No Change in Standard of Care for HPV+ Oropharyngeal Cancer

Roxanne Nelson, BSN, RN

August 20, 2018

The standard of care for human papillomavirus (HPV)–positive oropharyngeal cancer remains radiation therapy and cisplatin, say experts, after interim results from a large phase 3 trial comparing another regimen showed worse outcomes.

Patients who were treated with radiation and cetuximab had worse overall and progression-free survival, but overall rates of serious (grade 3 to 5) adverse events were similar for both study groups. These top-line results from RTOG 1016 were outlined in a press release issued by the National Cancer Institute (NCI), which funded the trial.

Full results will be presented at the plenary session at the American Society for Radiation Oncology (ASTRO) annual meeting on October 22 and will later be published in a peer-reviewed journal.

"This trial is the first randomized clinical trial specifically designed for patients with HPV-positive oropharyngeal cancer, and it establishes cisplatin with radiation as the standard of care," said one of the lead investigators, Maura Gillison, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.

Quynh-Thu Le, MD, chair of the head and neck cancer committee for NRG Oncology and professor and chair of radiation oncology at Stanford University in California, was another lead investigator. "The primary objective of the trial was to determine whether the substitution of cetuximab for cisplatin would result in comparable 5-year overall survival while reducing toxicity in the enrolled patient population," she explained.  

Cetuximab with radiation is already US Food and Drug Administration approved for use in head and neck cancer, including oropharyngeal cancer, and is an accepted standard of care, especially for patients who cannot tolerate cisplatin.

The hope was that this regimen would offer similar efficacy but have fewer side effects than the standard regimen of radiation of cisplatin.

However, the results showed that it was inferior in efficacy. "We were surprised by the loss of tumor control with cetuximab," commented Andy Trotti, MD, from the Moffitt Cancer Center in Tampa, Florida, another lead investigator.

In addition, the overall rates of serious (grade 3 to 5) adverse events were similar for patients in both groups. However, as the researchers expected, toxic side effects were different: Adverse events of renal toxicity, hearing loss, and bone marrow suppression were more common in patients in the cisplatin group, while body rash was more common in the cetuximab group.

Study Details

The multicenter trial enrolled 849 patients with HPV-positive oropharyngeal cancer who were stratified according to T stage (T1-2 vs T 3-4), N stage (N0-2a vs N2b-3), Zubrod performance status (0 vs 1), and smoking history (≤10 pack-years vs >10 pack-years).

All patients received image-guided intensity-modulated radiation therapy (IMRT) once daily on days 1 to 4 and twice daily on day 5 each week  for 6 weeks. The cohort was also randomly assigned to receive high-dose cisplatin intravenously (IV) over 1 to 2 hours on days 1 and 22 or cetuximab IV over 1 hour once weekly for 7 weeks.

The data monitoring committee overseeing the trial recommended that the data be released after an interim data analysis, as it showed that cetuximab with radiation was associated with poorer outcomes.  Cetuximab combined with radiation has been previously approved for patients with head and neck cancer, including oropharyngeal cancer, and is an accepted standard of care, especially for patients who are unable to tolerate cisplatin.

The study had three planned interim analyses, and these results are from the third and final analysis, conducted after a median follow-up of 4.5 years.

"In addition to the primary endpoints, the trial also examined several secondary endpoints, including patient-reported quality of life, treatment cost-effectiveness, the impact of tobacco exposure, and molecular predictors of outcomes," said Le.

Experts Weigh In

Approached for an independent comment,  Brian O'Sullivan, MD, professor of radiation oncology at Princess Margaret Cancer Centre in Toronto, Ontario, Canada, speculated about the results. "There are a number of possibilities about why the result may have turned out this way," he said. "Some of the reasons are potentially related to the fact that we know so much more about the behavior of this disease now compared to when the trial was designed."

 Different subgroups could readily have fared differently, he noted. "Interpretation also could vary depending on what is being assessed as an outcome, such as did patients have different local, regional or distant failure patterns intrinsically within such groups, and were these influenced in different ways by the two treatments?"

But the bottom line, he reiterated, is that "radiation therapy with cisplatin remains the standard of care until we see results of this and other trials."

Another expert pointed out that the findings were "a surprise" but added that he needed to see more data to be able to comment.

"The standard of care is radiation therapy plus cisplatin, but this may change when we see data from other studies which are evaluating the role of chemotherapy and also the proper dosing of radiation therapy," said Louis B. Harrison, MD, professor and chair of radiation oncology and vice president at Moffitt Cancer Center.

The study was funded by the National Cancer Institute (NCI) and led by NRG Oncology, part of NCI's National Clinical Trials Network.

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