Irinotecan (CPT-11) in Patients with Advanced Colon Carcinoma Relapsing after 5-Fluorouracil-Leucovorin Combination

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1 Clinical Report Chemotherapy 2002;48:94 99 Irinotecan (CPT-11) in Patients with Advanced Colon Carcinoma Relapsing after 5-Fluorouracil-Leucovorin Combination N.B. Tsavaris a A. Polyzos b K. Gennatas c Ch. Kosmas a M. Vadiaka a A. Dimitrakopoulos a A. Macheras d G. Papastratis e H. Tsipras e H. Margaris e E. Papalambros f A. Giannopoulos f Ch. Koufos a a Department of Pathophysiology, Oncology Unit, and b First Department of Internal Medicine Propedeutic, Oncology Unit, Laikon General Hospital, University of Athens, School of Medicine; c Oncology Unit of Areteion Hospital, and d Third Surgical Department, Sotiria Hospital, University of Athens, School of Medicine; e Third Surgical Department, Genimatas General Hospital; f First Surgical Department, Laikon General Hospital, University of Athens, School of Medicine, Athens, Greece Key Words CPT-11 W Advanced colon carcinoma W Performance status W 5-Fluorouracil W Leucovorin Abstract The purpose of the present study was to investigate the association between performance status (PS) and mean dose of irinotecan (CPT-11) in patients with recurrent advanced colorectal cancer relapsing after 5-fluorouracil and leucovorin chemotherapy. Patients who had completed their last chemotherapy course with 5-fluorouracil and leucovorin for at least 6 weeks and progressed were included. Based on PS, we administered a starting dose of 250 mg/m 2 in patients with a PS (group A), and 350 mg/m 2 for those with a PS 1 80 (group B). Of a total of 90 treated patients, all were evaluable, 18 had a partial response (PR) (20%), 39 stable disease (43%), and 15 progressed (37%). No significant difference was noticed between patients with PS 6 90 or ^ 80 (p = 0.925), or between those who received a mean dose of CPT or ^300 (p = 0.602), for response, survival and time to progression. Toxicity was increased in group B as expected, with significant differences for acute cholinergic syndrome (p = 0.02), diarrhea after the first 24 h (p = 0.03) and severe diarrhea (p = 0.03). According to these results, we conclude that response to CPT-11 is independent of its dose, and that a dose of 250 mg/m 2 every 3 weeks might be a cost-effective and less toxic alternative in this setting. However, further adequately powered phase II or III randomized studies might be required in order to confirm this observation. Introduction Copyright 2002 S. Karger AG, Basel Irinotecan, CPT-11, is a novel topoisomerase I inhibitor, originally developed in Japan. Preclinical data had suggested that colon tumors might be sensitive to inhibition of topoisomerase I [1]. In phase II studies, response rates of 15 25% have been observed in 5-fluorouracilrefractory patients [2 6]. Toxicities of irinotecan are primarily neutropenia and diarrhea, the severity of which may be related to the extent of glucuronidation of the drug and its primary metabolite, SN-38 [7]. The purpose of the present study was to evaluate the new cytotoxic agent CPT-11, which is ABC Fax karger@karger.ch S. Karger AG, Basel /02/ $18.50/0 Accessible online at: Nicolas B. Tsavaris, MD Medical Oncology Unit, Department of Pathophysiology Athens University School of Medicine, Laikon General Hospital GR Athens (Greece) Tel./Fax , tsavari1@otenet.gr

2 used as second-line treatment in patients with advanced colon carcinoma failing or relapsing after 5-fluorouracil and leucovorin standard chemotherapy. The aim of this study was to explore the association between the Karnofsky performance status (PS) and the mean dose of CPT-11 treatment administered to patients with advanced colorectal cancer failing or relapsing after 5-fluorouracil and leucovorin chemotherapy. Patients and Methods Patients Ninety patients with a histologic diagnosis of adenocarcinoma of the colon or rectum, PS 6 70 and a life expectancy 12 months, were included in the present study; a summary of baseline patient characteristics is listed in table 1. Eligibility Criteria All patients had a histologic diagnosis of adenocarcinoma of the colon or rectum. Patients should have measurable disease, PS 6 70, a life expectancy 12 months, absence of brain metastases or active ischemic cardiac disease and normal hematological, renal or hepatic function tests, unless the abnormalities were the result of direct tumor invasion. All had previously received 5-fluorouracil and leucovorin and relapsed during or after this treatment, which ended at least 6 weeks prior to study entry. All patients presented with clinical and laboratory signs of progressive disease. Informed consent was obtained from all patients according to institutional policies. PS and Dose of CPT-11 Based on the evaluation of baseline PS and after a careful interview