HEMATOLOGICAL ONCOLOGY, VOL. 1 0 . 3 7 4 2 (1992)
GASTRIC CANCER: CHEMOTHERAPY OF ADVANCED DISEASE JOHN S . MACDONALD Division of Medical Oncology. Temple University, Comprehensive Cancer Center, 3322 N . Broad Street, Philadelphia, P A 19/40, U . S . A .
The chemotherapy of advanced gastric cancer has been tantalizing to oncologists over the last 15 years (Macdonald et al., 1989; Gohmann and Macdonald, 1989). The reason for this is that there have been a number of regimens which appear to have significant activity in causing partial and in some cases complete regression of disease in patients with disseminated gastric carcinoma. In comparison to other sites in the GI tract (colon and pancreas), malignancies of the stomach appear to be the most responsive to chemotherapy. This discussion will briefly review single agent and combination chemotherapy and discuss the regimens that are currently of great interest in treatment of advanced gastric cancer. Table 1 reviews the single agent chemotherapy of gastric cancer. The points that may be made quite simply and clearly are that a large number of agents have been tested and there certainly are some agents including 5-FU, doxorubicin and mitomycin-C that have activity in the disease. It should be pointed out however that the incidence of complete response is vanishingly small and that there is no evidence that single agent chemotherapy impacts survival. Clearly, with the availability of a number of single agents with activity, the next inevitable step was to develop combination chemotherapy regimens. Table 2 reviews in summary form combination chemotherapies that have been tested in greater than 20 patients over the last 20 years. Whcn a regimen has been tested in large numbers of patients in a variety of studies, the results have been collated to provide a larger data base. There are several points in regard to combination chemotherapy that may be made from the analyses of the data in Table 2. First, the FAM regimen has been widely tested. Table 2 reports results collated from studies in which over 400 patients received FAM. The results demonstrate that the regimen is active with a response rate of 33 per cent. I t is important to note, however, (Macdonald et al., 1989; Gohmann and Macdonald, 1989) that FAM produces complete responses in less than 5 per cent of patients. Clearly, if the aim of therapy of disseminated carcinoma is complete response and therefore cure, then FAM is a halfway technology since it rarely produces complete responses. However, a major contribution of the FAM regimen is that its efficacy in producing partial responses in advanced gastric cancer stimulated a number of investigators to either build upon the regimen or to explore a variety of new approaches to combination chemotherapy in gastric carcinoma. There are a number of recently reported regimens which are of considerable interest in gastric cancer (Poon et af., 1989). First a comment must be made in regard to S-FU+leucovorin. 5-FU + leucovorin has been shown unequivocably to be active in advanced colon cancer and in some studies (Poon et a/., 1989) it doubles both the response rate and median survival of colon cancer patients when compared to 5-FU alone. Tn advanced gastric cancer, the role of 0278-0232/92/0 1003746 $05.00 0 1992 by John Wiley & Sons, Ltd.
38
J . S. MACDONALD
Table I , Single-agent chemotherapy in advanced gastric cancer No. responses/ No. patients YOResponses
Drug 5-Fluorouracil Mitomycin C Adriamycin Hydroxyurea BCNU Chlorambucil Mechlorethane Mcthyl-CCNU Cis-platinum Triazanate Mcthotrcxatc R a z ox an c 4’ Epidoxorubicin Miloguazone Carboplatin (CBDCA) Bisantrcne ni-AMSA
84/392 6312 1 1 17/68 613 1 4/23 3/18 3/23 3/37 8/36 4/26 3/28 0119 8/22 113 1 0122 1/26 01125
21
13/27 3/25 5/19
48 12 27
30 25 19 17 17 13 8 22 15 11 0
36 3 0 4 0
References Comis (1974) Cornis (1974)
Macdonald et al. (1989) Macdonald et cd. (1989) Schnitizler el a/. (1986) Moore et al (1968) Hurleyrtal (1961) Macdonald et a/. (1989) Lacave e f id. (1983); Beer et a/ (1983) Bruckner et a/. ( 1982) Bruckner e / a / . (1 982) Hruckner et a/. ( 1 982) Cazap et a/. (1 986) Ravry e l a/. ( I 986) Kelsen ct a/. (1984) Panettiere et a/. (1 9x6) The Southeastern Cancer Study Group (1981)
5-FU (with moderate dose folinic
