In Pursuit of Less Toxic Treatments for HPV+ Oropharyngeal Cancers

Missak Haigentz Jr, MD

While the prognosis remains good for individuals with HPV-positive oropharyngeal cancers, the incidence of these cancers continues to rise, and researchers are currently seeking less intense treatment options that are equally effective but not as toxic for patients.

Oncogenic HPV infection is now a recognized etiology in approximately half of oropharyngeal squamous cell cancers. HPV-positive cancers typically have better outcomes and a lower likelihood of second primary cancers than their HPV-negative counterparts.

On the other hand, the incidence of oropharyngeal cancers is growing—now surpassing cervical cancer—and the increase is expected to continue over the next 30 years, particularly for men currently aged ≤40 years.

“This is a major public health concern of our time,” said Missak Haigentz Jr, MD, presenting an update on treatments for head and neck cancers at the 33rd Annual Chemotherapy Foundation Symposium.

Effective therapies exist, often involving combinations of chemotherapy, radiotherapy, and surgery, but long-term effects of these complex treatment regimens can negatively impact quality of life for survivors.

Multiple studies have corroborated a survival advantage in patients with HPV-associated disease, with 5-year survival of HPV-positive patients approaching 80%, noted Haigentz, an associate professor of Clinical Medicine at the Albert Einstein College of Medicine, Montefiore Medical Center.

Although current staging classifications do not account for HPV status, Haigentz said, HPV status is the most important prognostic factor, followed by smoking status. For example, a patient who is HPV-positive and a never or light smoker would have the best prognosis, whereas a patient who is HPV-negative and a smoker is likely to have poorer outcomes; HPV-positive smokers appear to have an intermediate prognosis, he said.

It is well established that patients with head and neck cancers have severe, acute, and frequently long-term toxicities from curative therapy, with some resulting in chronic functional impairment. These toxicities include mucositis, dysphagia (including feeding tube dependence), xerostomia, dental complications, hypothyroidism, lymphedema, and fibrosis.

“As physicians, it is our obligation to consider any opportunity to reduce treatment morbidity in the management of these patients,” Haigentz stressed.

He suggested that HPV-associated cancers’ more favorable prognoses can set the stage for “treatment deintensification, where a gentler therapy may be sufficient to cure a patient,” underscoring that such an approach assumes treatment efficacy will be preserved. Alternatively, for poor-risk, HPV-negative patients, treatment intensification is needed. All this makes patient selection crucial, said Haigentz.

Several strategies for treatment deintensification for HPV-positive oropharyngeal cancers are under clinical evaluation, for example, replacing concurrent cisplatin with cetuximab or reducing radiation doses. “Some of these studies employ selection strategies, which I think are ideal for evaluating and tailoring therapy based on personalized risk.”

A phase III trial under the auspices of the Radiation Therapy Oncology Group (RTOG 1016) is comparing high-dose cisplatin with cetuximab in patients with oropharyngeal cancer whose tumors are p16-positive. The primary endpoint of the study, which accrued nearly 1000 patients and closed in 2014, is 5-year overall survival. Haigentz said that outcomes over the next several years are eagerly awaited to shed light on the efficacy of replacing chemotherapy with the targeted agent.

Other ongoing international studies comparing chemotherapy with cetuximab have novel endpoints, including the DE-ESCALATE study in the UK where the endpoint is severe toxicity, and the TROG 12.01 study in Australia, where the primary outcome is symptom severity.

Additionally, NRG Oncology is evaluating chemoradiotherapy versus accelerated radiotherapy alone in p16- positive patients (NCT02254278), and the trial is currently recruiting participants. Other treatment strategies being studied include minimally invasive trans-oral surgical procedures [Transoral Laser Microsurgery and Trans-Oral Robotic Surgery (TORS)] to limit morbidities from surgery and subsequent radiotherapy.

With the caveat that avoiding overtreatment in some patients might jeopardize outcomes for others, Haigentz said that patient selection presents a unique opportunity to be able to impact quality of life and treatment morbidity.

“Rather than being stronger, perhaps we need to be smarter,” he suggested, stressing that to define new patient care paradigms, a robust, ongoing clinical trials program in oropharyngeal cancer is essential.

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