Rethinking Traditional Therapies for Oropharyngeal Cancer

Rise of HPV-related squamous cell carcinoma a big factor

By Brian B. Burkey, MD, MEd, FACS

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Despite the decreased incidence of tobacco use, the number of oropharyngeal cancers diagnosed in the U.S. has increased rapidly over the past decade. This rise is expected to continue for at least three more decades ‒in the U.S. and in most other developed countries as well.

This “epidemic” of oropharyngeal cancer is attributable to a corresponding rise in the prevalence of human papillomavirus (HPV)-related squamous cell carcinoma (SCC), which is now more common than HPV-related cervical cancer.

The emergence of this new twist on an old disease has fascinated head and neck surgeons across the country, and Cleveland Clinic’s head and neck cancer multidisciplinary team is very active in elucidating the facets of this disease. Much of our ongoing research was presented at the 2014 Multidisciplinary Head and Neck Cancer Symposium in Scottsdale, Arizona. Members of our team, some of whom are also staff in the Head & Neck Institute, made oral and poster presentations at the meeting highlighting the unique nature of this disease and how it is distinct from the tobacco-related cancers that were seen so often in the past. Summaries of some of those presentations follow.

The Disease, Not the Treatment, Can Determine Outcomes

Because of unexpectedly good outcomes, we were able to stop a phase 3 trial of two cisplatin-based regimens of concurrent chemoradiation therapy (CCR) for locally advanced SCC of the head and neck.1 Excellent results were observed in both arms, primarily because of the high incidence of HPV-related oropharyngeal cancer (71 percent) among study participants. With alocoregional control rate of 99 percent at two years of follow-up and recurrence-free and overall survival rates of 90 percent each, the treatment response in patients with HPV-positive SCC in our study was superior to that seen in studies of other head and neck cancers.

We are confident our findings will have an impact on future clinical trials. These findings should make physicians wary of results of oropharyngeal cancer studies published in the past two decades that were not randomized by HPV status, since those outcomes may not depend on the type of treatment as much as on the type of disease treated.

This same trial also showed therapeutic and cost benefits in using cisplatin alone in CCR regimens for the treatment of advanced head and neck cancer rather than cisplatin and 5-fluorouracil (5-FU) combined.2 The simpler regimen achieved equal results with less morbidity and less expense.2

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A New Era in Treatment

HPV-positive SCC of the oropharynx also exhibits a quite distinct pattern and timing of recurrence. In a review of 285 patients treated for oropharyngeal cancer with chemoradiation therapy from 2002 to 2013, only 11 percent of those with HPV-positive tumors developed a distant metastasis, compared with 20 percent of those with HPV-negative tumors.3 The time from treatment cessation to development of those tumors also was longer in the HPV-positive group (21.6 months vs. 7.0 months). However, the HPV-positive tumors were much more likely to metastasize to multiple organ systems rather than to a single organ system, and these distant metastases arose in unusual locations (e.g., the pleura, bone and brain) (Figure).

Burkey Graph_RGB

Distribution and number of distant metastases in a Cleveland Clinic study of nearly 300 patients with oropharyngeal squamous cell carcinoma, according to tumor HPV status.

Furthermore, patients who developed a distant metastasis often experienced a surprisingly long survival with treatment (median, 36 months).4 These data challenge us to reconsider the way we evaluate, treat and follow HPV-positive oropharyngeal cancers, and they make us rethink the old paradigms that were ingrained in us during the era dominated by tobacco-related, HPV-negative SCC.

Normal Diet Despite Aggressive Therapy

Finally, our work shows that patients with HPV-positive oropharyngeal cancer can enjoy excellent functional outcomes despite aggressive therapy, and this too should make us think differently about how we compare treatment options.

In a cohort of almost 200 patients rendered free of HPV-positive oropharyngeal SCC after CCR from 2002 to 2012, 91 percent returned to a normal diet while only 2.5 percent were left dependent on tube feedings.5 The rate of late toxicity was even lower in patients treated with intensity-modulated radiation therapy rather than with traditional radiation methods and was likewise lower in those who did not receive concomitant 5-FU.

Rare Chance to Study an Evolving Disease

Our research in this area continues, and more was presented at the American Head & Neck Society meeting in July 2014. This work focused on evaluating patients’ understanding of HPV and HPV-positive SCC as well as on opportunities for prevention through patient education and vaccination.

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Moreover, surgeons and physicians at Cleveland Clinic recently received approval to participate in an NIH-sponsored phase 2 randomized trial that will compare four postoperative treatment regimens in advanced HPV-positive SCC of the oropharynx following transoral resections.

It is rare to have the opportunity to study a disease in evolution, and the clinicians and scientists in our head and neck cancer multidisciplinary team are excited to be taking a leading role in understanding and defining better treatment methods for this unique disease.

Dr. Burkey is Head of the Section of Head and Neck Surgery and Oncology as well as Vice Chairman of the Head & Neck Institute. He can be reached at 216.445.8837 or

1. Rodriguez CP, Adelstein DJ, Rybicki LA, et al. A phase III randomized trial of two cisplatin-based concurrent chemoradiation (CCRT) regimens for locally advanced head and neck squamous cell carcinoma (LAHNSCC) [abstract]. J Clin Oncol. 2013;31(18 suppl):Abstract 6035.
2. Greskovich JF, Gordian M, Lorenz R, et al. Improving healthcare value in patients with stage III-IVb squamous cell carcinoma of head and neck (HNSCC): comparative effectiveness of 2 arms of a randomized, phase 3 trial of definitive chemoradiation (chemoRT). Definitive management of head-and-neck squamous cell carcinoma [abstract]. Int J Radiat Oncol Biol Phys. 2014;88(2 suppl):466-467.
3. Trosman S, Al-Khudari S, Koyfman SA, et al. Distant metastatic failure patterns in squamous cell cancer of the oropharynx (SCCOP) treated with chemoradiation: the impact of human papillomavirus (HPV) definitive management of head-and-neck squamous cell carcinoma [abstract]. Int J Radiat Oncol Biol Phys. 2014;88(2 suppl):471.
4. Al-Khudari S, Guo S, Chen Y, et al. Solitary dural metastasis at presentation in a patient with untreated human papillomavirus-associated squamous cell carcinoma of the oropharynx. Head Neck. 2013 Dec 24 [Epub ahead of print].
5. Koyfman S, Bledsoe TB, Barnett J, et al. Modest late toxicity and excellent quality of life in patients with human papillomavirus (HPV+)-associated oropharyngeal carcinoma treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy: definitive management of head-and-neck squamous cell carcinoma [abstract]. Int J Radiat Oncol Biol Phys. 2014;88(2 suppl):478.