A less toxic chemotherapy regimen for advanced anal cancer achieved at least similar disease control in a randomized comparison with a widely used standard-of-care regimen. Carboplatin plus paclitaxel led to an objective response rate (ORR, primary endpoint) of 59% versus 57% for the combination of 5-fluorouracil (5-FU) and cisplatin. Both progression-free survival (PFS) and overall survival (OS) favored carboplatin-paclitaxel.
A less toxic chemotherapy regimen for advanced anal cancer achieved at least similar disease control in a randomized comparison with a widely used standard-of-care regimen.
Carboplatin plus paclitaxel led to an objective response rate (ORR, primary endpoint) of 59% versus 57% for the combination of 5-fluorouracil (5-FU) and cisplatin. Both progression-free survival (PFS) and overall survival (OS) favored carboplatin-paclitaxel.
Serious adverse events occurred in 62% of patients treated with 5-FU and cisplatin as compared with 36% of those in the carboplatin-paclitaxel arm, Sheela Rao, MD, of the Royal Marsden Hospital in London, and co-authors reported in the Journal of Clinical Oncology.
"The results of this study have led to an immediate change in patient care," Rao said in a statement. "While treatment with cisplatin and 5-fluorouracil was generally considered a reasonable option for advanced anal cancer, we now know that carboplatin and paclitaxel is more effective and better tolerated. In our study, these patients lived 7 months longer overall and experienced less treatment side effects."
The findings did not surprise co-author Cathy Eng, MD, of Vanderbilt University Medical Center in Nashville.
"In fairness and full disclosure, I wrote the first paper about what was the largest retrospective analysis, at the time, looking at frontline systemic therapy [for advanced anal cancer]," she told MedPage Today. "I was one of the few people who had already thought about utilizing carboplatin and paclitaxel. At my institution, we conducted a retrospective analysis of treatment-naive patients, and that served as the premise for my support, as well as Al Benson's [of Northwestern University in Chicago, co-author of the current study] support for a trial comparing the two systemic regimens."
The trial provided a randomized test for two chemotherapy regimens that have won support in the oncology community on the basis of retrospective, anecdotal, and small single-arm trial evidence. Limited phase II data formed the basis for international guideline support for 5-FU-platinum as the first-line standard for advanced anal cancer data from phase II, Rao and co-authors noted.
To provide higher-quality data to inform clinical decision making, investigators at 31 centers in the U.S., Europe, and Australia performed a randomized trial to compare carboplatin-paclitaxel and 5-FU/cisplatin. The primary endpoint was ORR. Primary and secondary endpoints were assessed by means of a hierarchic model to compare the regimens and "pick the winner," the authors said.
Data analysis included 91 randomized patients, 84 of whom received the study treatment and 74 were included in the modified intention-to-treat population. The patients had a female predominance (60-70%), the median age of 61, and metastatic (versus locally advanced) disease in almost 90% of the cases. More than 90% of the patients were HIV-negative. Human papillomavirus (HPV) status was not prospectively determined, but more than 90% of anal carcinoma cases arise from HPV infection, Eng noted.
After a median follow-up of 28.6 months, the ORR did not differ significantly between treatment arms, nor did the rate of complete response (17% with 5-FU/cisplatin, 12.8% with carboplatin-paclitaxel). Disease burden or stage did not affect the likelihood of complete response, the researchers reported. At the time of data analysis, 22.9% of patients in the 5-FU/cisplatin group had disease progression versus 15.4% in the carboplatin-paclitaxel group.
Median progression-free survival was 5.7 months with cisplatin/5-FU and 8.1 months with carboplatin-paclitaxel, a difference that did not achieve statistical significance in an unadjusted (HR 1.27, P=0.375) or adjusted analysis (HR 1.17, P=0.564).
Patients allocated to carboplatin-paclitaxel lived almost 8 months longer (median overall survival 20.0 vs 12.3 months). The difference was statistically significant before adjustment (HR 2.00, 95% CI 1.15-3.47, P=0.014), but not after adjustment for performance status, HIV status, disease status, and region (HR 1.78, 95% CI 0.98-3.23, P=0.059).
The two regimens had different adverse-event profiles. More neutropenia and anemia occurred with carboplatin and paclitaxel, whereas nausea, vomiting, mucositis, and diarrhea were more common with 5-FU/cisplatin. No grade 5 (fatal) toxicity occurred in either group. Serious adverse events occurred significantly more often with 5-FU/cisplatin (P=0.016).
"Carboplatin plus paclitaxel was associated with a more favorable toxicity profile and the significant trend toward prolonged OS," Rao and co-authors concluded. "These data support the consideration of carboplatin plus paclitaxel as a new standard of care in untreated advanced anal cancer and a cytotoxic platform for the development of future phase III trials."
On the basis of the findings, either regimen would be appropriate as initial systemic therapy for advanced/metastatic anal cancer, said Eng. Either regimen would be an appropriate chemotherapy backbone for future studies of novel agents. The PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) already have National Comprehensive Cancer Network support for patients with previously treated anal cancer, and studies have already begun to evaluate the agents in the first-line setting.
Moreover, the results have implications beyond anal cancer, noted Eng: "This is a malignancy that is heavily associated with HPV, so discoveries in this cancer could lead to breakthroughs for other HPV-associated cancers."