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A phase II study was conducted to assess the response rate and toxicity profile of the combination of irinotecan (CPT-11, Camptosar) and cisplatin (Platinol) administered weekly to patients with untreated advanced
ABSTRACT: A phase II study was conducted to assess the response rate andtoxicity profile of the combination of irinotecan (CPT-11, Camptosar) andcisplatin (Platinol) administered weekly to patients with untreated advancedadenocarcinoma of the stomach or gastroesophageal junction. Patients withhistologic proof of adenocarcinoma of the stomach or gastroesophageal junctionand with adequate liver, kidney, and bone marrow functions were included.Patients were treated with 65 mg/m2 of irinotecan plus 30 mg/m2 of cisplatin,both administered intravenously 1 day per week for 4 consecutive weeks, followedby a 2-week recovery period. Response rate, time to progression, survival, andtoxic effects were analyzed. Thirty-six (95%) of 38 registered patients wereassessable for toxicity and response. The median number of 6-week cycles perpatient was 2.5 (range: 1 to 7 cycles). Four patients (11%) achieved a completeresponse and 17 (47%) had a partial response for an overall response rate of58%. Median time to progression of carcinoma was 24 weeks, and median survivalwas 9 months (range: 1 to 23+ months). There was one treatment-related death.Major toxic effects included diarrhea, neutropenia, and fatigue. The combinationof irinotecan and cisplatin is active against gastric or gastroesophagealadenocarcinoma and should undergo further study. The addition of other activedrugs or radiation therapy to this regimen would be of interest. [ONCOLOGY15(Suppl 5): 52-54, 2001]
Gastric carcinoma continues to bea significant health problem despite its declining incidence. Gastric carcinoma is the leading cause ofcancer-related death in many countries. In 2001, it is estimated that there willbe 21,700 new cases of gastric carcinoma in the United States and 12,800 deathsare expected. Although advanced disease remains incurable, chemotherapy canbe palliative. Compared with the best supportive care alone, combinationchemotherapy improved quality of life and overall survival in four smallrandomized trials.[2-5] New classes of agents that have shown some degree ofactivity against gastric and esophageal adenocarcinomas include topoisomerase Iinhibitors and taxanes. Among the topoisomerase I inhibitors, irinotecan(CPT-11, Camptosar) is of particular interest due to its activity against thesetumors.[6,7]
We conducted a phase II study of the combination of irinotecanand cisplatin (Platinol) administered on a weekly schedule to patients withpreviously untreated advanced gastric carcinoma.
Patients and Methods
Patients with histologically proven advanced gastric orgastroesophageal adenocarcinoma were eligible for inclusion in the study.Patients needed to have measurable carcinoma. Normal bone marrow, liver, andrenal functions, life expectancy of more than 3 months, and a performance status(Zubrod scale) of 2 or less were also required. All patients provided a writteninformed consent. As part of the pretreatment evaluation, a complete blood cellcount, multichannel chemical survey, and electrolyte measurement were performed.All patients underwent computed tomography of the abdomen and pelvis (ifindicated), chest radiography, and other imaging studies if necessary. Acomplete history was obtained and a physical examination was performed prior tostudy entry.
Chemotherapy was administered in the outpatient setting. Allpatients received hydration before and after receiving cisplatin. Premedicationconsisted of intravenous (IV) dexamethasone, lorazepam, and ondansetron (Zofran)to prevent emesis. Patients received extensive verbal and written instructionsregarding early institution of therapy for diarrhea. Patients also received oralmedications to reduce the severity of delayed nausea and vomiting, andloperamide to reduce the severity of diarrhea.
Chemotherapy consisted of 65 mg/m2 of irinotecan IV given over90 minutes followed by 30 mg/m2 of cisplatin IV over 60 minutes. Both drugs wereadministered 1 day per week for 4 consecutive weeks, followed by a 2-weekrecovery period. Thus, one cycle was 6 weeks in duration (4 weeks of treatmentand 2 weeks of recovery).
Response was evaluated after the first, second, and fourthcycles, and every two cycles thereafter. Patients continued therapy until therewas evidence of progressive disease or unacceptable toxicity.
Standard toxicity and response assessment criteria were used. Itwas believed that a response rate of at least 30% would justify continuing andexpanding the trial in the future. An optimal two-stage Simon design was usedto determine the exact number of patients to be accrued. The hypotheses werethat H0: P ≤ P0 (0.10) vs H1:P ³ P1 (0.30) with a = 0.05 and b = 0.10 (90% power). Thus, a total of 35evaluable patients were to be accrued in the study.
