (dissipating within 24 hours) but it may require
                                           narcotic analgesia (in about one third of patients). It is
                                           routinely managed by prophylactic pre-medication.
Lethargy                                   Post RE treatment lethargy (approximately 40% of
                                           cases) may occur anywhere between 1 week and 8
                                           weeks post treatment and can last up to 10 days.
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Side-effect                                Dose Modification (FOXFIRE TRIAL)
Nausea                                     Post RE treatment mild nausea (40-50% of cases) is
                                           most common in patients who have received multiple
                                           courses of chemo. Symptoms rarely last more than 24
                                           hours and can be managed by prophylactic antiemetics
                                           medication.
Gastritis/Duodenitis/Ulceration            Discuss with consultant. One of the most common
                                           potentially serious complications. Incidence rate of
                                           gastritis/duodenitis can be reduced by experience and
                                           meticulous attention to the administration procedure so
                                           as to ensure that there is minimal chance of SIR-
                                           spheres entering small arteries supplying the gut
Radiation Hepatitis                        Discuss with consultant. The other most common
                                           potentially serious complication. Radiation hepatitis is
                                           largely, but not totally, preventable by using correct SIR-
                                           sphere dose and making allowances for dose reduction
                                           where there is increased risk of causing radiation
                                           damage, such as in poor liver reserve or small volume
                                           tumour mass in liver – see SIR-Sphere user manual
Pancreatitis                               Discuss with consultant
                                           Rare complication is acute pancreatitis resulting from
                                           SIR-sphere refluxing back down hepatic artery and
                                           lodging in the pancreas and liver abscess from infection
                                           of necrotic tumour.
Haematological                             Discuss with consultant
                                           There is some evidence that there is a decrease in
                                           leukocyte (lymphocyte and neutrophils) levels following
                                           RE with a nadir 6-8 weeks after the RE procedure. The
                                           mechanism of leucopenia is unknown, although current
                                           clinical data (2009) suggest this adverse effect may
                                           have clinical sequelae when RE is used in combination
                                           with systemic radiosensitisers eg 5FU/Oxaliplatin.




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COLORECTAL CANCER; Chemo Radiation Regimens
Dose modification: based on experience of 5FU regimens in anal/rectal cancer

Table 1 – Radiotherapy modifications in case of haematological acute toxicity
Toxicity grade (CTC)         Neutrophils                             Platelets                  Radiotherapy
                             (x109/L)                                (x109/L)
           0-2               1.0                      and           50                 Continue RT
            3                0.5 – 0.9                 and/or        10 – 49             Interrupt RT until
                                                                                         neutrophils >1.0 and
                                                                                         platelets >50
            4                <0.5                      and/or        <10                 Interrupt RT until
                                                                                         neutrophils >1.0 and
                                                                                         platelets >50

Table 2 – Chemotherapy dose modifications in case of combination of haematological and
non-haematological toxicity (ACT II)
 Wait until full recovery ie. neutrophils 1.0 and platelets 50
 If within 2 weeks continue using dose modification below
 If > 2 weeks discuss with consultant
Haematological Parameters                                  Non-haematological CTC grade
NB. Wait until full recovery before                        (diarrhoea, stomatitis, mucositis)
treatment                                        0-1                   2                  3               4
Neutrophils x10 /L9
                               1.0         Wait until full      Wait until full   Wait until full    No further
And/or                                     recovery then        recovery then        recovery         treatment
Platelets x109/L               50         give full dose       give full dose      then give
                                                                                    50% dose
                                                                                    reduction
Neutrophils x109/L          0.5-0.9         Wait until full      Wait until full   Wait until full    No further
And/or                                     recovery then        recovery then        recovery         treatment
Platelets x109/L            10-49          give 25% dose        give 30% dose       then give
                                              reduction            reduction        50% dose
                                                                                    reduction
Neutrophils x109/L             <0.5         Wait until full      Wait until full   Wait until full    No further
And/or                                     recovery then        recovery then        recovery         treatment
Platelets x109/L                <10        give 50% dose        give 50% dose       then give
                                              reduction            reduction        50% dose
                                                                                    reduction


