Irinotecan and Cisplatin in Advanced Gastric or Gastroesophageal Junction Carcinoma

Introduction

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.[1] 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.[2] 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.[2] 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.[1] In the West, the most frequent site of gastric carcinoma is the proximal half of the stomach[3]; the reason(s) for this remain elusive and may be multifactorial.

Chemotherapeutic Options

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(Drug information on fluorouracil) (5-FU), mitomycin(Drug information on mitomycin) (Mutamycin),[7] etoposide(Drug information on etoposide),[8] and cisplatin(Drug information on cisplatin) (Platinol).[9]

In a pivotal study by the North Central Cancer Therapy Group (NCCTG),[10] treatment with FAM (5-FU/doxorubicin [Adriamycin]/mitomycin) was compared with 5-FU alone and 5-FU plus doxorubicin(Drug information on 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),[11] FAMTX with ECF (epirubicin [Ellence]/cisplatin/5-FU),[12] and FAMTX vs ELF (etoposide/leucovorin/5-FU) vs 5-FU plus cisplatin that have been reported in the past several years[13] 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(Drug information on irinotecan) (Camptosar), [20] UFT (a combination of uracil and tegafur(Drug information on tegafur)),[21] 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]

Irinotecan/Cisplatin Combination: Early Findings

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.[20]

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.

Patient Characteristics

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.

Methods of Treatment

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.

Results

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.

Conclusions

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.