Japanese Journal of Clinical Oncology 34:8-13 (2004)
© 2004 Foundation for Promotion of Cancer Research
Weekly Irinotecan in Patients with Metastatic Gastric Cancer Failing Cisplatin-based Chemotherapy
Gastric Cancer Branch, Research Institute and Hospital, National Cancer Center, Korea
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: The goal of this study is to determine the efficacy and toxicity of weekly irinotecan as second-line chemotherapy in advanced gastric cancer after failure of cisplatin-based regimen.
Methods: Gastric cancer patients failing cisplatin-based chemotherapy received 125 mg/m2 of irinotecan weekly for 4 weeks followed by 2-week rest, until disease progression.
Results: Thirty-seven patients were enrolled into this study. The objective response was documented in seven of 35 patients with measurable lesion (response rate 20%, 95% CI: 6.1–33.9). Eight patients (22.9%) had stable disease and overall tumor control rate was 42.9%. The disease remained stable in both of two patients without measurable disease. At a median follow-up duration of 15.8 months, median time to progression and overall survival were 2.6 months (95% CI: 2.4–2.8) and 5.2 months (95% CI: 3.6–6.7), respectively. Neutropenia and diarrhea were the main toxicities. Among 37 patients treated, grade 3/4 (G3/4) neutropenia occurred in 43.2/24.3% of patients, respectively, and was accompanied with fever in three patients. Non-hematologic toxicities consisted mainly of delayed diarrhea (G3/4, 18.9/0%) and nausea/vomiting (G3/4, 18.9/0%). These toxicities were manageable and there was no treatment-related death.
Conclusions: This weekly schedule of irinotecan was modestly active against cisplatin-refractory gastric cancer and relatively well-tolerated with appropriate dose modification.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Gastric cancer is the most common cancer in Korea (1), and the second most common cause of cancer death in the world (2–4). 5-FU/cisplatin is one of the most widely accepted chemotherapy regimens with a response rate of 20–51% in published literature (5–7). Published phase III trials suggested that 5-FU/cisplatin showed longer time to progression than other chemotherapy regimens, although superiority in overall survival was not demonstrated (6,7). Recently, Ajani et al. reported that docetaxel in combination with 5-FU/cisplatin showed prolonged overall survival compared with 5-FU/cisplatin alone (8). Thus, cisplatin-based chemotherapy is currently the mainstay of gastric cancer chemotherapy. While overall prognosis of the patients failing cisplatin-based chemotherapy is relatively poor (6,7), many of these patients still have good performance status at the time of cisplatin-failure and are candidates for second-line chemotherapy. Yet, there is no established second-line chemotherapy for gastric cancer. Clinical reports of second-line chemotherapy in gastric cancer patients demonstrate divergent results, partly due to the variability in the responsiveness to first-line chemotherapy and the nature of prior chemotherapy (cisplatin-based or not).
Irinotecan, a DNA topoisomerase I inhibitor, has shown promising activity in a number of gastrointestinal cancers and proven antitumor activity as a single agent or combined with other agents (9–12). Futatsuki et al. (9) reported that irinotecan monotherapy, at a dose of 100 mg/m2 every week or 150 mg/m2 every 2 weeks, yielded the response rate of 20% in pretreated gastric cancer patients, 69% of whom were previously treated with cisplatin. In this trial, weekly treatment with 100 mg/m2 of irinotecan achieved a slightly higher response rate than the treatment with 150 mg/m2 of irinotecan every 2 weeks (9). The reported response rate of irinotecan monotherapy in the second-line setting was encouraging, although time-related parameters (i.e. time to progression and overall survival) did not appear in this paper. Weekly administration of 125 mg/m2 of irinotecan for four consecutive weeks followed by a 2-week rest, showed significant activity against colorectal cancer as a second-line chemotherapy (13,14). According to a phase II trial in colorectal cancer patients, weekly irinotecan at a dose of 125 mg/m2 appears to have superior efficacy and comparable toxicity compared with weekly irinotecan at a dose of 100 mg/m2 (15). Based on this background, we conducted a phase II trial addressing the efficacy and toxicity of weekly administration of 125 mg/m2 of irinotecan for four consecutive weeks followed by a 2-week rest, in gastric cancer patients failing cisplatin-based chemotherapy during the treatment. Time to progression and survival, as well as response rate and toxic effects, were analyzed.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility
To be eligible for this study, patients were required to have: histologically-confirmed gastric cancer that progressed while receiving, or within 6 months after, the discontinuation of prior cisplatin-based chemotherapy; Eastern Cooperative Oncology Group performance status (ECOG PS)
1; adequate major organ functions [absolute neutrophil count (ANC) 
1500/mm3, platelet count 100 000/mm3, bilirubin upper normal limit (UNL), AST/ALT 2.5x UNL, creatinine UNL]; and to have signed informed consents. Patients with bidimensionally measurable lesion (at least 1 cm in diameter by spiral CT) were preferred, but measurable lesion was not prerequisite for the enrolment. Exclusion criteria were: inadequate cardiovascular function (New York Heart Association class III or IV heart disease, active angina or myocardial infarction within the past 6 months, history of significant ventricular arrhythmia requiring medication with antiarrhythmics or significant conduction system abnormality); other malignancy within the past 3 years except non-melanomatous skin cancer or carcinoma in situ of the cervix; pregnant or nursing women; serious concurrent infection or non-malignant illness that is uncontrolled or whose control may be jeopardized by complications of study therapy; and psychiatric disorder that would preclude compliance. Male and female patients with reproductive potential must use an approved contraceptive method if appropriate (e.g. intrauterine device, birth control pills or barrier device) during, and for 3 months after, the study.