A total of 38 patients were entered in the study. The median agewas 58.5 years (range: 20 to 75 years). Twenty-nine (76%) of 38 patients hadpoorly differentiated carcinoma and most patients (76%) had a primary carcinomalocated in the proximal portion of the stomach.
Thirty-six of 38 patients (95%) were assessable for response andtoxicity. A total of 98 treatment cycles were administered; the median number of6-week cycles per patient was 2.5 (range: 1 to 7 cycles). A total of 353 (93%)of the planned 380 weekly doses were administered. Twenty-five patients requiredgranulocyte colony-stimulating factor support after the first chemotherapycycle. Twenty-seven (7%) of 380 planned weekly doses were canceled because oftoxicity, and 52 (15%) of 353 weekly doses were delayed for the same reason.Fifty-three (66%) of the 79 delayed or canceled weekly doses occurred at thetime of the third or fourth week of treatment.
Among 36 evaluable patients, the overall response rate was 58%:4 (11%) patients had a complete response and 17 (47%) had a partial response(see Table 1). Five patients (14%) had a minor response, 8 (22%) had progressivedisease during therapy, and 2 (6%) had stable disease. Median time to diseaseprogression was 24 weeks(95% confidence interval [CI]: 16 to32 weeks), and median survival of all 36 patients was 9 months (95% CI:7.5 to 10.5 months; range: 1 to 23+ months).
There was one treatment-related death: an elderly woman died ofneutropenic sepsis associated with multiple organ failure. The major toxiceffects were diarrhea, neutropenia, and fatigue. It is interesting to note thatpatients or caretakers reported higher grades of diarrhea in the first or secondtreatment cycle than in later courses. A possible explanation is that patientsmay not have followed instructions for this toxic effect until they hadexperienced severe diarrhea. Severe diarrhea was less common in the subsequentcycle.
Results of this study demonstrate that irinotecan in combinationwith cisplatin is active in previously untreated patients with advanced gastriccarcinoma. Irinotecan has been shown to have single-agent activity againstgastric carcinoma. For example, data from Japan showed that single-agentirinotecan was active in patients with treated and untreated gastriccarcinoma. Results of a recent European study showed that 17% of 34previously untreated patients with gastric carcinoma responded to single-agentirinotecan.
Irinotecan in combination with cisplatin has also been studiedin Japan, with demonstrated response rates greater than 40%.[9,10] In both ofthese Japanese phase II studies, cisplatinwas administered every 4 weeks and irinotecan every 2 weeks. Shirao et alreported a 42% response rate among 24 previously untreated patients withadvanced gastric carcinoma who received irinotecan plus cisplatin. The majortoxic effect was neutropenia. In the study by Boku et al, a 59% responserate was observed among 29 previously untreated patients who received irinotecanplus cisplatin. The majortoxic effects were neutropenia and diarrhea.
In the study reported herein, which included the largest groupof untreated patients studied thus far, we used a different treatment schedulefrom that developed by the Japanese investigators. Both drugs were administered1 day per week for 4 consecutive weeks followed by a 2-week recovery period.This schedule was based on results described by Saltz et al, which showedthat the schedule was well tolerated by patients with advanced gastrointestinalcarcinoma. The combination of irinotecan plus cisplatin administered accordingto this schedule resulted in a response rate of 52% in 23 untreated patientswith adenocarcinoma of the esophagus.
We observed that 66% of all delays or cancellations of weeklydoses occurred at the time of the third or fourth weekly dose. The delays orcancellations were predominantly caused by unresolved diarrhea, fatigue, orneutropenia, which increased the hardship on the patients and/or increased thecost of care. Therefore, we are conducting a study in which both agents areadministered 1 day per week for 2 weeks, followed by 1 week of recovery. Thus,patients still receive four doses in a 6-week cycle; however, the 2-weekrecovery period has been divided. It is our hypothesis that cisplatin maycontribute to excessive fatigue; thus, either the cisplatin dose may be reducedor cisplatin may be replaced by other agents. Further investigations would be ofinterest.
In conclusion, the combination of irinotecan and cisplatin isactive in advanced gastric or gastroesophageal junction carcinoma. Furtherdevelopments in Japan and Europe will help to define the role of this agent inthe overall treatment approach to this disease. Additional investigations ofirinotecan combined with other active agents and with radiotherapy arewarranted.
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