Chemoradiation should remain standard for HPV-positive oropharyngeal cancer

MUNICH — Patients with HPV-positive, low-risk oropharyngeal cancer should undergo chemoradiotherapy instead of cetuximab plus radiotherapy, according to late-breaking study results presented at European Society for Medical Oncology Congress.

Perspective from Ezra E.W. Cohen, MD; Jean-Pascal Machiels, MD, PhD

Patients who received cetuximab and radiotherapy combination achieved shorter OS, worse locoregional control and worse distant control than patients who received standard cisplatin with radiotherapy. Researchers observed no significant difference between groups with regard to toxicity.

Oropharyngeal cancer incidence is increasing dramatically in the Western world due to the greater prevalence of HPV-associated malignancies.

“These patients typically are younger — often in their 50s — and the good news is they respond well to treatment, often living 3 or 4 decades after treatment” Hisham Mehanna, PhD, BMedSc, MBChB, FRCS, FRCS(ORL-HNS), chair of head and neck surgery and director of Institute of Head and Neck Studies and Education at Institute of Cancer and Genomic Sciences in the United Kingdom, said during a press conference. “The corollary of that is treatment has significant toxicity, so they have to withstand these effects.”

Use of cetuximab (Erbitux, Eli Lilly) — an EGFR inhibitor approved in the United States for treatment of head and neck cancer — plus radiotherapy has been proposed as a less toxic alternative to cisplatin plus radiotherapy. Although the cetuximab-radiotherapy combination has been used in practice, no randomized trials evaluating the approach had been performed.

Mehanna and colleagues conducted the randomized, controlled De-ESCALaTE HPV trial to see whether a de-escalation strategy that used cetuximab plus radiotherapy could confer a similar survival benefit with less toxicity than standard cisplatin plus radiotherapy.

The international, multicenter study included 334 patients (mean age, 57 years; 80% men) with low-risk HPV-positive disease. Researchers randomly assigned 166 patients to radiotherapy (70 Gy in 35 fractions) plus cisplatin (three doses of 100 mg/m²). The other 168 patients received radiotherapy plus cetuximab, administered in a 400 mg/m² loading dose, followed by weekly doses of 250 mg/m².

Severe overall toxicity — defined as grade 3 to grade 5 — served as the primary outcome measure. Other key outcomes included OS and quality of life.

Researchers observed no significant difference between the cisplatin or cetuximab groups with regard to all-grade events per patient (overall, 29.15 vs. 30.05; acute, 19.96 vs. 20.35; and late, 9.44 vs. 9.87) or mean number of severe events per patient (overall, 4.81 vs. 4.82; acute, 4.43 vs. 4.35; and late, 0.41 vs. 0.48).

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Results also showed no significant difference in quality of life or swallowing difficulty between groups.

However, researchers reported a significantly higher mean number of serious adverse events per patient in the cisplatin group (overall, 1 vs. 0.58; mild, 0.2 vs. 0.1; moderate, 0.44 vs. 0.21; severe or life-threatening, 0.34 vs. 0.27).

“The surprise of the study was in survival, which was significantly worse for cetuximab,” Mehanna said.

A higher number of patients in the cetuximab group developed recurrence (29 vs. 10) or died (20 vs. 6).

Two-year survival rates were 97.5% with cisplatin and 89.4% with cetuximab (P = .001), equating to an HR of 4.99 (95% CI, 1.7-14.67). Investigators calculated a number needed to treat for harm of 12.

The survival outcomes appeared driven by differences in both locoregional recurrence (3% with cisplatin vs. 12% for cetuximab; P = .003) and distant recurrence (3% with cisplatin vs. 9% with cetuximab; P = .009).

The results show cisplatin should remain the standard of care for this low-risk, good-prognosis group of patients, Mehanna said.

“It is disappointing for our patients and clinicians that we haven’t been able to find something that is less toxic. It is good news, though, because we were using those treatments already and now we know which one we should be using,” Mehanna said.

Several other strategies are being studied. They include surgery with radiotherapy, radiotherapy with immunotherapy, and radiotherapy alone.

“The fact that the cisplatin [regimen] resulted in a difference not only in locoregional control but also distant metastases makes us cautious about de-escalation of treatment regimens that remove systemic chemotherapy,” Mehanna said. “We need to be careful and wait for more results before we move on to changing practice, and that really is very important.” – by Mark Leiser

Reference:

Mehanna H, et al. Abstract LBA9_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

Disclosures: Cancer Research UK provided funding for this study. Mehanna reports honoraria from AstraZeneca; speakers bureau roles with Merck, Merck Sharpe & Dohme, and Sanofi Pasteur; research funding from AstraZeneca, GlaxoSmithKline, GlaxoSmithKline Biologicals SA, Merck Sharpe & Dohme, Sanofi Pasteur and Silence Therapeutics; and travel accommodation expenses from Merck, Merck Sharpe & Dohme, and Sanofi Pasteur. Please see the abstract for all other authors’ relevant financial disclosures.

Perspective

Ezra E.W. Cohen, MD

The De-ESCALaTE study reveals two critical facets to keep in mind as we go forward. From a practical perspective, we now have solid evidence that cisplatin plus radiation is the standard of care for patients with locally advanced, HPV-positive head and neck cancer. Cetuximab is not an acceptable alternative except for those patients who have a contraindication to cisplatin. From a research perspective, this study lends an element of caution as we plan other de-intensification strategies. We do have to test these strategies prospectively before implementing them in regular practice because, although an approach may make sense, it still has to be proven. Otherwise, we risk sacrificing survival.

Ezra E.W. Cohen, MD

Moores Cancer Center

UC San Diego

Disclosures: Cohen reports no relevant financial disclosures.

Perspective

Jean-Pascal Machiels, MD, PhD

This study was performed in a curative setting for patients with HPV-positive disease. We know these patients have a very good prognosis when treated with chemoradiation. A previous study of radiotherapy plus cetuximab showed similar activity to chemoradiation. The common belief was that this treatment could be used instead of chemoradiation for these patients because it might decrease toxicity.

However, this study clearly shows the toxicity is the same between chemoradiation and radiation plus cetuximab, even if there are more serious adverse events with chemoradiation.

Clearly, we have a signal that the chemoradiation has more activity in this setting and it should remain the standard of care.

We cannot extrapolate this result to HPV-negative disease, but clearly we should mandate chemoradiation with cisplatin as the standard of care for those with HPV-positive disease.

Jean-Pascal Machiels, MD, PhD

Cliniques Universitaires Saint-LucBrussels

Disclosures: Machiels reports advisory board roles with or speakers honoraria managed by his institution from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Incyte, Innate, Janssen, Merck Serono, Novartis, Pfizer and Roche; travel expenses from Amgen, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Pfizer; data safety monitoring board roles with honoraria from Debio and Nanobiotix; and an uncompensated advisory role with Merck Sharpe & Dohme. He also serves as an investigator and study coordinator with European Organisation for Research and Treatment of Cancer.