Reponses to topoisomerase-I inhibitors in extensive small-cell lung cancer: chance or chromosomes?

For a cancer that is widely regarded as exquisitely sensitive to both radiation therapy and chemotherapy, we seem to have reached a plateau in the treatment of small-cell lung cancer, and no significant advances have seen in extensive-stage disease for several decades. The 2002 article from the Japan Clinical Oncology Group (JCOG) that found the combination of irinotecan and cisplatin to be superior to the standard regimen of etoposide and cisplatin was the first positive news on this front in some time and set off two parallel phenomena. One group of physicians, perhaps frustrated by the therapy they knew, quickly switched to the new combination. Others began to perform comparable trials to see whether the JCOG results could be duplicated in a US population, recalling previous disappointing US trials of agents more successful in Japan (mitomycin, bleomycin, and tegafur and uracil). Two such comparison trials have been completed, and a third, led by the Southwest Oncology Group, has enrolled 470 of a projected 620 patients without unexpected toxicities (R. Natale, personal communication, January 2006). This study uses the same chemotherapy regimens of the JCOG study but not the random assignment to subsequent thoracic radiation therapy. The topoisomerase-I drugs are particularly intriguing because of their synergism in preclinical studies. Topoisomerase-I drugs may inhibit repair of DNA damage produced by platinating agents and seem like ideal partners for doublet therapy in small-cell lung cancer. The JCOG planned to enroll 230 patients, but enrollment was halted because an interim analysis found a statistically meaningful difference in survival between the two groups; a total of only 154 patients, who were evenly split between the two groups, was enrolled (Table 1). Although the differences for progression-free and median survival were significantly in favor of the irinotecan/cisplatin arm (experimental arm), the complete response rate was higher in the etoposide/cisplatin arm, and the 1and 2-year survival statistics were not statistically significant. Furthermore, the study was restricted to patients less than 70 years of age with good performance scores. The second random assignment to thoracic radiation was not completed. The following question was thus posed: is this a new standard of care? To answer this question, the Hoosier Oncology Group and collaborators in the United States, Canada, and Australia designed a study in which patients were randomly assigned at a 2:1 ratio to receive a modified irinotecan/cisplatin regimen or etoposide/cisplatin. The philosophy behind the modified irinotecan arm was that only 50% of the day 15 irinotecan was administered in the JCOG study, and it was anticipated that this schedule would increase the dose-intensity for irinotecan by changing from a 4-week regimen to a 3-week regimen. There was no upper age cutoff, and patients with Eastern Cooperative Oncology Group performance scores of 0 to 2 were initially eligible, although the group with a performance score of 2 was later dropped as a result of excessive toxicity. With this approach, they were able to deliver more than 92% of the planned doses of all agents. There was greater hematologic toxicity with etoposide/cisplatin and more gastrointestinal toxicity with irinotecan/cisplatin, but there were no differences in response rates, time to progression, or median survival. Eckhardt et al evaluated the role of oral topotecan in combination with cisplatin. Topotecan is also a camptothecin and a topoisomerase-I inhibitor and, in the intravenous form, is US Food and Drug Administration approved for second-line therapy for small-cell lung cancer. In a multinational, randomized, controlled trial, Eckhardt et al randomly assigned 784 patients to either oral topotecan for 5 days with intravenous cisplatin on day 1 or intravenous etoposide/cisplatin in a standard regimen. Part of their rationale for this program was the observation that protracted drug exposure may produce greater topoisomerase-I–DNA complex formation and superior cytotoxicity. They found no difference in overall survival, the primary end point, between the two groups. Although they expressed survival in weeks, not months, their survival statistics were similar to the 10 months seen in the other trials, except for the one arm of the JCOG study. Response rates and 1-year survival were also not different between the two groups. Toxicity was felt to be tolerable in both arms, and there were no important differences in Lung Cancer Symptom Scores. So, at this point in time, we have been unable, in both US and international patients, to duplicate the results of Noda et al. Is this a random, statistical fluke, the one in 20 studies that goes against the grain, or does this represent a genuine difference? Although there are clear differences in trial design and drug dosing, these seem unlikely to account for the differences. One place to look is the obvious possibility of pharmacogenetic differences between a fairly homogenous Japanese population and the much more heterogeneous US and European populations. The Southwest Oncology Group study, which looks at the ability to use genetic markers to predict toxicity and clinical outcomes, may answer this question. Meanwhile, what are the alternatives? We already know that the addition of a third active agent, paclitaxel, to etoposide and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 13 MAY 1 2006