Treatment of Advanced and Metastatic Gastric Cancer

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Slide 1 :

Treatment of Advanced and Metastatic Gastric Cancer Grand Rounds 2.10.06 Caron Rigden, M.D.

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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 1930’s distal cases declining as proximal cardia/ge junction have been rising 90% cases are adenocarcinoma

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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

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ASCO 2004 Update

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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 (p<0.005) DFS: Surgery alone – 19 months Chemoradiation – 30 months (p<0.001) 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

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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 -> 5 weeks XRT/5FU CIVI (200mg/m2) -> rest 4-5 weeks -> 5FU (425mg)/LV (20mg) D1-5 x 2 (28 day cycle) Total XRT 4500 cGy ARM B ECF -> 5 wks xrt + CIVI 5FU (200mg/m2) -> 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 -> surgery -> 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

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Follow-up

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ASCO 2005

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ASCO 2005

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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 -> surgery Arm B surgery -> 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

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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

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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

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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

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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

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