BACKGROUND:Achieving locoregional control in high-risk patients with head and neck cancer who are poor candidates for standard continuous-course (chemo) radiotherapy due to advanced age, comorbidities, or very advanced disease is challenging. At our Institution, we have significant experience with a regimen of split-course, accelerated, hypofractionated radiotherapy (SCAHRT) for these patients.PATIENTS AND METHODS:The SCAHRT regimen consisted of 60-72 Gy in 20-24 fractions separated by several weeks mid-course to allow for toxicity recovery and disease reassessment. It was used for patients with advanced age, significant co-morbidities, anticipated intolerance to definitive (chemo)radiation, and those with oligometastatic disease. Disease-free and overall survival rates were calculated using Kaplan-Meier analysis.RESULTS:Fifty-eight out of 65 patients (89%) completed both courses of treatment. Patients without metastatic or recurrent disease were evaluated for treatment response and survival (n=39). Among this group, total tumor response was 91%, and median locoregional failure-free survival and overall survival were 25.7 and 8.9 months, respectively.CONCLUSION:In high-risk patients unable to tolerate continuous-course definitive (chemo)radiation, SCAHRT is a safe, well-tolerated and effective method of achieving durable locoregional disease control. In properly selected patients, this regimen is preferable to purely palliative approaches.

OBJECTIVES:Long term swallowing dysfunction in patients with oropharynx squamous cell carcinoma (OPSCC) treated with concurrent chemoradiation (CRT) is declining. While the use of intensity modulated radiotherapy (IMRT) is commonly believed to be a potential cause, we hypothesize that the increasing incidence of human papillomavirus (HPV) related disease may also favorably impact this outcome. MATERIALS AND METHODS:We reviewed 130 HPV+ and 17 HPV- patients with stage III-IV OPSCC treated exclusively with conventional 3-field radiotherapy with chemotherapy between 2002 and 2010. The rates of normal diet, limited diet (significant restrictions in the types of foods eaten, and/or requiring nutritional supplementation for weight maintenance) and feeding tube dependence (FTD) were compared between HPV+ and HPV- patients. Cox proportional hazards modeling were used to perform univariate analysis (UVA) to examine predictors of a combined endpoint of dietary limitation, which included limited diet and/or FTD. These outcomes were also compared to our previously reported cohort of OPSCC patients treated between 1989 and 2002 to assess changes in toxicity over time given the changing disease epidemiology, in the setting of identical treatment regimens. RESULTS:With a median follow-up of 55 months, HPV+ patients more frequently had resumed a normal diet (87% vs. 65%) at last follow up and had lower rates of limited diet (9% vs. 18%) and FTD (4% vs. 18%) compared to HPV- patients (p=0.02). HPV status was the only significant predictor of reduced swallowing dysfunction on UVA (HR 0.19; p=0.008). When compared to our 1989-2002 cohort, patients treated between 2002 and 2010 had less FTD (7.5% vs. 34%, p<0.001) and dietary limitations (26% vs.46%, p<0.001) at 6 months post treatment. CONCLUSIONS:HPV+ patients with OPSCC have reduced late swallowing dysfunction after chemoradiation compared to HPV- patients. The changing epidemiology of OPSCC may play a role in toxicity reduction in these patients, independent of the increasing use of IMRT.

Chemoradiotherapy results in excellent outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC). This trial compared 2 chemoradiotherapy regimens.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Patients (pts) with oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiation therapy (CRT) have historically had significant long term toxicity. We hypothesize that HPV + patients treated with chemoIMRT have more favorable long term toxicity profiles and quality of life than historical data suggests. Pts with stage III-IVb OPSCC and known tumor HPV status treated with CRT between 2002 and 2012 and rendered disease free were identified from an IRB approved registry. HPV + disease included pts who tested positive for HPV DNA by in-situ hybridization, or had diffuse and strong (>75%) staining for p16 by immunohistochemistry. Radiation therapy (RT) was administered once (79%) or twice daily (21%) to a total dose of 70-74.4 Gy, with a 3-field approach (3D-RT) in the earlier years (65%) and IMRT (35%) more recently. Most patients were treated with Cisplatin and 5-Fluorouracil (62%), while more recently patients were treated with Cisplatin (26%), or Cetuximab (9%) at standard dosing. Toxicity was scored according to CTCAE v4.0. Significant late toxicity was defined as any grade ≥3, or any persistent grade 2 fibrosis, dysphagia, osteoradionecrosis, trismus, pain, hoarseness, or hearing loss that occurred >3 months after the completion of treatment. Xerostomia, taste and skin changes were excluded from this combined endpoint. Logistic regression analysis was performed to identify pt, tumor, and treatment related variables associated with significant late toxicity. Of the 197 pts included in this study, the majority were Caucasian (95%) and male (91%), and 32% were never smokers. The median age was 56, median KPS 90, and median f/u was 39.4 months (range: 3.1-137.8). At last follow-up, 91% of patients returned to a normal diet, while 6.5% had a limited oral diet and 2.5% were feeding tube dependent. Of the 41 pts (20%) who required dilation for a stricture, 21 pts had their dysphagia resolve. The use of 5-FU based chemotherapy (76% vs 37%; p<0.0001) and the use of 3D-RT (70% vs 44%; p=0.0005) were independently associated with the need for a feeding tube. Similarly, 5-FU based chemotherapy (43% vs 16%; p=<0.0001) and 3D-RT (44% vs 13%; p<0.0001) were significantly associated with higher rates of significant late toxicity. In patients treated with once daily IMRT and non-5-FU based chemotherapy, the rate of significant late toxicity was 5.7%. Not using IMRT was associated with the highest risk of late toxicity on MVA (OR 3.4; p=0.005). Pts with HPV + OPSCC treated with IMRT and non 5-FU based chemotherapy have excellent long term functional recovery and low rates of significant late toxicity. .

Introduction: Preoperative chemoradiotherapy improves local control in patients with locoregionally advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ). Distant failure remains common, however, suggesting potential benefit from additional chemotherapy. This phase II study investigated the addition of induction chemotherapy to surgery and adjuvant chemoradiotherapy.Methods: Patients with cT3-4 or N1 or M1a (American Joint Committee on Cancer 6th edition) adenocarcinoma of the esophagus and GEJ were eligible. Induction chemotherapy, with epirubicin 50 mg/m(2)/d, oxaliplatin 130 mg/m(2)/d, and fluorouracil 200 mg/m(2)/d continuous infusion for 3 weeks, was given every 21 days for three courses, followed by surgery. Adjuvant chemoradiotherapy consisted of 50 to 55 Gy at 1.8 to 2.0 Gy/d and two courses of cisplatin (20 mg/m(2)/d) and fluorouracil (1000 mg/m(2)/d) during weeks 1 and 4 of radiotherapy.Results: Between February 2008 and January 2012, 60 evaluable patients enrolled. Resection was accomplished in 54 patients (90%) and adjuvant chemoradiotherapy in 48 (80%) patients. Toxicity included unplanned hospitalization in 18% of patients during induction chemotherapy and 19% of patients during adjuvant chemoradiotherapy. There was one chemotherapy-related and two postoperative deaths. With a median follow-up of 43 months, the projected 3-year locoregional control is 88%, distant metastatic control 46%, relapse-free survival 41%, and overall survival 47%. Symptomatic response to chemotherapy and the percentage of remaining viable tumor at surgery proved the strongest predictors of survival and distant control.Conclusions: Chemotherapy, surgery, and adjuvant chemoradiotherapy are feasible and produce outcomes similar to other multimodality treatment schedules in locoregionally advanced adenocarcinoma of the esophagus and GEJ. Symptomatic response and less residual tumor at surgery were associated with improved outcomes.

Evidence about the benefit of IMRT to reduce serious late effects specifically in pts with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) treated with CRT is sparse. We investigated the impact of IMRT vs standard 3-field radiation therapy (3D-RT) on late effects outcomes in this pt cohort. Pts with HPV + stage III-IVb OPSCC treated with CRT between 2002 and 2012 and rendered disease free were identified from an IRB approved registry. Pts who tested positive for HPV DNA by in-situ hybridization, or had diffuse and strong (>75%) staining for p16 by immunohistochemistry were included. Radiation therapy (RT) was administered once (79%) or twice daily (21%) to a total dose of 70-74.4 Gy. 3D-RT was used in the earlier years (65%) while IMRT with daily cone beam CT and 2-3 mm CTV and PTV expansions, respectively, was used more recently (35%). Most patients were treated with Cisplatin and 5-Fluorouracil (62%), while more recently patients were treated with Cisplatin (26%), or Cetuximab (9%) at standard dosing. Toxicity was scored according to CTCAE v4.0. Significant late toxicity was defined as any grade ≥3, or any persistent grade 2 fibrosis, dysphagia, osteoradionecrosis, trismus, pain, hoarseness, or hearing loss that occurred >3 months after the completion of treatment. Xerostomia, taste and skin changes were excluded from this combined endpoint. Logistic regression analysis was performed to identify factors associated with significant late toxicity. Of the 197 pts included in this study, the majority were white (95%), men (91%), and 32% were never smokers. The median age was 56, median KPS 90, and median f/u was 39.4 months. At last follow-up, 91% of patients returned to a normal diet, while 6.5% had a limited oral diet and 2.5% were feeding tube dependent. 5-FU based chemotherapy (43% vs 16%; p = <0.0001) and 3D-RT (44% vs 13%; p<0.0001) were significantly associated with higher rates of significant late toxicity. In patients treated with once daily IMRT and non-5-FU based chemotherapy, the rate of significant late toxicity was only 5.7%. On MVA, not using IMRT was associated with the highest risk of significant late toxicity (OR 3.4; p = 0.005), overshadowing smoking status, T stage, neck dissection and chemotherapy type. Pts with HPV + OPSCC treated with IMRT have fewer significant late effects than those treated with 3D-RT. Nearly all pts treated with IMRT and non 5-FU based chemotherapy have minimal significant late effects and excellent long term pharyngeal function.

