CALGB pancreatic cancer

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CALGB pancreatic cancer Powered By Docstoc
					 Highlights in Upper
Gastrointestinal Cancer
       ECLU July 2007
Professor David Cunningham, MD FRCP
        Royal Marsden Hospital
         Surrey & London, UK
Pancreatic Cancer
Advanced Disease
    Locally advanced/metastatic pancreatic cancer
                             GEM-CAP trial
                                            GEMCITABINE, n = 266
                                            1000mg/m2 weekly ×7 q8 weeks
Locally advanced                            thereafter weekly ×3 q4 weeks
or metastatic
Pancreatic Ca                 R             GEM-CAP, n = 267
                                            Gemcitabine 1000mg/m2 weekly ×3 q4 weeks
                                            Capecitabine 1660mg/m2/day for 21 days q4 weeks

 Stratification:
 - LA v Metastatic
 - PS 0/1 v 2

 Primary endpoint: Overall survival
 Secondary endpoints: Toxicity, QOL, ORR,
 pain assessment

                                                                            Cunningham ECCO 2005
                         Locally advanced/metastatic pancreatic cancer
                                  GEMCAP provisional results

                                                                                           12-month
                         100                                                                survival
                                                                       GEMCAP (n=267)         26%
Patients surviving (%)




                         75                                            Gemcitabine (n=266)    19%


                                                               Hazard ratio = 0.80 (95% CI: 0.65–0.98)
                         50
                                                               Log rank p=0.026


                         25

                                       6.0       7.4
                          0
                               0   3         6    9       12    15    18              21       24      27
                                                        Time (months)


                                                       Cunningham D, et al. Eur J Cancer Suppl 2005;3:4 (Abstract PS11)
Locally advanced/metastatic pancreatic cancer
              GEM-CAP toxicity
                       GEM        GEM-CAP
                       (n=145)    (n=153)

 Anaemia                6%         3%
 Neutropenia           26%        36%
 Thrombocytopenia       6%        11%
 Fever                  3%         2%
 Nausea                 5%         6%
 Vomiting               5%         5%
 Lethargy              17%        20%
 Diarrhoea              5%         7%
 Stomatitis             0%         1%
 Hand foot syndrome     0%         5%
                                        Cunningham ECCO 2005
     SAKK GEMCAP versus gemcitabine:
 phase III study in advanced pancreatic cancer
   R
   A
   N   n=160
               GEMCAP
   D           Gemcitabine 1,000mg/m2 weekly x2 every 3 weeks
   O           Xeloda 650mg/m2 twice daily, days 1–14
   M           every 3 weeks
   I
   S
   A
   T           Gemcitabine
   I           1,000mg/m2 weekly x7 every 8 weeks,
   O           thereafter weekly x3 every 4 weeks
       n=159
   N

 Primary endpoint: overall survival

                                                 Herrmann R, et al. JCO 2007
         SAKK GEMCAP versus gemcitabine:
     phase III study in advanced pancreatic cancer
                         100
                                                            GEMCAP (n=160)
                                                            Gemcitabine (n=159)
Patients surviving (%)




                         80
                                                                      GEM         GEM-CAP
                                                  RR                  12%             15%
                         60                       mOS (Months)        7.2                8.4
                                                                             P = 0.234

                         40                       KPS ≥ 90 mOS*        7.4               10.1
                                                                             P = 0.014

                                                                             * Post-hoc analysis
                         20


                          0
                               0   6   12     18     24          30         36            42
                                            Time (months)



                                                                        Herrmann R, et al. JCO 2007
    Locally advanced/metastatic pancreatic cancer
                  NCIC CTG PA.3
• Overexpression of epidermal growth factor (EGFR) pathway is
  commonly seen in pancreatic cancer; associated with more
  aggressive disease and poorer outcome
• Erlotinib (Tarceva): small molecule tyrosine kinase inhibitor of EGFR
• Preclinical synergy observed between gemcitabine + erlotinib in
  xenograft models (Ng Mol Cancer Ther 2002)