Table 3 – Radiotherapy regimen modifications in case of diarrhoea (ACT II)
Toxicity     Diarrhoea (no colostomy)              Diarrhoea (colostomy)                      Radiotherapy
 Grade
 (CTC)
CTC 0-2      None – increase of 4-6             None – moderate increase             Continue
             stools/day or nocturnal            in loose watery colostomy
             stools                             output compared with pre-
                                                treatment but not interfering
                                                with normal activity

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Toxicity     Diarrhoea (no colostomy)         Diarrhoea (colostomy)                   Radiotherapy
 Grade
 (CTC)
CTC 3        Increase of 7 stools/day or   Severe increase in loose     Interrupt for 1-7 days.
             incontinence; or need for      watery colostomy output      Radiotherapy may
             parenteral support for         compared with pre-           recommence if stools or
             dehydration                    treatment, interfering with  stoma controlled on anti
                                            normal activity              diarrhoeal medication.
                                                                         If stools not normalised,
                                                                         irradiation must be
                                                                         stopped indefinitely
CTC 4        Physiologic consequences       Physiological consequences Interrupt for 1-2 weeks.
             requiring intensive care; or   requiring intensive care; or Radiotherapy may only
             haemodynamic collapse          haemodynamic collapse        recommence if stools or
                                                                         stoma adequately
                                                                         controlled.
                                                                         If stools not normalised,
                                                                         irradiation must be
                                                                         stopped indefinitely


12.     5-Fluorouracil Single Agent (IV and oral) plus Radiotherapy
        NB. When 5-Fluorouracil is used in combination with radiotherapy, doses must be
        according to the following regimens.

12a.    Bossett Regimen: 5FU350-FA20 + RT (CTIS: 282, 283)
        Folinic acid          20mg/m2     IV bolus                        Days 1 to 5 and 29 to 33
        5-Fluorouracil        350mg/m2 IV bolus/infusion                  Days 1 to 5 and 29 to 33

        Interval between cycles:     Repeat weeks 1 and 5 during a 5-6 week course of
                                     radiotherapy.
        Number of cycles:            Colorectal cancer:
                                     Neoadjuvant, adjuvant or local recurrence:       Weeks 1 + 5 of
                                                                                      of a 5-6 week
                                                                                      course of RT
        Tests before starting course of chemo:             FBC, U&Es, LFTs, tumour markers CEA,
                                                           CA19-9, Crcl (calculated)
        Test to OK/Confirm each cycle of chemo:            FBC, U&Es, LFTs
        Supportive drugs with each cycle:                  Moderate risk antiemetics (due to
                                                           radiotherapy)
                                                           Chlorhexidine mouthwash 10mls QDS
                                                           Loperamide 2-4mg QDS PRN
        Patient information:                Chemotherapy treatment booklet (local information)
                                            Your chemotherapy record (NWLCN red book)
                                            BACUP information sheet
        Additional information:
               Administration notes:
               Sucking ice cubes or ice lollies 5 minutes before and for 30 minutes after injection (if
               tolerated) of 5FU may reduce the incidence of stomatitis.
        Dose modifications: See 5FU-Chemo Radiation table Colorectal pages 54/55
                              If Grade 3 or 4 toxicity develops during days 1 to 5 chemo, consider
                              omitting chemo during days 29 to 33
        Reference: J Clin Oncol 2005 Bossett et al
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13.     Capecitabine plus Radiotherapy
13a.   Capecitabine 1650 + RT (CTIS: 1028)
       Capecitabine      825mg/m2                 Oral twice a day                      Days 1 to 5
                                           2
       Repeat day 7      ie. total 1650mg/m /day
                         See dose table page 62-64