acid) 5-FU (with high dose leucovorin)
Ftorafur
Machover et a/. (1986) Arbuck e t a / . (1987) Bjerkeset et a/. ( I 986)
5-FU t leucovorin is less well defined. There is one study from France by Machover and colleagues ( 1 986) which demonstrated a 48 per cent response rate for a moderately high dose leucovorin regimen. The median survival however was only S t months in this study. A study by Arbuck and colleagues (1987) showed a response rate of 12 per cent in advanced gastric carcinoma when a high dose weekly 5-FU +leucovorin regimen was used. However, 50 per cent of patients entered into this study had failed previous chemotherapy. A clinical trial performed by the Southwest Oncology G r o u p which randomized patients between a short-term continuous infusion of 5-FU + leucovorin (200 mg/m2) versus bolus 5-FU leucovorin (200 mg/m2) showed response rates for both arms t o be equal at approximately 20 per cent. It is fair to say that a n optimal regimen of 5-FU leucovorin has not been defined for advanced gastric cancer but work certainly will continue to evaluate this combination in stomach cancer. Of considerable interest in the treatment of patients with stomach cancer has been the E A P regimen (Preusser rt nl., 1989; Wilke et ul., 1989; Lerner et nl., 1990). This regimen as noted in Table 2 has been reported to produce response rates in excess of SO per cent in patients with advanced stomach cancer. Another point of major interest with E A P is that the complete response rate is significant (as high as 20 per cent). The EAP regimen combines etoposide, adriamycin, and cisplatinum in a n 8-day schedulc (Preusser r t a/., 1989; Wilke ct ul., 1989). The E A P regimen. or the same drugs used in similar schedules, has significant toxicity with myelosuppression being dose-limiting. Although there has been great interest in the results reported from Germany (Preusser P t al.. 1989) and Brazil (Katz et al., 1989) recording response rates of greater than SO per cent. a recent publication from the D a n a Farber Cancer Center (Lcrner ct al., 1990) has reported a more modest response rate. I n the original abstract prepared for the 1990 American
+
+
+ + +
++
FAM (5-FU+ adriamycin+mitomycin C) FAMtx (5-FU + adriamycin+ methotrexate) FA Me (5-FU + adriamycin + methyl-CCNU) FAP (5-FU +adriamycin+ cis-platinum) 5-FU +mitomycin C +cytosine arabinosidc 5-FLJ + adriamy&+ BCNU FAm triazinate FAM BCNU FAM +methyl CCNU Mitomycin C + RCNU + cis-platinum + 5-FU Adriamycin + mitomycin C 5-FlJ Methyl CCNU 5-FU+ Mitomycin C 5-FU Adriamycin 5-FU BCNU Triazinate + mitomycin C EAP (etoposide + adriamycin + cis-platinum)
Drug combination
I
2 1 1 6 2 2 3 1 1 1
1
12 2 4 4 3 3 1
151/453 81/162 25/80 36/93 24/6 1 62/146 4/22 9/41 14/49 25/38 13/46 421224 23/96 4/30 2 1/so 8/28 43/67 18/25 12/28
No. No. responses/ series No. patients 33 50 31 39 39 42 18 22 29 66 29 19 24 13 26 29 64 (21% CR) 72 (12%CR) 43 (1 1% CR)
% Responses
6.5 7-5 7.0 8.0 3.2 7.5 NA 6.0 6.4 NA 3.5 5.5 5.0 6.5 5.5 5.5 9 6 6
Median duration of survival (months)
References Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Ahlgren ef al. ( I 984) De Lisi et al. (1986) Gohmann and Macdonald (1989) Kim and Kim (1986) Douglas ~t u1. (1984) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) O’Connell Pt al. (1986) Preusser et al. (1 989) Wilkeetal. (1989) Lerner et al. (1990)
Table 2. Multiple drug combination chemotherapy in advanced gastric cancer
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Society of Clinical Oncology Meetings, the overall EAP response rate in patients with advanccd gastric cancer was 43 per cent. This included 1 1 per cent complete responses. However? at the time of presentation, this response rate had fallen below 30 percent. The Dana Farber investigators also found EAP to have significant toxicity. The median granulocyte nadir was 239/d1 and the median platelet nadir was 81 OOOjdl in the Dana Farber experience. In evaluating EAP-like regimens, it is important to realize that the appropriate role for these programmes has yet to be defined. There is now much interest in evaluating EAP as a neoadjuvant approach (Wilke et al., 1989). However, before new uses of EAP arc adopted, one needs to carefully evaluate the true response rate produced by EAP and also to explore ways to modify toxicity. In