Treatment Protocol and Dose Modifications
Irinotecan (Campto®, Aventis Pharmaceuticals, Bridgewater, NJ) was administered at 125 mg/m2 for 90 min in an outpatient setting weekly for 4 weeks followed by a 2-week break. Each cycle consisted of 6 weeks. If treatment was withheld on week 4, the next course of therapy could begin 1 week earlier (i.e. on day 36) if all toxicities were of grade 0 or 1 by that time (15). Treatment was continued until tumor progression or occurrence of unacceptable toxicity. To reduce the diarrhea, we routinely premedicated patients with ursodeoxycholic acid (200 mg p.o. bid for 3 days), magnesium oxide (1 g p.o. tid for 4 days), and sodium bicarbonate (1 g p.o. bid for 4 days) (16,17). Diarrhea was treated with loperamide and octreotide. Atropine 0.25–0.5 mg was given for cholinergic symptoms or for diarrhea that occurred during or shortly after treatment administration. Prophylactic granulocyte colony stimulating factor (G-CSF) was not allowed.
Toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) prior to the commencement of each irinotecan administration. Complete blood count and blood chemistry (alkaline phosphatase, AST, ALT, total bilirubin, BUN, creatinine) were performed each day of planned irinotecan infusion and at the starting day of each cycle, respectively. If grade 2 leukopenia (WBC, 2000–3000/mm3) occurred on the day of planned irinotecan administration, irinotecan dose was reduced by 20%. If grade 3 or higher leukopenia developed, irinotecan was skipped. Irinotecan was skipped in cases of grade 2 or higher non-hematologic toxicity and was not resumed until the adverse effect resolved or improved to grade 1 or 0. Subsequent irinotecan dose was reduced by 20% for grade 2 diarrhea or abdominal cramping, and by 40% for grade 3 diarrhea or abdominal cramping. Irinotecan dose was reduced by 20% for the other grade 3 or higher non-hematologic toxicities. In cases of dose reduction due to non-hematologic toxicities, dose escalation to the previous level was not permitted.
Patient Evaluation
History and physical examination were performed before treatment and at each day of planned irinotecan administration. Abdominal CT was performed before treatment (no earlier than 4 weeks before treatment) and every two cycles thereafter unless clinically indicated. Response was assessed using WHO criteria (18). A complete response (CR) was defined as the disappearance of all clinical and normalization of tumor markers for a period of at least 4 weeks. A partial response (PR) was defined as 50% decrease in the bidimensional tumor measurements, without the appearance of any new lesions or progression of any existing lesions. Progressive disease (PD) was defined as any of the following: (i) a 25% increase in the sum of the products of all measurable lesions, (ii) appearance of any new lesion or (iii) reappearance of any lesion that had disappeared. Stable disease was defined as tumor response that did not meet the criteria for CR, PR or PD. The duration of response was defined as interval from the day of first response to the day of disease progression. Confirmation CT was not routinely performed 4 weeks after PR documentation, unless symptoms or signs suggested disease progression. The time periods to disease progression and survival were dated from the time of enrolment in the study. This trial was designed to detect a response rate of 25% as compared to a minimal, clinically meaningful response rate of 5%. A two-stage optimal design proposed by Simon was used for this trial (19), with a 90% power to accept the hypothesis and 5% significance to reject the hypothesis. Allowing for a follow-up loss rate of up to 15%, the total sample size was to be 35 patients with measurable disease. The analyses of survival and time to progression were estimated by the Kaplan–Meier method.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Baseline Patient Characteristics
From September 2001 to September 2003, 37 metastatic gastric cancer patients who failed cisplatin-based chemotherapy were entered into this study (Table 1). Thirty-five patients progressed during prior cisplatin-based first-line chemotherapy for metastatic disease, and two patients had recurrent disease within 6 months of the discontinuation of cisplatin-based adjuvant chemotherapy. Median age was 58 years (range: 22–69). They were 30 male (81%) and seven female (19%) patients with ECOG PS 0 or 1 (8.2/91.8%). Prior chemotherapy included 5-FU/cisplatin (81.1%), capecitabine/cisplatin (13.5%), and docetaxel/5-FU/cisplatin (5.4%) (Table 1). Two patients also received adjuvant 5-FU/mitomycin C prior to 5-FU/cisplatin. Median interval between the last dose of cisplatin and the irinotecan treatment was 4 weeks (95% CI: 3.5–4.2). Nineteen patients (51.3%) received third-line chemotherapy after irinotecan discontinuation. Most (84.2%) of these third-line chemotherapy regimens were docetaxel-containing.
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Drug Delivery
Thirty-seven patients received 94 cycles of irinotecan (total 286 doses). The median number of chemotherapy cycles received was two (range: 1–8) per patient and median duration of treatment was 2.5 months (range: 0.5–10.9). Dose reduction was required in 119 of 286 doses (41.6%) and 49 of 94 cycles (52.1%), with 41 of 286 doses (14.3%) skipped. The reasons for dose reduction/omission included delayed diarrhea (34.9%), neutropenia (25.6%), nausea/vomiting (9.3%), anorexia (9.3%), stomatitis (4.7%), abdominal pain (4.7%), infection (4.7%) and others (7%). Median relative dose-intensity (DI) was 70% (planned DI, 83.3 mg/m2/week; actual DI, 58.3 mg/m2/week).
Efficacy
Seven among 35 patients with measurable lesion showed partial response as the best response [response rate, 20% (95% CI: 6.1–33.9)]. Median duration of response was 3.0 months (95% CI: 1.6–4.4). Another eight patients (22.8%) had stable disease and overall tumor control rate was 42.8% (Table 2). Two patients without measurable disease showed stable disease at the initial assessment, with time to progression being 3.6 and 9.9+ months, respectively. At a median follow-up duration of 15.8 months (range: 2.0–25.8) for 37 patients, median time to progression (TTP) was 2.6 months (95% CI: 2.4–2.8) and median overall survival (OS) was 5.2 months (95% CI: 3.6–6.7). One-year survival rate was estimated to be 21.9% (95% CI: 5.7–38.1). Among 12 patients with prior response to cisplatin-based first-line chemotherapy for metastatic disease, two patients (16.7%) responded to irinotecan. Among 21 patients who had SD or PD as the best overall response to the first-line chemotherapy for metastatic disease, three patients (14.3%) responded to irinotecan.
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Toxicity
The most common hematologic toxicity was grade 3/4 neutropenia that occurred in 25 of 37 patients (67.6%) and 28 of 94 cycles (31.1%) (Table 3). Febrile neutropenia was observed in three patients (8.1%), but treated successfully with antibiotics and G-CSF. Non-hematologic toxicities consisted mainly of delayed diarrhea. Grade 2/3 delayed diarrhea occurred in 16.2/18.9% of patients. Delayed diarrhea was reversible in all patients after treatment with loperamide and octreotide. Acute cholinergic-like syndrome developed in 11 patients (29.7%) during infusion of irinotecan. Grade 2/3 nausea and vomiting occurred in 32.4/18.9% of patients. There were no grade 4 non-hematologic toxicities. Sixteen episodes of hospitalization occurred due to treatment: diarrhea (n = 9), febrile neutropenia (n = 3), infection (n = 2) and nausea/vomiting (n = 2) in 15 patients. Three patients withdrew consent after the episodes of diarrhea/abdominal cramping (two patients) and febrile neutropenia (one patient). Two patients died within 30 days of the last dose of irinotecan: one (M/61) died of progression of disease, the other (M/67) died of intracerebral hemorrhage of unidentified cause, 5 weeks after initial documentation of PR (the best overall response of this patient was determined as SD). The death of the latter patient was considered unlikely to be treatment-related, because of the lack of predisposing factors to bleeding (such as thrombocytopenia).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Currently, there is no established second-line chemotherapy against cisplatin-refractory metastatic gastric cancer, prognosis of which is generally poor. This phase II trial demonstrates that weekly irinotecan at a dose of 125 mg/m2 is feasible with modest activity against cisplatin-refractory gastric cancer. Patients with both measurable and non-measurable disease were entered into this study. The reasons for this were: (i) to allow accrual of more patients for better evaluation of safety profile of 125 mg/m2 of weekly irinotecan and (ii) to study a population more accurately reflecting the composition of patients treated in clinical practice. Our data suggesting a response rate of 20% in this group of patients, are largely consistent with previous data reported by Futatsuki et al. (9). They reported that irinotecan monotherapy, at a dose of 100 mg/m2 every week or 150 mg/m2 every 2 weeks, showed a response rate of 20% in pretreated gastric cancer patients, 69% of whom received prior cisplatin. Response was documented in 19.4% of cisplatin-pretreated patients in the aforementioned study (9). Our study confirms that various schedules of intermittent irinotecan administration yield reproducible and comparable response rates in this patient group.