       Interval between cycles:     Repeat day 7 ie. administer Monday to Friday each week during
                                    5 weeks of radiotherapy. Repeat tests every 2 weeks. Ideally
                                    RT should be delivered within 2 hours of capecitabine.
       Number of cycles:            Colorectal cancer:
                                    Neoadjuvant, adjuvant, local recurrence:          Monday to
                                                                                      Friday during 5-6
                                                                                      weeks of
                                                                                      radiotherapy
       Tests before starting course of chemo:             FBC, U&Es, LFTs, tumour markers CEA,
                                                          CA19-9, Crcl (calculated). Do EDTA if
                                                          <50mls/min
       Tests to OK/Confirm each cycle of chemo:           FBC and U&Es (weekly), LFTs (every 2-3
                                                          weeks), Crcl (calculated).
       Supportive drugs with each cycle:                  Low risk antiemetics, chlorhexidine
                                                          mouthwash 10mls QDS
       Patient information:               Chemotherapy treatment booklet (local information)
                                          Your chemotherapy record (NWLCN red book)
                                          BACUP information sheet
                                          Capecitabine patient diary
                                          Patient must receive nurse capecitabine counselling
       Additional information:
              Administration notes:
              Patients must receive specific capecitabine counselling prior to treatment from a
              capecitabine trained nurse/pharmacist as per local policy. Patients must be given
              written and verbal information on capecitabine including how to take the tablets,
              when to stop (ie. In the event of toxicity and after 14 days), and whom to contact
              when side effects occur. Written information should be sent to the patient’s GP.
              Capecitabine tablets should be taken with water 30 minutes after food and
              approximately 12 hours apart. Capecitabine interacts with warfarin and phenytoin
              and therefore patients on these drugs must have their blood levels monitored more
              regularly. Capecitabine is contraindicated with allopurinol.
       Dose modifications: See Capecitabine table page 11
       Reference: IJROBP 2005 Kim JC et al




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ANAL CANCER
Chemo-Radiation Regimens
14.    Mitomycin/5FU + RT
       UKCCR Regimen Local Disease (CTIS: Anal RT wk1–IP: 708, wk 5–IP: 709)
                                           (CTIS: Anal RT wk1–OP: 742, wk 5–OP: 738)
       Chemotherapy administered during weeks 1 and 5 of a 4-5 week course of radiotherapy.
                                          2
       Mitomycin C    under 70yrs 12mg/m              IV bolus                  Day 1only
                      Over 70yrs  10mg/m2             IV bolus                  Day 1 only
                                              2
       5-Fluorouracil             *1000mg/m / day IV 24 hour infusion**         Days 1 to 4 and
                                                                                Days 29 to 32
                                  *(or 750mg/m2/day for 5 days)
                                  **outpatient regimen administer each 5FU over 7 hours

       Interval between cycles:     1 cycle only weeks 1 and 5 of a 5 week course of RT
       Number of cycles:            Anal cancer 1st line chemo during weeks 1 and 5 of a 5 week
                                    course of RT: 1 cycle only
       Tests before starting course of chemo:            FBC (including manual film for haemolysis
                                                         screen), U&Es, LFTs, tumour markers CEA,
                                                         CA19-9, Crcl calculated. Do EDTA if
                                                         <60mls/min
       Tests to OK/Confirm each cycle of chemo:          FBC (including manual film for haemolysis
                                                         screen), U&Es, LFTs, Crcl (calculated).
                                                         Do not give mitomycin C unless
                                                          Creatinine within normal range
                                                          Bilirubin <30 micromol/L
                                                          WBC >3.0 x 109/L
                                                          Neutrophils 1.5 x 109/L
                                                          Platelets 100 x 109/L
                                                          No red blood cell fragmentation seen in
                                                            blood film
       Supportive drugs with each cycle:                 Low risk antiemetics
                                                         Chlorhexidine mouthwash 10mls QDS
                                                         Consider prophylactic antibiotics during 6
                                                         weeks chemoradiation
       Patient information:                Chemotherapy treatment booklet (local information)
                                           Your chemotherapy record (NWLCN red book)
                                           BACUP information sheet
                                           Written information on mechanical (if via CVAD)
       Additional information:
              Administration notes:
              Mitomycin is a vesicant and should be administered in accordance with the NWLCN
              administration policy.
              If 5FU administered using an ambulatory infusion pump via a central venous access
              device (CVAD), refer to relevant protocol for care of CVAD. Joint care with the
              community nursing services should be arranged in advance to support the patient
              and to assist with disconnecting the chemotherapy and flushing the CVAD. Written
              community nursing referral should be completed and the patient should be
              discharged with a home spillage kit, sharps container and a small supply of
              equipment to flush the line and dress the entry site of the CVAD.
       Dose modifications: Table: Mito-5FU + RT below
       Reference: Int J Radiat Oncol Biol Phys 1991;21:1115-25. Cummings BJ
                     UKCCR anal Cancer Trial. Lancet 1996;348:1049-54
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Table: Mito-5FU+RT - UKCCR
  Side-effect: Mito-5FU-RT                        Dose Modification    (Source: R Phillips/H Wasan/ Act ll
                                                  Trial)
  Haematology
  Neutrophils        Platelets             Hb
  x109/L             x109/L                g/dl
  1.5    and        100         and      10    Full dose
  <1.5      or        <100        or       <10    Delay 1 week until recovery.
                                                  Discuss with consultant if >3 weeks, otherwise dose
                                                  reduce as below

