Chemotherapy and radiotherapy for cancer of the cervix

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Chemotherapy and radiotherapy for cancer of the cervix Powered By Docstoc
					  The role of radiotherapy in
 the management of cervical
   and endometrial cancers

                                        Dr Jane Orton
                     St James’s Institute of Oncology
                                               Leeds



Leeds – April 2009                 Leeds – April 2009
Cervical cancer




                  Leeds – April 2009
Incidence
       In 2004, the age-standardised annual incidence rate of cervical
        cancer in the UK is 8 per 100,000 females
           2,726 new cases diagnosed
           accounts for 2% of all female cancers
       Cervical cancer is the second most common cancer in the under
        35s, with 569 new cases diagnosed in the UK in 2004, but account
        for < 6% of deaths
       There are two peaks in the incidence rates for cervical cancer, the
        first is for women in their 30’s, and the second is for women in their
        80’s
       Cervical screening 1975-2004 →
           45% reduction in cases of cervical cancer
       In 2005 there were 1,061 deaths from cervical cancer
           Highest number of deaths occurs in women over 75


                                    Leeds – April 2009
Epidemiology - 1
   HPV types associated with CIN & invasive cancer
       16, 18 , 31, 35, 39
   HPV 18 associated with
       poorly differentiated tumours
       ↑incidence of LN involvement
       poor response to treatment
   HPV 16 associated with
       large cell keratinising tumours
       ↓recurrence rates




                                 Leeds – April 2009
Epidemiology - 2
   Other cofactors
       smoking doubles the risk of developing invasive cervical cancer
   Steroid hormones
       ↑expression of E6 & E7 HPV16 oncogenes which bind to p53 →
        apoptotic failure and carcinogenesis
       long-term use of OCP → greater progression of dysplasia to CIS
       Depo-Provera use is associated with a relative risk of 1.2 – 2.4
        (at 5 yrs) for invasive cancer




                                Leeds – April 2009
Epidemiology - 3
   Cervical intraepithelial neoplasia CIN
       mean age of CIN is ~ 15 years younger than that of ♀
        with cervical cancer
       a large prospective study suggests mean time to
        development of CIS is related to CIN grade
           58 months for grade 1
           38 months for grade 2
           12 months for grade 3
           66% of ♀ with dysplasia develop CIS in 10 yrs



                                Leeds – April 2009
Histological types
   Squamous cell carcinoma (85%)
         keratinising
         non-keratinising
         verrucous carcinoma
         papillary (transitional) carcinoma
   Adenocarcinomas (15%)
         mucinous
         endometrioid
         papillary villoglandular
         clear cell
         serous carcinoma
   Small cell carcinomas
   Adenosquamous



                                      Leeds – April 2009
Histopathology
   Squamous cell carcinoma                 Small cell carcinoma




                        Leeds – April 2009
Staging - 1
   FIGO staging is based on clinical examination
    and should be used for reporting purposes –
    nodal status is not included
   Information from imaging is used to inform
    management
   Post surgical staging - TNM




                        Leeds – April 2009
Staging - 2
   Stage 1 disease - confined to cervix
   Stage 2 disease – extension to upper two thirds
    of vagina or parametria
   Stage 3 disease – extension to the lower third of
    vagina or extension to pelvic side wall or
    hydronephrosis
   Stage 4a disease – extension to pelvic organs
   Stage 4b – metastatic disease


                        Leeds – April 2009
Role of imaging
   MRI scan
       local extent of disease within pelvis
       detects pelvic and abdominal lymphadenopathy
       visualises the renal tract
   Chest Xray
   PET CT scan



                           Leeds – April 2009
Treatment of stage I disease
   Surgery
       radical hysterectomy
           includes vaginal cuff and pelvic lymphadenectomy
   Radiotherapy
       radical brachytherapy
       radical radiotherapy ∓ cisplatin chemotherapy
        concurrently



                                Leeds – April 2009
NCI statement
   In February, 1999, the NCI issued an alert that
    chemoradiotherapy should be considered for all
    patients with cancer of the cervix
   Five RCT demonstrated that the addition of
    chemotherapy improves survival by 10-12%




                        Leeds – April 2009
Concurrent chemoradiotherapy
for cancer of the cervix

   Concomitant CT and RT improves overall survival
    and progression-free survival
       absolute benefit 12% and 16% respectively




                            Leeds – April 2009
Concomitant chemotherapy and
radiotherapy
   Mechanisms
       spatial co-operation
       independent cell kill
       enhanced tumour response
       radiosensitisation
   Sequencing and timing
       normal – tissue toxicity



                              Leeds – April 2009
Treatment of cervical cancer

   Stage IB-IVA disease
       concurrent chemoradiotherapy
           pelvic radiotherapy 48Gy in 24#
           cisplatin 40mgm-2 weekly q 5 weeks
           intracavitary treatment 21Gy to point A 3# q weekly




                                Leeds – April 2009
Radiotherapy planning –
beam’s eye view




               Leeds – April 2009
EBRT with brachytherapy
volume




              Leeds – April 2009
Canadian trial
   The results of the Canadian NCIC trial did not
    corroborate these findings. They compared an
    optimal regimen of RT versus RT in combination
    with weekly Cisplatin and failed to demonstrate a
    benefit in disease-free survival




                        Leeds – April 2009
Why the difference?
   Concurrent chemoradiotherapy adds no
    incremental benefit to optimally delivered
    radiotherapy
   Difference in prognostic factors
       In the NCIC trial there was a significant differential
        decrease in Hb in the combined modality treatment
        arm compared to the control RT arm




                              Leeds – April 2009
The haemoglobin story - 1
   Maintenance of Hb>12g/dl during RT results in
    improved outcomes
   The 5-year survival
       74% for patients Hb≥ 12 g/dl
       52% for patients Hb>11–11.9 g/dl
       45% for patients Hb<11g/dl




                            Leeds – April 2009
The haemoglobin story - 2
   At each Hb level, patients who were transfused and
    maintained at a specific Hb level had a survival rate that
    was not significantly different from patients who were at
    that level spontaneously
   Significant reduction in both pelvic and distant recurrence
    in patients whose Hb level during RT was ≥12 g/dl
    compared with <12 g/dl
   A reduction in the rate of distant recurrence was
    observed in patients with and without pelvic recurrence




                            Leeds – April 2009
Overall treatment time

    Stage       Treatment Time, weeks   10-year pelvic failure, percent   10-year DSS, percent
    Stage IB    7                       5                                 86
                7.1-9                   22                                78
                >9                      36                                55
    Stage IIA   7                       14                                73
                7.1-9                   27                                41
                >9                      36                                43
    Stage IIB   7                       20                                72
                7.1-9                   28                                60
                >9                      34                                65




                                        Leeds – April 2009
Acute side effects
   Fatigue
   Diarrhoea
   Cystitis

   Nausea
   Pancytopenia
   Hypomagnesia

                   Leeds – April 2009
Long term morbidity
   Bowel
   Bladder
   Vaginal stenosis
   Radiation induced menopause
   Pelvic insufficiency fractures




                        Leeds – April 2009
Late complications




               Leeds – April 2009
Survival by stage




               Leeds – April 2009
Survival by cell type




                Leeds – April 2009
Survival by size




                   Leeds – April 2009
Where does the truth lie?
   Positive trials
       relatively low radiation doses
       prolonged overall treatment time
       confounding effect of anaemia


   What is the true magnitude of benefit for
    concurrent chemoradiotherapy with ‘optimal’
    radiotherapy regimens?

                            Leeds – April 2009
Neoadjuvant chemotherapy
   Chemotherapy cycle length
       > 14 days        ≤ 14 days
   Planned cisplatin dose intensity
       < 25mg/m2/week   ≥ 25mg/m2/week
   Planned cisplatin total dose
       ≤150mg/m2        >150mg/m2




                         Leeds – April 2009
Adjuvant chemotherapy
   Peters RTCT of adjuvant chemoradiotherapy in high risk
    early stage cancer of the cervix follow up data showed
    that 60% received 4, 71% received 3 cycles of
    chemotherapy beyond chemoradiotherapy
       reduced rate of distant metastases




                                Leeds – April 2009
Endometrial cancer




              Leeds – April 2009
Background
   Every year more than 6,430 cases of uterine
    cancer are diagnosed in the UK
   Uterine cancer causes around 1,650 deaths in
    the UK each year
   75% of cases present with disease confined
    to uterus
   Primary treatment is surgery
   Role of external beam radiotherapy unclear


