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Several years ago, I participated in a clinical trial with a combination of carboplatin and irinotecan for treatment of extensive SCLC, just now being published (abstract here). As a bit of background about the potential utility of irinotecan, the well established cornerstone of treatment of extensive SCLC for about two decades has been a platinum agent (cisplatin or carboplatin) with etoposide, but an important trial in Japan suggested that a cisplatin/irinotecan regimen may be superior to cisplatin/etoposide (abstract here). Subsequent work done in the US did not support that conclusion, and one leading consideration is that there are meaningful differences in the activity and side effect profiles of different chemotherapy drugs in different racial populations, due to factors like the enzymes that alter metabolism of these agents. Nevertheless, irinotecan and its cousin topotecan are still high on the list of drugs most active in SCLC.
The clinical trial in which I participated combined irinotecan with carboplatin, the alternative to cisplatin that is often substituted because of generally comparable activity and a more favorable side effect profile. In this trial, both agents were given IV on a single day every three weeks. There were two different groups of patients enrolled, with 40 patients in each: one had received no prior treatment for extensive SCLC, and the other had previously received first line chemotherapy (with cisplatin or carboplatin and etoposide) and had now relapsed. For the group that had received prior chemo, a lower dose of irinotecan was given (150 mg/square meter vs. 200 mg/square meter every three weeks). Patients received up to six cycles of this combination.
Although we tend to focus more attention on newer treatments with investigational agents, this study suggested that there may be value in the tools that are available now. Overall, the results were fairly favorable, with a median overall survival of 10 months that was the same in both groups. Both groups had a complete response rate of 12-13% , and the overall response rate was 65% for the previously untreated patients, 50% for the patients with relapsed SCLC. The primary side effects were from low blood counts (which unfortuantely included 3 deaths from infection in the setting of low blood counts) that was more of a problem in the first line patients treated with a higher dose of irinotecan, as well as diarrhea, another well known side effect of irinotecan.
While the results seen in the first line patients were overall pretty comparable to those seen with other alternatives (including a small but real risk of treatment-related death), the findings among the 40 patients treated for relapsed SCLC were more encouraging. Seeing more than 10% of patients experience a complete response with relapsed disease is unusual and favorable, as was an overall response rate of 50% in this population. There has been a great deal of buzz about newer agents like amrubicin (see posts here and here) for relapsed SCLC, based on the same general response rate. Particularly at the lower irinotecan dose used in previously treated patients, the carbo/irinotecan regimen was overall convenient (IV therapy just one day every three weeks), and not a particularly high risk for infections or other serious side effects.
There was one other interesting observation from this trial, which was that there was a 65% response rate of brain lesions among the 15 patients who were enrolled with asymptomatic or previously treated brain metastases. While we tend to presume that our systemic therapies are not effective in the brain, there is actually evidence that patients can have response rates in the brain that are in the same range as response rates in the chest or elsewhere in the body (see prior post). In fact, some agents may be more able to get into the brain and be associated with better responses of brain metastases, and irinotecan has shown some promise in that regard. Though these results are only limited to 15 patients with brain metastases, they do suggest that this regimen may be particualrly useful for patients with brain metastases or a high risk for developing them.
Overall, the trial highlights that the carbo/irinotecan combination given every three weeks has encouraging activity and a modest side effect profile, particularly among the patients with relapsed SCLC who received a lower dose of irinotecan but had a very favorable response rate and survival. While more of our focus lies in the agents like amrubicin that are still unavailable to us, this combination with commercially available chemo agents appears to have performed just as well in a similar sized trial, even if it's with less fanfare.
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