                                     Gemcitabine 1000mg/m2 weekly x7 followed by 1
                                     week rest, then weekly x3 q4w + placebo (n=284)
Randomization
                                     Gemcitabine 1000mg/m2 weekly x7 followed by 1
Stratification:                      week rest, then weekly x3 q4w + erlotinib
•LA vs metastatic                    100mg/day or 150mg/day (n=285)
•PS
•Centre

Primary endpoint: Overall survival
Secondary endpoints: PFS, QOL, ORR, toxicity, correlation of
EGFR status with outcome
                                                                          Moore JCO 2007
                   Locally advanced/metastatic pancreatic cancer
                         NCIC CTG PA.3 – Overall Survival
              100
                                                                         HR = 0.81*
                                                                         95% CI (0.67, 0.97)
                         80                                              P = 0.025



                         60
         Per cen t age




                                                              Gemcitabine + Erlotinib
                         40                                   Median = 6.37 months
                                                              1 Year Survival = 24%

                                  Gemcitabine + Placebo
                         20       Median = 5.91 months
                                  1 Year Survival = 17%


                          0
                              0             6                  12                18              24
                                                         Time (Months)
* Adjusted for PS, pain and disease extent at randomization                                    Moore JCO 2007
   Locally advanced/metastatic pancreatic cancer
   NCIC CTG PA.3 – PFS, ORR & adverse events
                   100
                                                                           HR = 0.76*
                                                                           95% CI (0.63, 0.91)
                               80                                          P = 0.003


                               60
              Pe r cen t age




                                                                 Gemcitabine + Erlotinib
                                                                 Median = 3.75 months
                               40                                N=285
                                        Gemcitabine +
                               20       Placebo
                                        Median = 3.55 months
                                        N=284
                                0
                                    0                 5                      10                  15
                                                           Time (Months)
              * Adjusted for PS, pain and disease extent at randomization

     Treatment arm                            ORR                            Erlotinib (%)            Placebo (%)
Gemcitabine + erlotinib                       8.6%         Events           Any        G3,4           Any    G3,4
                                                          Rash               72          6            29       1
Gemcitabine + placebo                         8.0%
                                                          Diarrhea           56          6            41       2
Locally advanced/metastatic pancreatic cancer
    NCIC CTG PA.3 – Rash and Survival
               100
                                                                  HR [Rash]= 0.71
                                                                  p<0.0001
               80

                                              Grade 2
               60
  Percentage




                         Grade 0         Grade 1
               40



               20



                0
                     0             5               10               15              20
                                                im
                                               T e (Months)


                                   Grade 0              Grade 1          Grade >2
                                    N= 79               N= 108            N= 103
  Median Survival                      5.29              5.75              10.51
  1 year Survival                      16%               11%               43%
                                                                                         Moore JCO 2007
 Locally advanced/metastatic pancreatic cancer
                CALGB 80303


                                              Gemcitabine 1000mg/m2 d1 8 15 q28d
                                              Placebo
Locally advanced
or metastatic
Pancreatic Ca                R
N=602
                                              Gemcitabine 1000mg/m2 d1 8 15 q28d
        Primary endpoint:                     Bevacizumab 10mg/kg d1 d15 q28d
        • Overall survival

        Secondary endpoints:
        • objective response rate, duration of
        response, progression-free survival, toxicity

               Trial closed by DSMB as crossed futility boundary

                                                                     Kindler et al ASCO 2007
                                               CALGB 80303:
                       1.0
                       0.8
                                 Progression-Free Survival by Treatment Arm




                                                                     Bevacizumab
                                                             Bevacizumab 4.9 mo
Proportion Surviving




                                                                     Placebo
                                                             Placebo      4.7 mo
                       0.6




                                                             HR = 1.00 HR=1.00
                                                             P = 0.99 p=0.99
                       0.4
                       0.2
                       0.0




                             0        5       10        15         20       25

                                            Months from Study Entry

                                                                            Kindler et al ASCO 2007
                                          CALGB 80303:
                                 Overall Survival by Treatment Arm
                       1.0




                                                          Bevacizumab 5.8 mo
                       0.8




                                                          Placebo Bevacizumab
                                                                      6.1 mo
Proportion Surviving




