Abstract
Background: We conducted a phase II study of topotecan (Tp) with cisplatin (CDDP) in previously untreated Japanese patients with extensive-disease small cell lung cancer (ED-SCLC). Patients and Methods: In stage 1, a total of 30 patients were allocated to Tp 0.65 mg/m2 with CDDP 60 mg/m2 day 1 or Tp 1.00 mg/m2 with CDDP day 5 following prophylactic granulocyte colony stimulating factor (G-CSF) from day 6. In stage 2, the selective combination in 29 patients was evaluated for response rate, toxicity and overall survival. Results: In stage 1, Tp 1.00 mg/m2 with CDDP day 5 was selected this schedule had a better hematological profile. In stage 2, the response rate was 83%, and grade 3/4 adverse events were hematological-toxicities. The median survival time was 17.5 months and the 1 year survival rate was 79%. Conclusion: Combination of Tp and CDDP on day 5 with G-CSF support is safe and effective for previously untreated ED-SCLC Japanese patients.
Most patients with previously untreated small cell lung cancer (SCLC) are highly sensitive to chemotherapy and radiation therapy. As cisplatin (CDDP) is the most important drug for SCLC chemotherapy, the standard chemotherapy regimen for treatment of extensive-disease (ED)-SCLC has been the combination of CDDP plus etoposide (PE regimen). Although this combination has produced objective response rates as high as 80%, median survival times range from 9 to 11 months, with a 2-year survival rate of less than 10% (1-3). Several novel strategies failed to improve patient survival time. Therefore, investigation of therapy resulting in improvement of survival is still ongoing.
Inhibitors of topoisomerase I (Topo I, an enzyme necessary for DNA replication) are active against SCLC. A randomized study of the Topo I inhibitor, irinotecan, plus CDDP versus PE in previously untreated Japanese patients with ED-SCLC indicated survival benefit of Topo I inhibitor (4). Topotecan (Tp), a cytotoxic water-soluble semisymthetic camptothecin analogue, acts as an inhibitor of Topo I. Tp demonstrated anti tumor activity towards human cancer cell lines and animal tumor models, then a combination of Tp and CDDP had synergistic effect in vitro studies (5, 6). The combination effect of Tp and CDDP is not influenced by the order of administrating the two drugs. On the contrary, adverse effects are influenced (7). Therefore Tp has been evaluated as useful for ovarian and uterine cervical carcinoma, besides second-line therapy in SCLC (8-10). The combination regimen of Tp with CDDP has been documented in use for previously untreated ED-SCLC patients (11, 12). In addition, no difference in efficacy and tolerability was recorded in Tp and CDDP combination regimen compared with standard regimen in a phase III study for the first-line therapy of previously untreated ED-SCLC patients (13, 14).
Although the standard regimen for ED-SCLC in North America and Europe is a combination of CDDP plus etoposide (3), the combination of irinotecan plus CDDP is the standard regimen in Japan due to the significant prolongation of survival obtained from the interim analysis of a phase III clinical study by the Japan Clinical Oncology Group (JCOG) (4), with similar results to the phase II clinical trial (15) on this regimen.
Since there are different antitumor efficacies of Topo I inhibitor between Japanese patients and North American and European populations, the present phase II clinical trial was planned to investigate antitumor effects of Tp plus CDDP in Japanese patients with ED-SCLC, for whom irinotecan plus CDDP is the standard regimen.
The recommended schedule was evaluated at stage 1 due to the need for estimation of different schedule dependency on efficacy and safety for Japanese patients. Based on findings from two clinical studies on irinotecan plus CDDP (phase II and phase III), the clinical efficacy of the combination of CDDP plus Tp, which has the same Topo I inhibitory activity with irinotecan, is evaluated in this phase II clinical trial to investigate whether the efficacy of irinotecan plus CDDP is based on the mode of action of Topo I inhibitor plus CDDP in Japanese patients.
In a completed phase I study, we determined the recommended dose of Tp 0.65 mg/m2 and 1.00 mg/m2 as in combination with CDDP day 1 and day 5 schedules, respectively, with fixed dose of CDDP at 60 mg/m2 (16). We found novel potential of the Tp combination regimen with CDDP against previously untreated Japanese patients with ED-SCLC in a phase II study. In present study, the dose of CDDP at 60 mg/m2 was fixed. A prophylactic G-CSF concomitant treatment was employed from consideration of dose limiting factors of this combination. In addition to efficacy and safety evaluation of Tp plus CDDP combination, the treatment effect of the combination regimen of Topo I inhibitor with CDDP in Japanese patients was also evaluated.