  0.5-0.9     or      25-49       or       any    Delay until recovery then 5FU: 25% dose reduction

  <0.5     or    <25              or       any    Delay until recovery then 5FU: 50% dose reduction
  Renal Function
  Crcl                           60ml/min        Full Dose
                              41-59 mls/min       Mitomycin 30% dose reduction (8mg/m2)
                             40ml/min       Consider alternative regimen
  Diarrhoea or Stomatitis
                                   Grade 3        5FU: 25% dose reduction
                                   Grade 4        Omit 5FU
  Haemolytic Uraemic Syndrome (HUS)               Do not give mitomycin unless
  Extremely rare with this dose of                 Serum creatinine within normal range
  mitomycin.                                       Bilirubin <30 micromol/L
  Usually fatal if it does occur                   WBC 3.0 x 109/L
                                                   Neutrophils 1.5 x 109/L
                                                   Platelets 100 x 109/L
                                                   No red blood fragmentation seen in blood film
  HUS suspected                                   If early HUS suspected: Stop mitomycin
  Eg. red blood cell fragmentation                permanently
                                                  Treat with prednisolone 40mg OD x 7 days



ANAL CANCER
Chemotherapy Alone Regimens
15.    CISP60-5FU-4day CHEMO ALONE (CTIS: 1364 via CVAD, 1218 via NS)
       Prehydrations                                                                                Day 1
       Cisplatin            60mg/m2         IV over 2 hours                                         Day 1
       Post hydrations                                                                              Day 1
       5-Fluorouracil       1000mg/m2/day   Continuous infusion                                     Day 1 to 4

       Interval between cycles: Repeat every 21 days
       Number of cycles:          Anal cancer –Relapsed/metastatic:       4-6 cycles
       Tests before starting course of chemo:        FBC, U&Es, Mg, LFTs, Crcl calculated do
                                                     EDTA if <60mls/min. tumour markers CEA,
                                                     CA19-9.
       Tests to OK/Confirm each cycle of chemo:      FBC, U&Es, Mg, LFTs, Crcl (calculated). Do
                                                     EDTA if rising creatinine
       Supportive drugs with each cycle:             5HT3 antiemetics as per local protocol
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                                                         Chlorhexidine mouthwash 10mls QDS.
                                                         Loperamide 2-4mg QDS PRN (max
                                                         16mg/day)
       Patient information:                Chemotherapy treatment booklet (local information)
                                           Your chemotherapy record (NWLCN red book)
                                           BACUP information sheet
                                           Written information on mechanical pump (if via CVAD)
       Additional information:
              Administration notes:
              Cisplatin:
              Weigh patient before and after cisplatin infusion or monitor urine output. If weight
              gain >1.5kg or symptomatic of fluid retention; inform doctor, patient may require
              diuretics. Inpatients should be on a fluid-balance chart and weighed daily. Average
              urine output of at least 100ml/hr is expected during and for 6 hours after cisplatin
              infusion. Outpatients should be encouraged to drink 3 litres of fluid within the
              following 24 hours. If 5FU administered using an ambulatory infusion pump via a
              central venous access device (CVAD), refer to relevant protocol for care of CVAD.
              Joint care with the community nursing services should be arranged in advance to
              support the patient and to assist with disconnecting the chemotherapy and flushing
              the CVAD. Written community nursing referrals should be completed and the patient
              should be discharged with a home spillage kit, sharps container and a small supply
              of equipment to flush the line and dress the entry site of the CVAD.
       Dose modifications: See 5FU-CISP-4 day table page 33
       Reference: Eur J Cancer 1993;558, 29A (Suppl 6):S104

