Phase II Trial of Continuous Course Re- irradiation Concurrent with Weekly Cisplatinum and Cetuximab for Recurrent Squamous Cell Carcinoma of The Head And Neck: A Preliminary Report Min Yao, MD, PhD University Hospitals Case Medical Center Cleveland, Ohio

Disclosure The study was funded by a research grant from Bristol-Myers Squibb.

UT Southwestern Medical Center Randall Hughes, MD Larry Myers, MD Lucien Nedzi, MD Irma Smith, CSA Baran Sumer, MD John Truelson, MD John Yordy, MD, PhD University Hospitals Case Medical Center Min Yao, MD, PhD Pierre Lavertu, MD Medical College of Wisconsin Dian Wang, MD Stuart Wong, MD Participating Institutions

Eligibility 1)Pathologically confirmed recurrent or second primary SCC of the upper aerodigestive tract (excluding nasopharynx and salivary gland tumors). No metastatic disease 2)Unresectable disease or positive margins after surgical resection. 3)Majority of recurrent tumor in areas previously irradiated to > 45 Gy, but not exceeding 75 Gy. 4)Prior radiotherapy completed more than 6 months prior to study entry 5)No prior chemotherapy for recurrent disease 6)KPS > 70 %. Adequate bone marrow, hepatic and renal function

Treatment Schema Week 1: cetuximab 400mg/m 2 as a loading dose Weeks 2-7 cetuximab 250mg/m 2 weekly cisplatinum 30mg/m 2 weekly continuous course IMRT Gy/30/6 weeks

Intensity-Modulated Radiotherapy GTV Clinically and radiographically defined gross tumor or in patients after surgery, tumor bed that include pre- operative gross disease Integrated boosts CTV = GTV cm PTV = CTV cm (0.2 – 0.3 cm with IGRT) GTV 60 to 66 Gy/30 fractions PTV 60 Gy/30 fractions

Critical Structures Spinal cord PRV = cord cm (0.2 cm with IGRT) Cumulative dose not to exceed 54 Gy (including prior radiotherapy) Brainstem PRV = brainstem cm (0.2 cm with IGRT) Cumulative dose not to exceed 60 Gy (including prior radiotherapy) Intensity-Modulated Radiotherapy

A patient with unresectable nodal recurrence 6 years after postop XRT for an oral tongue cancer

Intensity-Modulated Radiotherapy

Patient Population 48 patients rerolled between March 2009 – May 2013 Male 36, Female 12, median age 62 Two withdrew and 46/48 received protocol treatment 40% re-PORT after attempted surgical resection with positive margin Median follow-up 9 months

Kaplan-Meier curve for overall survival The 1 year survival probability is 0.60 (95% CI: 0.41 – 0.75) Treatment Outcome

Kaplan-Meier curve for progression-free survival The 1 year progression- free survival probability is 0.38 (95% CI: 0.21 – 0.55)

Treatment Delivery Only one patient did not complete the treatment course, received only 3 cycles of chemo All other patients completed the treatment course

Acute Toxicity: Highest Grade Grade Acute Toxicity345Total% lymphopenia dysphagia6 613 rash: dermatitis assoc. w/ XRT anorexia5 511 mucositis5 511 neutropenia31 49 fatigue3 37 hemoglobin21 37 hyponatremia3 37 hypophosphatemia3 37 leukocytes21 37 dehydration2 24 hyperglycemia2 24 hypoalbuminemia2 24

Late Toxicity 90 days after treatment Grade Late Toxicity123Total% dysphagia % hemoglobin % lymphopenia % fatigue36 920% xerostomia52 715% edema: head & neck6 613% mucositis33 613% fibrosis23 511% hypoalbuminemia32 511% trismus41 511% weight loss5 511% platelets4 49% hypomagnesemia3 37% hypothyroidism12 37% nausea3 37% pain: gastrointestinal: oral cavity 3 37% pain: musculoskeletal: Neck12 37%

Conclusions Compared to RTOG 9610 and RTOG 9911, the treatment is better tolerated with superior one year overall survival. Longer follow up is needed, with future analysis of failure pattern and prognostic indicators