Study Supports Dialing Back Radiation for Some Patients With HPV-Positive Oropharyngeal Cancer

Anthony J. Cmelak, MD

Patients with less aggressive, human papillomavirus (HPV)-positive oropharyngeal cancer can be effectively treated with a lower-dose radiation regimen depending upon their response to combination induction therapy, according to study results that will be presented at the 2014 ASCO Annual Meeting.¹

This strategy has the potential to significantly reduce debilitating toxicities typically associated with radiation therapy for patients with this tumor type while maintaining high rates of progression-free survival (PFS) and overall survival (OS), lead author Anthony J. Cmelak, MD, said during a press briefing Friday as the ASCO conference opened in Chicago. The abstract will be presented in an oral session Monday.

If validated through further study, the approach could represent a new paradigm for treating patients with non-bulky, HPV-associated disease, noted Cmelak, who is a professor of Radiation Oncology at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. He said the results also indicate that chemoselection strategies merit additional investigation.

Strategy Enhances Outcomes

The findings come at a time when the incidence of HPV-associated disease—which typically has a better prognosis than HPV-negative disease—appears to be rising, with approximately 70% of newly diagnosed oropharyngeal cancers related to the virus, according to ASCO. In prior studies, patients who were HPV-positive tended to be younger, and thus likely to live for 30 or 40 years with adverse events stemming from their cancer treatment, Cmelak said.The Eastern Cooperative Oncology Group E1308 trial enrolled 90 patients with resectable, stage III or IVA/B oropharyngeal squamous carcinomas. The median age of the participants was 57 years; 46% of the group had never smoked while 84% were not currently smoking.

The phase II trial employed a two-step design in which patients first received an induction regimen consisting of cisplatin (75 mg/m²) on day 1, along with paclitaxel (90 mg/m²⁾ and cetuximab (250 mg/m²) on days 1, 8, and 15, every 21 days for 3 cycles.

After the induction regimen, 62 participants (among 80 evaluable patients) exhibited a complete clinical response, defined as no sign of disease on endoscopic exams. These patients then went on to receive a reduced dose of intensity-modulated radiation therapy (IMRT) of 54 Gy while those who did not respond were treated with the standard 70 Gy IMRT dose. All patients received cetuximab along with radiation.

of <T4, and no contralateral lymph node involvement (27 individuals) experienced 96% rates of PFS and OS at 2 years.

By contrast, the 2-year rates for all patients who received high-dose IMRT, which turned out to be 15 participants (3 patients did not receive radiation), were a 65% PFS and an 87% OS.

The study met its primary endpoint of PFS at a rate consistent with a 2-year PFS rate of 85% established in E2399, an earlier ECOG study aimed at organ preservation.² Cmelak said E2399 demonstrated that patients with HPV-positive tumors experienced “markedly better” response rates to induction chemotherapy as well as subsequent concurrent chemoradiation than did participants who were HPV-negative.

Toxicities Are Important Factor

Although lower-dose IMRT proved beneficial, the strategy evaluated in the E1308 study would not be appropriate for patients with HPV-negative or larger tumors, Cmelak noted in an ASCO press release.Cmelak said the lower-dose IMRT regimen amounted to a 23% reduction in the overall radiation dose compared with the standard. As a result, he said, toxicities experienced by patients in the lower-dose IMRT group were “very mild.”

Cmelak said only one patient experienced a long-term toxicity of grade 3 severity, and that was an instance of low magnesium at 30 months. Other grade 3 toxicities associated with the induction regimen included rash acneiform (21%), neutropenia (9%), and thromboembolism (3%). For concurrent chemoradiotherapy, grade 3 toxicities included mucositis (31%), dysphagia (17%), rash (13%), and lymphopenia (13%).

In general, adverse events associated with high-dose radiation include hypothyroidism, swallowing dysfunction, dental problems, and an increased risk of stroke, said Cmelak.

Patricia A. Ganz, MD, who served as moderator for the press briefing, said the epidemiology of oropharyngeal cancer is changing to include higher rates of HPV-associated disease as opposed to risk factors linked to tobacco or alcohol. She said this shift has presented an opportunity to reduce standard therapies and tailor therapy for these patients.

“This is another way of tailoring and targeting therapy and reducing the long-term toxicities in a group of individual patients who are likely to fare very well with this therapy,” said Ganz, MD, director of the Division of Cancer Prevention and Control Research at UCLA’s Jonsson Comprehensive Cancer Center in Los Angeles.

She said that if patients are “going to survive a long time, we want to modify our upfront therapy” so that they will not experience draining symptoms. “Because late effects can be very substantial in this population, if they’re going to survive a long time, we want to modify our upfront therapy so that they will not have these long-term sequelae,” said Ganz. ‘This is really an important survivorship question.”

References

1. Cmelak A, Li S, Marur S, et al. E1308: Reduced-dose IMRT in human papilloma virus (HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC). Presented at: 2014 ASCO Annual Meeting Press Briefing; May 30, 2014; Chicago, IL. Abstract LBA6006.
2. Cmelak AJ, Li S, Goldwasser MA, et al. Phase II trial of chemoradiation for organ preservation in resectable stage III or IV squamous cell carcinomas of the larynx or oropharynx: results of Eastern Cooperative Oncology Group Study E2399. J Clin Oncol. 2007;25(25):3971-3977.

<<<

View more from the 2014 ASCO Annual Meeting

Among the patients who received the lower-dose IMRT, the 2-year PFS and OS rates were 80% (90% CI, 0.70-0.88) and 93% (90% CI, 0.85-0.97), respectively. Participants who were nonsmokers had the best outcomes; notably, patients with a smoking history of ≤10 pack-years, non-bulky tumors