ABSTRACT: Chemotherapy for advanced gastric and gastroesophageal junction carcinomas remains suboptimal. Both irinotecan (Camptosar) and cisplatin (Platinol) are active against this group of malignancies. This article focuses on the results of an ongoing phase II trial with this combination in patients with advanced gastric or gastroesophageal junction carcinoma. Data from this trial suggest that the combination of irinotecan and cisplatin is active in untreated as well as previously treated patients with gastric or gastroesophageal junction carcinoma. [ONCOLOGY 14(Suppl 14):19-21, 2000]
Gastric carcinoma is a significant health problem around the world. In a number of countries, it represents the number 1 cause of cancer death. It is the second most common malignant disorder in the world, accounting for more than 750,000 new cases and for more than 500,000 deaths each year. Its incidence, however, has been declining globally since World War II. Although the incidence of gastric carcinoma is one of the lowest in North America, it is the tenth leading cause of cancer death in both men and women in the United States. In 2000, there will be more than 21,500 new cases of gastric cancer in the United States and 13,000 deaths from the disease. Countries with an extremely high incidence of gastric carcinoma include Japan, Costa Rica, Peru, Brazil, China, Korea, Chile, Taiwan, and the countries of the former Soviet Union.
Early detection of gastric carcinoma is performed only in Japan, and solely on a limited basis; therefore, it is commonly diagnosed in advanced stages. Thus, in approximately 50% of patients with newly diagnosed gastric carcinoma, the disease has already spread beyond locoregional confines. In the West, the most frequent site of gastric carcinoma is the proximal half of the stomach; the reason(s) for this remain elusive and may be multifactorial.
Although advanced disease is incurable, chemotherapy can palliate symptoms. Combination chemotherapy, when compared with best supportive care in patients with advanced gastric carcinoma, has resulted in improvements in the quality of life and increased duration and rates of overall survival.[4-6] Several older active drugs have produced these results: fluorouracil (5-FU), mitomycin (Mutamycin), etoposide, and cisplatin (Platinol).
In a pivotal study by the North Central Cancer Therapy Group (NCCTG), treatment with FAM (5-FU/doxorubicin [Adriamycin]/mitomycin) was compared with 5-FU alone and 5-FU plus doxorubicin. No significant difference in survival was detected among patients treated with these three regimens. However, the response rates were higher with combination chemotherapy than with 5-FU alone.
Despite a number of randomized studies comparing FAM with FAMTX (5-FU/doxorubicin/methotrexate), FAMTX with ECF (epirubicin [Ellence]/cisplatin/5-FU), and FAMTX vs ELF (etoposide/leucovorin/5-FU) vs 5-FU plus cisplatin that have been reported in the past several years for the treatment of advanced gastric carcinoma, no standard therapy has emerged. Outside clinical trials, the recommended chemotherapy is either a cisplatin-based or a 5-FU-based combination.
A number of new drugs have shown activity against gastric carcinoma: the taxanes,[14-19] irinotecan (Camptosar),  UFT (a combination of uracil and tegafur), and S-1.[22,23] In addition, a few newer combinations have been investigated.[24-26] Several new oral agents, such as S-1, also hold promise in the treatment of gastric carcinoma.[27,28]
The preliminary results of our study of the combination of irinotecan and cisplatin in patients with advanced gastric or gastroesophageal junction carcinoma are reported here. Irinotecan, a topoisomerase I inhibitor, is an active agent against gastric carcinoma as well as other tumor types. In patients with gastric carcinoma, early data suggest that irinotecan has a single-agent activity of 20% in the untreated setting and nearly 15% in the treated setting.
Irinotecan has been combined with cisplatin to assess the activity of the combination. In the Japanese studies of this combinaton,[26,29] irinotecan was given every 2 weeks and cisplatin was given once in every 4-week cycle. Our study utilized a weekly schedule in which both agents were given 1 day per week for a total of 4 weeks, followed by a 2-week break.
