Deintensification therapy for HPV+ head and neck cancers

The oropharynx is now the leading anatomical site for human papilloma virus (HPV) related cancers in the United States, and HPV is projected to be the leading cause of oropharyngeal squamous cell carcinoma (OPSCC) by 2030. An evolving approach to intervention for these cancers involves deintensification therapy—a de-escalation of the treatment intensity traditionally applied to head and neck cancers.

To discuss deintensification therapy in this context, the Penn Medicine Physician Interviews podcast recently welcomed otorhinolaryngologist Karthik Rajasekaran, MD, and radiation oncologist Michelle Gentile, MD, in a two-part discussion of deintensification therapy in HPV+ head and neck cancers.

The first part of the interview provides an overview of the interaction of ENT surgery and radiation therapy in the pursuit of deintensification therapy for head and neck cancers at Penn Medicine. The second part concerns the role of radiotherapy (proton and IMRT) in recent groundbreaking clinical trials of deintensification therapy for OPSCC at the Abramson Cancer Center.

A younger, healthier demographic

Multiple clinical studies have demonstrated, that HPV+OPSCCs have more favorable outcomes than their HPV-negative counterparts, which are typically treated with an aggressive combination of chemotherapy, radiation, and surgery. Among the findings of these reports is that the lifelong side effects of aggressive treatment can be avoided by reducing the intensity of therapy in HPV+ OPSCCs.

Drs. Rajasekaran and Gentile note that individuals with HPV+ OPSCC cancers are a younger, nonsmoking, high-functioning demographic with an excellent long-term prognosis by comparison to their HPV-negative counterparts.

The recognition that HPV+ patients tend to have a better response to therapy brought about a sea-change in clinical perspectives of initial approaches to treatment of these cancers, as well as adjuvant therapies.

“When we first started treating these patients, we were treating all squamous cell cancers the same way, as if they were smoking-related cancers,” Dr Rajasekaran says. But with innovation and experience, the paradigm of treatment changed for surgeons.

“We started realizing that these patients may not need as much treatment as we were doing with the HPV-negative or smoking-related cancers,” he concludes.

The advent of deintensification therapy at Penn Medicine

Developed at Penn Medicine, transoral robotic surgery (TORS) brought about a new and innovative method of head and neck surgery in that it offered a modality for minimally invasive surgery within the confines of the oropharynx. Reaching these cancers in open surgery may involve splitting the jaw and other severe measures—and almost always, life-long disability as a result.

The introduction of TORS, Dr. Rajasekaran observes, meant that in some situations, and in some HPV+ cancers, removal or resection of a tumor could be achieved by deintensification—a lesser degree of treatment offering less exposure to post-surgical toxicities. Eventually, the promise of deintensification evolved to embrace the complete armamentarium for HPV+ head and neck cancers, including adjunctive chemotherapy and radiation therapy.

Deintensification in practice: a collaborative effort

In patients with a tonsil or a tongue-based cancer, and either no lymph node involvement, or a single small lymph node, deintensification of therapy can be obtained by surgery alone. In other patient profiles, including patients with five or fewer involved lymph nodes, diminishing the effects of treatment may take the form of surgery with limited radiation therapy, or radiation with limited chemotherapy in the absence of surgery.

Given the availability of these options and the vast variety of patient presentations, Drs. Rajasekaran and Gentile note the joint character of therapy for HPV+OPSCC, and the possibilities for deintensification.

“There’s a mutual trust,” Dr. Rajasekaran says, referring to the department partnership. “When we look at these tumors, if the surgeon feels like they can truly get negative margins, and our radiation oncologists believe that’s true, then we move forward.”

Dr Gentile adds that the team tries to tailor treatment to each patient so that they’re getting not only the best care, but the best chance of less side effects, reflecting that this effort includes predicting ahead of time who is “low risk,” and who will do well with deintensification. “There’s very specific pathologic criteria that allow us to move forward with these deintensification approaches,” she says.

Patients are followed closely following treatment with visits alternating between Drs. Rajasekaran and Gentile, typically every three months for the first one to two years.

“Most of these patients do really well,” Dr. Gentile says. “It’s very rare to see recurrences, and if we see something that’s suspicious, we’re catching it very, very early and are ready to be aggressive about it.”

In the second part of the Penn Medicine Physician Interviews podcast discussion of deintensification therapy in HPV+ head and neck cancers, Drs. Rajasekaran and Gentile discuss recent groundbreaking clinical trials of proton and photon radiotherapy for deintensification of treatment in these cancers.

Penn Clinical Research in radiotherapy for treatment deintensification in HPV+ head and neck cancers

In recent years, Penn Otorhinolaryngology-Head and Neck Surgery and Penn Radiation Oncology have participated together and individually in a series of important clinical trials relevant to HPV+ head and neck cancers. These include the evaluation of treatment deintensification in HPV+ OPSCC in the context of surgery and proton radiation therapy, and a groundbreaking comparison of the efficacy of proton therapy vs photon therapy in these cancers.

AVOID Clinical Trial

Conducted at the Abramson Cancer Center, the AVOID (Alternative Volumes of Oropharyngeal Irradiation for De-intensification) clinical trial (NCT02159703), was a single-arm phase 2 clinical trial to evaluate disease recurrence and toxicity in patients with HPV associated OPSCC after surgery and deintensified RT, targeting the at-risk cervical lymph node regions only and avoiding the primary tumor operative bed.

The object of AVOID was to test the hypothesis that surgery prior to RT results in a significant reduction of treatment toxicities in regionally advanced head and neck squamous cell carcinoma through radiotherapy volume reduction. The primary endpoint of the trial was to evaluate the toxicity from the beginning of radiotherapy until 90 days after the end of the treatment.

Results: Median follow-up of the patients enrolled was 2.4 years. Measured 2-year local recurrence-free survival was 97.9%; regional recurrence-free survival was 97.9%; distant metastasis-free survival was 96.2%; and progression-free survival was 92.1%. Overall survival was 100% at the two-year mark.

The study authors concluded that for selected patients with HPV-associated OPSCC, postoperative radiotherapy that avoided the resected primary tumor site to target only the at-risk neck after transoral robotic surgery may be safe.

A participating surgeon in the trial, Dr. Rajasekaran was a co-author in subsequent publications of the trial findings. The trial, he says, initiated a standard of care unique to Penn Medicine involving a combined effort between ENT surgeons and radiation-oncologists.

“It’s a really unique strategy that to my knowledge is only really used at Penn,” Dr. Gentile notes, adding that the incidence of recurrence in treated patients is very low. “It’s a very safe approach, and it allows patients to probably have better swallowing outcomes long-term than somebody who would require radiation to that primary site that was already resected.”

Intensity-Modulated Proton Beam Therapy or Intensity-Modulated Photon Therapy in Treating Patients With Stage III-IVB Oropharyngeal Cancer

This randomized, non-inferiority, phase 3 trial (NCT01893307) was conducted at 21 sites in the United States, including the Abramson Cancer Center, where the PI was Alexander Lin, MD, of Penn Radiation-Oncology. Dr. Lin was a co-author for the trial findings publication in the Lancet, which concluded that intensity-modulated proton therapy (IMPT) was a new standard-of-care treatment option for patients with oropharyngeal cancer.

In this trial, IMPT showed non-inferiority to intensity-modulated radiation therapy (IMRT) for progression-free survival, improvement in overall survival, similar disease control, and reduced high-grade toxicity. Treatment-related and post-progression deaths occurred more frequently with IMRT.

“This is a really interesting trial,” Dr. Gentile observed. “Basically, the results show that whether someone got photon or proton treatment, there was no difference in local, regional, or distant recurrences. But there was a surprising 10% survival benefit in favor of proton therapy at five years.”

At Penn Medicine, Dr. Gentile adds, proton therapy is often used for patients with HPV-positive cancers, with measures, including objective data, to ensure that it is an appropriate choice versus photon therapy.

To refer a patient to either the Department of Otorhinolaryngology-Head and Neck Surgery or the Department of Radiation Oncology, please call 877-937-7366 or refer a patient online.