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Background Patients with HPV-positive oropharyngeal squamous cell carcinoma (OPC) have high survival rates when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab, an antibody against the epidermal growth factor receptor, can preserve high survival rates and reduce treatment toxicity is unknown. Methods In a randomized, non-inferiority, multicenter trial, patients with locoregionally-advanced p16-positive OPC were stratified by American Joint Committee on Cancer T (T1-T2 vs. T3-T4) and N (N0-N2a vs. N2b-N3), Zubrod Performance Status (0 vs. 1), and tobacco smoking history (≤ vs. >10 pack-years) and randomized 1:1 to radiotherapy plus cetuximab 400 milligrams per square meter of body surface area (mg/m2), followed by 250 mgs/m2 for seven weekly doses or cisplatin 100 mgs/m2 for two doses, 21 days apart. The sample size was 800 eligible patients. The primary endpoint was overall survival (OS) with non-inferiority margin 1.45 (hazard ratio). Findings From June 2011 through July 2014, 849 patients (805 eligible; 399 cetuximab; 406 cisplatin) were randomized at 182 centers in the United States and Canada. With median follow-up 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criterion for OS. Estimated 5-year OS was 77·9% (95% confidence interval [CI] 73·4-82·5) in cetuximab group versus 84·6% (95%CI=80·6-88·6) in cisplatin group (hazard ratio [HR], 1·45, 1-sided 95% upper CI, 1·94; non-inferiority p=0·5056; 1-sided log-rank p=0.0163). PFS was significantly lower in cetuximab group than in cisplatin group (HR 1·72, 95%CI=1·29-2·29; 5-year rates, 67·3% vs. 78·4%), and LRF was significantly higher (HR 2·05, 95%CI=1·35-3·10; 5-year rates, 17·3% vs. 9·9%). The rate of moderate-to-severe toxicity that was acute (77·4% vs. 81·7%, p=0·1586) and late (16·5 vs. 20·4%, p=0·1904) was similar in the cetuximab and cisplatin groups, respectively. Interpretation For patients with HPV-positive OPC, radiotherapy plus cetuximab demonstrated inferior OS and PFS compared to radiotherapy plus cisplatin; toxicity rates were similar (NCT01302834). Funding National Cancer Institute USA, Eli Lilly and The Oral Cancer Foundation

A B S T R A C T PurposeTo investigate the feasibility of intensity-modulated radiation therapy (IMRT) with or without chemotherapy, and to assess toxicities, failure patterns, and survivals in patients with nasopharyngeal carcinoma (NPC). Patients and MethodsRadiation consisted of 70 Gy given to the planning target volumes of primary tumor plus any Nϩ disease and 59.4 Gy given to subclinical disease, delivered over 33 treatment days. Patients with stage T2b or greater or with Nϩ disease also received concurrent cisplatin (100 mg/m 2 ) on days 1, 22, and 43 followed by adjuvant cisplatin (80 mg/m 2 ) on day 1; fluorouracil (1,000 mg/m 2 /d) on days 1 through 4 administered every 4 weeks for three cycles. Tumor, clinical status, and acute/late toxicities were assessed. The primary objective was to test the transportability of IMRT to a multi-institutional setting. February 2003 and November 2005, 68 patients with stages I through IVB NPC (of which 93.8% were WHO types 2 and 3) were enrolled. Prescribed IMRT (target delineation) was given to 83.8%, whereas 64.9% received chemotherapy per protocol. The estimated 2-year local progression-free (PF), regional PF, locoregional PF, and distant metastasis-free rates were 92.6%, 90.8%, 89.3%, and 84.7%, respectively. The estimated 2-year PF and overall survivals were 72.7% and 80.2%, respectively. Acute grade 4 mucositis occurred in 4.4%, and the worst late grade 3 toxicities were as follows: esophagus, 4.7%; mucous membranes, 3.1%; and xerostomia, 3.1%. The rate of grade 2 xerostomia at 1 year from start of IMRT was 13.5%. Only two patients complained of grade 3 xerostomia, and none had grade 4 xerostomia. Results Between ConclusionIt was feasible to transport IMRT with or without chemotherapy in the treatment of NPC to a multi-institutional setting with 90% LRPF rate reproducing excellent reports from single institutions. Minimal grade 3 and lack of grade 4 xerostomia were encouraging.

Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. PFS and OS were higher in patients with p16-positive OPC, but outcomes did not differ by EGFR expression.

Tumor HPV status is a strong and independent predictor of OS after disease progression and should be a stratification factor for clinical trials for patients with recurrent or metastatic OPC.

Purpose Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx. Patients and Methods p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics. Results p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes. Conclusion Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.

Despite a high incidence of grade 5 toxicity, 1- and 2-year OS rates for split-course bid radiation therapy and concurrent cisplatin/paclitaxel exceed results generally seen with chemotherapy alone.

Background: Therapy for gastrointestinal stromal tumors (GIST) has changed significantly with the use of imatinib mesylate (IM). Despite the success of this drug in metastatic GIST, disease progression remains a perplexing clinical issue suggesting the need for multimodality management. There have been no prospective studies either evaluating the neoadjuvant use of IM in primary GIST or as a preoperative cytoreduction agent for metastatic GIST. Methods: RTOG 0132/ACRIN 6665 was a prospective phase II study evaluating safety and efficacy of neoadjuvant IM (600 mg/day) for patients with primary GIST or the preop use of IM in patients with operable metastatic GIST. The trial continued postop IM for 2 years. Results: Sixty-three patients were entered (52 analyzable), 30 patients with primary GIST (Group A) and 22 with recurrent metastatic GIST (Group B). Response (RECIST) in Group A was (7% partial, 83% stable, 10% unknown), in Group B (4.5% partial, 91% stable, 4.5% progression). Two-year progression free survival (Group A 83%, Group B 77%). Estimated overall survival (Group A 93%, Group B 91%). Complications of surgery and IM toxicity were minimal. Conclusion: This trial represents the first prospective report of preop IM in GIST. This approach is feasible, requires multidisciplinary consultations, and is not associated with notable postop complications.