The protocol was approved by the investigational review board of The University of Texas M. D. Anderson Cancer Center. All patients provided written informed consent prior to registration. Patients with histologic proof of advanced gastric or gastroesophageal junction carcinoma were enrolled, and all patients were required to have measurable carcinoma. Patients who had previously received one regimen of chemotherapy or immunotherapy were eligible. A life expectancy of at least 12 weeks and a performance status of up to 2 (Zubrod scale) were needed. In addition, patients were required to have a normal total bilirubin, serum creatinine, absolute granulocyte count, and platelet count.
Thus far, 45 patients (39 men and 6 women) have been entered in our study (30 untreated). The median age of the patient population is 53 years (range: 20 to 75 years). The median number of cycles is 2.5 (range: 1 to 7; total: 119 cycles). A total of 35 patients had proximal primary tumors and 10 had distal primary tumors.
Chemotherapy was administered in an outpatient setting. All patients received hydration prior to and after receiving cisplatin. Patients were premedicated for the prevention of emesis and received extensive instructions regarding prevention of diarrhea. The following drug dose and schedule was used: irinotecan at 65 mg/m2 (50 mg/m2 for the treated group); cisplatin at 30 mg/m2. Both drugs were given weekly on the same day for 4 weeks, followed by a 2-week break. Treatment was continued until progression of cancer or intolerance of therapy. Response to therapy was evaluated after each 6-week cycle.
The observed responses to combination chemotherapy with irinotecan and cisplatin for advanced gastric or gastroesophageal junction carcinoma are shown in Table 1. There was one treatment-related death (an elderly patient who died of neutropenic sepsis and multisystem organ failure). The toxic effects predominantly included neutropenia and diarrhea. Table 2 lists the toxic effects seen in untreated patients.
The combination of irinotecan and cisplatin has been investigated in two separate studies in Japan.[26,29] The response rate observed for chemotherapy-naive patients is approximately 50%. This combination is also active in patients who have had prior chemotherapy. Our preliminary data suggest that the combination of irinotecan and cisplatin is active in the treatment of advanced gastric carcinoma. This combination resulted in responses in treated as well as untreated patients.
Because of the delays in treatment and cancellations of doses we have experienced in our study, we believe modification of the cisplatin dose may be warranted. In addition, modification of the schedule may be necessary, so patients receive therapy for 2 weeks and rest for 1 week (with the duration of a single cycle still equaling 6 weeks). Despite these recommendations for change, we believe that the combination of irinotecan and cisplatin is worthy of future investigation in patients with upper gastrointestinal carcinoma.
1. Parkin DM, Pisani P, Ferlay J: Global cancer statistics. CA Cancer J Clin 49:3-64, 1999.
2. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. CA Cancer J Clin 50:7-33, 2000.
3. Blot WJ, Devesa SS, Kneller RW, et al: Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265:1287-1289, 1991.
4. Murad AM, Santiago FF, Petroianu A, et al: Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72:37-41, 1993.
5. Pyrhönen S, Kuitunen T, Kouri M: A randomized, phase III trial comparing fluorouracil, epidoxorubicin and methotrexate (FEMTX) with best supportive care in nonresectable gastric cancer. Ann Oncol 3(suppl 5):12, 1992.
6. Glimelius B, Hoffmann K, Haglund U, et al: Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol 5:189-190, 1994.
7. Comis R, Carter SK: Integration of chemotherapy into combined modality treatment of solid tumors. Cancer Treat Rev 1:221-238, 1974.
8. Kelsen DP, Magill G, Cheng E, et al: Phase II trial of etoposide (VP-16) in the treatment of upper gastrointestinal malignancies (abstract). Proc Am Soc Clin Oncol 1:96, 1982.
9. Lacave A, Izarzugaza I, Aparicio L, et al: Phase II clinical trial of cis-dichlorodiammineplatinum in gastric cancer. Am J Clin Oncol 6:35-38, 1983.