Patients and Methods
Study design. A two-stage study was designed (Figure 1). At stage 1, two arms (arm A and arm B) were compared evaluating tumor response and toxicity to select the superior arm. In stage 2, 15 cases were added to the selected arm. The cases in stage 1 and stage 2 of the selected arm were combined for evaluation of efficacy and safety of this combination.
Eligibility. Japanese patients with histological and/or cytological documented SCLC were eligible for this study. Each patient was required to meet the following criteria: ED-SCLC, previously untreated, having measurable lesion; performance status (Eastern Cooperative Oncology Group: ECOG PS) of 0-1; age 20 to 74 years; adequate organ function (hemoglobin level >9.5 g/dl, leukocyte count 4,000 to 12,000/mm2, neutrophill cell count >2,000/mm2, platelet count >100,000/mm2, aspartate aminotransferase (AST) level <2.5 times of the normal upper limit, total bilirubin value <1.5 mg/dl, serum creatinine below the normal upper limit, resting partial pressure oxygen >60 torr; a life expectancy of at least 3 months; hospitalized; and written informed consent obtained. The protocol and informed consent procedures were reviewed and approved by the Institutional Review Board of each participating institute. This study was subjected to Good Clinical Practice (GCP) and Declaration of Helsinki.
Treatment schedule. Tp of 0.65 mg/m2 for CDDP day 1 schedule (arm A) or 1.00 mg/m2 (or 1.2 mg/m2, if the nadir of the first cycle for leucocytes of >2,000/mm2 and platelet of >50,000/mm2, the dose from next cycle could be increased) for CDDP day 5 schedule (arm B) were intravenously administered at over 30 min by drop infusion for the first 5 consequent days within one cycle of 21 days. Tp was provided by Nippon Kayaku Co., Ltd. as 1.1 mg/vial formulation to be dissolved in 500 to 1,000ml of saline. CDDP was also intravenously administered at over 2 h by drop infusion at day 1 (arm A) or day 5 (arm B). Prophylactic G-CSF was administered from day 6 (day after final Tp administration) until recovery from nadir for leucocytes of >10,000/mm2 or neutrocytes of >5,000 mm2. For each patient, 4 cycles were planned.
Dose modification. When grade 4 neutropenia, more than grade 3 febrile neutropenia with over 38.5°C or thrombocytopenia (<25,000/mm2) occurred, the Tp dose was reduced from 0.65 to 0.5 mg/m2 for arm A or 1.0 to 0.8 mg/m2 for CDDP day 5 schedule (or 1.2 to 1.0 mg/m2 if applicable), respectively. When the leukocyte count >4,000/mm2, neutrocyte count >2,000/mm2, platelet count >100,000/mm2 and hemoglobin value >8,0g/dl or recovery tendency was observed, the treatment was able to proceed to the next cycle. Treatment could be delayed for up to 30 days from day 1 of the current cycle to allow a patient sufficient time to recover from study drug-related toxicity.
Evaluation. All patients underwent weekly evaluations that included assessment of symptoms (subjective and objective findings), a physical examination, a complete blood cell count, blood chemistry (including measurement of AST, alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (Al-P), total bilirubin, total protein, serum creatinine, blood urea nitrogen (BUN), serum electrolytes) and urinalysis. Toxicity was evaluated according to NCI CTCAE version 3 criteria (17). Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) (18), assessed by computed tomographic (CT) scanning, as with staging at enrollment. All the observed responses were reviewed by an extramural panel.
Statistical analysis. This study was made up of two different stages, one for the CDDP schedule selection (stage 1) and the other for the evaluation of the selected schedule (stage 2). The primary aim of this study was to assess the anti-tumor effect of the combination. Thus, involvement of 15 cases for the two CDDP administration schedules (on day 1 and day 5) were adequate based on the following premises: 8 cases of rejection region, 70% expected efficacy rate, 35% threshold response rate, one-sided significance level α=0.042 and power 1-β=0.869.
The anti-tumor activity was estimated by response rate and 95% confidence intervals. Toxicity was estimated by subjective and objective findings and incidence by, in comparison between CDDP day 1 and day 5 schedules. Since the stage 1 study was not statistically powered, the two arms were analyzed separately.
At stage 2, clinically useful threshold and expected efficacy rate were set as 60% and 85% respectively. On this basis, 26 cases were required based on α=0.05 (bilaterally) and β=0.2 (one-sided), thus the target number of cases use 30. In addition to stage 1, 15 cases were planned to be enrolled for the selected superior arm. The primary endpoint of stage 2 was to assess the anti tumor efficacy of Tp in combination with CDDP, taking the toxicity profile into account. The secondary endpoint was overall survival, and the several survival curves were estimated by means of the Kaplan and Meier method.
Results
From August 2005 through July 2008, a total of 44 chemotherapy-naive Japanese ED -SCLC patients were enrolled into this study from 16 institutions. All 44 cases were eligible. In stage 1, 30 patients were randomly assigned to the arms of CDDP day 1 and day 5 schedules. In stage 2, 14 patients were enrolled for arm B, in addition to stage 1 (total 29 cases for this schedule). All enrolled patients were included in analyses of tumor response and toxicity. Survival times of 29 patients for CDDP day 5 schedule were evaluated. Patients' characteristics are listed in Table I. For arm B, 6 female patients were enrolled in stage 1. Median ages for patients in arms A and B in stage 1 were 62 (55 to 74) and 66 (56 to 74) years, respectively. There were no enrolment criteria or protocol violations. Total cycles for each stage are listed in Table II. Median treatment of cycles was 4 in both stage 1 and stage 2.
Response. Clinical response for stage 1 is listed in Table II. Arm A resulted in 12 partial responses (PRs), 1 case of stable disease (SD) and 1 case not evaluated (NE). The response rate was 80% (95% CI of 51.9 to 95.7%). Arm B had 12 PRs, 2 case of SD and 1 case of progressive disease (PD). The response rate of arm B was 80% (95% CI of 51.9 to 95.7%). In stage 1, there was no difference in the response rate between arm A and arm B. It is notable that 1 complete response (CR) was observed in stage 2. Total response for CDDP day 5 schedule (29 cases in stage 1 and 2) was 1 CR, 23 PRs, 3 SDs, and 2 NEs with median response rate of 83% (95% CI of 64.2 to 94.2%). As of November 2009, when the final analysis was conducted, the median overall survival was 17.5 months (95% CI of 14.8 to 20.8 months) for CDDP day 5 schedule. A Kaplan-Meier curve for survival of patients in arm B is indicated in Figure 2. Overall survival rate for this group was 79% (95% CI of 64.6 to 94.1%) at 1 year.
Toxicity. The toxicity profile in stage 1 is listed in Table III. No death or febrile neutropenia was observed for any of the 30 patients in stage 1. The main grade 3/4 adverse events in stage 1 were hematological toxicities: leukopenia, neutropenia, thrombocytopenia and anemia; were observed as 40%, 67%, 67% and 60% for arm A and 7%, 40%, 60% and 47% for arm B, respectively. Arm A had a tendency for higher incidence of adverse events than arm B. Non-hematological events (subjective and objective findings) in stage 1 were nausea, anorexia, constipation, vomiting, fatigue and alopecia, with a range of 53% to 93%. As Grade 3 events, anorexia, fatigue and body weight loss were observed each for 1 patient. There was no difference in non-hematological toxicity profile between the two CDDP schedules. Over 50% of patients in stage 1 experienced increased AST and/or ALT, with 2 cases of grade 3 AST increase. Because no difference in the efficacy between the two arms was observed, the CDDP day 5 schedule was employed for stage 2, taking the hematological toxicity profile into account with lower incidence of grade 3 events in arm B compared with arm A in stage 1. The toxicity profile of stage 2 is listed in Table III. No death or febrile neutropenia was observed in this group. The main adverse events in stage 2 were similar to those of arm B in stage 1, both in nature and grade.
Discussion
In this study, Tp at 0.65 mg/m2 and 1.00 mg/m2 were employed for CDDP day 1 and day 5 schedules, respectively, based on the results of a previous phase I study. In stage 1, CDDP schedules of day 1 and day 5 administration were evaluated to select optimum combination with Tp, taking response and toxic profile into account. In stage 2, additional patients were enrolled onto the superior regimen to evaluate response rate as primary endpoint and overall survival (time and 1-year rate) as secondary endpoints. In stage 1, both arms had similar responses, with different hematological toxicity profiles. In arm A, the incidence of grade 3/4 hematological events were slightly higher than those in arm B. From the safety point of view, the CDDP day 5 schedule was employed for further study.
Although the primary endpoint of stage 1 was the response rate of this combination by schedule, there were no substantial difference between the two schedules, hence the toxicity profile was taken into account for the selection of the superior arm.
In a previous report from North America/Europe, death from sepsis with the CDDP day 1 regimen was shown, indicating the possibility of severe hematological toxicity (19), and then the validity of CDDP day 5 schedule was suggested (7, 12, 19). Although the administration timing of CDDP in the combination is the same for Japanese patients, in arm A in this study, no death or febrile neutropenia was observed, likely due to the contribution of G-CSF from day 6. The response rate for the 29 cases of CDDP day 5 schedule group was 83%, including 1 CR. The median survival time was 17.5 months and the 1-year survival rate was 79%. Among observed adverse events, grade 3/4 events were hematological. Major non-hematological adverse events were digestive organ toxicity, (anorexia, nausea, vomiting and constipation), and alopecia, with grade 1/2. These events were also observed in Tp mono therapy (20), thus no CDDP contribution of to stimulation of toxicity was considered. However, AST/ALT increases did occur, in 50% of CDDP day 5 schedule cases. These hepatic events were transient and did not influence on study continuation. Similar incidence of such as increase was reported for irinotecan (4). Since the total treatment of completed cycles for both stages 1 and 2 was expected to be 4, high tolerability was estimated. The response rate to Tp combination with CDDP in this study was very much improved compared with the 39% response to Tp mono therapy (21). On the other hand, no difference in the toxic profile was observed, suggesting that the contribution of CDDP was solely for efficacy. The toxicity difference between two schedules is considered as the influence on renal function disorder caused by CDDP as observed in the regimen of CDDP day 1 schedule (7).
The response rate of this combination was equally matched to that of irinotecan in combination with CDDP, but superior in median survival time and 1-year survival rate. Furthermore, this regimen had a better profile for incidence and grade of diarrhea than that of irinotecan.
The median survival times and 1-year survival rate in this study were similar to those obtained in Japanese patients with irinotecan regimen. Noda et al. showed survival benefit for CDDP plus irinotecan in comparison with PE (4). However, two similar trials (22, 23) did not show any benefit of irinotecan in combination with CDDP over PE. The sample size or ethnic effect has been considered as the reason for this difference (22). Taking these studies together, irinotecan is an active drug for SCLC in some populations and settings. Superior results of Topo I inhibitor and CDDP regimens in Asian individual, Japanese, and Korean, have been reported (24-26).
The clinical efficacy of Topo I inhibitor plus CDDP is summarized in Table V. The response rates, median survival times and survival rates of patients treated with Tp plus CDDP and irinotecan plus CDDP regimens are better than the combination of etoposide plus CDDP. Since it is known that the efficacies of etoposide and CDDP combination in Japan and North America/Europe are similar, there may be difference in response to the CDDP combination with Topo I inhibitor or with Topo II inhibitor in Japanese patients. Recently, an ethnic effect for response to chemotherapy, such as the gefitinib study, has been revealed (27). These results suggest the possibility of an ethnic effect in non-small cell lung cancer therapy, and study of such as effect may lead to a novel therapy against ED-SCLC. Tp, when compared with irinotecan, has a lower rate of associated diarrhea. Therefore, Tp combined with CDDP therapy resulted in a higher response rate and survival time from this study. It is possible that this combination therapy regimen of Tp for previously untreated ED-SCLC patients may be as useful as irinotecan combination with CDDP therapy.
Conclusion
The combination of Topo I inhibitor, Tp on 5 consecutive days and CDDP on day 5 with G-CSF support is a safe and active regimen for therapy-naive Japanese patients with ED-SCLC. This regimen appeared to be well-tolerated in this patient population. Future clinical trials should elucidate the role of Tp in first-line treatment of ED-SCLC.
Acknowledgements
This study was supported by an unrestricted grant from Nippon Kayaku Co., Ltd., Tokyo, Japan.
- Received July 13, 2011.
- Revision received August 18, 2011.
- Accepted August 19, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved