Dr. Alan Sandler’s sweeping review of the role of irinotecan (CPT-11, Camptosar) in the treatment of small-cell lung cancer (SCLC) leaves few stones unturned. Some perspective, however, is necessary. To date, with the exception of the Japan Clinical Oncology Group trial, which demonstrated the superiority of irinotecan in combination with cisplatin compared to standard therapy with etoposide and cisplatin, no other new platinum agent combination has proven superior to standard therapy in the treatment of extensive SCLC. The Noda study, published recently in the New England Journal of Medicine, has sparked considerable interest and anticipation in the medical oncology community.
Dr. Alan Sandler’s sweeping review of the role ofirinotecan (CPT-11, Camptosar) in the treatment of small-cell lung cancer (SCLC)leaves few stones unturned. Some perspective, however, is necessary. To date,with the exception of the Japan Clinical Oncology Group trial, whichdemonstrated the superiority of irinotecan in combination with cisplatincompared to standard therapy with etoposide and cisplatin, no other new platinumagent combination has proven superior to standard therapy in the treatment ofextensive SCLC. The Noda study, published recently in the New England Journalof Medicine, has sparked considerable interest and anticipation in the medicaloncology community.
Extensive-Stage, Chemonaive SCLC
In a randomized phase III study, Noda and colleagues compared standardetoposide and cisplatin to an experimental regimen of irinotecan andcisplatin, as piloted by Kudoh and others in Japan. The study originallyintended to randomize responders secondarily to either observation or radicalthoracic radiotherapy (50 Gy in 2-Gy fractions per day × 5 weeks), but thiscomponent of the study was abandoned. Updated analyses demonstrated asignificant benefit for irinotecan/cisplatin compared to etoposide/cisplatin,with 1- and 2-year survival rates, respectively, of 58.4% and 19.5% for theirinotecan-containing regimen vs 37.7% and 5.2% for the etoposide-containingregimen (P = .0021).
This difference could not be attributed to an imbalance in the delivery oftreatment: 69% of those receiving irinotecan/cisplatin tolerated all fourcycles, compared to 71% of those receiving etoposide/cisplatin. Also, there wasno obvious discrepancy in baseline demographics. As expected, theirinotecan/cisplatin regimen produced significantly more grade 3 or higher diarrhea(16% vs 0%, P = .001) but significantly less neutropenia (66% vs 92%, P = .0002) and grade 3 or higher thrombocytopenia (5% vs 18%, P = .01).
Thus, in Japan, the irinotecan/cisplatin combination has become the standardfor comparison in future studies of extensive disease. However, it should benoted that patients over age 70 were excluded, and the study precluded priorradiotherapy. Two separate North American trials alluded to by Dr. Sandleroneongoing and one plannedwill either refute or corroborate the Japaneseresults. An intergroup trial will recapitulate the Japanese effort, usingidentical doses. The other trial employs a more standard 3-week schedule,comparing etoposide (100 mg/m²/d × 3) and cisplatin (80 mg/m² on day 1) toirinotecan (65 mg/m² on days 1 and 8) and cisplatin (30 mg/m² on days 1 and 8)every 3 weeks.
The rationale for this altered schedule of irinotecan and cisplatin isfourfold: (1) elimination of day 15 irinotecan dosing, which was omitted orreduced in 50% of patients enrolled in the Japanese study; (2) symmetrical3-week schedules for both arms; (3) reduced dose of cisplatin in an effort toreduce toxicity; (4) exploitation of putative cisplatin/irinotecan synergy usinga weekly combination schedule. This study employs a 2:1 irinotecan/cisplatin vsetoposide/cisplatin randomization and targets a 50% 1-year and 15% 2-yearsurvival rate for the irinotecan/cisplatin arm vs 37.5% and 7.5%, respectivelyfor the control arm.
As Dr. Sandler points out, irinotecan has activity similar to that oftopotecan (Hycamtin) in the relapse setting. In the only trial evaluating therole of irinotecan in previously treated SCLC, the response rate in 28 patientswith refractory disease was only 3.7%, with a median time to progression of 1.3months and median survival of 2.8 months. On the other hand, among the 17patients with chemosensitive relapse accrued to this effort, the response ratewas nearly 10-fold higher at 35%, with a median time to progression of 3.4months and median survival of 5.9 monthsvirtually identical to the results ofa pivotal randomized phase III trial comparing topotecan to the CAV regimen(cyclophosphamide [Cytoxan, Neosar], doxorubicin [Adriamycin], vincristine).
This critical distinction between chemorefractory and chemosensitive SCLCrelapse has been observed with other agents as well, making it imperative thatnewer approaches for refractory patients be evaluated. Unfortunately, themajority of patients with extensive disease who relapse are no longer sensitiveto additional cytotoxics.
Irinotecan/New Agent Combinations
Dr. Sandler alludes to new combinations of irinotecan that do not includestandard cisplatin or carboplatin (Paraplatin). For example, in a small subsetof patients enrolled in a phase II study of irinotecan and ifosfamide(Ifex), 8 of 11 with SCLC responded to the combination. Bahadori et aldemonstrated preclinical synergy between irinotecan and gemcitabine (Gemzar) inSCLC cell lines. Rocha Lima and colleagues from the Medical University of SouthCarolina (Charleston) completed a phase I trial of irinotecan in combinationwith gemcitabine, demonstrating that both agents could be combined at nearlyfull dose. The maximum tolerated dose of gemcitabine was 1,000 mg/m² ondays 1 and 8, in combination with irinotecan, 100 mg/m² on days 1 and 8, every 3weeks. Using this schedule, the Cancer and Leukemia Group B (CALGB) has almostcompleted accrual to a salvage trial in both chemosensitive and chemorefractory,relapsed SCLC. The results of this effort should be available in the next 6 to12 months.
Integrating irinotecan into standard therapy for limited disease is atherapeutic challenge. Multiple studies have demonstrated the superiority ofearly concurrent chemoradiation, compared to delayed concurrent or sequentialchemoradiation. The use of two cycles of etoposide and cisplatin administeredduring thoracic radiation, followed by two additional cycles, has emerged as thestandard of practice. Turrisi et al showed the superiority of concurrenttwice-a-day radiotherapy with etoposide and cisplatin, compared to once dailyfractionation. A 5-year survival rate in excess of 25% has been observed.Although irinotecan in combination with cisplatin has demonstrated therapeuticsuperiority to a standard regimen in extensive SCLC, this advantage may bedifficult to prove in limited disease. The risk of excess toxicity and thepotential loss of efficacy cannot be dismissed.
Kinshita and colleagues conducted a phase I study of first-line irinotecanand cisplatin with concurrent thoracic radiotherapy in patients with limiteddisease, combining irinotecan on days 1, 8, and 15 every 4 weeks and cisplatinon day 1 with split-course radiotherapy, 2 Gy daily for 2 weeks, followed by a2-week rest period every cycle. The study accrued 17 patients, ranging inage from 43 to 74 years. The maximum tolerated dose of irinotecan with thisschedule was 40 mg/m², and of cisplatin, 60 mg/m². Fatigue was dose-limiting;there was no grade 3 or higher diarrhea. Unsurprisingly, the overall response rate washigh (93.6%). However, survival data are not yet available. Notably, this trialemployed split-course thoracic radiotherapy, which in early radiation trialsproved inferior to standard, uninterrupted thoracic radiotherapy.
The Radiation Therapy Oncology Group (RTOG) plans to initiate a pilot studyintegrating cisplatin and irinotecan on a weekly basis during uninterruptedtwice-daily radiotherapy, followed by three additional cycles of combinationirinotecan/cisplatin. A recently completed phase I trial at Fox Chase CancerCenter in locally advanced non-small-cell lung cancer demonstrated the safetyof irinotecan at a dose of 30 mg/m²/wk × 7, in combination with cisplatin,25 mg/m²/wk × 7, and full-dose standard, single daily thoracicradiotherapy to a total dose of 63 Gy. These results strongly suggest thatthe integration of these two agents into the limited-disease SCLC setting shouldbe feasible.
The enthusiasm for irinotecan must be tempered, to some extent, until ongoingand planned North American trials either confirm or refute the early Japanesedata. Until then, irinotecan will not become part of standard induction therapyin treatment-naive SCLC. Nevertheless, the data to date are promising and demandfurther, aggressive evaluation.
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