We evaluated the combination of docetaxel and irinotecan, a novel non-platinum-containing regimen, in the first- or second-line treatment of patients with recurrent or metastatic SCCHN. Both drugs were given on a weekly schedule of administration based on prior phase I experience [13
]. Phase II trials of docetaxel and irinotecan, using weekly or every 3 weeks schedules of administration, have been conducted in many other solid tumors [26
]. To the best of our knowledge, this is the only phase II study of docetaxel and irinotecan in recurrent or metastatic SCCHN. Although objective responses were observed, the pre-specified criteria for efficacy were not met. In the first-line setting (group A), 4 objective responses were observed as required per study design but one was unconfirmed which did not allow the study to accrue beyond the first stage of a two stage Simon design. The statistical design assumed a target response rate of 40% in group A which in retrospect was rather high for the cooperative group setting and with the application of RECIST. Other cooperative group studies in comparable patient populations, such as E5397 and E1595, showed that single-agent chemotherapy with cisplatin achieves an objective response rate of 10% and median survival of 8 months (E5397) [34
] and that cisplatin doublets (cisplatin/5-FU or cisplatin/paclitaxel) result in objective response rates of 26–27% and median survival of 8.1–8.7 months (E1395) [3
]. In the current study, docetaxel and irinotecan produced a response rate of 17% (22% counting an unconfirmed response), median PFS of 3.3 months and median of OS 8.2 months. Therefore, survival results with docetaxel and irinotecan may be comparable to platinum-based combinations.
The group of patients treated in the second-line setting (group B) is one of the largest that have been studied so far and it was characterized by a high representation of patients with distant metastasis (78%) and previous treatment with paclitaxel (81%). In these patients, the efficacy of docetaxel and irinotecan with a response rate of 3% (6% counting an unconfirmed response), median PFS of 1.9 months and median OS of 5.0 months cannot be considered satisfactory. As single agent, irinotecan may be inactive in previously treated recurrent or metastatic SCCHN [11
], whereas data with single-agent docetaxel is limited in a similar setting but activity has been reported [35
The docetaxel and irinotecan regimen we used in our study was associated with expected toxicities which were predominantly non-hematologic, including diarrhea, anorexia, and fatigue. Although most of the patients had received paclitaxel in the past, grade 3 or 4 neuropathy was not seen. Grade 4 toxicity was observed in 30% of chemotherapy naive patients in this study versus 42% and 50% with cisplatin/paclitaxel and cisplatin/5-FU, respectively, in E1395, whereas there was no treatment-related death versus 5% and 7% with cisplatin/paclitaxel and cisplatin/5-FU, respectively [3
]. However, there were some differences in the toxicity criteria used between these ECOG studies so the rates of grade 3 and 4 toxicities may not be directly comparable. Polymorphisms in the UGT1A1 gene have demonstrated racial variability and have been shown to be associated with differences in observed toxicities among patients treated with irinotecan. We could not demonstrate any correlation of toxicities with UGT1A1 genotypes, possibly because of the small sample size, or the low dose of irinotecan used in this study 40
COX-2 and VEGF are overexpressed in SCCHN and have been suggested as potential predictors of outcome [14
]. Moreover, COX-2 expression has been reported to correlate with the expression of VEGF in SCCHN. Based on preclinical observations it has been proposed that docetaxel may have an antiangiogenesis effect [37
]. We elected to assess VEGF as well as COX-2 on baseline tumor tissue and attempted to associate its expression with outcome. However, in the clinical setting examined we could not demonstrate that expression of either COX-2 or VEGF correlated with worse survival possibly because of insufficient sample size [38
]. Patients with high serum VEGF levels had a trend towards improved PFS with docetaxel and irinotecan versus patients with low levels at baseline, an observation that may require further evaluation in subsequent studies.
The docetaxel and irinotecan regimen we used was feasible and was associated with a toxicity profile potentially favorable to cisplatin-based combinations. However, its antitumor activity is unlikely to be superior to platinum-based combinations in the first-line treatment of recurrent or metastatic SCCHN, whereas its antitumor activity in the second-line setting was rather disappointing. It has been reported that selected patients, such as those with tumors with high levels of excision repair cross complementation group 1 (ERCC1), may benefit less from platinum-based chemotherapy [39
]. Whether docetaxel and irinotecan, a non-platinum doublet, will be beneficial in selected patients, such as those with tumors with high ERCC1, is a worthwhile hypothesis to be evaluated in future clinical trials in patients with SCCHN.