Less Intensive Treatment May Be Possible For Some Patients with HPV-Associated Head and Neck Cancer

Written By: Katharine Price, MD

In my experience as a head and neck medical oncologist, fear of long-term side effects of cancer treatment is second only to the fear of cancer recurrence. Treating the head and neck region using surgery, radiation, and chemotherapy, can result in significant permanent side effects including dry mouth, altered or absent taste, difficulty swallowing, and chronic pain. Until recent years, the trend in the treatment of head and neck cancer was to intensify treatment to try and improve outcomes for patients – alter the radiation schedule, add chemotherapy, or combine multiple chemotherapy drugs together. Although there were some modest improvements in cancer outcomes and survival, it was at the cost of more patients experiencing more intense and permanent sequelae of cancer treatment.

Approximately 10-15 years ago, researchers noted that the human papillomavirus (HPV) was present in an increasing number of cancers of the oropharynx (tonsil and base of tongue). The increase was quite dramatic – in the 1980’s only 16% of cancers were associated with HPV, but in the 2000’s this percentage had risen to greater than 70%! Subsequent research showed that HPV was causing cancers of the oropharynx, and that the chance of long-term survival or cure with standard treatments was significantly better.

Once HPV was established as a cause of head and neck cancer, it became evident that HPV-associated cancer was truly a different disease than cancer of the head and neck caused by smoking and alcohol use. HPV cancers often occur in patients at a younger age, and frequently in patients who have never smoked. HPV cancers are much more common in men (8 times more common), and most people who develop a cancer caused by HPV are healthy without significant medical conditions. On a molecular level, HPV cancers have fewer mutations (alterations in tumor genetic make-up) than those caused by smoking. And notably, HPV cancers appear to be more sensitive to standard cancer therapies including radiation and chemotherapy.

The rising number of HPV cancers in younger, healthier patients means that there are more long-term survivors of head and neck cancer, and that these individuals will potentially live decades with the side effects of their cancer therapy. This new reality has driven a wave of research in head and neck oncology looking to change treatment paradigms for HPV-associated head and neck cancer with two fundamental goals: preserve the high cure rates and minimize treatment-related long-term side effects.

Long-term, permanent side effects of treatment for HPV oropharynx cancer is primarily driven by the extent (radiation field) and dose of the radiation therapy that is administered. The resurgence in recent years of minimally-invasive, robotic surgery to remove oropharynx cancer has minimized the long-term side effects of surgery and allows for a lesser dose of radiation therapy after surgery. In 2013 our multidisciplinary cancer care team – head and neck surgeons, radiation oncologists, medical oncologists, swallow therapists, and dentists – at Mayo Clinic began testing a new approach to treating patients with human papillomavirus (HPV)-related oropharynx cancer that allowed patients to receive a significantly lower dose of radiation than what is typically given with standard radiation regimens. Because the treatment was experimental, it was given in the setting of a research study, or clinical trial. The study enrolled 80 patients between September 2013 and June 2016 at the Mayo Clinics in Rochester, Minnesota, and Scottsdale, Arizona. All patients were diagnosed with a squamous cell cancer of the tonsil or base of tongue that was associated with HPV and was confined to the head and neck region, and had never smoked or had only smoked for a short period of time in the past. All patients first underwent surgery to remove the cancer from the tonsil or back of tongue and the lymph nodes in the neck. Most of the surgeries were performed through the mouth with the use of a robot (transoral robotic surgery), allowing for complete removal of the cancer with minimal long-term consequences.

Approximately one month after surgery, patients then had two weeks of radiation therapy given twice daily, Monday through Friday (10 total days on treatment, 20 total radiation treatments) along with a small dose of chemotherapy each week (total 2 doses of chemotherapy). The patients were divided into two groups based on pathologic risk factors (microscopic features that contribute to a risk of cancer recurrence) which determined their total radiation dose. Cohort A consisted of patients with one or more intermediate risk factors on pathologic analysis including lymphovascular space invasion, perineural invasion, ≥2 lymph nodes involved with cancer, any single lymph node containing cancer > 3 cm, or a primary tumor > 4 cm. Patients in Cohort A received a total radiation dose of 30 Gy along with a small dose of chemotherapy (docetaxel) each week. Cohort B included patients with the high-risk pathologic feature of extranodal extension (microscopic extension of cancer cells outside the lymph node capsule) and these patients received a total dose of radiation of 36 Gy along with the same chemotherapy.

How does this experimental regimen compare with standard treatment for oropharynx cancer? There are two widely accepted standard treatment options for HPV oropharynx cancer that is confined to the head and neck region, and thus potentially curable. The first option involves seven consecutive weeks of daily radiation therapy (Monday through Friday) to a total dose of 70 Gy along with high-dose chemotherapy, typically cisplatin. The second option entails having surgery first to remove the cancer in the throat and the lymph nodes in the neck followed by six consecutive weeks of daily radiation therapy (Monday through Friday) to a total dose of 60 Gy with or without chemotherapy (also cisplatin). In both of these standard treatment pathways, patients receive a significant dose of radiation therapy and require months to recover from the short-term toxicities of treatment. The typical progression of radiation-related side effects include dry mouth and absent taste in the first 1-2 weeks of radiation followed by progressively more intense mouth sores (mucositis) and thick saliva for the remainder of treatment. Collectively, these side effects make it difficult to keep eating and drinking, and a significant number of patients – approximately 20% in modern studies – require a feeding tube in the stomach (PEG) to safely complete treatment. Side effects gradually lessen over the weeks to months that follow treatment, although improvement is slow but steady. Most patients will return to work approximately 3 months after the completion of therapy and most patients need a full year before they feel almost back to their baseline level of functioning. Cisplatin chemotherapy can cause short-term side effects of nausea, decreased blood counts, electrolyte disturbances, ringing in the ear, and injury to the kidneys.

In contrast, our study with a shortened course of radiation (half of standard dosing) and low-dose chemotherapy after surgery allowed for less short-term toxicity and a faster recovery then seen with standard treatment. Effectively, the twice daily radiation therapy for two weeks was half the total dose of radiation therapy compared with the standard six weeks of radiation after surgery. In our study, patients generally felt well while they were going through the two weeks of treatment, but then quickly developed mouth sores and thick saliva at the end of treatment which was intensive for 1-2 weeks and then rapidly improved. As a result, only one patient required a feeding tube in the stomach to get through treatment safely, and most patients were back to work and eating a full diet by one month post completion of radiation therapy. We chose to substitute the chemotherapy docetaxel for cisplatin as it does not have significant short or long-term complications in small doses as given in the experimental treatment. The only notable side effect we saw during treatment was an allergic reaction during the docetaxel infusion in a handful of patient which was easily treatable with medications such as diphenhydramine (Benadryl).

Not only are short-term (acute) toxicities improved with the de-intensified treatment, but long-term toxicity rates and quality-of-life are as well. Historically, for standard treatment regimens of radiation and chemotherapy, the rates of significant long-term side effects (grade 3 or 4) are high (10-80%) depending on the study. In our study, there were no grade 3 or 4 toxicities seen beyond 3 months. The most frequent long-term grade 2 toxicities seen were dry mouth and mild swallowing dysfunction. Grade 2 (moderate) and grade 3 (severe) toxicity rates before radiation and at 1 and 2 years after radiation were 11.4% and 2.5%, 1.4% and 0.0%, and 6.7% and 0.0%, respectively. The most frequent grade 2 events were dysphagia, xerostomia, and oral mucositis. There were no long-term complications seen from the chemotherapy on the study. Quality of life was measured by several well-established tools (surveys) and showed improvement over the year following treatment compared to baseline measurements done after surgery and before radiation. The only quality of life measurement that showed a temporary decline was a tool looking at quality of life related to dry mouth, which declined slightly immediately after radiation therapy and then recovered.