and clinical examination, the patients received CPT-11 according to the PS, i.e., a starting dose of 250 mg/m 2 (PS 70 80) or 350 mg/m 2 (PS ). Patients with a PS (6 patients) started therapy with 350 mg/m 2 and were evaluated as patients with PS 90. We administered a lower dose of CPT-11 in patients with low PS, in order to avoid the possible side effects of CPT-11 and consequent PS worsening. Treatment Protocol Treatment was carried out in the Day Clinic. In 44 patients with a PS 1 80, CPT-11 was administered intravenously at a dose of 350 mg/m 2 and in 46 patients with a PS at a dose of 250 mg/m 2. CPT-11 was administered in 90-min intravenous infusions and repeated every 21 days in both groups. The treatment was continued until tumor progression or unacceptable toxicity. In the event of grade 1 II myelosuppression, 1II diarrhea and 1 II mucositis (WHO classification), treatment was delayed until recovery. Dose Modifications The dose of 350 mg/m 2 was kept stable if no toxicity was encountered. The dose of 250 mg/m 2 was increased by 10% in the next administration if no toxicity was encountered. For each grade of toxicity regarding myelosuppression, diarrhea, acute cholinergic syndrome and mucositis, the dose of CPT-11 was decreased by 10% (I: 10%, II: 20%, III: 30%). Patients with cholinergic toxicity grade 1 III continued the therapy with 250 mg/m 2 if they had started as group A. Table 1. Patients clinical characteristics Patient characteristics Number Number 90 Sex men women Median age 66 (42 70) Performance status (Karnofsky) Involved metastatic sites liver lymph nodes pulmonary other local recurrence In the case of severe toxicity, the treatment was discontinued. Selected patients who were in remission (complete response, CR, or partial response, PR) after completion of chemotherapy with a single metastasis, especially in the pelvis, received consolidation radiotherapy at that site. Before each treatment cycle, every patient had a complete blood count, SMA-12, ECG, chest roentgenography and abdominal CT scan. Between the treatment cycles, complete blood counts were performed weekly. Patients were evaluated for response between the treatment cycles during the 2-week rest period. A CR was defined as complete disappearance of all clinically evident disease. PR was defined as a decrease of more than 50% in the sum of the products of the largest perpendicular diameters of the measurable lesions. A 25 50% decrease which does not meet the criteria of a PR was defined as stable disease. Progressive disease was an increase of the above measurements or the appearance of a new lesion. Toxicity was estimated according to WHO criteria. Acute cholinergic syndrome was evaluated as severe (grade III), moderate (grade II), mild (grade I) and absent (grade 0); severe was defined as intensive symptoms controlled with therapy, moderate as symptoms controlled with therapy, and mild when therapy was not always necessary. Statistical Analysis The aim of the following analysis was to explore the association between the PS and the mean dose of the treatment administered to patients with advanced colorectal cancer failing or relapsing after 5- fluorouracil and leucovorin chemotherapy. The data analysis had the following specific goals: (a) To explore whether there are statistically significant differences in the response to the treatment between the two groups of patients according to the PS and the mean dose of CPT-11 administered. (b) To indicate whether there are statistically significant differences in the survival time for patients with different PS or for patients receiving a different dose of CPT-11. CPT-11 in Advanced Colon Carcinoma Relapsing after 5-FU-Leucovorin Chemotherapy 2002;48:

3 Table 2. Response to treatment according to the PS and mean dose of CPT-11 (Pearson s 2 test, Fisher s exact algorithm) a Total response Response n % CR 0 0 PR SD PD b Response according to PS PS 690 PS ^80 p value PR 8 (17.8) 10 (22.2) SD 20 (44.4) 19 (42.2) PD 17 (37.8) 16 (35.6) Total 45 (100) 45 (100) PR/SD 28 (62.2) 29 (64.4) PD 17 (37.8) 16 (35.6) Total 45 (100) 45 (100) c Response according to mean dose Mean dose ^300 Mean dose 1300 p value PR 10 (20.4) 8 (19.5) SD 19 (38.8) 20 (48.8) PD 20 (40.8) 13 (31.7) Total 49 (100) 41 (100) PR/SD 29 (59.2) 28 (68.3) PD 20 (40.8) 13 (31.7) Total 49 (100) 41 (100) SD = Stable disease; PD = progressive disease. Percentages are shown in parentheses. (c) To indicate whether there are statistically significant differences in the time to progression for patients with different PS or for patients receiving a different dose of CPT-11. The statistical tests employed to explore the association between the response to the treatment (measured in an ordinal scale), the PS and the mean dose of CPT-11 were Pearson s 2 test (exact algorithm) [8, 9]. In order to compute the survival time between the groups, the Kaplan-Meier method was employed; the statistical test used to explore the differences in the survival functions was the logrank test (or Mantel-Cox) [8, 9]. The statistical test used to explore the differences in the time to progression according to the PS or to the mean dose was the Mann-Whitney test because the assumptions required for parametric methods were not satisfied [8, 9]. Results Patients Ninety patients with a histologic diagnosis of adenocarcinoma of the colon or rectum, a PS 6 70 and a life expectancy of 12 months were included in the present study; all were evaluable for response and toxicity (table 1). Data Description Based on PS, two groups of patients were established: one group with patients with PS 6 90 and another with patients with PS ^ 80. Based on the mean dose of the treatment, another two groups of patients were established: one group with patients who received a mean dose ^300 (49 patients) and another with patients who received a mean dose 1300 (41 patients). All patients who were evaluable for response, time to progression and survival were considered. Response No patient experienced a CR, 18 (20%; 95% confidence interval, CI: %) had a PR, 39 (43%; 95% CI: %) had stable disease, while 33 (37%; 95% CI: 27 47%) progressed (table 2). The median duration of response was 3.3 months (range ) (table 2), median time to progression 3.2 months (range 2 7.4) and median overall survival 6.6 months (range 6 9). Response to Treatment according to PS Prior to Treatment Table 2 shows the distribution of response for patients with PS 6 90 and for those with PS ^ 80 prior to treatment. The null hypothesis tested that response to treatment is independent of the PS. No difference in the response to treatment was found for the two groups of PS. No significant difference was noticed between the examined groups (p = 0.925, p = 1.00). Response to Treatment according to the Mean Dose of CPT-11 Administered Table 2 shows the distribution of response for patients receiving a mean dose of CPT-11 ^300 and for those receiving a mean dose The null hypothesis tested that the response to treatment is independent of the mean dose of CPT-11 administered. No difference in the response to treatment was found for the different doses of CPT-11. No significant difference was noticed between the examined groups (p = 0.602, p = 0.390). 96 Chemotherapy 2002;48:94 99 Tsavaris et al.

4 Fig. 1. Survival time for patients with different mean doses of CPT-11. Fig. 2. Survival time for patients with different PS. Table 3. Mean and median survival time for each PS group (PS 690 or PS ^80) and mean dose group (6300 mg/m 2 or ^300 mg/m 2 ) Survival time, months mean 95% CI median 95% CI PS ^ Mean dose ^ Survival Time for Patients with Different PS The survival time was recorded for all 90 patients whose condition was monitored for the incidence of remission and relapse (table 3, fig. 1, 2). None of the patients were alive at the time of completion of the study. There were no patients lost to follow-up and there was no case of a patient who died from a cause other than the disease. Table 3 provides the mean and median survival times for the patients in each PS group, as calculated with the Kaplan-Meier method. Figure 1 shows the estimated survival functions for each treatment group as estimated with the Kaplan-Meier method. The log-rank test, which was computed to test the differences in survival distributions of each group, was not found to be significant at the level of 0.05 (logrank test value = 3.65 with 1 d.f.). Survival Time for Patients Receiving Different Mean Doses of CPT-11 Mean and median survival times according to mean dose of CPT-11 (1 or ^300 mg/m 2 ) are shown in table 3. Figure 2 shows the estimated survival functions for each treatment group, as estimated with the Kaplan-Meier method. The log-rank test was not found to be significant at the 0.05 level (log-rank test value = 1.61 with 1 d.f.). Time to Progression according to PS Prior to Treatment Table 4 shows the mean time to progression for patients with PS 6 90 and for those with PS ^ 80 prior to treatment. The null hypothesis tested that time to progression was independent of the PS. No statistically significant difference in time to progression was found for the two PS groups (p = 0.325). CPT-11 in Advanced Colon Carcinoma Relapsing after 5-FU-Leucovorin Chemotherapy 2002;48:

5 Table 4. Time to progression for each PS group (PS 690 or PS ^80) and mean dose group (6300 mg/m 2 or ^300 mg/m 2 (Mann-Whitney test, Fisher s exact algorithm) Table 5. Toxicity expressed in number of cycles and percentages Parameters Dose ^300 Dose 6300 n % n % p PS ^ p value Mean dose ^ p value Mean time to progression Number of patients Number of cycles Acute cholinergic syndrome Diarrhea (the first 24 h) Diarrhea (after the first 24 h) Diarrhea (severe) Neutropenia (grade III), requiring G-CSF Anemia (14 grade/dl drop in Hb) Thrombocytopenia (grade III) Nausea-vomiting (grades 1II) Alopecia (grades III IV) Hospitalization Loperamide tablets 3,760 5, Time to Progression according to the Mean Administered Dose Table 4 shows the mean time to progression for patients who received a mean dose of CPT-11 ^300 and for those who received a mean dose The null hypothesis tested that the time to progression is independent of the mean dose of CPT-11 administered to the patients. No statistically significant difference in the time to progression was found for the different doses of CPT-11 (p = 0.965). Toxicity Toxicity was found to have increased in patients receiving CPT mg/m 2 in comparison to those receiving CPT-11 ^300 mg/m 2 as expected (table 5). Significant differences in toxicity were noticed for acute cholinergic syndrome (p = 0.025), diarrhea after the first 24 h (p = 0.04) and severe diarrhea (p = 0.03). Despite the increased dose of CPT-11 in patients receiving CPT mg/m 2 in comparison to those receiving CPT-11 ^300 mg/m 2, no statistically significant difference was noted in the number of loperamide tablets used for diarrhea (p = 0.06). Other parameters of toxicity did not present any significant difference between the examined groups. Three patients receiving CPT-11 ^300 mg/m 2 with stable disease, and 2 who had progressed stopped therapy because of severe toxicity (acute cholinergic syndrome: 2; severe diarrhea: 3). Ten patients receiving CPT mg/m 2 needed hospitalization because of severe diarrhea and dehydration, but they continued the therapy. Discussion Two large randomized clinical studies have established CPT-11 as the standard second-line treatment against either 5-fluorouracil/leucovorin and continuous 5-fluorouracil regimens or best supportive care alone, respectively [10, 11], in patients with advanced colorectal cancer failing prior 5-fluorouracil and leucovorin regimens. In both studies, the benefit was independently correlated with PS by Cox s proportional hazards model. In the study of Cunningham et al. [10], where more patients with PS = 2 were included (almost 15%), the benefit of secondline CPT-11 over best supportive care was less apparent in those with PS 2. In our study, no significant differences were found in response rate, survival and time to progression between the different group of patients according to the PS and the dose of CPT-11. The analysis of the present study permitted us to conclude that PS and the dose of CPT-11 are independent of response and survival. Therefore, our results point further to the notion that all patients, independently of PS, should have a trial of second-line CPT-11 chemotherapy after failing or progressing on 5-fluorouracil and leucovorin regimens administered for the treatment of advanced colorectal cancer. A significant percentage of patients responded (20%). On the other hand, 43% of the patients demonstrated stable disease. These are fairly satisfactory results for second-line chemotherapy in advanced colorectal cancer. However, given the very optimistic response rate in the 98 Chemotherapy 2002;48:94 99 Tsavaris et al.

6 present study, further investigations are required to confirm these findings. According to the results so far, we conclude that response to CPT-11 is independent of its dose, and that a dose of 250 mg/m 2 every 3 weeks might be a cost-effective and less toxic alternative in this setting. However, further adequately powered phase II or III randomized studies might be required in order to confirm this observation. References 1 Giovanella BC, Stehlin JS, Wall ME, et al: DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science 1989;246: Bognel C, Rekacewicz C, Mankarios H, et al: Prognostic value of neural invasion in rectal carcinoma: A multivariate analysis on 339 patients with curative resection. Eur J Cancer 1995;31A: Rothenberg ML, Burris HA 3rd: Irinotecan as second line therapy for patients with 5-FU refractory colorectal cancer. Proc Am Soc Clin Oncol 1994;13: Conti JA, Saltz LB et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 1994;13: Pitot HC, O Connell MJ: A phase II trial of CPT-11 in patients with metastatic colorectal carcinoma: A North Central Cancer Treatment Group Study. Proc Am Soc Clin Oncol 1994; 13: Gupta EL, Mick R: Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhea. Cancer Res 1994;54: Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of treatment. Cancer 1981; 47: Kaplan EL, Meier P: Non parametric estimation for incomplete observations. J Am Stat Assoc 1958;53: Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50: Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352: Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998;352: CPT-11 in Advanced Colon Carcinoma Relapsing after 5-FU-Leucovorin Chemotherapy 2002;48: