Abstract IA17: Treatment de-intensification strategies for head and neck cancer
Authors: Burtness Barbara 
Published: December 2017

Abstract
Oropharynx cancer (OPC) which is human papillomavirus (HPV)-related is more treatment-responsive and has a higher cure rate than tobacco-associated OPC. HPV-related cancers arise in patients who have a younger median age, lower comorbidity index, and lesser tobacco history than patients whose cancers are not HPV-related. Failure within the radiation field is relatively less common, while distant metastases account for a higher proportion of recurrences among patients with HPV-related cancers. Thus, treatment paradigms developed in an era when tobacco-associated head and neck cancer predominated focus on intense local therapy for a relatively treatment-resistant cancer among patients with many competing mortality risks, and may represent inappropriate treatment for patients with HPV-related cancers. Existing approaches based on high-dose cisplatin and 70 Gy of radiation in a primary treatment volume, as well as significant radiation to elective nodal areas, are not well supported by data from patients with HPV-related OPC and are of concern for a number of reasons. These include the possibility of increased noncancer mortality from concurrent cisplatin and full-dose radiation, as suggested by the long-term results of INT91-11; high rates of chronic radiation sequelae of swallowing impairment, chronic pain, lymphedema, hypothyroidism, osteonecrosis, dental loss, xerostomia, PTSD-like effects, and employment disability; inadequate systemic therapy in patients at increased risk for distant metastases; and cost.
These considerations have led to trials exploring a number of approaches to treatment deintensification. Trial designs have been challenging as normative data from patients with HPV-related OPC are scarce and event rates low. Numerous strategies have been envisioned to minimize toxicity, cost, or late sequelae, or do a better job of fitting treatment modality to failure pattern. When novel treatment schemes were initially proposed, there was concern that these would be a barrier to accrual, or that treating investigators would deviate from protocol because of skepticism about the novel approaches. In this context, initial trials either proposed very incremental changes, were conducted as single-arm studies, incorporated surgical staging after radiation, or utilized randomized phase II designs. The primary strategy to reduce late treatment sequelae of swallowing dysfunction has been reduction of radiation dose from 70Gy to 54-60Gy. Langdijk has demonstrated that a dose of &gt;56 Gy to pharyngeal constrictors predicts long-term swallowing dysfunction. As well, shortened radiation courses reduce acute toxicity because the highest grades of mucositis, dermatitis, and pain are documented at the highest cumulative radiation doses. Omission of chemotherapy, or substitution of cetuximab for cisplatin, is envisioned to reduce acute toxicity and chronic effects on hearing and renal function. Upfront transoral resection has been proposed to permit better staging, resulting in fewer patients being exposed to cisplatin, as well as potentially to permit reduced radiation dose.
The first trial specifically designed to enroll only HPV-related OPC and to test treatments which could minimize late sequelae was E1308. Patients with resectable p16 or HPV16 ISH + OPC were treated with induction cisplatin, paclitaxel, and cetuximab. This novel regimen was employed to build on prior ECOG experience with carboplatin, paclitaxel or carboplatin, paclitaxel and cetuximab induction therapy, both of which had demonstrated high response rates in HPV-related oropharynx cancer, including in the latter case biopsy-proven complete responses. Cisplatin was substituted for carboplatin to support accrual, given concerns from some investigators that carboplatin would be inadequate if followed by reduced radiation dose. Patients with clinical CR were treated with 54 Gy radiation and concurrent cetuximab. 2-year PFS and OS rates were 80% and 94% for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with &lt; T4, &lt; 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 ≤ 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or impaired nutrition (10% v 44%; P = .025).
Identical concerns about the impact of high-dose cisplatin and full-dose radiation on late function and noncancer mortality have also led to questions about the appropriateness of current standard of care in the postoperative setting. E3311 is a trial of transoral resection for T1-2 p16+ oropharynx cancer. Based on pathology, patients with N0 and N1 disease, without extranodal extension, are observed. Those with high node number, positive margins, or ENE receive postoperative radiation with cisplatin. Patients intermediate between those groups are randomized between 50 and 60 Gy. The study is anticipated to close to accrual in late 2017. A recent analysis of the National Cancer Database demonstrates that—despite single-institution retrospective data which had appeared to show that this was not the case— ENE is associated with inferior OS in patients with HPV-positive OPSCC, although both groups have 3-year OS of over 85%. Thus, elimination of cisplatin may be beneficial here as well, and ECOG has proposed a non-inferiority trial of postoperative radiation with cetuximab vs. the standard of radiation and cisplatin.
Current trials utilize T stage and smoking history to identify favorable-risk patients in whom treatment deintensification strategies will be important. Future studies may be able to utilize biomolecular characteristics such as TRAF3 mutation, mutational load, or inflamed phenotype to more precisely define favorable populations, as well as to aid in selection of cytotoxic vs. immunotherapy, or project rates of distant disease.
Citation Format: Barbara Burtness. Treatment de-intensification strategies for head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA17.