Irinotecan, as a single agent, is known to be active against chemo-naive gastric cancer (20,21) and pretreated colorectal cancer (22,23). According to papers published by Cunningham et al. (22) and Rougier et al. (23), irinotecan treatment at a dose of 300–350 mg/m2 every 3 weeks achieved a better survival rate than continuous infusion of 5-FU and best supportive care in colorectal cancer patients failing 5-FU-based chemotherapy. Weekly administration of 125 mg/m2 of irinotecan for four consecutive weeks followed by a 2-week rest, a dose schedule used in the current study, also showed significant activity against colorectal cancer as a second-line chemotherapy (14,24). The current trial showed that second-line chemotherapy with 125 mg/m2 of irinotecan weekly is feasible with manageable toxicities in gastric cancer patients, as previously shown in the colorectal patients (14,24).
There have been no randomized trials that compare the efficacy and tolerability of the 125 and 100 mg/m2 starting dose levels of irinotecan, the latter of which was used in the study reported by Futatsuki et al. (9). A phase II trial suggested that 125 mg/m2 appeared to be the preferred starting dose for weekly irinotecan administration for colorectal cancer, based on the ability to adjust drug dose on a weekly basis based on patient tolerance, the superior efficacy, and generally comparable toxicities compared with 100 mg/m2 weekly (15). Actual median DI for these two dose levels (125 and 100 mg/m2) were reported as 73% and 81%, respectively, in the aforementioned study (15). The toxicity profile appears to be similar between the current study (125 mg/m2 weekly) and the study reported by Futatsuki et al (100 mg/m2 weekly or 150 mg/m2 biweekly) (9). Incidences of grade 3–4 neutropenia (45.9%) and delayed diarrhea (18.9%) in the current study were similar to those shown in the study reported by Futatsuki et al. (42.1% and 22.4%, respectively). Collectively, the current study did not demonstrate striking differences in either toxicity or activity (response rate of 20%) from the study reported by Futatsuki et al. (response rate of 19.4% in cisplatin-pretreated patients), presumably due to, at least in part, frequent dose reduction (41% of doses: median DI of 70%) required for the current dose schedule.
The response rate of irinotecan in the current study, 20%, is slightly lower than rates reported in combination chemotherapy trials (12,25). Ajani et al. reported nine partial responses (response rate, 31%) among 29 previously treated patients with advanced adenocarcinoma of the stomach or gastroesophageal junction (12). Forty-seven percent of the study patients received platinum-based first-line chemotherapy in this trial (12). Kim et al. reported six partial responses (response rate, 26%) among 23 patients with advanced gastric cancer, whose disease progressed while receiving, or after discontinuing platinum-based chemotherapy (25). According to a report by Cascinu et al., paclitaxel as a single agent achieved a response rate of 22.2% among 36 patients with advanced gastric cancer unresponsive or progressing after PELF chemotherapy (5-FU, leucovorin, cisplatin and epidoxorubicin) (26). Taken together with the reported lack of efficacy of some other second-line chemotherapy regimens (27,28), irinotecan could be considered as one of the most promising agents against cisplatin-refractory gastric cancer, given the reproducible activity as a single agent in the second-line setting, as indicated by the current study. Overall survival (median 5.2 months) of the current study was comparable to the published data from most second-line chemotherapy trials where cisplatin-refractory gastric cancer patients were included as study subjects (12,25–28). On the other hand, it should also be noted that all of our patients had good initial ECOG PS (0 or 1) and many (51.3%) of them received third-line chemotherapy.
In conclusion, weekly irinotecan at this dose schedule is modestly active against cisplatin-refractory gastric cancer and relatively well-tolerated with the dose-modification scheme used in the present trial. Further efforts are needed to develop irinotecan-based combination chemotherapy regimens with enhanced efficacy as a second-line therapy.
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FOOTNOTES |
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+ For reprints and all correspondence: Hark Kyun Kim, Gastric Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, 411-769, Korea. E-mail: hkim{at}ncc.re.kr
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Received November 11, 2003; accepted December 8, 2003
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