Treatment of Advanced and Metastatic Gastric Cancer

1
Treatment of Advanced and Metastatic Gastric
Cancer

• Grand Rounds 2.10.06
• Caron Rigden, M.D.

2
Gastric CancerCA Cancer J Clin 2005 55
10-33CA Cancer J Clin 2005 55 75Stewart
World Cancer Reports IARC Press, Lyon 2003

• Worldwide 4th most common malignancy
• 2nd leading cause
  cancer mortality
• U.S. 13th most common malignancy
  
• 8th leading cause of
  cancer mortality
• U.S. 2005 estimated 21,860 cases/11,550 deaths
• 60 cases in developing countries
• cases have been declining in u.s. since 1930s
• distal cases declining as proximal cardia/ge
  junction have been rising
• 90 cases are adenocarcinoma

3

• Two-thirds of patients present with locally
  advanced or metastatic disease in the United
  States.
• Of those who undergo curative resection 60
  relapse both locally and with distant metastasis.
  Thus, both adjuvant therapy and therapy for
  metastatic disease are of considerable
  importance.

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Adjuvant RadiationTherapyBudach, Ann Oncol 1994
5 37S

• No proven survival advantage postoperative
  radiation therapy alone.
• May be improvement in locoregional recurrence
  rates in patients with serosal penetration (T3),
  nodal involvement, or positive surgical margins.

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Adjuvant Chemotherapy

• More than 30 trials comparing adjuvant
  chemotherapy to surgery alone
• Varied results
• Meta-analysis suggesting possible benefit, but no
  single trial showing conclusive evidence of a
  benefit
• 
  Earle,
  Eur J Cancer 1999 35 1059
• 
  Mari,
  Ann Oncol 2000 11 837
• 
  
  Hermans, JCO 1994 12 879
• Utilized in parts of Europe and Japan
• 
  

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Adjuvant ChemoradiationMacDonald, NEJM 2001
345 725
7
ASCO 2004 Update
8
Adjuvant Therapy Arm

• One cycle 5FU (425mg/m2) LV (20mg/m2) daily x 5
  days
• One month later 45 Gy with 5FU (400mg/m2) and LV
  (20mg/m2) D1-4, and last 3 days of radiation
• One month after completion of radiation
• 5FU (425mg/m2) LF (20mg/m2) D1-5 q30 days for
  two cycles.

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Results-Median f/u 5 YearsMacDonald NEJM 2001
345 725

• Median OS
• Surgery alone - 27 months
• Chemoradiation - 36
  months (plt0.005)
• DFS
• Surgery alone 19 months
• Chemoradiation 30
  months (plt0.001)
• Pivotal trial establishing chemoradiation as
  standard of care in United States

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7.4 years f/u ASCO 2005 Update
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7.4 years F/U ASCO 2004 Update
12

• Subgroup analysis showed the benefit of adjuvant
  chemoradiation did not differ with regards to
• T stage
• N stage
• Tumor location-proximal vs. distal
• Extent of LN dissection D0 vs. D1 vs.
  D2

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Ongoing Trial CALGB 80101

• Follow-up study to Intergroup 0116
• assess the efficacy of ECF versus 5FU as the
  adjuvant chemotherapy
• Target accruel 536 patients
• Currently over 200 patients enrolled
• Prelimary toxicity evaluation shows less grade
  III/IV toxicity with the ECF arm

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CALGB 80101

• ARM A
• 5FU (425mg)/LV (20mg) D1-5 -gt 5 weeks XRT/5FU
  CIVI (200mg/m2) -gt rest 4-5 weeks -gt 5FU
  (425mg)/LV (20mg) D1-5 x 2 (28 day cycle)
• 
  Total XRT 4500 cGy

• ARM B
• ECF -gt 5 wks xrt CIVI 5FU (200mg/m2) -gt ECF x
  2 q21d
• E (50 mg/m2) D1
• C (60 mg/m2) D1
• F (200 mg/m2) CIVI D1-21 Total XRT
  4500 cGy

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Neoadjuvant Chemotherapy MAGIC TrialCunningham
ASCO 2005

• Evaluate the efficacy of preoperative and
  postoperative ECF vs. surgery alone
• 503 patients, stage II or greater
• Adenocarcinoma stomach/ge junction/distal
  esophagus
• ECF was chosen secondary to high RR in two prior
  randomized trials for locally advanced and
  metastatic gastric cancer
• 
  Webb JCO 1997 Ross JCO 2002

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Schema

• Arm A Surgery alone-(type of surgery and
  extent of nodal dissection left to discretion of
  surgeon)
• Arm B ECF x 3 -gt surgery -gt ECF x 3
• Epirubicin (50mg/m2) D1
• Cisplatin (60mg/m2) D1
• Fluorouracil (200mg/m2) CIVI D1-21
  
• Cycles q3weeks

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Patient Characteristics

• ECF
• Median Age 62(29-85)
• Male 205 (82)
• Female 45 (18)
• WHO 0 68
• WHO 1 32

• Surgery
• Median Age 62 (23-81)
• Male 191 (70)
• Female 61 (25)
• WHO 0 68
• WHO 1 32

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Patient Characteristics

• ECF
• Site
• Stomach 74
• LE 15
• GE junction 11
• Median tumor 5cm
• diameter (3-7)

• Surgery
• Site
• Stomach 74
• LE 14
• GE junction 12
• Median tumor 5cm
• diameter (3-7)

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Preoperative Profile

• 95 of patients in surgical arm received surgery
• 95 of patients in ECF arm initiated chemotherapy
• 86 completed preoperative chemotherapy
• 88 underwent surgery

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Postoperative Chemotherapy Profile

• Only 55 of patients that underwent resection
  commenced postoperative chemotherapy
• citing early death/disease
  progression/never having surgery
• as main reasons for not initiating
  post-op chemotherapy
• 42 completed postoperative chemotherapy

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• Toxicities
• No significant difference between both
• hematologic and nonhematologic toxicities
• in the preoperative and postoperative time
  period
• 25 had neutropenia

• Postoperative Morbidity/Mortality was the same
  between both arms.

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Postoperative Staging
23
Follow-up
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ASCO 2005
25
ASCO 2005
26
Survival Results
Results unchanged on multivariate analysis
adjusted for age, PS, site of Disease and gender.
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Conclusions for Magic Trial

• First trial with neoadjuvant chemotherapy to show
  PFS/OS benefit
• Pathologic staging showed improvement in
  downsizing of primary tumor
• Chemotherapy tolerated fairly well
• Value of post-operative chemotherapy unknown
  (only 42 completing tx)
• Follow-up study Magic B planned comparing ECX
  perioperative with ECX bevacizumab perioperative.

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Ongoing SAAK Trialwww.cancer.gov

• Phase III for locally advanced operable disease
• Arm A DCF -gt surgery
• Arm B surgery -gt DCF

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Chemotherapy for Metastatic Disease

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Single Agents Active in Gastric Cancer

• 5-fluorouracil
• Cisplatin
• Doxorubicin/epirubicin
• Mitomycin C
• Etoposide
• Reponse rates up to 20, median duration
  approximately 4-6 months

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Combination Regimens vs. Best Supportive Care

• 4 trials showing improved survival of 4-8 months
  with combined chemotherapy
• Small studies
• QOL reported to be better
  
  
• 
  
  Scheithauer et al. 1995 ELF vs. BSC
• 
  Pyrhonen et al. 1995
  FEMTX vs. BSC
• 
  Glimelius et al. 1997
  ELF vs. BSC
• Murad et al. 1999 FAMTX vs. BSC

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Outcomes From Phase III Trials
Mayer
ASCO 2005
33

• No combination regimen has clearly proven
  superior efficacy.
• In Europe ECF is largely used
• In the U.S. cisplatin and 5-FU based regimens
  have been the standard
• Newer cytotoxic agents have proven efficacy in
  early phase trials
• paclitaxel, docetaxel
• capecitabine
• irinotecan
• oxaliplatin
• S-1
• Will any of these agents improve treatment in the
  metastatic setting?

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Recent Phase III Trials Reported

• TAX 325 TCF vs CF
• IFL vs CF
• Ongoing REAL-2

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TAX 325 Moiseyenko, ASCO 2005

• Arm A
• D 75mg/m2 D1
• C 75mg/m2 D1
• F 750mg/m2 CIVI D1-5
• cycles q21 days

• Arm B
• C 100mg/m2 D1
• F 1000mg/m2 CIVI D105
• cycles q28 days

• International Phase III
• 457 chemotherapy-naive patients
• Median age 55
• 97 had metastatic disease
• Patient characteristics well balanced

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TAX 325 Results
Moisieyenko, ASCO 2005
TTP primary endpoint RR/OS secondary endpoints
37

• RESULTS
• DCF superior to CF in terms RR, TTP, OS
• DCF more toxic
• QOL maintained longer with DCF

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IF vs. CF Dank et. al, ASCO 2005

• Arm A
• Irinotecan (80mg/m2) D1
• LV (500mg/m2) D1
• 5FU (2,000mg/m2) CIVI 22hrs
• Cycle weekly for 6/7 weeks

• Arm B
• Cisplatin (100mg/m2) D1
• 5FU (1000mg/m2) CIVI
• D1-5
• cycle q28 days

• 97 metastatic
• No palliative/prior treatment within 12 months
• Baseline characteristics with slightly worse PS
  in IF arm
• Phase III trial, 337 patients randomized

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Dank et al, ASCO 2005
40
Dank et al, ASCO 2005
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Dank et al, ASCO 2005
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IF vs. CF

• Negative study
• Toxicity less than CF
• Potential alternative therapy

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REAL-2 Sumpter et al,
British J CA 2005 92 1976

• 2x2 randomized study comparing ECF to
• alternative regimens substituting oxaliplatin
  for cisplatin and capecitabine for
  5-fluorouracil.
• ECF (E 50mg/m2) (C 60mg/m2) (FU 200mg/m2)
• EOX (E 50mg/m2) (O 130mg/m2) (C 1000/1250mg/m2)
• ECX (E 50mg/m2) (C 60mg/m2) (X 1000/1250mg/m2)
• EOX (E 50mg/m2) (O 130mg/m2) (X 1000/1250mg/m2)
• Cycles q21 days
• X given 14/21 days

44
REAL-2 Sumpter et al,
British J CA 2005 92 1976

• patients stratified by PS, extent of disease
• no prior chemotherapy
• interim analysis after 80 patient accrual
• allowed increase in X to 1250mg/m2
• reached target accrual 1000 patient, now awaiting
  final data with primary endpoint OS

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REAL-2 Second Interim Analysis Sumpter et al,
British J CA 2005 92 1976

• Trend toward superior
• RR with EOX
• Secondary analysis with no greater toxicity with
  increased dose of X compared to standard F
• Substitutions does not appear to impair efficacy

• Await final results

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Ongoing Metastatic Phase III trialcancer.gov

• United States
• cisplatin/S-1 vs. cisplatin/5FU
• 28 day cycles
• S-1 given daily 21/28 days
• Japanese Trials with S-1
• German Irinotecan vs. BSC

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Cochrane Meta-analysis 2005

• Compared
• 5FU/C/anthracycline vs. 5FU/C
• 5FU/C/anthracycline vs. 5FU/A
• irinotecan containing vs. non-irinotecan
  continaining regimens
• Results
• 3 drug combination favored over non-anthracycline
  or non-cisplatin combinations (1-2 month survival
  benefit)
• 2. statistically non-significant benefit to
  irinotecan containing regimens with less toxicity

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Conclusion

• No dramatic improvement with new studies.
• DCF with slight improvement, but increased
  toxicity
• IF possible alternative for those unable to
  tolerate a platinum agent
• REAL-trial results with provide role for
  oxaliplatin and capecitabine