HPV Associated Head & Neck Squamous Cell Carcinoma

HPV Associated Head & Neck Squamous Cell Carcinoma
Provided by the Johns Hopkins University School of Medicine and 
the Institute for Johns Hopkins Nursing.

While therapeutic advances for patients with head and neck squamous cell carcinoma (HNSCC) have slightly improved survival rates over the past 10 to 15 years, 30% to 40% of this patient population still face recurrences or distant metastases.1-5 Among those with oropharyngeal HNSCC, epidemiological and molecular studies have demonstrated that there are distinct biological differences between human papilloma virus (HPV) and non-HPV associated carcinomas. The decreasing rate of smoking in the United States has been associated with a general decreasing rate of smoking-associated–HNSCC, but there has been an epidemic rise in HPV-associated oropharyngeal HNSCC. Interestingly, these HPV associated tumors have been shown to improve the prognosis towards numerous standard of care oncologic treatments.4 Yet, these HPV-associated HNSCC patients still face the possibility of recurrence and distant metastasis.5 The rate of regional recurrences and distant metastasis of non-HPV associated HNSCC are significantly worse as these failure rates are still approximately 50% for patients with non-HPV associated HNSCC.

Disease Stage and Treatment Strategies
While modified staging for patients with HPV-associated HNSCC is currently being developed, the standard of care for patients with early stage (stages I and II) HNSCC versus advanced stage (stages III and IV) disease is typically characterized by a single modality therapy versus multimodality therapy, respectively. For patients with oropharyngeal tumors, stage I and II disease can be treated with either surgery or radiation alone, while patients with advanced disease should undergo either surgery followed by adjuvant external beam radiation or concurrent chemoradiation therapy.6 Chemotherapy in patients with HNSCC is thought to “sensitize” the tumor killing of primary radiation therapy. Employing a triple modality of surgery, radiation, and chemotherapy and the use of epidermal growth factor receptor-inhibiting/blocking agents for advanced diseases that are prognostically poor are still being investigated. For patients with HPV-associated oropharyngeal tumors with improved prognosis, multiple tertiary medical centers are currently evaluating “de-intensification” clinical trials.7

An important consideration for patients with HNSCC is the morbidity rate associated with various treatment modalities. While traditional open surgical approaches for patients with advanced tumor stage oropharynx had required tracheostomy and extensive reconstructive surgery, recent advances in transoral robotic surgery for patients with oropharyngeal tumors have allowed surgical resections with minimal postoperative morbidity. There are now active studies evaluating the comparative dysphagia scores between the surgical pathway versus the chemoradiation pathway for patients with locally advanced oropharyngeal tumors.

As described in detail later in this activity, a great deal of recent research has also focused on modulation of immune function as a potential treatment strategy for patients with HNSCC, and several immune-modifying agents are currently being evaluated in clinical trials.

Decision Point Question 1
RP is a 51-year-old CEO of a mid-sized company who presents with a right nontender neck mass that he has had for several weeks. He has a distant history of smoking but quit 10 years ago. He first noted the mass while shaving, which is located just inferior to the jaw bone. The mass has not increased in size over several weeks and is not tender. RP denies any dysphagia, otalgia, and odynophagia. RP has been dieting and exercising to lose weight, and he has lost just under 10 lbs over the past several weeks. He denies any changes in his voice, but he notes that he experiences more throat clearing when he speaks in public. He denies any coughing when he eats or drinks. An ultrasound-guided fine needle aspiration shows squamous cell carcinoma. Computed tomography (CT) images of his neck show a 2.5 cm cystic neck mass in level 2 with no asymmetry in the oropharynx. CT of the lung showed 1 nonspiculated 4 mm nodule in the left lower lobe. An ear, nose, and throat evaluation showed no primary tumor on endoscopy in the clinic; RP’s bronchoscopy was negative.

Which of the following would NOT be part of the workup for this patient?
Positron emission tomography (PET)/CT
p16 immunohistochemistry (IHC) test
Operative endoscopy and possible tonsillectomy
Swallowing evaluation with speech therapy

There are several salient features of RP’s presentation that should be underscored. Clinicians should appreciate that the nodal compartments of the neck are subdivided into multiple levels, where the metastatic nodal disease can direct the hunt for the primary tumor. Upper nodal disease – levels I through III – are more indicative of primary cancer of the head and neck, while level IV to V supraclavicular nodes should prompt an investigation of the esophagus and lung with squamous carcinoma histology.8

Secondly, clinicians should be aware of the distinct clinical behavior of HPV-associated oropharyngeal squamous cell carcinoma. HPV-associated head and neck cancer arise primarily from the oropharynx, namely from the tonsil or the base of tongue. While there are some sub-sites that have shown to be associated with HPV positivity, there is no clear indication that their clinical prognosis are affected with their HPV association. Of the various tests, the p16 immunohistochemistry test has been clearly linked to prognosis. While p16 is not a HPV derived oncoprotein, its presence is an excellent surrogate marker for HPV-associated disease.9

