RTOG 1016: Cisplatin Still Standard for HPV-Related Oral Cancer

Roxanne Nelson, BSN, RN

October 26, 2018

SAN ANTONIO — Cisplatin plus radiation therapy should remain the standard of care for human papillomavirus (HPV)-positive oropharyngeal cancer, according to new findings from a major randomized phase 3 trial.

The two-arm trial compared systemic therapy (either cisplatin or cetuximab [Erbitux]) plus radiation in patients with locoregionally advanced HPV-positive oropharyngeal cancer.

Estimates of 5-year overall survival were 84.6% with cisplatin versus 77.9% with cetuximab in the Radiation Therapy Oncology Group (RTOG) 1016 trial.

"We've now established that high-dose cisplatin chemotherapy in combination with radiation therapy is the standard of care for HPV-related oral cancers," said lead author Andy Trotti, MD, a radiation oncologist at the Moffitt Cancer Center in Tampa, Florida. "Prior to this study, there were no definitive, state-of-the-art trials in this specific cancer population."

Trotti presented his findings during the plenary session here at the American Society for Radiation Oncology (ASTRO) 2018.

HPV-related oropharynx cancer was formally recognized in 2008 as a distinct cancer from smoking- and alcohol-related cancers, Trotti explained. Multiple studies have shown that with treatment it has a very high rate of survival (approximately 85%) and local control.

The current trial was designed to see if combination cetuximab/radiation would be less toxic than cisplatin/radiation without compromising survival for patients with the disease.

"We wanted to see if this was a disease site where we could de-intensify treatment to reduce the short- and long-term toxicity," Trotti said. "The priority objective was to show that cetuximab was not inferior to cisplatin in overall survival and to evaluate toxicity."

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

But what they found was that "cetuximab was not noninferior, and in fact, cisplatin was superior," he said.

Daniel Ma, MD, a radiation oncologist at the Mayo Clinic, Rochester, Minnesota, who was not involved with the study, said that the most important take-home message of RTOG 1016 is that treatment de-intensification should not be done outside the context of a clinical trial. 

"Like many academic head and neck oncologists, I regularly get questions from community providers about whether de-escalation can be done for their patients," he told Medscape Medical News. "I give them the same answer I tell my patients: the excellent historical results we wish to replicate were achieved with standard-of-care treatment, and de-escalation should only be done in the context of a clinical trial," he explained.

Changing Dynamics of Oral Cancers

Interim results of the study were released last August, as reported by Medscape Medical News. The data monitoring committee for the trial recommended that the data be released after the interim analysis, as it showed that cetuximab with radiation therapy was associated with poorer outcomes. 

The US Food and Drug Administration had previously approved cetuximab with radiation for patients with head and neck cancer, including oropharyngeal cancer. Cetuximab with radiation is currently an accepted standard of care, especially for patients who cannot tolerate cisplatin.

The number of cases of oral cancer associated with HPV has risen over the past several decades, even as rates for other head and neck cancers have generally declined. HPV now causes the majority of oropharyngeal cancers in the United States, and the incidence is rising, especially among men. From 1988 to 2004, the incidence of HPV-associated oropharyngeal squamous cell cancer (OPSCC) rose more than 200%, while rates of HPV-negative disease dropped by half.   

Survival rates are also higher than for non-HPV related OPSCC. The estimated risk of death is 50% lower among patients with HPV-positive than those with HPV-negative disease.

Meet the New/Old Boss

The RTOG 1016 trial enrolled 849 patients (805 in the final analysis) with HPV-positive oropharyngeal cancer who were stratified according to T stage (T1-2 vs T3-4), 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 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.

Cisplatin was associated with superior overall survival compared with cetuximab (HR, 1.45) and superior estimated 5-year progression-free survival (78.4% vs 67.3%; HR, 1.72).

Estimated 5-year rates of local-regional failure were also better in the cisplatin arm (9.9% vs 17.3%) as was distant metastases (8.6% vs 11.7%).

Grade 3-5 toxicities were similar between groups (82% for cisplatin vs 77% for cetuximab), without showing a significant difference (P = .16). However, Trotti noted that the traditional reporting of overall adverse event rates tends to obscure important differences in the magnitude of the toxicity profiles. Thus, he explained, the new metric T-score method does a much better job of capturing the frequency of high-grade events.

Using the Acute Toxicity Burden/T-score method, which captures all grade 3-4 acute adverse events, the result was 3.19 for cisplatin vs 3.35 for cetuximab, which extrapolates to a 40% higher toxicity burden (P < .001).

The same was true for late toxicity. Traditional assessment showed no significant difference between groups (20% vs 17%; P = .19), but the T-score again showed a 40% higher burden with cisplatin (0.38 vs 0.27; P = .12).

"RTOG 1016 establishes the first standard of care in HPV-related oropharynx cancer," concluded Trotti. "Cisplatin has been with us for 40 years, since 1971, so in other words, it's 'meet the new boss, same as the old boss.'" 

De-escalation Must Remain in Clinical Trials

Mayo Clinic's Ma reiterated that RTOG 1016 confirms the "signal we have heard from several retrospective series and subgroup analyses — that concurrent cisplatin is superior to cetuximab for HPV-associated oropharynx cancer patients."

Another important message is that there is a clear need for more prospective trials to help define the optimal subpopulation for reducing therapy, he noted. Questions looking at the role of tumor genomics in treatment sensitivity, or if imaging can help with patient selection, need to be addressed. "These types of questions will need to be answered as RTOG 1016 demonstrates that one size does not fit all," said Ma.

And finally, Ma emphasizes that "while the de-escalation community clearly has its work cut out, we should not ignore that we are in the midst of a cancer epidemic in a younger, otherwise healthy population."

Disease control remains paramount, but standard treatment has high rates of long-term toxicity and post-treatment depression rates as high as 50% in some series. "As Hippocrates states, 'The art is long, but life is short.' We owe it to our patients to put in the hard, prospective work to learn how we can preserve both quality of life and disease control," he said.

The study was supported by grants from NRG Oncology, the National Cancer Institute (NCI) Community Oncology Research Program (NCORP), the NCI, Imaging and Radiation Oncology Core (IROC), Eli Lilly, and the Oral Cancer Foundation. Trotti and Ma have reported no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2018. LBA 4. Presented October 23.

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