We found that measurements of efficacy including recurrence rates and survival rates were comparable to standard treatment regimens. Patients were followed for an average of three years before study results were reported. For the study patients as a whole, the local-regional control rate at two years was 96%, meaning that 96% of patients had no evidence of cancer in the head and neck two years after completion of treatment. When broken down by cohorts, patients in Cohort A (intermediate risk) had 100% local-regional control (no recurrences in the head and neck), and patients in Cohort B (high risk) had a local-regional control rate of 93%. For the study as a whole, 95% of patients were alive at two years with no evidence of distant metastases (spread of cancer outside the head and neck). As anticipated, more recurrences were seen in the high risk group than in the intermediate risk group. One patient in Cohort A (2.8%) and nine patients in Cohort B (20.9%) experienced some type of disease recurrence (local-regional or distant).

It is well-established that a cancer diagnosis and cancer treatment is a significant financial stressor for patients and their families. As part of the study, we conducted a financial analysis of the shortened treatment compared with standard of care therapy. Total average treatment cost for patients receiving the shortened treatment was $45,884, of which $17,791 comprised chemotherapy and radiation therapy charges and $28,093 were surgical or imaging/examination charges. Average total charge for patients receiving standard 6-week adjuvant therapy during this same time period was $57,845, of which $26,603 comprised chemotherapy and radiation therapy charges and $31,242 were surgical imaging/examination charges. This study had a 33% reduction in radiation therapy cost and a 21% reduction in total treatment cost compared with standard adjuvant therapy. As health care costs continue to grow, it is important to look for treatment options that can lessen financial toxicity for patients with cancer and their families.

The 2-year results from our study demonstrated the feasibility and promise of this treatment regimen for patients with a minimal smoking history and HPV-associated oropharynx cancer. In particular, this appears to be a promising regimen for patients with HPV oropharynx cancer with intermediate risk factors after surgery (Cohort A). Currently, our Mayo group is conducting a larger follow-up study that is a head-to-head comparison of our two week post-surgical regimen to the standard of care post-surgical regimen (6 weeks of daily radiation therapy with or without chemotherapy). This study is randomized to allow a clean, objective comparison between these two treatments.

Our hope is that our ongoing larger study will help to define which patients can safely receive this de-intensified regimen and eventually to allow such patients to receive the shorter regimen as standard treatment outside of a clinical trial. For now, however, our shortened regimen of twice-daily radiation and weekly chemotherapy after surgery is still considered experimental and can only be given in the setting of a clinical trial.

The future is looking bright for the treatment of HPV-associated oropharynx cancer. Our research effort is only one of many different approaches that are being studied across the country and the world to minimize how much treatment patients with HPV head and neck cancers require to cure the disease and maintain quality of life and function. The greatest joy that we have as doctors and researchers is seeing our patients back years later with no evidence of cancer and enjoying all that life has to offer. We learn so much from each and every patient, and extend tremendous gratitude to all of our patients who participated in the trial to help redefine the future for head and neck cancer.

My final parting thought – from oncologist to patient – is to PLEASE encourage all family members and friends to vaccinate their children and young adults against HPV. These are preventable cancers, and prevention is truly the ultimate and least toxic of all cancer treatments.

Reference: 1Ma DJ, Price KA, Moore EJ, Patel SH, et al. Phase II Evaluation of Aggressive Dose De-Escalation for Adjuvant Chemoradiotherapy in Human Papillomavirus–Associated Oropharynx Squamous Cell Carcinoma. J Clin Oncol 37:1909-1918.

Editors Note: Katharine A. Price, M.D., is Associate Professor of Oncology and Chair of the Head and Neck Cancer Tumor Group in the Division of Medical Oncology at Mayo Clinic in Rochester, Minnesota. Dr. Price is a Connecticut native who completed undergraduate studies in French at Harvard University before attending medical school and internal medicine residency at Mayo Clinic in Rochester, Minnesota. During residency training she developed an interest in head and neck cancer. She completed her oncology training at Memorial Sloan-Kettering Cancer Center in New York, New York, before returning to Mayo Clinic to join the staff in 2010. Since that time she has focused her clinical practice and research on the care and treatment of patients with head and neck cancer.

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