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ASCO 2014: Lower-Dose Radiation May Reduce Long-Term Side Effects Without Compromising Survival in Certain HPV-Positive Head and Neck Cancers

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Key Points

  • Customizing radiation doses based on response to induction chemotherapy may allow lower doses of radiation to be administered to some patients with HPV-positive oropharyngeal cancer without compromising outcomes.
  • Two-year progression-free survival and overall survival were 80% and 93%, respectively, among patients who received reduced doses of intensity-modulated radiation therapy.
  • For higher-risk patients who went on to receive full-dose intensity-modulated radiation therapy, the 2-year progression-free survival was 65% and overall survival was 87%.

According to a phase II study, customizing radiation doses based on response to induction chemotherapy and other prognostic factors may allow lower doses of radiation therapy to be administered to some patients with human papillomavirus (HPV)-positive oropharyngeal cancer without compromising outcomes. This approach may potentially result in significant reductions in toxicity while maintaining high rates of progression-free and overall survival. In the E1308 trial, reported at the 2014 ASCO Annual Meeting in Chicago (Abstract LBA6006), 95% of patients were alive 2 years after starting treatment.

“Treatment for head and neck cancer can be quite grueling, so it’s very encouraging to see we can safely dial back treatment in patients with less aggressive disease and an overall good prognosis, particularly for young patients who have many years to deal with long-term side effects,” said lead study author Anthony Cmelak, MD, Professor of Radiation Oncology at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. “However, we need longer follow-up, as well as confirmatory phase III data, before we can recommend applying this strategy in practice.”

An estimated 70% of newly-diagnosed oropharyngeal cancers are related to HPV, and the incidence of HPV-related disease appears to be rising. Patients with HPV-positive tumors tend to have better outcomes compared to patients with HPV-negative disease.

Based on Predecessor Study

“E1308 was based on a predecessor study, a large phase II study looking at patients with larynx and oropharyngeal cancers as an organ preservation approach, using induction chemotherapy with paclitaxel and carboplatin for two cycles followed by concurrent chemoradiation at a full dose of 70 Gy,” Dr. Cmelak explained at an ASCO press briefing on patient care and quality of life. “What we found in this study was that patients with HPV-associated cancers had markedly better response rates to induction chemotherapy, as well as overall survival through the entire regimen, with a 2-year progression-free survival of 86% vs 53% for patients with non–HPV-associated cancers.”

In addition, patients with HPV-associated cancers were younger, tended to be nonsmokers, and would have to deal with long-term side effects of treatment (including hypothyroidism, swallowing dysfunction, xerostomia, dental problems, and increased risk of stroke) for much longer portions of their lives due to the high doses of radiation.

In the current study, the investigators hypothesized that “using lower doses in these good responding patients could alleviate the long-term side effects of radiation while still maintaining approximately 85% 2-year progression-free survival that we saw using the higher doses of radiation in the predecessor study,” Dr. Cmelak explained. The results were “consistent with our hypothesis,” he stated.

Primary Progression-Free Survival Endpoint Met

The 90 patients in the study had resectable stage III/IVA HPV-positive oropharyngeal squamous carcinoma and received induction chemotherapy with paclitaxel, cisplatin, and cetuximab (Erbitux). The 62 patients who had a complete clinical response to induction chemotherapy received a reduced dose (54 Gy) of intensity-modulated radiation therapy, while the other patients received standard-dose intensity-modulated radiation therapy (70 Gy). Both groups of patients also received cetuximab along with radiation.

The study met its primary endpoint of progression-free survival. “In all 62 patients who went on to receive low-dose radiation, the 2-year progression-free survival rate was 80%,” Dr. Cmelak reported. The 2-year overall survival was 93%. Patients with ≤10 pack-years of smoking had slightly higher rates, 92% for progression-free survival and 97% for overall survival. For higher-risk patients treated who went on to receive full-dose intensity-modulated radiation therapy, the 2-year progression-free survival was 65% and overall survival was 87%.

“The results show that the toxicity was very mild,” Dr. Cmelak said. Patients in general had very few grade 4 toxicities; only one patient had one grade 3 toxicity long-term, and that was low magnesium at 30 months.”

A Step in the Right Direction

In response to a reporter’s question about whether these findings should change treatment recommendations, Dr. Cmelak said, “not based on a phase II study. It will take bigger studies and in a randomized fashion to prove that we can do this without risking patients’ lives.”

“As we try to treat with more precision, this is one step in that direction. But I don’t think that any of us would say that we are at the point where we know exactly how to modify the doses for HPV-positive cancers,” remarked Gregory A. Masters, MD, ASCO expert on head and neck cancers and Director, Medical Oncology Fellowship, and attending physician at the Helen F. Graham Cancer Center in Newark, Delaware.

Patients will be followed on this study for 5 years to capture late recurrences. Researchers are also planning another randomized phase II study that will explore an even less intensive approach involving reduced-field intensity-modulated radiation therapy to treat only areas of initial gross tumor in patients with low-risk HPV tumors.

This research was supported by the National Institutes of Health. Dr. Cmelak reported a consultant or advisory role with and honoraria from Bristol-Myers Squibb. For full disclosures of the study authors, view the study abstract at abstract.asco.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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