Patients with HPV-associated oropharyngeal tumors respond remarkably well to standard therapy, whether they are treated with surgery/external beam radiation therapy (XRT) or chemotherapy/XRT. As a result, most of the clinical studies for these HPV-associated tumors entail de-intensification. Patients with HPV-associated HNSCC do not present with metastatic disease to distant sites. For patients with locally advanced HPV HNSCC, PET/CT is not warranted. For unknown primary tumors, some clinicians use PET/CT to see if it can provide a more sensitive image to a localized the primary site, but there is no definitive evidence to warrant its use in examining patients for distant metastasis.

Outside of a standard workup for patients with HNSCC, patients with HPV-associated HNSCC require a swallowing evaluation prior to the initiation of any treatment. All forms of treatment will affect swallowing function in patients’ oropharyngeal tumors, so patients will need counseling regarding the risks involved with all treatment options. Clinical evidence shows that swallowing counseling and therapy can improve peritreatment swallowing function.10 When patients with oropharyngeal tumors have been treated with chemotherapy/XRT, they also require a thorough evaluation by the otolaryngologists who may schedule the patient for an operative endoscopy and possible tonsillectomy, particularly those with unknown primary tumors.

Decision Point Question 2
RP’s p16 test results were positive, and his ears, nose, and throat physician consented RP for an operative endoscopy and bilateral tonsillectomy. The final pathology of his tonsil tissues showed no evidence of malignancy, and his chest CT did not show any metastatic disease.

Which treatment would be the LEAST appropriate for RP?
Concurrent platinum-based chemotherapy and intensity-modulated radiation therapy to the oropharynx and neck
Transoral robotic surgery for resecting the ipsilateral base of the tongue
Induction taxane/platinum/5-fluorouracil-based chemotherapy
Continuation of swallowing therapy during oncologic therapy

As noted, patients with HPV-associated carcinomas do not require increasing intensifications of their treatments. These patients respond remarkably well to either surgery and XRT or concurrent chemoradiotherapy. Most centers have adopted either concurrent platinum-based chemotherapy with IMRT or transoral robotic surgery (TORS) followed by IMRT. There is currently a multi-institutional clinical trial examining the role of TORS in their ability to de-intensify radiotherapy for patients with locally advanced HPV-associated oropharyngeal tumors.11

Detecting Primary Tumors

For unknown primary tumors, the p16 status of the neck can narrow the primary site to the oropharynx, as is in RP’s case. Patients can receive standard chemotherapy/XRT to the oropharynx and the neck without exposing the nasopharynx and the larynx. This standard care in treating the nasopharynx to the larynx would spare the patient of significant morbidity of extensive radiotherapy.
Methods of localizing the primary site for these unknown primary tumors are currently being actively studied by academic centers throughout the country. Radiographic methods include imaging with PET/CT and MRI imaging. The problem with MRI imaging is that the quality of the scans is still inconsistent. While the soft tissue characterization of the tongue in an MRI image is unparalleled, major problems with MRI as a modality include movement artifacts and cost. PET/CT has been purported to provide a functional dataset of hypermetabolic tissues including malignancies; however, there has not been any definitive clinical evidence that PET/CT can significantly improve detection rates for unknown primary tumors for oropharyngeal subsites. Most recently, surgical methods to localize primary tumors were evaluated. Using robotic methods to resect both tonsil and the tongue base, some have reported 70% detection rates of the primary site for these unknown primary tumors.12

Decision Point Question 3
After concurrent platinum-based chemoradiation to the ipsilateral oropharynx and the neck, the neck lesion regressed. RP underwent interval PET/CT scans 3 months after completing radiation treatment. No uptake in the head and neck region was noted, but there were nonspecific uptakes in the mediastinum, which were labeled as reactive changes that were associated with subcentimeter lymph nodes. An endoscopy 6 months after treatment showed no evidence of disease. On RP’s 18-month follow-up examination, his neck lymphadenopathy was equivocal. The treating physician ordered repeat PET/CT scans that demonstrated multiple PET-avid lesions in the lung without any uptake in the head and neck region. Bronchoscopy biopsy demonstrated squamous cell carcinoma (SCCA).

< What is the next BEST oncologic intervention for RP?
Treat with methotrexate
Perform p16 IHC test on the mediastinal lesions
Treat with cetuximab and concurrent platinum-based chemotherapy
Treat with stereotactic radiation to half of the metastatic site
Blocking anti-PD-1 monoclonal antibodies (mAbs)

When these patients develop recurrent or metastatic disease, the Cetuximab in Combination with Cisplatin or Carboplatin and 5-Fluorouracil in the First-Line Treatment of Subjects with Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (EXTREME) study showed that cetuximab combined with platinum-based chemotherapy should be first-line therapy for patients who are not candidates for surgical salvage.13 However, it should be noted that the survival advantage in the cetuximab and chemotherapy group, measured either in progression-free survival time or overall survival time, ranged in the order of several months.14 Oncologists, therefore, have resorted to methotrexate as a second-line treatment for the eventual failures for cetuximab.

