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
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
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
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
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
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
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 doxorubicina 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
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,
16. Tamura F, Ohtsu A, Boku N, et al: Three-hour infusion of
paclitaxel for advanced gastric cancer (abstract). Proc Am Soc Clin Oncol
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
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
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.