The incidence of mouth and throat cancer is on the rise due to transmission of the human papilloma virus (HPV), but physicians at Memorial Sloan Kettering (MSK) Cancer Center have managed to significantly reduce the intensity of treatment and improve quality of life for these patients.

The Changing Demographic of Oropharyngeal Cancer: Including HPV as a Parameter

The most common treatment modalities for oropharyngeal cancer (OPC) include concurrent chemoradiation therapy, robotic surgery with postoperative radiation or chemoradiation, and induction chemotherapy followed by chemoradiation therapy—a combination known as trimodality therapy. Trimodality therapy can leave patients with debilitating side effects, including long-term issues with speech and swallowing. At MSK, fewer than 8% of oropharyngeal cancers are treated with trimodality therapy

 compared with the North American average of 41%.

 This massive decrease is due to a number of factors, but has occurred primarily because MSK employs a multidisciplinary approach to treatment planning as well as careful upfront patient selection for robotic surgery or nonsurgical treatment.

Historically, head and neck squamous cell cancer has been described as a homogenous disease of multiple anatomic sites that is strongly associated with tobacco and alcohol use.

But the increase in the HPV infection rate means that this virus is now the major cause of squamous cell carcinomas of the oropharynx, responsible for more than 80% of cases. This increase has been seen predominantly in developed countries, particularly in younger men, and is associated with sexual behaviors that increase HPV exposure.

Importantly, although HPV-related OPC is a “rapidly emerging disease,”

HPV-positive status is associated with a more favorable prognosis compared with HPV-negative disease.

 HPV-positive OPC shares histologic features with HPV-negative OPC, but there are fundamental biological differences. For example, HPV-positive OPC exhibits activated mutations of PIK3CA, a loss of TRAF3, and amplification of E2F1.

 This has important implications for targeted therapy.

However, this critical and now widely recognized parameter has not been accounted for in the current, seventh edition of the American Joint Committee on Cancer (AJCC) staging system, meaning that many patients with OPC are still being treated with therapy that is more aggressive than necessary. To address this, MSK physicians took part in the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S), a global initiative formed to incorporate HPV data into the development of prognoses.

 An independent validation of the ICON-S system recently demonstrated superior stratification of overall survival (OS) and progression-free survival (PFS) in comparison with the seventh edition of AJCC.

Robotic Surgery: Patient Selection Is Key

In 2014, MSK’s Head and Neck Service began convening surgery, radiation oncology, and medical oncology specialists for a weekly disease management team (DMT) review of every patient case involving a diagnosis of squamous cell carcinoma of the oropharynx. Pathology and radiology results are assessed prior to case review by a multidisciplinary tumor board, and an individualized treatment plan is designed for each patient by team consensus.

Robotic surgery now allows for tumors from the back of the throat to be surgically removed in a minimally invasive fashion with optimal visualization through the open-mouth transoral robotic surgery (TORS) system. At MSK, a formal radiology review is performed to identify factors that lead to postoperative chemoradiation, including extra capsular spread and being at high risk for positive margins. Only specifically selected patients who meet these criteria are offered TORS.

In nonselective approaches, surgery often leads to positive margins or removing nodes with extensive extracapsular spread of disease requiring postoperative chemoradiation (trimodality) therapy. Primary surgery may reduce, or possibly eliminate, the need for postoperative adjuvant chemotherapy or radiation therapy, depending on the final pathology results. Adjuvant therapy de-escalation remains a major rationalization for considering primary surgery over primary chemoradiation therapy.

Radiation Therapy: Review, Adaptive Replanning, and Dose De-Escalation

Another effort to explore the de-intensification of adjuvant therapy following robotic surgery of Oropharyngeal cancer is addressed by a clinical trial (ECOG 3311; NCT01898494) that is currently open at MSK. This trial offers patients the possibility of being randomized to receive a reduced dose of postoperative radiation or possibly avoid postoperative radiation entirely, based on pathologic parameters after robotic surgery. This national trial will examine feasibility and PFS. Secondary endpoints include assessment of OS, swallowing function, and adverse events.

As with surgery, a highly selective approach is taken with regard to patient suitability for radiation therapy.1 At MSK, each patient with head and neck cancer has a weekly MRI to determine treatment response. This allows the treating physician to adapt the radiation plan in real time to allow for more precise delivery of radiation to the tumor target while sparing the normal tissue.