Once the patient fails cetuximab, anti-PD-1 mAbs should the optimal choice. In this context, immunotherapeutic modalities with immune checkpoint inhibitors (blocking programmed cell death protein 1 [PD-1] antibodies) for these recurrent/metastatic HNSCC patients have been altering the therapeutic landscape.15 While definitive phase III randomized clinical trials are still underway, preliminary reports from earlier trials have provided evidence of a therapeutic “tail” that demonstrated prolonged survival advantage on the order of years, much like the clinical experience of blocking PD-1 antibodies in non-small–cell lung cancer patients. During the 2016 American Society of Clinical Oncology and American Association for Cancer Research Annual Meetings, investigators presented the results of the CHECKMATE 141 clinical trial, which compared the EXTREME regimen versus the PD-1 blocking agent nivolumab.19,20

The study was discontinued early due to the clear superiority of PD-1 blocking agents. The 12-month OS rate was 36% with nivolumab versus 17% for patients randomized to standard chemotherapy. In addition, nivolumab was associated with approximately a doubling of the number of patients whose tumors shrunk and the number of patients who remained free of disease progression after 6 months. Finally, patient-rated quality of life improved or remained stable in nivolumab therapy but decreased among patients randomized to standard chemotherapy. On August 5, 2016, the US Food and Drug Administration (FDA) approved the humanized anti-PD-1 monoclonal antibody pembrolizumab for the treatment of recurrent or metastatic HNSCC with disease progression after platinum-containing chemotherapy.21-22

In a recent nonrandomized, open-label international study of patients who received pembrolizumab for treatment of advanced solid tumors, data were analyzed for 174 patients with recurrent or metastatic HNSCC who had disease progression during or after platinum-based chemotherapy. These patients were treated with pembrolizumab 10 mg/kg IV every 2 weeks or 200 mg IV every 3 weeks. The overall response rate was 16%. Of patients who responded, 82% had durable responses lasting 6 months or longer. Common adverse events (ie, events that occurred in at least 20% of patients) included fatigue, decreased appetite, and dyspnea.19 Pembrolizumab was approved under the FDA’s accelerated approval process, which requires the manufacturer to conduct a randomized, multicenter clinical trial, further characterizing the clinical benefit of pembrolizumab.21

In addition, there are other immune checkpoint inhibitors that are nearing FDA approval for treating patients with recurrent and metastatic HNSCC. They encompass blocking PD-1 monoclonal antibodies as well as blocking programmed cell death ligand 1 (PD-L1) monoclonal antibodies. PD-1 are molecules expressed on T-cells that suppresses the antitumor function of these T-cells when bound to its ligand, PD-L1. Blocking this interaction has been shown to unleash the immune suppressive mechanism of PD-1. PD-L1 inhibition in patients with HNSCC has shown regression in approximately 20% to 30% of the recurrent/metastatic HNSCC patients.

With the impending FDA approval of blocking PD-1 mAbs in patients with HNSCC, pharmaceutical companies and academic researchers have been actively looking to improve the clinical efficacy of these immune checkpoint inhibitors. There are many preclinical data to support the use of combination immune checkpoint inhibitors, and there have been concomitant clinical data that suggest 2 checkpoint inhibitors may work better than 1.23 In patients with melanoma, combination of CTLA-4 and PD-1 blocking agents have shown improved survival benefits than single agents alone. Others have combined co-activators (T-cell stimulating agents) with immune checkpoint inhibitors, and early clinical results also suggest improved clinical benefit. For patients with HNSCC, however, it is unclear which combination has the most clinical efficacy. Regardless, anti-PD-1 mAbs have displaced cetuximab and established itself as the primary platform for recurrent and metastatic HNSCC.

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11. Transoral surgery followed by low-dose or standard-dose radiation therapy with or without chemotherapy in treating patients with HPV positive stage III-IVA oropharyngeal cancer. ClinicalTrails.gov Web site. Available at: https://clinicaltrials.gov/ct2/show/NCT01898494. Updated November 19, 2015. Accessed July 12, 2016.
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13. Cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil in the first-line treatment of subjects with recurrent and/or metastatic squamous cell carcinoma of the head and neck (EXTREME). ClinicalTrails.gov Web site. Available at: https://clinicaltrials.gov/ct2/show/NCT00122460. Updated July 11, 2014. Accessed July 11, 2016.
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21. US Food and Drug Administration. Pembrolizumab (KEYTRUDA). August 9, 2016. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm515627.htm. Accessed August 11, 2016.
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