say experts discussing results from InterAAct, the first international prospective randomized trial in advanced anal cancer.
In the head-to-head trial, both combinations achieved a similar overall response rate — 59% for carboplatin plus paclitaxel and 57% for 5-FU plus cisplatin.
However, the 5-FU/cisplatin regimen was associated with significantly more adverse events, and there was a trend toward longer survival with carboplatin plus paclitaxel.
Median overall survival was 12.3 months for cisplatin plus 5-FU vs 20 months for carboplatin plus paclitaxel (adjusted hazard ratio [HR], 1.78; P =.059).
Serious adverse events were reported by more patients on cisplatin plus 5-FU vs carboplatin plus paclitaxel (62% vs. 36%; P =.016). The two regimens had different toxicity profiles, with more neutropenia and anemia observed in the carboplatin plus paclitaxel group, but more nausea, vomiting, mucositis, and diarrhea with cisplatin plus 5-FU.
“I think many of us were not surprised that the response rate was equivalent for the two arms but are pleasantly surprised by the difference in toxicity and the impact on survival,” said coauthor Cathy Eng, MD, chair in surgical and medical oncology at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.
“We feel fairly confident that the carbo/taxol arm is the new arm to build upon,” she added.
“I think in comparison to the standard 5-FU/cisplatin, which was the control arm of the trial, this regimen should be considered the new standard of care,” said Eng.
Eng told Medscape Medical News that she doesn’t think that it needs further validation. “This is considered a rare cancer in the US,” she said. “The primary endpoint was feasibility of this international effort, which we established. If the response rate was equivalent, the less toxic regimen would be considered.”
“We fulfilled our primary endpoint of wanting to identify the best chemotherapy backbone to build upon,” she added.
These findings were initially presented at the European Society of Medical Oncology 2018 annual meeting, and reported by Medscape Medical News at the time. The full results were published earlier this month in the Journal of Clinical Oncology.
“The InterAAct trial has established carboplatin-paclitaxel as a new standard of care in this population in the frontline setting,” commented Sarbajit Mukherjee, MD, assistant professor of oncology at Roswell Park Comprehensive Cancer, Buffalo, New York, who was approached for an independent comment. “Clinicians should start using this regimen now, and it is also supported by the National Comprehensive Cancer Network guidelines.”
He emphasized the need for caution in interpreting the survival data because overall survival was not the primary endpoint of the study. “However, I do think that we should use this chemo regimen as a backbone for future randomized studies in this rare disease population,” said Mukherjee, who was not involved with the study.
Anal cancer is rare, accounting for less than 3% of all gastrointestinal malignancies, but there has been a “dramatic” rise in incidence in recent decades, as previously reported by Medscape Medical News.
Most patients present with localized or locally advanced disease and are treated with chemoradiotherapy with curative intent, the authors explain. However, metastatic dissemination occurs in about 10% of these patients, whereas <10% of all anal cancer patients present with metastatic disease de novo.
For patients with metastatic disease and for those with inoperable disease, the prognosis is poor, with relative 5-year survival rates of about 30%. Palliative chemotherapy is routinely offered, but to date, there have been no randomized controlled trials to inform clinicians of the optimal chemotherapy regimen in this setting.
International guidelines have suggested a platinum agent combined with fluoropyrimidine for the first-line treatment of advanced anal cancer, but this recommendation is based on limited evidence from single-arm phase 2 studies. The International Rare Cancers Initiative Anal Cancer Working Group recognized the evidence gap in clinical decision-making for patients with advanced cancer as an area of unmet clinical need, prompting the global InterAAct trial.
The trial involved 91 patients with locally recurrent inoperable or metastatic squamous cell carcinoma of the anus from 60 sites in North America, Europe and Australia. They were randomly assigned to receive either cisplatin 60 mg/m2 (day 1) plus 5-FU 1000 mg/m2 (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m2 (days 1, 8, and 15) every 28 days. Patients were treated for 24 weeks or until disease progression, intolerable toxicity, or withdrawal of consent.
A “pick the winner” study design was used, in which the least toxic regimen would be selected as the “winner” if no significant difference in objective response rate between treatment groups was detected.
At a median follow-up of 28.6 months, the overall response rate did not differ significantly between both groups. The complete response rate was 17% with 5-FU/cisplatin and 12.8% with carboplatin-paclitaxel. Disease progression occurred in 22.9% of patients in the 5-FU/cisplatin group and 15.4% in the carboplatin-paclitaxel group.
The median progression-free survival was 5.7 months for cisplatin plus 5-FU compared with 8.1 months for carboplatin plus paclitaxel. The difference was not statistically significant. After adjusting for confounders, the HR was 1.17 (P = .564).
As already noted, there was a trend toward a significant difference in overall survival of almost 8 months favoring the carboplatin plus paclitaxel regimen. In addition, there was a significant difference in toxicity between the two regimens.
Commenting on the study, Michael Buckstein, MD, PhD, assistant professor, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York City, noted that even though “this study technically did not meet its endpoint of improved objective response rate and there was only a trend toward improved overall survival, the results presented here, especially with regard to toxicity, are very encouraging for a rare disease in a challenging population.”
Buckstein, who was not associated with the current research, added: “The trial is small, had problems in accrual, very few HIV patients, and was technically negative, so it’s hard to say this should be a ‘standard of care’ but it certainly should be considered ‘standard of practice’ and strongly considered for first-line therapy.”
The next US trial to follow InterAAct will look at the addition of immunotherapy to carboplatin/paclitaxel. This is the phase 3 EA2176 trial of carboplatin/paclitaxel ± nivolumab (plus maintenance), and it will have a primary endpoint of progression-free survival. “It will likely be open this summer, if not early fall, and will enroll 208 patients,” Eng commented.
The current study was supported by Cancer Research UK, AGITG, and ECOG-ACRIN. Eng has disclosed relationships with Bayer Schering Pharma, Foundation of Medicine, Array BioPharma, and Natera. Mukherjee and Buckstein have disclosed no relevant financial relationships.
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