Patients with high-risk squamous cell anal cancer had a moderate reduction in locoregional failure but a substantial increase in toxicity with the addition of cetuximab (Erbitux) to standard chemoradiation, a multicenter clinical trial showed.
A fourth of patients had locoregional failure at 3 years, as compared with an expected rate of 35% derived from historical data. A third of the 61 patients had grade 4 toxicity, and three treatment-related deaths occurred, reported Joseph A. Sparano, MD, of Montefiore Medical Center in New York City, and colleagues.
"Although these findings suggest that the addition of cetuximab to chemoradiation therapy for anal cancer may reduce locoregional failure rates, toxicity was substantial, and locoregional failure still occurs in approximately 20%, indicating the continued need for more effective and less toxic therapies," they wrote online in the Journal of Clinical Oncology.
"Although cetuximab improved clinical outcomes when added to radiation therapy in squamous cell carcinoma of the oral cavity, similar benefit was not observed when cetuximab was added to cisplatin plus radiation therapy in this population, suggesting that the evaluation of cetuximab plus radiation therapy without chemotherapy may also be considered an option in future trials."
A small multicenter trial of patients with HIV-associated anal cancer, conducted by Sparano, Madhur Garg, MD, also of Montefiore, and colleagues, demonstrated a 3-year locoregional failure rate of 42% with the addition of cetuximab to chemoradiation, and a fourth of the patients had grade 4 toxicity.
Taken together, the two trials failed to make a case for further investigation of cetuximab in combination with chemoradiation for anal cancer, according to the authors of an accompanying editorial, who also noted that chemoradiation is not standard of care for anal cancer.
"The toxicity and 5% death rate in both studies will deter both wider adoption and further testing in larger phase III trials, despite the modestly encouraging locoregional failure rate," said Rob Glynne-Jones, MD, and Mark Harrison, MD, of the Center for Cancer Treatment and Mount Vernon Hospital in Northwood, England.
"Future trials should be specifically designed for patients with both human papillomavirus (HPV)-negative and HPV-positive squamous cell carcinoma of the anus, stratified according to smoking habit and different TNM staging, and ideally should have different therapeutic goals," Glynne-Jones and Harrison added. "Successful validation of these approaches will allow for more effective selection of individualized treatment of patients, in both the context of routine care and clinical trials."
Sphincter-sparing definitive chemoradiation offers a potential to cure squamous cell anal cancer. However, about a third of patients have locoregional failure, which is associated with significant morbidity, risk of distant recurrence, and mortality, the authors noted.
The rationale for evaluating cetuximab in anal cancer came from observations that the EGFR inhibitor enhances radiation therapy activity in HPV-positive oropharyngeal squamous cell carcinoma. About two-thirds of anal cancers occur in HPV-positive individuals.
Sparano's group reported findings from a phase II cooperative group trial involving immunocompetent patients with stage I-III squamous cell carcinoma of the anal canal. After accrual of 28 patients, investigators revised eligibility criteria to limit enrollment to patients with high-risk stage II, IIIA, or IIIB disease.
The trial had a primary objective of locoregional failure, and investigators hypothesized that the addition of cetuximab would reduce the failure rate at 3 years by 50% as compared with a historical 3-year locoregional failure rate of 35%.
Two-thirds of the patients had stage III disease, and most had other high-risk features. Women accounted for 80% of the study population.
The results showed a 3-year locoregional failure rate of 23% (95% CI 13-36%, P=0.03) by binomial proportional estimate, using the prespecified endpoint. A post hoc Kaplan-Meier analysis yielded an estimated 3-year locoregional failure rate of 21%. The progression-free and overall survival at 3 years were 68% and 83%, respectively.
The most common grade 3/4 adverse events among 62 patients who received at least one dose of treatment were diarrhea (68%, all grade 3), neutropenia (50%, 24% grade 4), nausea (32%), dehydration (32%, all grade 4), and hypokalemia (24%). The type and frequency of adverse events were generally similar between the first 28 patients and the 34 enrolled after the modification of eligibility criteria.
The trial of HIV-associated anal cancer involved 45 patients with stage I-III disease. All patients received cetuximab concurrently with cisplatin-fluorouracil chemotherapy, along with irradiation of the primary tumor and regional lymph nodes. As in the trial of immunocompetent patients, investigators hypothesized that the addition of cetuximab would reduce locoregional failure by 50% at 3 years.
The binomial proportional estimate of locoregional failure was 42%. Post hoc Kaplan-Meier analysis yielded a 3-year estimate of 20%.
In addition to a 26% incidence of grade 4 toxicity, two (4%) treatment-related deaths occurred.
The study of by Garg's group was supported by the National Cancer Institute and the NIH. Sparano disclosed relevant relationships with MetaStat, Genentech, Eisai, Novartis, AstraZeneca, Celgene, Prescient Therapeutics, Bayer Health Care Pharmaceuticals, Juno Therapeutics, Eli Lilly, Celldex Therapeutics, Merck, Deciphera Pharmaceuticals, Merrimack Pharmaceuticals, AstraZeneca/MedImmune, and Tapimmune. One or more co-authors disclosed relationships with Merck, Antiva Biosciences, Agenovir, Hologic, CEL-SCI, AMAG Pharmaceuticals, Amgen, Celgene, TRM Oncology, Epic Pharma, INSYS Therapeutics, UpToDate, Calimmune, and Sangamo BioSciences. Glynne-Jones disclosed relevant relationships with Eisai, Servier Laboratories, Amgen,Eli Lilly, Roche, Merck Serono, and Sanofi.
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