regard to toxicity, if EAP efficacy is convincingly confirmed, it would be very appropriate to evaluate granulocyte colony stimulating factor to modify myelosuppression of the regimen. The German group that described EAP has also reported upon interesting variant of 5-FU + leucovorin (Wilke ef al., 1990). This regimen is called E L F and combines 5-F‘U +leucovorin with etoposide in doses similar to that drug’s use in EAP. The German investigators use this in patients thought not to be appropriate medical candidates for EAP. The results of this regimen have been reported in sketchy fashion but show response rates greater than 50 per cent. Clearly, this approach needs t o be confirmed. Another European originated regimen which has stirred considerable interest is the FAMTX chemotherapy programme (Table 2). The FAMTX regimen was originally reported by Klein e t a / . ( 1986) and was shown to have a response rate in excess of SO per cent including substantial numbers o f complete responses. A more recent phase I1 study performed by the EORTC (Wils et a/.. 1986) showed a response rate of 44 per cent. Very recently (May 1990) a phase IIT clinical trial in which FAM was compared to FAMTX was reported by the EORTC (Wils et al.. 1990). In this study, 107 pacients were treated with FAMTX and 105 received FAM. The median survivals were 40 weeks for FAMTX and 29 weeks for FAM. Both the survival and response differences were highly statistically significant. The results of this phase I11 study are clearly of interest but the very low response rate for FAM, considering that the pooled results for FAM (Table 2) demonstrate a response rate in excess of 30 per cent, is surprising. Also, the abstract in which the phase 111 study was reported, noted that only 55 of 107 patients were evaluable at the time of abstract preparation for FAMTX and 47 of 105 patients were evaluable for FAM. Thus, the bulk of patients were not available for response. Before one draws firm conclusions from this study, it will be critically important to evaluate the data when all patients are evaluable. In summary, the chemotherapy of advanced gastric cancer continues to evolve. There are not clear and convincing data to nominate any one approach as ‘standard’ therapy. Regimens such as FAMTX, EAP. and E L F or newer approaches that may be built upon their regimen certainly bear watching over the next several years. I t is clear that the chemotherapy of gastric cancer will continue to be a fertile field of clinical rescarch for the foreseeable future. REFERENCES Ahlgren, J., Smith, F., Harvey, J. et ul. (1984). A phasc I1 study of FAM plus triazinate for advanced measurablc gastric carcinoma. Proc. Am. SOC. Clin.Oncol., 3, 145. Arbuck, S . G., Douglas, H. 0. Jr., Trave, F., e t a / . (1987).A phasc I1 study of 5-fluorouracil and high dose folinic acid in gastric carcinoma. J . Clin. Oncol., 5, 1 15 122. Beer, M., Cocconi, G., Ceci, G . ,et ul. (1983). A phase I1 study of Cisplatin in advanced gastric cancer. Eur. J. Crmcer Clin. Oncol., 19,7 17-720. krenherg, J. L., Goodman, P. J.. Oishi, N., et al. (1989).5-Fluorouraciland folinic acid: For the treatment of metastatic gastric cancer. Pror. ASCO, 87, 101. Bjerkeset, T., Fjosna. H. ( I 986). Comparison of oral ftorafur and intravenous 5-fluorouracil in patients with advanced cancer of thc stomach, colon or rectum. Oncologj,,43,212 215.
GASTRIC CANCER
41
Bruckner, H., Lokich, J., Stablein, D. (1982). Studies of Baker’s antifol, methotrexate and razoxane in advanced gastric cancer: A gastrointestinal tumor study group report. Cancer Treat. Rep., 66, 1713-1717. Cazap. E., Bruno, M., Levy, D., et a/. (1986). Phase I1 trial of 4-epidoxorubicin (4epi-dcx) in advanced gastriccancer. Proc. Am. Soc. Clin. Oncol., 5,91. Comis, R. (1974). Intcgration of chemotherapy into combined modality treatment of solid tumors. Cancer Treat. Rev., 1,221-233. De Lisi, V., Cocconi, G., Tonato, M. et a/. (1986). Randomized comparison of 5-FU alone or combined with carmustine, doxorubicin and mitomycin (BAFMi) in the treatmcnt of advanced gastric cancer. Cancer Treat. Rep., 70,481 4 8 5 . Douglass, H., Lavin, P., Goudsmit, A., et a/. (1984). An eastern cooperative oncology group evaluation of combinations of methyl-CCNU. mitomycin-C, adriamycin, and 5-fluorouracil in advanced measurable gastriccancer (Est 2277). J. Clin. Oncol.. 