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Toxicity rates high after cetuximab therapy for anal carcinoma
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The addition of cetuximab to chemoradiotherapy was associated with a lower incidence of locoregional failure in patients with squamous cell carcinoma of the anal canal, according to results from the phase 2 Eastern Cooperative Oncology Group—American College of Radiology Imaging Network Cancer Research Group Trial.
However, locoregional failure still occurred in some patients, and toxicity rates were high.
“Although these findings suggest that the addition of cetuximab to chemoradiation 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,” Joseph A. Sparano, MD, FACP, associate chair for clinical research in the department of oncology at Montefiore Medical Center and professor of medicine & obstetrics, gynecology, and women’s health at the Albert Einstein College of Medicine, and colleagues wrote.
Approximately 1.8 cases of squamous cell carcinoma of the anal canal per 100,000 people occur in the United States annually, and 1% of women and 28% of men with anal cancer also have HIV infection. The use of chemoradiation may serve as a potential cure; however, it is associated with high rates of adverse events and toxicities.
In a separate study of patients with stage I to stage III squamous cell carcinoma of the anal canal and HIV infection, Sparano and colleagues observed high rates of grade 4 toxicity and a 62% complete response rate after therapy with cetuximab (Erbitux, Eli Lilly) — an anti-EGFR antibody that prolongs survival when used in combination with radiation therapy.
In addition to studying patients with anal cancer and HIV, the researchers wanted to further “exploit” the strong association between anal cancer and HPV in patients without HIV. Therefore, Sparano and colleagues conducted a concurrent study in patients without HIV.
The analysis included 61 patients (median age, 56 years; 20% men) who received chemoradiation therapy (CRT) — including cisplatin, fluorouracil and radiation therapy — to the primary tumor and regional lymph nodes, followed by eight once-weekly doses of concurrent cetuximab. Concurrent radiation therapy consisted of 1.8 Gy once per day for 5 days per week for a minimum of 5 weeks based on prechemotherapy tumor volumes (45 Gy-54 Gy).
The primary objective was to observe at least a 50% reduction in locoregional failure rate after 3 years, assuming a 35% rate based on historical data.
Among the patients, 5% had stage I disease, 31% had stage II and 64% had stage III. Twenty-five of 28 patients (89%) with available specimens were HPV positive. Other poor risk factors included T3 and 4 lesions in 54% of patients and positive regional nodes in 54%.
Forty-nine patients completed treatment (79%), whereas nine discontinued due to treatment-related adverse events (15%) and four withdrew before the end of therapy.
The 3-year locoregional failure rate was 23% (95% CI, 13-35) based on binomial proportional estimate and 21% (95% CI, 7-26) based on a Kaplan-Meier estimate in a post-hoc analysis.
The objective response rate was 65% (95% CI, 52-77).
At 3 years, the PFS was 68% (95% CI, 55-79) and OS was 83% (95% CI, 71-91).
Grade 4 toxicity occurred in 32% of patients. Five percent of patients died from treatment-related causes.
Common grade 3 to grade 4 adverse events observed included diarrhea (68%), neutropenia (50%), nausea (32%), dehydration (32%), hypokalemia (24%), infection (18%), anemia (15%) and thrombocytopenia (12%). Three patients died within 30 days of completing treatment — one was possibly treatment-related.
Although further research is needed in larger phase 3 trials, such investigation may be deterred as a result of the toxicity observed in both studies by Sparano and colleagues, according to Rob Glynne-Jones, MD, and Mark Harrison, MD, from the Center for Cancer Treatment, Mount Vernon Hospital, United Kingdom, wrote in an accompanying editorial.
“Both studies show concurrent cetuximab CRT regimens are close to the limits of normal tissue tolerance in terms of acute effects, but the CRT platform does not represent the standard of care,” the researchers wrote. “The toxicity and 5% death rate in both studies will deter both wider adoption and further testing in larger phase 3 trials, despite the modestly encouraging locoregional failure rate.”
Nevertheless, they state that further studies should focus on HPV–negative and HPV–positive anal cancer, divided based on smoking habits and different TNM staging.
“Successful validation of these approaches will allow more effective selection of individualized treatment of patients, in both the context of routine care and clinical trials,” they wrote. – by Melinda Stevens
Disclosures: Sparano reports stock ownership in MetaStat; advisory or consultant roles with AstraZeneca, Bayer Health Care Pharmaceuticals, Celgene, Celldex Therapeutics, Eisai, Eli Lilly, Genentech, Juno Therapeutics, Novartis and Prescient Therapeutics; and research funding from AstraZeneca/MedImmune, Deciphera Pharmaceuticals, Eisai, Genentech, Merck, Merrimack Pharmaceuticals, Prescient Therapeutics and TapImmune. Please see the full study for a list of all other researchers’ relevant financial disclosures. Glynne-Jones reports honoraria from Amgen, Eisai, Eli Lilly, Merck Serono, Roche and Servier Laboratories; and other financial relationships. Harrison reports no relevant financial disclosures.
Perspective
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Sparano and colleagues report a phase 2 trial of chemoradiotherapy plus the anti-EGFR agent cetuximab (Erbitux, Eli Lilly) in HIV–associated anal cancer. The important observation from this trial is that HIV–related anal cancer is treatable and potentially curable. Outcomes were comparable to those reported in non-HIV–related disease, with achievement of similar local disease control and long-term survival. There was a suggestion in this trial of a trend toward improved local tumor control compared with historical literature. The researchers’ companion trial of cetuximab added to chemoradiotherapy in non-HIV–related anal cancer indicated significant potentiation of toxicity and a trend toward better local tumor control compared with historical controls. At best, such observations are hypothesis generating, with conclusions from single-arm phase 2 trials limited by the risk for patient selection bias. Historical-control comparisons also are subject to stage migration, which may occur in more contemporary trials using potentially superior imaging and staging.
The researchers used the precedent for cetuximab improving outcome when combined with radiotherapy in oropharyngeal cancers compared with radiation therapy alone. However, cetuximab added to combined chemoradiotherapy in oropharyngeal cancer ultimately added no benefit compared with chemoradiotherapy alone, and enhanced therapy toxicity. Cetuximab also failed to improve outcomes when combined with definitive chemoradiotherapy in esophageal cancer in either squamous cell or adenocarcinoma; in one trial, therapy delivery was compromised with cetuximab due to greater toxicity.
Although EGFR is an attractive target in gastrointestinal malignancies, drugs like cetuximab are currently limited to the treatment of RAS wild-type metastatic colorectal cancer. Advancing the treatment of locally advanced anal cancer will be dependent on identifying superior radiosensitizing agents to improve local cancer control, and more effective systemic agents to reduce systemic disease recurrence. Anti–PD-1 immune checkpoint inhibitor therapy has now shown a signal of activity in metastatic anal cancer. Evaluation of such agents in combined modality therapy will likely follow.
Ang KK, et al. J Clin Oncol. 2014;32:2940-2950.
Crosby T, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70136-0.
Garg MK, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.69.1667.
Ilson D, et al. J Clin Oncol. 2014;32:5s (suppl; abstr 4007).
Morris VK, et al. J Clin Oncol. 2016;34 (suppl; abstr 3503).
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