In their recent article in Journal of Clinical Oncology regarding the InterAAct phase II trial in advanced squamous cell carcinoma of the anal canal (SCCA), Rao et al1 propose that carboplatin plus paclitaxel (CP) should be considered as a new standard of care because it provides similar efficacy to cisplatin and fluorouracil (CF), with a better safety profile. On the other hand, the triplet docetaxel plus cisplatin plus fluorouracil (DCF), which provided for patients a 47% progression-free survival rate at 12 months2 and a 25% probability of long-term remission,3 was not recommended at the same level. Authors should be commended for the promotion of their important study in this orphanage situation. However, because advanced SCCA is a rare disease for which current treatments lead to dismal prognosis, rate of cure, and quality of life, it is important to discuss all available effective treatment options.
First, the InterAAct trial was a phase II randomized noncomparative study to explore the potential interest of a chemotherapy regimen for further trials. On the basis of an objective response rate (ORR) estimated at 40% in the CF arm, a clinically relevant ORR difference between groups was defined as 10%. Thirty-nine and 35 patients were assessable for the primary objective in each arm. Unfortunately, the InterAAct trial failed to demonstrate its primary end point, with similar ORRs between CP (59%) and CF (57%). In addition, there was no significant difference in grade 3/4 adverse event (AE) rates between regimens (71% v 76%), and the quality-of-life data were not assessable because of low compliance. In addition, the 12-month progression-free survival rate was almost identical between arms (approximately 15%), and the complete response rate was in favor of CF (17.1% v 12.8%), even though the difference was not statistically significant. It means that the difference observed in overall survival was probably secondary to the sequences of further treatments, as stated by the authors. In fact, 24% of patients in the CP arm received an immunotherapy in second-line treatment compared with 6% of patients in the CF arm.1 Therefore, regarding the design and clinical outcomes of the 39 patients treated with CP, we believe that these results should be regarded as exploratory.4
In parallel, on the basis of preliminary results of an oligocentric study (Epitopes-HPV01),5 66 patients with advanced SCCA were included in 25 centers in Epitopes-HPV02 phase II and treated with DCF.6 Forty-seven percent of these patients were alive and without disease progression at 12 months, surpassing the primary end point of 25%. The complete response rate was 45%, with an ORR of 89%.2 Results were recently updated for 115 patients included in the Epitopes-HPV01 and Epitopes-HPV02 studies.3 Twenty-one patients (42.9%) in Epitopes-HPV01 and 15 (22.7%) in Epitopes-HPV02 were still alive and free of disease progression at data lock with a median follow-up of 22.9 and 32.4 months, respectively. Only two patients received immunotherapy in subsequent lines at the time of analysis. Therefore, the magnitude of DCF clinical efficacy is, to our knowledge, the best results reported to date for patients with advanced SCCA.
In addition to this long-term outcome, circulating tumor DNA (ctDNA) monitoring is another surrogate biomarker to investigate the magnitude of efficacy for patients with SCCA.7 In the InterAAct trial, the combination of CP or CF induced the conversion from positive to negative HPV ctDNA in five of 28 patients (17.9%), with a median duration of response of 46 weeks in these patients.1 In patients treated by DCF, 22 of 36 patients (61.1%) presented the conversion from positive to negative HPV ctDNA. For these patients, the median duration of response was not reached with a follow-up of 19.8 months.8
Therefore, these results indicate that the conclusion proposed by Rao et al1 to consider CP as a new standard of care is overstated. Likewise, the safety profile issue of DCF to prevent its prescription, as discussed by Rao et al, is not accurate. In fact, the modified biweekly DCF regimen had similar efficacy with significantly lower toxicity than the classic triweekly DCF regimen.2,3 Grade 3/4 AEs were observed in 53% of patients with SCCA exposed to modified DCF, with no febrile neutropenia.2 On the other hand, the CP regimen in the InterAAct trial induced 71% of grade 3/4 AEs in these patients.1 Finally, we have shown that DCF did not affect absolute lymphocyte count and conversely promoted antigen-specific T-cell lymphocytes, suggesting that it could be proposed as an effective backbone for combination with immunotherapy.2,9,10
In conclusion, we believe that patients with advanced SCCA should be treated with modified DCF in first-line settings. CP may be reserved for those patients with a contraindication to fluorouracil or cisplatin.