2, 1372-1381. Gohmann, J. J., Macdonald, J. S. (1989). Chemotherapy of gastric cancer. Cancer Invesfig.7(1), 39-52. Hurley, J., Ellison, E., Carey, L. (1961). Treatment of advanced cancer of the gastrointestinal tract with antitumor agents. Gastroenterology 41, 557-562. Katz, A,, Gansl, R., Simon, S., et nl. (1989). Phase I1 trial of VP16, adriamycin, and cisplatinum in patients with advanced gastric cancer. Proc. ASCO, 8,98. Kelson, D., Sternberg, C., Einzig, A,, et a/. (1984). Phase I1 study ofcarboplatin (CBDCDA) in advanced upper gastrointestinal tract malignancy. Proc. ASCO, 3, 141. Kim. R., Kim., C. (1 986). Chemotherapy of advanced gastriccancer with mitomycin-C BCNU, Cisplatin and 5-fluorouracil in combination. Proc. Am. Soc. Clin. Oncol., 5,78. Klein, H., Wickramanayake, P., Farrokh, G. (1986). 5-FU, adriamycin and methotrexate-a combination protocol (FAMTX) for treatment of metastasized stomach cancer. Proc. Am. Soc. Clin. Oncol., 5,84. Lacave, A., Izarzugaza, I., Aparicio, L., et al. (1983). Phase I1 clinical trial ofcisdichlorodiommineplatinumin gastric cancer. Am. J . Clin. Oncol., 6,35-38. Lerner, A., Steele, G . D., Mayer, R. J. (1990). Etoposide, doxorubicin, cisplatin (EAP) chcmotherapy for advanccd gastric adenocarcinoma: Results of a phase I1 trial. Proc. ASCO, 9, 103. Macdonald, J. S., Steele, G. J., Gunderson, L. L. (1989). Cancer of the stomach. In: DeVita, V. T., Hellman, S., Rosenberg, S. A., eds. Cancer Principles and Practice of Oncology. Philadelphia: Lippincott, 765-797. Machover, D., Goldschmidt. E., Chollet, P., et a1. (1986). Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high dose folinic acid. J . Clin. Oncol., 4,685496. Moore, G., Bross, I., Ausman, R., et al. (1968). Effects of chlorambucil (NSC-3088) in 374 patients with advanced cancer. Cancer Chemother. Rep., 52,661-666. O’Connell, M., Schutt, A., Moertel, C., et al. (1986). Phase 11 clinical trial of triazinate in combination with mitomycin C for patients with advanced gastric cancer. Proc. Am. Soc. Clin. Oncol., 5,82. Panettiere, F., Jones. S., Oishi, N., er nl. (1986). Bisantrcne hydrochloride in gastric adenocarcinoma: A Southwest Oncology Group study. Med. Pediatr. Oncwl., 14,78-80. Poon, M. A., O’Connell, M. J., Moertel, C. G., et a/. (1989). Biochemical modulation of fluorouracil. Evidencc of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J . Clin. Oncol., 7, 1407-1417. Preusser, P., Wilke, H., Achterrath, W., Fink, U., Lenaz, L., Heinicke, A., Meyer, J., Meyer, H . J., Buentc. H. (1 989). Phase I1 study with the combination ofetoposide, doxorubicin and cisplatin in advanced measurable gastric cancer. 1.Clin. Oncol., 7,1310-1317. Ravry, M.. Omura, G., Hill, G., et a/. (1986). Phase 11evaluation of mitoguazone in cancers of the esophagus, stomach, and pancreas: a Southeastern Cancer Study Group trial. Cancer Treat. Rep., 70,533-534. Schnitizler, G., Queisser, W., Heim, M., et nl. (1986). Phase I11 study of 5-FU and carmustine versus 5-FU, carmustine and doxorubicin in advanced gastric cancer. Cancer Treat. Rep., 70,477-479. The Southeastern Cancer Study Group (1981). m-AMSA treatment of advanced colorectal, pancreatic and gastric carcinoma. Proc. Am. Soc. Clin. Oncol., 22,454. Wilke, H., Preusser, P., Fink, U., Gunzer, U., Meyer, H. J., Meyer, J., Siewert, J. R., Achterrath, W., Lenaz, L., Knipp, H., Schmoll, H. J. (1989). Preoperative chemotherapy in locally advanced and non resectable gastric cancer: A phase I1 study with etoposide, doxorubicin and cisplatin. J. Clin. Oncol., 7, 1318 -1326. Wilke, H., Preusser, P., Fink, U., er al. (1990). Ncw developments in the treatment of gastric carcinoma. Sem. Oncol., 17(1), SUPPI.2,61-70. Wils, J., Bleiberg, H., Dalesio, O., et a/. (1986). An EORTC gastrointestinal group evaluation of the combination of sequential melhotrexate and 5-fluorouracil, combined with adriamycin in advanced measurable gastric cancer. J. Clin. Oncol., 4, 1799-1803.
42
J . S. MACDONALD
Wils, J . , Klein, H. O., Bleiberg, H., Buyse, M., Wagner, D. J . , Conroy, T., Diar-Rubio, E., Fickers. M . . Korsten, F., Leyvray, S., Reis, H., Duez, N. (1990). FAMTX (5-FU. adriamycin and methotrexate)- a step ahead in the treatment of advanced gastric cancer. Proc. ASCO, 9, 102.