Table: 5FU-CISP 4 day
  Side Effects: 5FU-CISP 4day                 Dose Modification (Source ACT II Trial)
  Haematology
  Neutrophils             Platelets
  x109/L                  x109/L
  1.5         and        100                Full dose
  1.0-1.4      or         50-99               Delay 1 week until recovery then full dose
  0.5-0.9      or         25-49               Delay until recovery then
                                              5-Fluorouracil 25% dose reduction
  <0.5            OR              < 25        Delay until recovery then
                                              5-Fluorouracil 50% dose reduction
  Renal function (NCLN 2009)
  Crcl                        60mls/min Full dose
                             45-59mls/min Cisplatin 25% dose reduction.
                                          5FU: full dose
                               <45mls/min 5FU: full dose
                                          Omit cisplatin
                                          Consider carboplatin 5AUC
  Stomatitis                    ≤ Grade 2 Full dose
                                  Grade 3 5-Fluorouracil: 25% dose reduction
                                  Grade 4 5-Fluorouracil: Omit
  Diarrhoea                      ≤Grade 2 Full dose
                                  Grade 3 5-Fluorouracil: 25% dose reduction
                                  Grade 4 5-Fluorouracil: Omit
  Hand-Foot syndrome                      Discuss with consultant
  DPD Deficiency                          1-3% of patients have markedly exaggerated 5FU
                                          toxicity due to reduced 5FU catabolism. Discuss
                                          with consultant.
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  Side Effects: 5FU-CISP 4day                  Dose Modification (Source ACT II Trial)

  Cardiotoxicity                               Uncommon. 5FU may provoke angina or MI in
                                               patients with ischaemic heart disease. Seek
                                               specialist opinion on upgraded anti-anginal
                                               medication and consider dose reduction or
                                               alternative non 5FU treatment.
  Neurotoxicity                                Uncommon – Cerebellar
                                               Consider alternative non 5FU treatment


16.    Docetaxel 100 (CTIS: 649) (Additional Private Care)
       For additional Private Care unless local NDP approved/PCT agreement to fund
       Dexamethasone              8mg BD              Oral                    Days 0 to 2
                                            2
       Docetaxel                  100mg/m             IV over 1 hour          Day 1

       Interval between cycles: Repeat every 21 days
       Number of cycles:             Additional Private Care only – 6 cycles
       Tests before starting course of chemo:             FBC, U&Es, LFTs
       Tests to OK/Confirm each cycle of chemo:           FBC, U&Es, LFTs
       Supportive drugs with each cycle:                  5HT3 antiemetics as per local protocol,
                                                          dexamethasone as above
       Patient information:                 Chemotherapy treatment booklet (local information)
                                            Your chemotherapy record (NWLCN red book)
                                            BACUP information sheet(s)
       Additional information:
              Administration notes:
              Dexamethasone 8mg must be taken orally twice a day for 3 days (the day before,
              the day of and the day after docetaxel) to prevent fluid retention and hypersensitivity
              reactions; therefore, the patient must be discharged with enough dexamethasone to
              take before their next cycle. Ensure patient understands how to take their steroids at
              home. Diabetic patients will need to monitor blood sugar levels more regularly and
              inform their doctor if they are having problems with the control of their blood sugar
              levels. IV dexamethasone should not be given to replace oral doses. Acute
              hypersensitivity reactions can occur, observe closely especially during the first two
              cycles. Assess for any drug-induced neuropathy. Prior to treatment, discuss hair
              loss and liaise with wig fitter. Scalp cooling should be offered.
       Dose modifications: See Docetaxel table below

Table: Docetaxel
Side effect: Docetaxel                          Dose Modification
Haematology
Neutrophils                    Platelets
x 109/L                        x 109/L
≥1.5          and              ≥100             Full dose. Do not give below these levels. Delay
                                                until recovery then discuss with consultant.
Renal Function
                                 Mild/Moderate No dose reduction necessary in mild/moderate renal
                                               impairment
                                       Severe Discuss with consultant
Hepatic Function (NLCN 2009)

Bilirubin      ALT/AST                 ALT
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Side effect: Docetaxel                             Dose Modification
micromol/L
               >1.5 x ULN and >2.5 x ULN           Give docetaxel 75mg/m2

