Combination Oral Chemotherapy for Second-line SCLC

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a retrospective review of 71 patients treated in either a second- or third-line setting for small-cell lung cancer (SCLC) at a single institution, three orally administered drugs (lomustine, etoposide, and cyclophosphamide) were shown to be effective in producing responses (overall response rate 38%) but had little effect on overall survival (median survival 19 weeks). Grade 3/4 hematological toxicity was observed in about one third of the treated patients, and three patients died with neutropenic fever. Currently, in a randomized phase-II trial for second-line SCLC in patients underway in France, this regimen is being compared with conventional intravenous chemotherapy.

Source: Lebeau B, et al. Oral second-line and third-line lomustine-etoposide-cyclophosphamide chemotherapy for small cell lung cancer. Lung Cancer. 2010;67:188-193.

Small-cell lung cancer (SCLC) remains a highly-lethal disease despite high response rates to initial chemotherapy. Upon relapse, the response to second-line chemotherapy is likely to be higher in those with a good performance status and longer time to relapse. In fact, retreatment with the first-line regimen should be considered for those who relapse > 6 months after the end of initial treatment. Various chemotherapy regimens have been evaluated in the phase-II setting, but none has emerged as significantly more effective than the others.1 Topotecan, administered orally as a single agent, has been shown to be superior to best supportive care (BSC),2 and is currently the only drug licensed in the second-line setting. However, in this randomized, phase-III trial,2 the partial response rate was only 7%. Nonetheless, disease stabilization was observed in 44%, and quality of life was measurably better, as was overall survival when compared with those receiving BSC. In contrast, Lebeau et al from Paris report their experience with an alternative three-drug oral regimen (lomustine, etoposide, and cyclophosphamide) used as second- or third-line therapy for patients with SCLC.

In this retrospective review, the data on 71 SCLC patients (36 treated as second line and 35 as third line) were analyzed. They received lomustine (CCNU) 80 or 120 mg on day 1 only, etoposide 100 mg from day 1 through day 6-14, and cyclophosphamide 100 mg from day 1 through day 6-14, every four weeks. The dosages of CCNU, and duration of administration of the other two drugs, were adjusted in a standardized way based upon age, performance status, weight, and hematological parameters. Evaluation, based on clinical status, response, and weekly blood counts, was performed before each cycle until progression.

The patients received between one and 20 cycles of treatment (mean = 3.7 for second-line and 3.0 for third-line treatment). Complete responses were observed for three patients in each line, and partial responses were noted in 13 patients in second-line and eight patients in third-line therapy, resulting in a total response rate of 27/70 = 38%. Median survival time, estimated from the start of second- or third-line treatment, was the same in the two subgroups: 4.4 months. But, the patients in the two subgroups presented different clinical characteristics. Hematologi-cal toxicity was commonly observed, and three patients died with neutropenic sepsis. Furthermore, 39% had grade 4 neutropenia and 34% had grade 4 thrombocytopenia.

Commentary

Although hematologic toxicity was common, this was not unexpected in this group of pretreated patients. The observed response rate is quite remarkable in this setting, but should be interpreted very cautiously, as it is derived from a single institution upon retrospective analysis. Furthermore, despite the response rates, overall survival, measured in weeks, was still quite dismal, and possibly less than observed with oral or intravenous topotecan. However, as the authors point out, the current report reflects the treatment of patients in both second- and third-line treatment, including those with poorer prognostic factors and poorer performance status.

Furthermore, this combination has the advantage of being orally administered and generally well tolerated. Whether it will become a standard second-line approach for SCLC will require clinical trials, and one such trial is currently underway in France. In the meantime, alternative therapies are emerging, offering even greater hope for this group of patients.3 Currently under investigation are anti-angiogenic agents, growth factor receptor inhibitors, inhibitors of downstream signaling pathways and drugs that promote apoptosis. Among the latter, inhibitors of prosurvival Bcl-2 proteins are currently entering the clinical arena and are an exciting prospect aimed at combating drug resistance in first- and second-line treatment for SCLC.

References

1. Hurwitz JL, et al. New advances in the second-line treatment of small cell lung cancer. Oncologist. 2009;14:986-994.

2. O'Brien ME, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006;24:5441-5447.

3. Blackhall FH, Shepherd FA. Small cell lung cancer and targeted therapies. Curr Opin Oncol. 2007;19: 103-108.