                                                                  Placebo
                                                          HR = 1.03
                       0.6




                                                          P = 0.78
                       0.4
                       0.2
                       0.0




                             0       5      10       15          20         25

                                         Months from Study Entry

                                                                            Kindler et al ASCO 2007
Locally advanced/metastatic pancreatic cancer
               CALGB 80303
                  Gemcitabine   Gemcitabine
                   Placebo      Bevacizumab
       CR (%)          2             1

       PR (%)          8            10

       SD (%)         31            36
Disease control
                      40            47
       rate (%)
    Median OS
                      6.1           5.8       P=0.78
     (months)
 PFS (months)         4.7           4.9       P=0.99

    1yr OS (%)        20            18
                                               Kindler et al ASCO 2007
 Locally advanced/metastatic pancreatic cancer
                SWOG S0205
                                    Gemcitabine
Locally advanced
or metastatic
Pancreatic Ca              R
N=735                               Gemcitabine
                                    Cetuximab


  Stratified by:                    Primary endpoint:
  • Metastatic v locally advanced   • Overall survival
  • PS 0,1 v 2
  • Prior pancreatectomy
  Both measurable and evaluable
  disease



                                                         Philip et al ASCO 2007
           S0205 Primary Endpoint:
            Survival of all Patients
                Overall Survival by Treatment Arm
100%                                                                              Median
                                                                  N    Events    in Months
                         Gemcitabine                             369    338          6
                                                                                    5.9
                         Gemcitabine and Cetuximab               366    331         6.4
                                                                                     6
80%                                                       P = 0.14


60%


40%
                                      HR = 1.09 (95% CI: 0.93, 1.27)


20%


 0%
       0            12                               24                          36
                         Months After Registration
                                                                           Philip et al ASCO 2007
 Locally advanced/metastatic pancreatic cancer
                SWOG S0205
                              Gemcitabine
                Gemcitabine
                               Cetuximab
      CR (%)         1             0

      PR (%)        13            12

      SD (%)        30            38

CR+PR+SD (%)        44            50
   Median OS                                     P=0.14
                    5.9           6.4
    (months)                                HR 1.09 (0.93-1.27)
                                                P=0.058
 PFS (months)       3.0           3.5
                                            HR 1.13 (0.97-1.31)
                                               P=0.0014
 TTF (months)       1.8           2.5
                                            HR 1.25 (1.08-1.45)
                                                   Philip et al ASCO 2007
             Immunotherapy – Telovac
•Telomeric degeneration causes cell senescence and death
•Telomerase confers cellular immortality; expressed in 85-90% of pancreatic cancer
•Telovac (GV1001) is a 16mer HLA class 2 peptide that stimulates immune response
to Telomerase
•Phase I/II data:
     • 48 chemo-naive patients with pancreatic cancer – 3 dose levels
     • Immune responses in 40 – 75% of patients; well tolerated
     • Encouraging OS of 8.6 months in one cohort

Stratified by:
                            Locally advanced or
•LA v Metastatic         metastatic pancreatic cancer
•PS 0 v 1 v 2                      n = 1,100



                                 8/52 GemCap                      GemCap
         GemCap                   followed by                           +
                                    GV1001                        GV1001
Pancreatic Cancer
Adjuvant Treatment
Adjuvant treatment in resected Pancreatic Cancer
                    ESPAC-1
        Pancreatic or ampullary adenocarcinoma, R0 or R1


                                         R
                                                                      CRT and
   Observation          Chemoradiation        Chemotherapy
                                                                    chemotherapy
      N=69                  N=73                 N=75
                                                                        N=72



                                 Treatment comparison



        Chemoradiotherapy                         Chemotherapy vs.
           vs. no CRT                             no chemotherapy
                 (144 vs. 145)                          (142 vs. 147)

                                                                 Neoptolemos et al, NEJM 2004
                          ESPAC-1
           Chemoradiotherapy v no chemoradiotherapy
                                              Median OS               2-year OS
                        No CRT                17.9 mths                  41%
                        CRT                   15.9 mths                  29%
                        (HR 1.28; 95%CI: 0.99 - 1.66; P=0.05)
Survival




                                        Months
                                                                Neoptolemos et al: NEJM. 2004
                     ESPAC-1
           Chemotherapy v no chemotherapy
                                         Median OS               2-year OS
                   No CT                 15.5 mths                   30%
                   CT                    20.1 mths                   40%
                   (HR 0.71; 95%CI: 0.55 - 0.92; P=0.009)
Survival




                                   Months
                                                            Neoptolemos et al: NEJM. 2004
Adjuvant treatment in resected Pancreatic Cancer
            CONKO-001 Trial Design


                                            Gemcitabine
  R0 or R1 resected
                                            1000mg/m2 d1,8,15 q28d x6
  Pancreatic Ca
                          R
  N=368
                                            Observation



  Stratified by:      Primary Endpoint:
  • R0 v R1           • Disease free survival
  • T1/2 v T3/4       Secondary Endpoints:
  • N+ v N-           • Toxicity, Quality of life, Overall survival



                                                                      Oettle JAMA 2007
Adjuvant treatment in resected Pancreatic Cancer
           CONKO-001- Results (ITT)




                                          Oettle JAMA 2007
Adjuvant treatment in resected Pancreatic Cancer
       CONKO-001- Sub-group analysis

        Disease-free survival (months)    Overall survival (months)

         Gem        Obs          P       Gem        Obs          P

 All     13.4        6.9       <.001     22.1       20.2        .06

 R0      13.1        7.3       <.001     21.7       20.8        .18

 R1      15.8        5.5       <.001     22.1       14.1        .07

 N-      24.8       10.4        .003     34.0       27.6        .04

 N+      12.1        6.4       <.001     18.5       18.2        .44

 T1-2    48.2       10.0        .02      50.2       27.6        .28

 T3-4    12.9        6.7       <.001     20.5       19.1        .11
Adjuvant treatment in resected Pancreatic Cancer
               ESPAC-4 proposal

                     Resected pancreatic
                           cancer




     Gemcitabine
           +                               Gemcitabine
     Capecitabine

Primary Outcome: Overall Survival
Secondary Outcomes: DFS, Toxicity, QOL
Hepatocellular carcinoma
      Advanced Hepatocellular Carcinoma
                Previous trials disappointing results
• Doxorubicin v BSC: n=106, MS 10.6 v 7.5 weeks1
  p=0.036
                                                 TTP            MS
 Author, year       n      Agent      PR (%)
                                               (months)       (months)
 Choi 1984         20   Doxorubicin    25                           3
                         5FU MTX
                   19                   0                         1.5
                          Cyc Vin
 Porta 1995        25      5-FU        10
 Yang 2003         47     Gem Cis      21        3.2              6.4
 Fuchs 2002        30      Gem          0        2.1              6.9
 Boucher 2002      21       ECF        14        5.9               10
 Park 2006         29      DCX         24        3.7              7.7
                                                          1   Lai et al Cancer 1988
     Phase III randomised trials in
  advanced hepatocellular carcinoma
Authors              Yeo et al     Beaugrand et al     Porta et al           Posey et al

Total no. of pts        188         746                  446                   339

Control arm          Doxorubicin   Placebo             Doxorubicin           Doxorubicin
                     (n=94)                            (n=223)               (n=169)

Median survival      6.83 months   9.2 months          7.75 months           5.6 months

Experimental arm PIAF*             Seocalcitol         Nolatrexed            T-138067
                 (n=94)                                (n=223)               (n=170)

Median survival      8.67 months   9.6 months          5 months              5.7 months

p-value              p=0.83        p=NS                p<0.05                p=0.85

PIAF: Cisplatin, interferon-2b,      Yeo et al JNCI 2005; Beaugrand et al J Hepatology 2005
doxorubicin, fluorouracil             Porta et al ASCO GI 2006; Posey et al ASCO 2005
     Advanced Hepatocellular Carcinoma
           Sorafenib vs. Placebo
• Raf-Kinase over-expressed
• Raf / MEK / ERK implicatated
• Sorafenib multi-targeted TKI against RAF family, VEGF,
  PDGFb, cKIT
                                                     Sorafenib
      Unresectable /
      metastatic HCC
                                    R
      Child-Pugh A
                                                     Placebo

         Primary endpoints: OS, time to symptomatic progression
         Secondary endpoint: TTP
         Stratified by vascular invasion, extrahepatic spread, ECOG PS,
         geographic region
                                                                          Llovet ASCO 2007
                                                 Phase III SHARP Trial
                                      Overall survival (Intention-to-treat)
                               1.00

                                                                                          Sorafenib
                                                                                          Median: 46.3 weeks
                               0.75                                                       (95% CI: 40.9, 57.9)
        Survival Probability




                                                                                          Placebo
                                                                                          Median: 34.4 weeks
                                                                                          (95% CI: 29.4, 39.4)
                               0.50



                               0.25

                                          Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88)
                                                              P=0.00058*
                                 0
                                      0     8     16     24     32     40     48    56    64    72     80 Weeks
    Patients at risk
         Sorafenib: 299                    274    241    205    161    108    67     38   12     0     0
          Placebo: 303                     276    224    179    126     78    47     25   7      2     0


*O’Brien-Fleming threshold for statistical significance was P=0.0077.                                Llovet ASCO 2007
                                                  Phase III SHARP Trial
Time to progression (Independent central review)
                                 1.00
    Probability of Progression




                                 0.75


                                                                                              Sorafenib
                                 0.50                                                         Median: 24.0 weeks
                                                                                              (95% CI: 18.0, 30.0)
                                                                                              Placebo
                                                                                              Median: 12.3 weeks
                                 0.25                                                         (95% CI: 11.7, 17.1)

                                                          Hazard ratio (S/P): 0.58 (95% CI: 0.44, 0.74)
                                                                          P=0.000007
                                   0
                                        0   6       12     18      24     30      36     42        48      54 Weeks
Patients at risk
     Sorafenib: 299                         196     126    80      50      28     14      8        2        0
      Placebo: 303                          192     101    57      31      12     8       2        1        0

                                                                                                          Llovet ASCO 2007
  Advanced Hepatocellular Carcinoma
        Sorafenib vs. Placebo


                          Sorafenib           BSC
    CR (%)                    0                0
    PR (%)                   2.3              0.7
    SD (%)                   71                67


Time to symptomatic progression (additional primary endpoint)
             – no significant difference (p=0.77)




                                                         Llovet ASCO 2007
Oesophagogastric Cancer
   Advanced Disease
     REAL-2: First line Phase 3 trial in
       Oesophagogastric cancer
               ECF               • Primary end point of demonstrating non-inferiority in
                                 both PPP comparisons for survival was met (upper
ITT=1002       ECX               limit of CI of HR<1.23)
PPP=961                               –Capecitabine vs 5FU: HR 0.86 (0.8-0.99)
               EOF
                                      –Oxaliplatin vs cisplatin: HR 0.92 (0.8-1.1)
               EOX               • Non-inferiority maintained in multivariate analysis

                                                 OS
      Arm            No. (ITT)                                           ORR, %
                                      Med, mo             1yr
  ECF                  263              9.9            37.7%             40.7%
  EOF                  250              9.3            40.4%             42.4%
  ECX                  245              9.9            40.8%             46.4%
  EOX                  244              11.2           46.8%             47.9%
   DCF*                227               9.2             40%               37%
    * TAX325

                                                Cunningham ASCO 2006; Van Cutsem JCO 2006
                                            Overall Survival (Per-protocol):
                                  100
                                             Fluoropyrimidine comparison
                                                                            N           Median     1 year       95% CI
                                   80
                                                     5FU                    484         9.6        39.4%        35.0 - 44.0

                                                                                                                40.1 – 49.0
    Probability of survival (%)




                                   60
                                                     Capecitabine           480         10.9       44.6


                                   40

                                                                                   HR 0.86 (0.8 – 0.99)
                                   20



                                    0
                                        0       1           2                  3               4            5            6
                                                           Time since randomisation (years)
Number at risk
                                                                                                                   5FU
5FU          484                               178         37                 8                2
Capecitabine 480                               206         52                 12               3            1      Capecitabine


                             HR for ITT population = 0.88 (0.77 – 1.00) p= 0.058
                                          Overall Survival (Per-protocol):
                                              Platinum comparison
                                   100                             N          Median         1 year       95% CI
                                                   Cisplatin       490        10.0           40.1%        35.7 - 48.4
                                   80
     Probability of survival (%)




                                                   Oxaliplatin     474        10.4           43.9%        39.4 – 49.0
                                   60




                                                                              HR 0.92 (0.8 – 1.1)
                                   40



                                   20



                                    0
                                         0     1            2             3             4             5             6
Number at risk                                            Time since randomisation (years)

Cisplatin                                490   187         41            10             1                     Cisplatin
Oxaliplatin                              474   198         48            10             4             1       Oxaliplatin


    HR for ITT population = 0.91 (0.79-1.04) p=0.159
               Survival by Regimen ECF vs EOX
                             (ITT)
                               100
                                                     OS (months)                    1-year OS
                                         ECF           9.9                      37.7% (31.8-43.6%)
                                80       EOX          11.2                      46.8% (40.4-52.9%)
 Probability of survival (%)




                                60



                                                               HR: 0.80 (95% CI: 0.66-0.97)
                                40
                                                               Log rank p=0.02

                                20




                                 0
                                     0     1                                2                   3
                                         Time since randomisation (years)
EOX is a new standard in the first line setting
                                     ECF   EOX
                    REAL-2: Toxicity

Patients (%)                   Grade 3 / 4 AEs                          ECX (n=229)
60
       *                                                                ECF (n=236)
50                                                                      EOX (n=232)
40                                                                      EOF (n=231)
30          * *

20
                                                         * *                        * *
10

 0




*p<0.01             Cunningham D et al. J Clin Oncol 2006;24(Suppl. 18S):934s (Abst LBA4017)
compared with ECF                               Starling N et al. Proc ASCO GI 2007 (Abst 74)
   Fluoropyrimidine substitution: XP vs FP

                                                    PFS (PPP)         OS (PPP)            ORR
                 XP
             Cisplatin +                               Med, mo         Med, mo
            Capecitabine
N=316                                     XP            5.6*              10.5            41%
                 FP                                                                     (p=0.030)
             Cisplatin +
                5FU                       FP            5.0*              9.3             29%

                                 *HR 0.81, 95% CI 0.63-1.04 (upper limit of hazard ratio less than 1.25)
                                                                                      Kang ASCO 2006


        Platinum substitution: FLO vs FLP
                 FLO
            Oxaliplatin/5FU/LV                     •    Trend towards improvement in
                                                        TTP- median 5.7 vs 3.8 mo
N=220                                                   (p=0.081)

                  FLP                              •    RR 34% vs 25%, p=0.0072
            Cisplatin/5FU/LV




                                                                                  Al Batran ASCO 2006
• Can Capecitabine replace infusional 5-FU?
  –YES!

• Can Oxaliplatin replace Cisplatin?
  –YES!
       Cetuximab combinations

                       FUFOX-C1                   FOLCETUX2
N                              52                             38
EGFR positive by IHC         58.5%                          100%
ORR                    65.2% (unconfirmed)                  51.9%
                        39.1% (confirmed)
 ORR (EGFR+)                 54.2%
 ORR (EGFR-)                 76.5%
TTP                        7.6 months                    6.5 months
OS                         9.5 months                        NR
Skin rash                  G1-2 65%                     G1-2 60.5%
                           G3-4 24%                      G3 18.4%


                                        1. Lordick ASCO 2007; 2. Di Fabio Annals 2006
                   REAL-3

                                       EOX +
                                       Panitumumab
Locally advanced
or metastatic
oesophagogastric
adenocarcinoma
                          R         Every 3 weeks
N=700

                                        EOX

        Planned to open late 2007
      First-line HER2-positive gastric cancer:
                TOGA phase III study
                                                      XP or FP (six cycles)


HER2-positive AGC
stage IIIb–IV                        R            Every 3 weeks
no prior therapy
                                                      XP or FP (six cycles)
                                                      + Herceptin (until
                                                      progression)
•   Primary endpoint: overall survival
•   Recruitment of 374 patients by July 2007 in >140 centres
•   224 patients randomised as of January 2007
HER2 = human epidermal growth factor receptor-2
Oesophagogastric Cancer
   Localised Disease
                   Oesophageal Cancer
              Resectable disease – Major Trials
                                 OE0-21 n=802               MAGIC2 n=503             INT01133 n=440

         Group                      S            CS             S              CS      S          CS

         Regimen                        CF x 2                   ECF 3+3               CF x 3 ± 2
         % with
                                   97            92            96              92     96          80
         surgery
         2 yr OS                   34            43           23*              36*    37          35
                                        0.79                       0.75                    1.07
         HR
                                    (0.67-0.93)                (0.60-0.93)             (0.87-1.32)
         p                              0.004                       0.009                  0.53
                                                                 *5 year OS


1. MRC Lancet 2002; 2. Cunningham et al NEJM 2006; 3. Kelsen et al NEJM 1998
                  Peri-operative Chemotherapy
                       MRC “MAGIC” trial
 Eligible patients:
 • Adenocarcinoma of the stomach
 or lower third of the oesophagus       Study entry and randomization
 (from 1999), suitable for curative
 resection                            S arm                CSC arm
 • Non-metastatic disease
 • Stage II or greater                N=253                 N=250
 Primary                              Surgery   Pre-operative chemotherapy:
 Overall survival                                          ECFx3
 Secondary
 Progression-free survival
                                                               3-6 weeks
 Surgical resectability
 Quality of Life

 Chemotherapy (ECF):                                      Surgery
 Epirubicin 50mg/m2, IV day 1
 Cisplatin 60mg/m2, IV day 1
 5-FU 200mg/m2/day, continuous                                   6-12 weeks
 infusion, days 1-21
 (cycles repeated every 3 weeks)
 Recruitment: July 1994-April 2002              Post-operative chemotherapy:
                                                           ECFx3
Cunningham et al NEJM 2006
Pre-operative chemotherapy and surgery
               trial profile
           CSC                       S
          N=250                    N=253


  Commenced pre-operative
      chemotherapy
       N=237 (95%)


  Completed pre-operative
     chemotherapy
      N=215 (86%)

   Proceeded to surgery     Proceeded to surgery
        N=229 (92%)             N=244 (96%)
     (N=209 completed
   peri-operative chemo)
                                        Cunningham et al NEJM 2006
       Surgical outcomes and pathology
Postoperative morbidity and mortality:                                 CSC                S
Postoperative deaths                                                    6%               6%
Postoperative complications                                           45.7%            45.3%
Median duration of post-operative hospital stay                       13 days         13 days

Pathology staging following surgery:                 CSC                S             P-value
Maximal tumour diameter (median)                    3.0 cm            5.0 cm           <0.001
Extent of tumour (gastric only)
                                         T1/T2       52%               37%             0.002
                                         T3/T4       48%               63%
Nodal status (gastric only)
                                         N0/N1       84%               71%              0.01
                                         N2/N3       16%               29%

Operation performed    Total
                                           59% of surgery performed
                       No. (%)
                                           (N=473) were
Total gastrectomy      278                 gastrectomies. Others:
                                           oesophagogastrectomy,
D1                     89 (32%)            non-resectional or
                                           unknown.
D2                     189 (68%)
                                                                             Cunningham et al NEJM 2006
                                               Survival
                            PFS*                                                          Overall
1.0                                                         1.0

0.9                        Logrank p-value = 0.0001         0.9                     Logrank p-value = 0.009
0.8                          Hazard Ratio = 0.66            0.8                       Hazard Ratio = 0.75
0.7                            (95% CI 0.53 - 0.81)         0.7                            (95% CI 0.60 - 0.93)
0.6                                                         0.6

0.5                                                         0.5

0.4                                                         0.4
0.3                                                         0.3
    Events Total                                                      EventsTotal
0.2                                                         0.2
     163 250           CSC                                            149 250            CSC
0.1                                                         0.1                          S
     190 253           S                                              170 253
0.0                                                         0.0
      0       12      24      36   48     60    72                0        12       24         36    48    60    72
                   Months from randomisation                                    Months from randomisation



                                        2 year survival 5 year survival Median survival
          CSC                                  50%          36%                                24 mo
          S                                    41%          23%                                20 mo
          Benefit to CSC arm                   9%           13%                                 4 mo



                                                                                                    Cunningham et al NEJM 2006
     Other Trials of Peri-operative Chemotherapy
                    The FNLCC 94012-FFCD 9703 Trial
                                     FP* q4w                     FP q4w
         Resectable                                  Surgery
                                     x 2-3                       x 2-3
         Gastric and
         OGJ Cancer
           n=224
                                         SURGERY (S) alone


                               FP              S only
                                                                 P value
                              n=113            n=111
         R0 (%)                 87              74                 0.04
         DFS      3yr          40%             25%                0.0033
                  5yr          34%             21%         HR = 0.65 (0.48-0.89)
         OS       5yr          38%             24%                0.021
                                                           HR = 0.69 (0.50-0.95)

*5-Fluorouracil 800 mg/m2 d1-5* +
Cisplatin 100 mg/m2 day 1                                                    Boige et al ASCO 2007
           FFCD: Overall survival
           1,00

           0,80

           0,60

           0,40

           0,20         logrank : p = 0,021


           0,00
                  0         1         2       3    4    5    6    7    years
At risk
A risque
                  111        79        53     38   27   16   13   7
                  113        93        65     53   41   27   17   14




 5-year OS: 24% (16-33%) vs 38% (28-47%)
 HR = 0.69 (0.50-0.95)                                                 Boige et al ASCO 2007
   Adjuvant Chemotherapy: S-1
• Oral cytotoxic composed of:
  – Tegafur (5FU prodrug)
  – Gimeracil (inhibits degradation of 5FU by inhibiting
    DPD)
  – Oteracil (decreases phosphorylation of 5FU in GI tract
    by inhibiting orotate phosphoribosyltransferase OPRT
    thus reducing GI toxicity of 5FU)
• ORR of 26-49% in various phase II trials in gastric
  cancer1


                               1Chollet   EJC 2003; Sakata EJC 1998; Koizumi Oncology 2000
Adjuvant S-1 treatment in D2 resected gastric cancer




                     Kindly provided by Professor M. Sasako (Sasako GI ASCO 2007)
 On-going and proposed phase III trials
           in gastric cancer
Trial                                    Setting      n
Advanced disease

XP or FP ± trastuzumab (TOGA)         HER2 +ve AGC   374

Capecitabine + cisplatin ± Avastin       MGC         760
ECXFOLFIRI vs FOLFIRIECX             AGC/MGC       416

ECX ± panitumumab (REAL-3)               AOGC        660
Operable disease

Perioperative ECX ± Avastin (STO-3)     Adjuvant     1 100
XELOX vs observation (CLASSIC)          Adjuvant     1 024
      UK NCRI MAGIC-B (ST03)
  Operable adenocarcinoma of             Bevacizumab dose:
                                         7.5mg/kg every 3 weeks
 stomach/GOJ (type III), ≥stage II
                                                   Target accrual
         RANDOMIZATION
                                            1100 patients over 3 years

ECX                 ECX + bevacizumab                Endpoints
 x3                         x3
                                         Primary: Survival
      5 wk break from chemo pre-op       Secondary:
          (8 wk break from last          Response rates
              bevacizumab)               Surgical resection rates
                                         Treatment-related morbidity
             SURGERY                     Disease Free Survival
                                         Quality of Life
             6-10 wk break
         before post-op chemo            Cost-effectiveness

ECX                 ECX + bevacizumab       Expected to open to in 2007
 x3                         x3
                                          Trial Manager (UK MRC CTU):
                                                  Monica Verma
                        Bevacizumab x6
                                             Email: mv@ctu.mrc.ac.uk

				
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