>22 and/or >3.5 x ULN and >6 x ULN                 Do not give
Neurotoxicity (? Source)
                               ≤ Grade 2           Full dose
                               ≥ Grade 3           Omit docetaxel
Cutaneous Reactions                                Reduce dose from 100mg/m2 to 75mg/m2 or from
Severe or cumulative cutaneous reactions           75mg/m2 to 60mg/m2 if already reduced.
(SPC)                                              If patient continues to experience severe reactions,
                                                   discontinue docetaxel
Neuropathy                                         Reduce dose from 100mg/m2 to 75mg/m2 or from
Severe peripheral neuropathy (SPC)                 75mg/m2 to 60mg/m2 if already reduced.
                                                   If patient continues to experience sever reactions,
                                                   discontinue docetaxel
Allergic Reactions (SPC)                   Mild    If hypersensitivity reactions occur, minor symptoms
                                                   such as flushing or localised cutaneous reactions do
                                                   not require interruption of therapy.

                                           Severe However, severe reactions such as severe
                                                  hypotension, bronchospasm or generalised
                                                  rash/erythema require immediate discontinuation of
                                                  docetaxel and appropriate therapy.

                                   Rechallenge Patients who have developed severe reactions
                                               should not be rechallenged with docetaxel.
                                               Discuss with consultant. Extreme caution is required
                                               as cross reactivity occurs with taxanes.




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   17.     Capecitabine Dose Tables
       Capecitabine 1250mg/m2 Twice a day dose table (QUASAR 2)
             Patient’s            1250mg/m2             Total dose                   Total no.
                     2
             BSA m                Twice a day            (mg/day)                      tabs
                                                                                     (14 days)
                                      AM dose   PM dose
                  ≤ 1.09                   2       3               2500                 70
               1.10 - 1.29                 3       3               3000                 84
               1.30 - 1.49                 3       4               3500                 98
               1.50 - 1.69                 4       4               4000                112
               1.70 - 1.89                 4       5               4500                126
                  ≥ 1.90                   5       5               5000                140


       Capecitabine 1000mg/m2 Twice a day dose table (QUASAR 2)
             Patient’s            1000mg/m2             Total dose                   Total no.
                     2
             BSA m                Twice a day            (mg/day)                      tabs
                                                                                     (14 days)
                                      AM dose   PM dose
                  ≤ 1.12                   2       2               2000                 56
               1.13 - 1.36                 2       3               2500                 70
               1.37 - 1.62                 3       3               3000                 84
               1.63 - 1.86                 3       4               3500                 98
                  ≥ 1.87                   4       4               4000                112


       Capecitabine 950mg/m2 Twice a day (SPC table)
                            Capecitabine Dose 950mg/m2 Twice a day (SPC table)
                           Dose per       Number of 150mg and/or 500mg tablets per
        Body Surface    Administration    administration (each administration to be
            Area             (mg)         given morning and evening)
               (m2)
                                                       150mg                     500mg
             ≤ 1.26                  1150                -                         3
           1.27 – 1.38               1300                2                         2
           1.39 – 1.52               1450                3                         2
           1.53 – 1.66               1600                -                         3
           1.67 – 1.78               1750                1                         3
           1.79 – 1.92               1800                2                         3
           1.93 – 2.06               2000                3                         3
           2.07 – 2.18               2150                1                         4
             ≥ 2.19                  2300                1                         4




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        Capecitabine 937.5mg/m2 Twice a day dose table (QUASAR 2)
             Patient’s             975mg/m2               Total dose                    Total no.
             BSA m2               Twice a day              (mg/day)                       tabs
                                                                                        (14 days)
                                      AM dose     PM dose
                  ≤ 1.19                   2         2                2000                 56
               1.20 - 1.44                 2         3                2500                 70
               1.45 - 1.74                 3         3                3000                 84
                  > 1.75                   3         4                3500                 98


          Body Surface           Capecitabine Dose 850mg/m2 Twice a day (Imperial table)
             Area                 Dose per     Number of 150mg and/or 500mg tablets per
              (m2)              Administration administration. (Each administration to be
                                    (mg)       given morning and evening)
                                                      150mg                  500mg
              ≤1.26                1000                  -                      2
            1.27-1.43              1150                  1                      3
            1.44-1.61              1300                  2                      2
            1.62-1.73              1450                  3                      2
            1.74-1.85              1500                  -                      3
            1.86-2.03              1650                  1                      3
            2.04-2.18              1800                  2                      3
              ≥2.19                1800                  2                      3


          Body Surface           Capecitabine Dose 825mg/m2 Twice a day (Imperial table)
             Area                 Dose per      Number of 150mg and/or 500mg tablets per
              (m2)              Administration  administration. (Each administration to be
                                    (mg)        given morning and evening)
                                                       150mg                  500mg
              ≤1.26                1000                   -                      2
            1.27-1.29              1000                   -                      2
            1.30-1.49              1150                   1                      2
            1.50-1.66              1300                   2                      2
            1.67-1.78              1450                   1                      2
            1.79-1.92              1500                   -                      3
            1.93-2.06              1650                   1                      3
            2.07-2.18              1800                   2                      3
              ≥2.19                1800                   2                      3




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          Body Surface           Capecitabine Dose 800mg/m2 Twice a day (Imperial table)
             Area                 Dose per     Number of 150mg and/or 500mg tablets per
              (m2)              Administration administration. (Each administration to be
                                    (mg)       given morning and evening)
                                                      150mg                  500mg
              ≤1.26                1000                  -                      2
            1.27-1.43              1000                  1                      2
            1.44-1.61              1150                  -                      -
            1.62-1.73              1300                  2                      2
            1.74-1.85              1450                  3                      2
            1.86-2.03              1500                  -                      3
            2.04-2.18              1650                  1                      3
              ≥2.19                1800                  2                      3


       Capecitabine 750mg/m2 Twice a day dose table (QUASAR 2)
                Patient’s          750mg/m2             Total dose                     Total no.
                    2
             BSA m                Twice a Day            (mg/day)                        tabs
                                                                                       (14 days)
                                      AM dose    PM dose
                  ≤ 1.14                   1         2               1500                 42
               1.15 - 1.49                 2         2               2000                 56
               150 - 1.84                  3         3               2500                 70
                  > 1.85                   3         4               3000                 84


       Capecitabine 625mg/m2 Twice a day dose table (QUASAR 2)
                Patient’s          625mg/m2             Total dose                     Total no.
                    2
             BSA m                Twice a Day            (mg/day)                        tabs
                                                                                       (14 days)
                                      AM dose    PM dose
                  ≤ 1.39                   1         2               1500                 42
                1.4 - 1.79                 2         2               2000                 56
                  > 1.80                   2         3               2500                 70


       Capecitabine 500mg/m2 Twice a day dose table (QUASAR 2)
                Patient’s          500mg/m2             Total dose                     Total no.
                    2
             BSA m                Twice a Day            (mg/day)                        tabs
                                                                                       (14 days)
                                      AM dose    PM dose
                  ≤ 1.24                   1         1               1000                 28
               1.25 - 1.77                 1         2               1500                 42
                  > 1.75                   2         2               2000                 56



77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                    Colorectal Page 65 of 66
WHO Performance Status

 Clinical Performance
         Status
           0                   Able to carry out all normal activity without restriction
           1                   Restricted in physically strenuous activity but ambulatory and able to
                               carry out light work
             2                 Ambulatory and capable of all self-care but unable to carry out any
                               work. Up and about more than 50% of waking hours
             3                 Capable only of limited self-care; confined to bed or chair more than
                               50% of waking hours
             4                 Completely disabled; cannot carry out any self-care; totally confined to
                               bed or chair




Cockroft & Gault Formula

The estimated GFR is given by:

Males:                 1.25 x (140 – age) x ideal body weight (kg)
                          Serum creatinine (mol/L)


Females:               1.05 x (140 – age) x ideal body weight (kg)
                          Serum creatinine (mol/L)


This formula usually under-estimates GFR by 10-30% compared with EDTA or measured 24-hour
creatinine clearance, so is used as a screening test.

 A Cockroft/Gault estimate of >50ml/min is accepted evidence of adequate renal function
Patients with Cockroft/Gault estimate of <50ml/min should have formal GFR measurement with
EDTA or 24hour urinary creatinine




77f9cd45-6ee6-4c98-b961-4cf271ec4790.doc                        Colorectal Page 66 of 66

				
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