GASTRIC CANCER: CHEMOTHERAPY OF ADVANCED DISEASE JOHN S . MACDONALD Division of Medical Oncology. Temple University, Comprehensive Cancer Center, 3322 N . Broad Street, Philadelphia, P A 19/40, U . S . A .
The chemotherapy of advanced gastric cancer has been tantalizing to oncologists over the last 15 years (Macdonald et al., 1989; Gohmann and Macdonald, 1989). The reason for this is that there have been a number of regimens which appear to have significant activity in causing partial and in some cases complete regression of disease in patients with disseminated gastric carcinoma. In comparison to other sites in the GI tract (colon and pancreas), malignancies of the stomach appear to be the most responsive to chemotherapy. This discussion will briefly review single agent and combination chemotherapy and discuss the regimens that are currently of great interest in treatment of advanced gastric cancer. Table 1 reviews the single agent chemotherapy of gastric cancer. The points that may be made quite simply and clearly are that a large number of agents have been tested and there certainly are some agents including 5-FU, doxorubicin and mitomycin-C that have activity in the disease. It should be pointed out however that the incidence of complete response is vanishingly small and that there is no evidence that single agent chemotherapy impacts survival. Clearly, with the availability of a number of single agents with activity, the next inevitable step was to develop combination chemotherapy regimens. Table 2 reviews in summary form combination chemotherapies that have been tested in greater than 20 patients over the last 20 years. Whcn a regimen has been tested in large numbers of patients in a variety of studies, the results have been collated to provide a larger data base. There are several points in regard to combination chemotherapy that may be made from the analyses of the data in Table 2. First, the FAM regimen has been widely tested. Table 2 reports results collated from studies in which over 400 patients received FAM. The results demonstrate that the regimen is active with a response rate of 33 per cent. I t is important to note, however, (Macdonald et al., 1989; Gohmann and Macdonald, 1989) that FAM produces complete responses in less than 5 per cent of patients. Clearly, if the aim of therapy of disseminated carcinoma is complete response and therefore cure, then FAM is a halfway technology since it rarely produces complete responses. However, a major contribution of the FAM regimen is that its efficacy in producing partial responses in advanced gastric cancer stimulated a number of investigators to either build upon the regimen or to explore a variety of new approaches to combination chemotherapy in gastric carcinoma. There are a number of recently reported regimens which are of considerable interest in gastric cancer (Poon et af., 1989). First a comment must be made in regard to S-FU+leucovorin. 5-FU + leucovorin has been shown unequivocably to be active in advanced colon cancer and in some studies (Poon et a/., 1989) it doubles both the response rate and median survival of colon cancer patients when compared to 5-FU alone. Tn advanced gastric cancer, the role of 0278-0232/92/0 1003746 $05.00 0 1992 by John Wiley & Sons, Ltd.
38
J . S. MACDONALD
Table I , Single-agent chemotherapy in advanced gastric cancer No. responses/ No. patients YOResponses
Drug 5-Fluorouracil Mitomycin C Adriamycin Hydroxyurea BCNU Chlorambucil Mechlorethane Mcthyl-CCNU Cis-platinum Triazanate Mcthotrcxatc R a z ox an c 4’ Epidoxorubicin Miloguazone Carboplatin (CBDCA) Bisantrcne ni-AMSA
84/392 6312 1 1 17/68 613 1 4/23 3/18 3/23 3/37 8/36 4/26 3/28 0119 8/22 113 1 0122 1/26 01125
21
13/27 3/25 5/19
48 12 27
30 25 19 17 17 13 8 22 15 11 0
36 3 0 4 0
References Comis (1974) Cornis (1974)
Macdonald et al. (1989) Macdonald et cd. (1989) Schnitizler el a/. (1986) Moore et al (1968) Hurleyrtal (1961) Macdonald et a/. (1989) Lacave e f id. (1983); Beer et a/ (1983) Bruckner et a/. ( 1982) Bruckner e / a / . (1 982) Hruckner et a/. ( 1 982) Cazap et a/. (1 986) Ravry e l a/. ( I 986) Kelsen ct a/. (1984) Panettiere et a/. (1 9x6) The Southeastern Cancer Study Group (1981)
5-FU (with moderate dose folinic
acid) 5-FU (with high dose leucovorin)
Ftorafur
Machover et a/. (1986) Arbuck e t a / . (1987) Bjerkeset et a/. ( I 986)
5-FU t leucovorin is less well defined. There is one study from France by Machover and colleagues ( 1 986) which demonstrated a 48 per cent response rate for a moderately high dose leucovorin regimen. The median survival however was only S t months in this study. A study by Arbuck and colleagues (1987) showed a response rate of 12 per cent in advanced gastric carcinoma when a high dose weekly 5-FU +leucovorin regimen was used. However, 50 per cent of patients entered into this study had failed previous chemotherapy. A clinical trial performed by the Southwest Oncology G r o u p which randomized patients between a short-term continuous infusion of 5-FU + leucovorin (200 mg/m2) versus bolus 5-FU leucovorin (200 mg/m2) showed response rates for both arms t o be equal at approximately 20 per cent. It is fair to say that a n optimal regimen of 5-FU leucovorin has not been defined for advanced gastric cancer but work certainly will continue to evaluate this combination in stomach cancer. Of considerable interest in the treatment of patients with stomach cancer has been the E A P regimen (Preusser rt nl., 1989; Wilke et ul., 1989; Lerner et nl., 1990). This regimen as noted in Table 2 has been reported to produce response rates in excess of SO per cent in patients with advanced stomach cancer. Another point of major interest with E A P is that the complete response rate is significant (as high as 20 per cent). The EAP regimen combines etoposide, adriamycin, and cisplatinum in a n 8-day schedulc (Preusser r t a/., 1989; Wilke ct ul., 1989). The E A P regimen. or the same drugs used in similar schedules, has significant toxicity with myelosuppression being dose-limiting. Although there has been great interest in the results reported from Germany (Preusser P t al.. 1989) and Brazil (Katz et al., 1989) recording response rates of greater than SO per cent. a recent publication from the D a n a Farber Cancer Center (Lcrner ct al., 1990) has reported a more modest response rate. I n the original abstract prepared for the 1990 American
+
+
+ + +
++
FAM (5-FU+ adriamycin+mitomycin C) FAMtx (5-FU + adriamycin+ methotrexate) FA Me (5-FU + adriamycin + methyl-CCNU) FAP (5-FU +adriamycin+ cis-platinum) 5-FU +mitomycin C +cytosine arabinosidc 5-FLJ + adriamy&+ BCNU FAm triazinate FAM BCNU FAM +methyl CCNU Mitomycin C + RCNU + cis-platinum + 5-FU Adriamycin + mitomycin C 5-FlJ Methyl CCNU 5-FU+ Mitomycin C 5-FU Adriamycin 5-FU BCNU Triazinate + mitomycin C EAP (etoposide + adriamycin + cis-platinum)
Drug combination
I
2 1 1 6 2 2 3 1 1 1
1
12 2 4 4 3 3 1
151/453 81/162 25/80 36/93 24/6 1 62/146 4/22 9/41 14/49 25/38 13/46 421224 23/96 4/30 2 1/so 8/28 43/67 18/25 12/28
No. No. responses/ series No. patients 33 50 31 39 39 42 18 22 29 66 29 19 24 13 26 29 64 (21% CR) 72 (12%CR) 43 (1 1% CR)
% Responses
6.5 7-5 7.0 8.0 3.2 7.5 NA 6.0 6.4 NA 3.5 5.5 5.0 6.5 5.5 5.5 9 6 6
Median duration of survival (months)
References Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Ahlgren ef al. ( I 984) De Lisi et al. (1986) Gohmann and Macdonald (1989) Kim and Kim (1986) Douglas ~t u1. (1984) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) Gohmann and Macdonald (1989) O’Connell Pt al. (1986) Preusser et al. (1 989) Wilkeetal. (1989) Lerner et al. (1990)
Table 2. Multiple drug combination chemotherapy in advanced gastric cancer
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Society of Clinical Oncology Meetings, the overall EAP response rate in patients with advanccd gastric cancer was 43 per cent. This included 1 1 per cent complete responses. However? at the time of presentation, this response rate had fallen below 30 percent. The Dana Farber investigators also found EAP to have significant toxicity. The median granulocyte nadir was 239/d1 and the median platelet nadir was 81 OOOjdl in the Dana Farber experience. In evaluating EAP-like regimens, it is important to realize that the appropriate role for these programmes has yet to be defined. There is now much interest in evaluating EAP as a neoadjuvant approach (Wilke et al., 1989). However, before new uses of EAP arc adopted, one needs to carefully evaluate the true response rate produced by EAP and also to explore ways to modify toxicity. In regard to toxicity, if EAP efficacy is