10. Cullinan SA, Moertel CG, Fleming TR, et al: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma: Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 253:2061-2067, 1985.
11. Wils JA, Klein HO, Wagener DJ, et al: Sequential high-dose methotrexate and fluorouracil combined with doxorubicin—a step ahead in the treatment of advanced gastric cancer: A trial of the Gastrointestinal Tract Cooperative Group. J Clin Oncol 9:827-831, 1991.
12. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261-267, 1997.
13. Wilke H, Wils J, Rougier P, et al: Preliminary analysis of a randomized phase III trial of FAMTX versus ELF versus cisplatin/FU in advanced gastric cancer (GC) (abstract). Proc Am Soc Clin Oncol 14:206, 1995.
14. Ajani JA, Fairweather J, Dumas P, et al: A phase II study of Taxol in patients with advanced untreated gastric carcinoma (abstract). Proc Am Soc Clin Oncol 16:263, 1997.
15. Einzig AI, Lipsitz S, Wiernik PH, et al: Phase II trial of Taxol in patients with adenocarcinoma of the upper gastrointestinal tract: The Eastern Cooperative Oncology Group (ECOG) results. Invest New Drugs 13:223-227, 1995.
16. Tamura F, Ohtsu A, Boku N, et al: Three-hour infusion of paclitaxel for advanced gastric cancer (abstract). Proc Am Soc Clin Oncol 16:307, 1997.
17. Taguchi T: A late phase II study of docetaxel in patients with gastric cancer (abstract). Proc Am Soc Clin Oncol 16:263, 1997.
18. Sulkes A, Smyth J, Sessa C, et al: Docetaxel in advanced gastric cancer: Results of a phase II clinical trial: EORTC Early Clinical Trials Group. Br J Cancer 70:380-383, 1994.
19. Einzig AI, Neuberg D, Remick SC, et al: Phase II trial of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy: The Eastern Cooperative Oncology Group (ECOG) results of protocol E1293. Med Oncol 13:87-93, 1996.
20. Kambe M, Wakui A, Nakao I, et al: A late phase II study of irinotecan (CPT-11) in patients with advanced gastric cancers (abstract). Proc Am Soc Clin Oncol 12:198, 1996.
21. Takiuchi T, Ajani JA: Uracil-tegafur in gastric cancer: A comprehensive review. J Clin Oncol 16:2877-2885, 1998.
22. Ohtsu A, Sakata M, Horikoshi N, et al: A phase II study of S-1 in patients with advanced gastric cancer (abstract). Proc Am Soc Clin Oncol 17:262, 1998.
23. Kurihara M, Koizumi W, Hasegawa K, et al: Late phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with advanced gastric cancer (abstract). Proc Am Soc Clin Oncol 17:262, 1998.
24. Kim YH, Shin SW, Kim JH, et al: Paclitaxel, 5-fluorouracil, and cisplatin combination chemotherapy for the treatment of advanced gastric carcinoma. Cancer 85:295-301, 1999.
25. Roth AD, Maibach R, Martinelli G, et al: Taxotere-cisplatin (TC) in advanced gastric carcinoma (AGC): An active drug combination (abstract). Proc Am Soc Clin Oncol 17:283, 1998.
26. Shirao K, Shimada Y, Kondo H, et al: Phase I-II study of irinotecan hydrochloride combined with cisplatin in patients with advanced gastric cancer. J Clin Oncol 15:921-927, 1997.
27. Humerickhouse RA, Schilsky RL: Thymidylate synthase inhibitors in clinical development. Cancer Therapeutics 1:100-113, 1998.
28. DeMario MD, Ratain MJ: Oral chemotherapy: Rationale and future directions. J Clin Oncol 16:2557-2567, 1998.
29. Boku N, Ohtsu A, Shimada Y, et al: Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer. J Clin Oncol 17:319-323, 1999.