                      Leeds – April 2009
Previous trials of RT in
endometrial cancer
   Aalders (1980) compared intravaginal brachytherapy
    alone with external beam radiotherapy (EBRT) plus
    brachytherapy
       no evidence of survival difference but combined treatment
        gave lower pelvic recurrence rates

   Results of PORTEC 1 and GOG99 called into
    question the benefit of EBRT in treatment of early
    stage intermediate risk patients

   Adjuvant EBRT in FIGO stage I disease may be over-
    treatment

                              Leeds – April 2009
Inclusion Criteria – all trials
FIGO Stage    Grade 1            Grade 2      Grade 3    Papillary
                                                        Serous/clear
                                                            cell
IA                                            ASTEC       ASTEC
                                               EN.5        EN.5

IB            GOG 99           GOG 99         ASTEC       ASTEC
                              PORTEC 1         EN.5        EN.5
                                              GOG 99
                                             PORTEC 1
IC            ASTEC            ASTEC          ASTEC       ASTEC
               EN.5             EN.5           EN.5        EN.5
              GOG 99           GOG 99         GOG 99
             PORTEC 1         PORTEC 1
IIA           ASTEC              ASTEC        ASTEC       ASTEC
               EN.5               EN.5         EN.5
              GOG 99             GOG 99       GOG 99


                        Leeds – April 2009
Eligibility Criteria - ASTEC
   Brachytherapy allowed if
       centre policy
       stated before randomisation
       used in both arms
   Positive para-aortic nodes an exclusion
   Positive pelvic lymph nodes
       eligible for ASTEC
       ineligible for EN.5

                              Leeds – April 2009
Sample size - ASTEC
   Sample size and data maturity

       1 30 deaths needed to detect a 10% (75% to 85%)
        difference in 5-year overall survival with 5%
        significance level and 90% power




                           Leeds – April 2009
 Distribution of FIGO Stage and
 Grade ASTEC trial

FIGO    Grade 1   Grade 2            Grade 3       Papillary   Clear cell
stage                                               serous
 IA      <1%       <1%                       1%      1%           1%
IB       <1%        2%                       13%     2%           1%
IC       23%       37%                       13%     1%           1%
IIA       1%        2%                       1%      <1%           0
IIB      <1%        0                         0      <1%           0


                        Leeds – April 2009
Trial Design

                          Surgery


     High risk pathology and no macroscopic disease

                     RANDOMISE


   No external beam RT                        External beam RT




                         Leeds – April 2009
Radiotherapy Details
                              EBRT
                              N=452
                                                                                         Distribution of EBRT dose used
EBRT +/-brachytherapy        416 (92%)




                                                                      80
Brachytherapy alone           10 (3%)
None                          24 (5%)




                                                                      60
                                     Percentage (%)
Missing                          2




                                                                      40
Median:
Total Dose (Gy)                 45




                                                                      20
Fractions                       25
Duration in days                34




                                                                       0
Treatment compliance                                                       5   10   15   20   25   30   35    40   45
                                                                                                   Total dose (Grays)
                                                                                                                        50   55   60   65   70


(% of patients who             82%
received total dose of 40-
46 Gy in 20-25 fractions)




                                                      Leeds – April 2009
Brachytherapy in ASTEC
   Similar proportions of women in both groups
    received brachytherapy

       235 (52%) in observation arm

       242 (54%) in EBRT arm




                           Leeds – April 2009
Acute and Late Toxicity
                                                No EBRT       EBRT
                                                 N=453        N=452


Acute toxicity (post surgery and                120 (26%)    271 (60%)
radiotherapy)

Worst score
Mild                                             77 (17%)    140 (31%)
Moderate                                          38 (8%)    111 (25%)
Severe/Life threatening                           3 (<1%)     19 (4%)



Late Toxicity
Grade 3/4                                               3%      7%

                                   Leeds – April 2009
Patient outcomes April 2007


                                                   Total
                                                  N=905
 Alive                                           774 (86%)
 Dead                                            133 (14%)
 Cause of death
                                                    90
   EC/treatment/after recurrence
   Other cause without recurrence                   41
 (Median follow-up 58 months)



                            Leeds – April 2009
 Overall survival
                                  1.0

                                  0.9

                                  0.8

                                  0.7
           Proportion surviving




                                  0.6
                                              HR=1.01, 95% CI=0.71 - 1.42, p=0.98
                                  0.5         5 year OS 84%

                                  0.4

                                  0.3

                                  0.2

                                  0.1                                 Events       Totals
                                              No EBRT                  66           453
                                              EBRT                     65           452
                                  0.0
                                        0         1             2                 3               4       5     6    7

PATIENTS at Risk                                                               Years from randomisation
  No EBRT                               453      432            379               288            216      144   83   37
  EBRT                                  452      422            378               287            218      145   80   34
                                                                      Leeds – April 2009
   Disease specific survival
                                             1.0

                                             0.9

                                             0.8
         Proportion Surviving from disease




                                             0.7

                                             0.6         HR=1.17, 95% CI=0.77 - 1.76, p=0.47

                                             0.5         5 year DSS 89%

                                             0.4

                                             0.3

                                             0.2

                                             0.1                                 Events      Totals
                                                         No EBRT                  42          453
                                                         EBRT                     48          452
                                             0.0
                                                   0         1             2                 3               4       5     6    7

PATIENTS at Risk                                                                          Years from randomisation
  No EBRT                                          453      432            379              288             216      144   83   37
  EBRT                                             452      422            378              287             218      145   80   34
                                                                                  Leeds – April 2009
    Recurrence-free survival
                                                     1.0

                                                     0.9
           Proportion surviving without recurrence




                                                     0.8

                                                     0.7

                                                     0.6
                                                                 HR=0.87, 95% CI=0.65 - 1.17, p=0.37
                                                     0.5         5 year RFS 78%

                                                     0.4

                                                     0.3

                                                     0.2

                                                     0.1                                Events      Totals
                                                                 No EBRT                 94          453
                                                                 EBRT                    81          452
                                                     0.0
                                                           0        1              2                3               4       5     6    7

PATIENTS at Risk                                                                                 Years from randomisation
  No EBRT                                                  453      416           355              274             205      136   79   34
  EBRT                                                     452      413           369              273             201      135   73   32
                                                                                         Leeds – April 2009
      Disease specific recurrence-free
      survival
                                                              1.0

                                                              0.9
            Proportion surviving without disease recurrence




                                                              0.8

                                                              0.7

                                                              0.6
                                                                        HR=0.92, 95%CI 0.65–1.29, p=0.62
                                                              0.5
                                                                                 5 year DSRFS 83%
                                                              0.4

                                                              0.3

                                                              0.2

                                                              0.1                                Events       Totals
                                                                        no EBRT                    70          453
                                                                        EBRT                       64          452
                                                              0.0
                                                                    0        1              2                 3               4      5     6    7
                                                                                                          Years from randomisation
PATIENTS at Risk
  no EBRT                                                       453          417           355               274             205     136   79   34
  EBRT                                                          452          413           369               273             201     135   73   32
                                                                                                    Leeds – April 2009
      Isolated vaginal or pelvic initial
      recurrence
                                  1.0                                                                       Events     Totals
                                                                             No EBRT                         28         453
                                  0.9                                        EBRT                            14         452

                                  0.8

                                  0.7
           Cumulative incidence




                                  0.6

                                  0.5                                                HR=0.53, 95% CI=0.29-0.97, p=0.038
                                                                               3% difference in 5 year cumulative incidence rate
                                  0.4                                                   (4% in EBRT to 7% in no EBRT)

                                  0.3                                                Only includes 42/123 total recurrences

                                  0.2

                                  0.1

                                  0.0
                                        0   1     2              3               4               5             6                7

PATIENTS at Risk                                            Years from randomisation
  No EBRT                           453     425   366           282              211            142             81              35
  EBRT                              452     420   376           281              212            142             78              32
                                                        Leeds – April 2009
Recurrences
              Control                  EBRT   Total




                  Leeds – April 2009
Subgroup analyses
   No evidence that effect of EBRT is smaller or
    greater in subgroups defined by
       age
       performance status
       nodal involvement
       depth of invasion
       grade
       extent of disease


                             Leeds – April 2009
     Overall survival by FIGO stage and grade


                                                                                Overall survival
                                 [no. events/no. entered]
                                  EBRT           No EBRT     O-E    Variance                        Hazard Ratio (Fixed)


FIGO/GRADE
  IA/IB G123, IC G12             44/373          47/356     -2.33      22.66                                                                 0.90 (0.60-1.36) p=0.625

  IC G3, IIA/IIB                 20/75           18/92      3.93         9.25                                                                1.53 (0.80-2.91) p=0.196



                                                                                 0            0.5            1             2             5
                                                                                  EBRT Better                              No EBRT Better
   Test of Interaction: p=0.18




                                                                    Leeds – April 2009
    Recurrence-free survival by FIGO
    stage and grade

                                                                       Recurrence-free survival
                                [no. events/no. entered]
                                 EBRT           No EBRT     O-E     Variance                     Hazard Ratio (Fixed)


FIGO/GRADE
  IA/IB G123, IC G12            56/373          65/356     -5.46       30.13                                                             0.83 (0.58-1.19) p=0.320

  IC G3, IIA/IIB                23/75           28/92      0.73        12.51                                                             1.06 (0.61-1.84) p=0.838



                                                                               0           0.5            1             2            5
                                                                                EBRTBetter                              No EBRTBetter
  Test of interaction: p=0.48




                                                                   Leeds – April 2009
      Meta-analysis: overall survival

Study                                     EBRT                        No EBRT                  Peto OR (IPD)                        N         Peto OR (IPD)
                                           n/N                           n/N                      95% CI                                         95% CI

PORTEC                                    57/354                      48/360                                                       714    1.22 [0.83, 1.79]
GOG                                       30/190                      36/202                                                       392    0.86 [0.57, 1.29]
ASTEC + EN5                               65/452                      66/453                                                       905    1.00 [0.71, 1.41]

Total (95% CI)                          152/996                       150/1015                                                     2011   1.02 [0.82, 1.27]
    Test for heterogeneity: Chi² = 1.51, df = 2 (P = 0.47), I² = 0%
   Test for overall effect: Z = 0.20 (P = 0.84)

                                                                                 0.1     0.2     0.5   1      2       5       10

                                                                                       Favours EBRT        Favours No EBRTl




                                                   0.2% difference in 5-year OS (87.8% in EBRT and 88% in no EBRT)
                                                                  95% CI of difference = -2.0% to 3.0%




                                                                            Leeds – April 2009
Conclusions - 1
   Adjuvant EBRT did result in a small reduction in isolated
    local recurrence in those with isolated local or pelvic
    recurrences (30% of those who relapsed)
       70% of women who relapsed had local and distant recurrence at
        the same time, or distant recurrence alone
       the reduction in isolated local recurrence does not translate into
        an impact on overall or recurrence free survival.
       in addition, the isolated local recurrence rate without EBRT (and
        with brachytherapy) is very small (7%)
       adjuvant EBRT is associated with more acute and long term
        toxicity than observation with or without brachytherapy, adjuvant
        EBRT following surgery to achieve isolated local control is
        probably not justified as the treatment of choice.


                                 Leeds – April 2009
Conclusions - 2
   No evidence that EBRT improves overall survival,
    disease specific or recurrence-free survival
   5-year overall survival 84%
   5-year disease specific survival 89%
   HR for OS combined with data from the PORTEC
    1 and GOG99 can exclude an absolute benefit of
    EBRT of more than 3% in 5-year overall survival




                       Leeds – April 2009
Vaginal brachytherapy
   Vaginal brachytherapy in phase II studies as
    effective as EBRT
       studies mostly in low risk patients
       less treatment related toxicity
       improved quality of life
   Brachytherapy is associated with vaginal
    stenosis in ~ 15% of those treated



                            Leeds – April 2009
PORTEC 2
   PORTEC 2
       Intermediate risk endometrial cancer
       Over 60 years of age
   Comparing
       Adjuvant pelvic radiotherapy
       Adjuvant vaginal brachytherapy
   427 patients randomised


                            Leeds – April 2009
PORTEC 2 - recurrences
Site of first recurrence                        EBRT   VBT


Vagina                                          2      1


Pelvis                                          1      2


Distant                                         11     15


                           Leeds – April 2009
PORTEC 2 - survival
   Median follow up 36 months

   Disease free survival at 3 years
       88.6% EBRT vs. 89.7% VBT


   Overall survival at 3 years
       90.35 ERBT vs. 90.8% VBT


                         Leeds – April 2009
VBT - conclusions
   VBT results in a reduction in vaginal
    recurrences

   No survival benefit




                          Leeds – April 2009

				
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