convincingly confirmed, it would be very appropriate to evaluate granulocyte colony stimulating factor to modify myelosuppression of the regimen. The German group that described EAP has also reported upon interesting variant of 5-FU + leucovorin (Wilke ef al., 1990). This regimen is called E L F and combines 5-F‘U +leucovorin with etoposide in doses similar to that drug’s use in EAP. The German investigators use this in patients thought not to be appropriate medical candidates for EAP. The results of this regimen have been reported in sketchy fashion but show response rates greater than 50 per cent. Clearly, this approach needs t o be confirmed. Another European originated regimen which has stirred considerable interest is the FAMTX chemotherapy programme (Table 2). The FAMTX regimen was originally reported by Klein e t a / . ( 1986) and was shown to have a response rate in excess of SO per cent including substantial numbers o f complete responses. A more recent phase I1 study performed by the EORTC (Wils et a/.. 1986) showed a response rate of 44 per cent. Very recently (May 1990) a phase IIT clinical trial in which FAM was compared to FAMTX was reported by the EORTC (Wils et al.. 1990). In this study, 107 pacients were treated with FAMTX and 105 received FAM. The median survivals were 40 weeks for FAMTX and 29 weeks for FAM. Both the survival and response differences were highly statistically significant. The results of this phase I11 study are clearly of interest but the very low response rate for FAM, considering that the pooled results for FAM (Table 2) demonstrate a response rate in excess of 30 per cent, is surprising. Also, the abstract in which the phase 111 study was reported, noted that only 55 of 107 patients were evaluable at the time of abstract preparation for FAMTX and 47 of 105 patients were evaluable for FAM. Thus, the bulk of patients were not available for response. Before one draws firm conclusions from this study, it will be critically important to evaluate the data when all patients are evaluable. In summary, the chemotherapy of advanced gastric cancer continues to evolve. There are not clear and convincing data to nominate any one approach as ‘standard’ therapy. Regimens such as FAMTX, EAP. and E L F or newer approaches that may be built upon their regimen certainly bear watching over the next several years. I t is clear that the chemotherapy of gastric cancer will continue to be a fertile field of clinical rescarch for the foreseeable future. REFERENCES Ahlgren, J., Smith, F., Harvey, J. et ul. (1984). A phasc I1 study of FAM plus triazinate for advanced measurablc gastric carcinoma. Proc. Am. SOC. Clin.Oncol., 3, 145. Arbuck, S . G., Douglas, H. 0. Jr., Trave, F., e t a / . (1987).A phasc I1 study of 5-fluorouracil and high dose folinic acid in gastric carcinoma. J . Clin. Oncol., 5, 1 15 122. Beer, M., Cocconi, G., Ceci, G . ,et ul. (1983). A phase I1 study of Cisplatin in advanced gastric cancer. Eur. J. Crmcer Clin. Oncol., 19,7 17-720. krenherg, J. L., Goodman, P. J.. Oishi, N., et al. (1989).5-Fluorouraciland folinic acid: For the treatment of metastatic gastric cancer. Pror. ASCO, 87, 101. Bjerkeset, T., Fjosna. H. ( I 986). Comparison of oral ftorafur and intravenous 5-fluorouracil in patients with advanced cancer of thc stomach, colon or rectum. Oncologj,,43,212 215.
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Bruckner, H., Lokich, J., Stablein, D. (1982). Studies of Baker’s antifol, methotrexate and razoxane in advanced gastric cancer: A gastrointestinal tumor study group report. Cancer Treat. Rep., 66, 1713-1717. Cazap. E., Bruno, M., Levy, D., et a/. (1986). Phase I1 trial of 4-epidoxorubicin (4epi-dcx) in advanced gastriccancer. Proc. Am. Soc. Clin. Oncol., 5,91. Comis, R. (1974). Intcgration of chemotherapy into combined modality treatment of solid tumors. Cancer Treat. Rev., 1,221-233. De Lisi, V., Cocconi, G., Tonato, M. et a/. (1986). Randomized comparison of 5-FU alone or combined with carmustine, doxorubicin and mitomycin (BAFMi) in the treatmcnt of advanced gastric cancer. Cancer Treat. Rep., 70,481 4 8 5 . Douglass, H., Lavin, P., Goudsmit, A., et a/. (1984). An eastern cooperative oncology group evaluation of combinations of methyl-CCNU. mitomycin-C, adriamycin, and 5-fluorouracil in advanced measurable gastriccancer (Est 2277). J. Clin. Oncol.. 2, 1372-1381. Gohmann, J. J., Macdonald, J. S. (1989). Chemotherapy of gastric cancer. Cancer Invesfig.7(1), 39-52. Hurley, J., Ellison, E., Carey, L. (1961). Treatment of advanced cancer of the gastrointestinal tract with antitumor agents. Gastroenterology 41, 557-562. Katz, A,, Gansl, R., Simon, S., et nl. (1989). Phase I1 trial of VP16, adriamycin, and cisplatinum in patients with advanced gastric cancer. Proc. ASCO, 8,98. Kelson, D., Sternberg, C., Einzig, A,, et a/. (1984). Phase I1 study ofcarboplatin (CBDCDA) in advanced upper gastrointestinal tract malignancy. Proc. ASCO, 3, 141. Kim. R., Kim., C. (1 986). Chemotherapy of advanced gastriccancer with mitomycin-C BCNU, Cisplatin and 5-fluorouracil in combination. Proc. Am. Soc. Clin. Oncol., 5,78. Klein, H., Wickramanayake, P., Farrokh, G. (1986). 5-FU, adriamycin and methotrexate-a combination protocol (FAMTX) for treatment of metastasized stomach cancer. Proc. Am. Soc. Clin. Oncol., 5,84. Lacave, A., Izarzugaza, I., Aparicio, L., et al. (1983). Phase I1 clinical trial ofcisdichlorodiommineplatinumin gastric cancer. Am. J . Clin. Oncol., 6,35-38. Lerner, A., Steele, G . D., Mayer, R. J. (1990). Etoposide, doxorubicin, cisplatin (EAP) chcmotherapy for advanccd gastric adenocarcinoma: Results of a phase I1 trial. Proc. ASCO, 9, 103. Macdonald, J. S., Steele, G. J., Gunderson, L. L. (1989). Cancer of the stomach. In: DeVita, V. T., Hellman, S., Rosenberg, S. A., eds. Cancer Principles and Practice of Oncology. Philadelphia: Lippincott, 765-797. Machover, D., Goldschmidt. E., Chollet, P., et a1. (1986). Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high dose folinic acid. J . Clin. Oncol., 4,685496. Moore, G., Bross, I., Ausman, R., et al. (1968). Effects of chlorambucil (NSC-3088) in 374 patients with advanced cancer. Cancer Chemother. Rep., 52,661-666. O’Connell, M., Schutt, A., Moertel, C., et al. (1986). Phase 11 clinical trial of triazinate in combination with mitomycin C for patients with advanced gastric cancer. Proc. Am. Soc. Clin. Oncol., 5,82. Panettiere, F., Jones. S., Oishi, N., er nl. (1986). Bisantrcne hydrochloride in gastric adenocarcinoma: A Southwest Oncology Group study. Med. Pediatr. Oncwl., 14,78-80. Poon, M. A., O’Connell, M. J., Moertel, C. G., et a/. (1989). Biochemical modulation of fluorouracil. Evidencc of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J . Clin. Oncol., 7, 1407-1417. Preusser, P., Wilke, H., Achterrath, W., Fink, U., Lenaz, L., Heinicke, A., Meyer, J., Meyer, H . J., Buentc. H. (1 989). Phase I1 study with the combination ofetoposide, doxorubicin and cisplatin in advanced measurable gastric cancer. 1.Clin. Oncol., 7,1310-1317. Ravry, M.. Omura, G., Hill, G., et a/. (1986). Phase 11evaluation of mitoguazone in cancers of the esophagus, stomach, and pancreas: a Southeastern Cancer Study Group trial. Cancer Treat. Rep., 70,533-534. Schnitizler, G., Queisser, W., Heim, M., et nl. (1986). Phase I11 study of 5-FU and carmustine versus 5-FU, carmustine and doxorubicin in advanced gastric cancer. Cancer Treat. Rep., 70,477-479. The Southeastern Cancer Study Group (1981). m-AMSA treatment of advanced colorectal, pancreatic and gastric carcinoma. Proc. Am. Soc. Clin. Oncol., 22,454. Wilke, H., Preusser, P., Fink, U., Gunzer, U., Meyer, H. J., Meyer, J., Siewert, J. R., Achterrath, W., Lenaz, L., Knipp, H., Schmoll, H. J. (1989). Preoperative chemotherapy in locally advanced and non resectable gastric cancer: A phase I1 study with etoposide, doxorubicin and cisplatin. J. Clin. Oncol., 7, 1318 -1326. Wilke, H., Preusser, P., Fink, U., er al. (1990). Ncw developments in the treatment of gastric carcinoma. Sem. Oncol., 17(1), SUPPI.2,61-70. Wils, J., Bleiberg, H., Dalesio, O., et a/. (1986). An EORTC gastrointestinal group evaluation of the combination of sequential melhotrexate and 5-fluorouracil, combined with adriamycin in advanced measurable gastric cancer. J. Clin. Oncol., 4, 1799-1803.
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Wils, J . , Klein, H. O., Bleiberg, H., Buyse, M., Wagner, D. J . , Conroy, T., Diar-Rubio, E., Fickers. M . . Korsten, F., Leyvray, S., Reis, H., Duez, N. (1990). FAMTX (5-FU. adriamycin and methotrexate)- a step ahead in the treatment of advanced gastric cancer. Proc. ASCO, 9, 102.
