Summary A rise in the annual incidence of oropharynx squamous cell cancer, specifically the lingual and palatine tonsils, in white men under the age of 50, non-smokers and non-alcoholics, has been observed over the past decade. This entity is associated with human papilloma virus-16 infection and the risk factors include an increased number of oral and vaginal sex partners at a younger age. The biology of HPV-related oropharynx cancer is distinct with p53 degradation, Rb pathway inactivation, and p16 upregulation. This is in contrast to tobacco related oropharynx cancer which is characterized by p53 mutation and downregulation of p16. The optimal method to detect virus in tumor is controversial and both in situ hybridization and PCR are commonly used; p16 immunohistochemistry may serve as a potential surrogate marker. HPV-related oropharynx cancer appears to be more responsive to chemotherapy and radiation than HPV negative orpharynx cancer. HPV-16 is a prognostic marker for improved overall survival and disease-free survival but has not yet been shown to be a predictive marker. Investigators continue to explore unanswered questions regarding the natural history of oral HPV infection, why the increase dominates in men, the potential of HPV vaccines for primary prevention, developing a commercially available accurate method to detect the virus in tumor, and treatment strategies that reduce toxicity without compromising survival. The goal of this review is to highlight our current understanding of the epidemiology, biology, detection, as well as current management and unresolved issues of HPV-related oropharyngeal HNSCC.

Squamous cell carcinoma arises from multiple anatomic subsites in the head and neck region. The risk factors for development of cancers of the oral cavity, oropharynx, hypopharynx, and larynx include tobacco exposure and alcohol dependence, and infection with oncogenic viruses is associated with cancers developing in the nasopharynx, palatine, and lingual tonsils of the oropharynx. The incidence of human papillomavirus-associated oropharyngeal cancer is increasing in developed countries, and by 2020, the annual incidence could surpass that of cervical cancer. The treatment for early-stage squamous cell cancers of the head and neck is generally single modality, either surgery or radiotherapy. The treatment for locally advanced head and neck cancers is multimodal, with either surgery followed by adjuvant radiation or chemoradiation as indicated by pathologic features or definitive chemoradiation. For recurrent disease that is not amenable to a salvage local or regional approach and for metastatic disease, chemotherapy with or without a biological agent is indicated. To date, molecular testing has not influenced treatment selection in head and neck cancer. This review will focus on the changing epidemiology, advances in diagnosis, and treatment options for squamous cell cancers of the head and neck, along with data on risk stratification specific to oropharyngeal cancer, and will highlight the direction of current trials.

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Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPVassociated OPSCC for reduced radiation dose as a means of sparing late sequelae. MethodsPatients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensitymodulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. ResultsOf the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of # 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2-year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with , T4, , N2c, and # 10 pack-year smoking history who were treated with # 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose # 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). ConclusionFor IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status.

Purpose To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in head and neck cancer patients through inhibition of myeloid derived suppressor cells (MDSCs). Experimental Design We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in head and neck squamous cell carcinoma (HNSCC) patients. Results Tadalafil augmented immune response, increasing ex vivo T cell expansion to a mean 2.4 fold increase compared to 1.1 fold in control patients (P= 0.01), reducing peripheral MDSC numbers to mean 0.81 fold change compared to a 1.26 fold change in control patients (P=0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P=0.002). Tumor specific immunity in response to HNSCC tumor lysate was augmented in tadalafil treated patients (P=0.04). Conclusions These findings demonstrate that tadalafil augments general and tumor-specific immunity in HNSCC patients and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor specific immune suppression in head and neck cancer patients, with potential for therapeutic application.

Although the study did not meet statistical significance in improvement in OS with the addition of fosbretabulin to carboplatin/paclitaxel, it represents the largest prospective randomized trial ever conducted in ATC. The regimen is well tolerated, with AEs and deaths primarily related to ATC and disease progression.

Background Severe treatment-related lymphopenia (TRL) occurs commonly in many cancers and is associated with early tumor progression. Data is lacking as to whether this occurs in squamous cell head/neck cancer. Methods Serial total lymphocyte counts (TLC) were retrospectively reviewed in patients with newly diagnosed squamous head and neck cancer undergoing chemoradiation and associated with treatment outcomes. Results The median baseline TLC in 56 patients was 1660 cells/mm3 which fell by 73% to 445 cells/mm3 two months after initiating chemoradiation (p<0.0001). HPV− patients with TLC<500 cells/mm3 at two months had significantly earlier disease progression than those with higher TLCs (HR 5.75, p=0.045). Conclusions Baseline TLCs were normal but at two months ~60% of patients had severe TRL regardless of HPV status. Severe TRL in HPV− patients is independently associated with earlier disease progression. Prospective studies are needed to confirm these findings which suggest that immune preservation is important in this cancer.

Patients evaluated in a multidisciplinary clinic are more likely to comply with SLP treatment recommendations.