Historically, all patients received about 6 to 7 weeks of radiation therapy. But because HPV-positive OPC responds better to treatment, our radiation oncologists now de-escalate the radiation dose delivered to normal tissues based on what the MRI shows. Even if the patient has had a gross total resection, the MRI helps to determine the anatomic changes with respect to all the normal tissues, such as the parotid glands and submandibular glands. Our radiation oncologists then adjust the treatment based on the change in each patient, which is why it is called adaptive radiotherapy. Before, we had only one plan and could not account for anatomic changes secondary to weight loss.

Leveraging Patient-Reported Outcomes to Improve Treatment of Oropharyngeal Cancers

We provide a variety of carefully selected clinical trials that offer promising new approaches for patients who are interested in participating. Some of these current trials are aiming to deescalate the intensity of treatment for HPV-related OPC, as well as reduce toxicity and side effects related to therapy. Others are designed to test novel therapies. Currently, we have a trial that shows promising results of treating selected patients with HPV-positive OPC with 30 Gy and chemotherapy. This is a reduction of almost 60% (from 70 Gy to 30 Gy) in radiation therapy. These preliminary results were reported at the 2017 ASCO Annual Meeting.

In an era in which HPV-related OPC is affecting an increasing number of younger patients with an excellent overall prognosis,6 there is a recognized need to maximize quality of life during and after treatment. As described, multimodality therapy in various sequences results in short- and long-term toxicities that affect swallowing, eating, and communication.

Measuring patient-reported outcomes (PROs) represents a vital component in the treatment of OPC at MSK. Validated quality-of-life instruments, some developed by experts at MSK,

 monitor the well-being of patients throughout treatment and beyond. Using a revolutionary new PRO platform—MSK Engage&mdash;patients can report their treatment experience to the MSK team. This information will be integrated into the electronic medical record and can then be evaluated by the DMT.

By measuring PROs as part of clinical care, referrals to ancillary departments—for speech and language pathology, swallowing rehabilitation, social work, and pain management&mdash;can promptly be made based on an individual patient’s needs during and after treatment. Understanding PROs also enables the DMT to develop novel treatment paradigms that will maintain high cure rates but minimize side effects in patients with OPC.

Hay AJ, Migliacci J, Zanoni DK, et al. Decision making in TORs for oropharyngeal squamous cell carcinomas: what is an acceptable tri-modality treatment rate? Poster presented at: 9th International Conference on Head and Neck Cancer; July 16-20, 2016; Seattle, WA. Abstract P495.

de Almeida JR, Li R, Magnuson JS, et al. Oncologic outcomes after transoral robotic surgery: a multi-institutional study.

2015;141(12):1043-1051. doi: 10.1001/ jamaoto.2015.1508.

Malm IJ, Fan CJ, Yin LX, et al. Evaluation of proposed staging systems for human papillomavirus-related oropharyngeal squamous cell carcinoma.

2017;123(10):1768-1777. doi: 10.1002/ cncr.30512.

Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. 

 2013;31(36):4550-4559. doi: 10.1200/ JCO.2013.50.3870.

O’Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. 

2016;17(4):440-451. doi: 10.1016/S1470-2045(15)00560-4.

Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer.

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Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. 

2015;517(7536):576-582. doi: 10.1038/nature14129.

Surucu M, Shah KK, Roeske JC, Choi M, Small W Jr, Emami B. Adaptive radiotherapy for head and neck cancer: implications for clinical and dosimetry outcomes. 

 2016;16(2):218-223. doi: 10.1177/1533034616662165.

Riaz N, Sherman EJ, Katbi N, J, et al. A personalized approach using hypoxia resolution to guide curative-intent radiation dose-reduction to 30 Gy: a novel de-escalation paradigm for HPV-associated oropharynx cancers (OPC). 

2017;35(suppl; abstr 6076). http://meetinglibrary.asco.org/ record/145919/abstract.

Chera BS, Eisbruch A, Murphy BA, et al. Recommended patient-reported core set of symptoms to measure in head and neck cancer treatment trials. J

Albornoz CR, Pusic AL, Reavey P, et al. Measuring health-related quality of life outcomes in head and neck reconstruction

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The incidence of mouth and throat cancer is on the rise due to transmission of the human papilloma virus, but physicians at Memorial Sloan Kettering Cancer Center have managed to significantly reduce the intensity of treatment and improve quality of life for these patients.

Richard Wong, MD

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