e15031 Background: Perioperative chemotherapy improves outcomes for pts with LRA ACA of the E/GEJ compared to surgery alone. Combination chemotherapy regimens are frequently employed, and toxicity requiring dose modification is common. We investigated whether induction chemotherapy DI was prognostic for survival in pts receiving a tri-modality treatment regimen. Methods: From 2/08 to 1/12, 60 pts with ≥ cT3 or N1 or M1a (AJCC 6th) ACA of the E/GEJ enrolled in a phase II trial of induction chemotherapy, surgery, and adjuvant chemoradiotherapy (CRT) at the Cleveland Clinic. Pts received 3 cycles of induction chemotherapy with EOF [epirubicin 50mg/m2 day(d) 1, oxaliplatin 130mg/m2 d 1, 5FU 200 mg/m2/d CIVI for 3 weeks] q 21 days, followed by surgery and adjuvant CRT. The CRT consisted of 50-55 Gy in 1.8-2.0 Gy daily fractions concurrent with 2 cycles of cisplatin 20mg/m2/d and 5FU 1000 mg/m2/d, both administered as CIVI over 96 hours q21 days. Stepwise Cox proportional hazards analysis was used to examine the impact of induction chemotherapy DI on overall survival (OS) and recurrence free survival (RFS). Results: Of the 60 pts enrolled, 58 completed induction therapy and 54 underwent curative intent surgery. Dose reductions for oxaliplatin and epirubicin were infrequently required, with 10% of patients receiving less than 90% scheduled dose of either agent. 5FU dose modifications, however, were commonly required due to diarrhea, mucositis and hand-foot syndrome, with 22 pts (37%) receiving <70% and 43 pts (72%) receiving less than 90% scheduled dose. Multivariable (MV) analysis was performed on the 54 pts who completed induction therapy and underwent curative intent resection. Induction chemotherapy DI (

6061 Background: Conflicting data exists about whether EGFR inhibition is more or less effective in pts with p16 positive or negative oropharynx cancer (OPC). We update results from two institutional clinical trials in pts with locoregionally advanced head and neck squamous cell carcinoma (LRA HNSCC) given chemoradiotherapy either with or without the oral EGFR inhibitor gefitinib (G), with specific attention to the subset of pts with p16-defined OPC. Methods: Between 1996-2000, 44 pts with LRA HNSCC were treated on a Cleveland Clinic IRB-approved protocol using concurrent cisplatin, fluorouracil and radiation without G (G- cohort). Between 2003-2007, 60 similar pts were treated using the same chemoradiotherapy regimen with the addition of G 250 mg daily for 2 years beginning on day 1 of radiation (G+ cohort). Available biopsy material from 64 OPC pts (23 G-, 41 G+) was retrieved and tested by immunohistochemistry for p16 (as a surrogate for human papillomavirus) positivity. Kaplan-Meier outcome projections were compared using the log-rank test. Results: With a median follow-up in excess of 7 years for all pts, survival and patterns of failure did not differ between the two trials. The 5-year overall survivals (OS) were 68% vs. 64% (p=0.73) and relapse-free survivals (RFS) 65% vs. 63% (p=0.85) in the G+ and G- cohorts respectively. OPC was more frequent in the more recently treated G+ cohort (68% vs. 53%). Excluding 14 pts for whom tumor was unavailable, OPC p16-positivity was also more frequent in the G+ cohort (74% vs. 63%). As expected, outcomes in the p16+ OPC pts were significantly better than in the p16- OPC pts including OS (66% vs. 58%, p=0.049) and RFS (69% vs. 56% p=0.027). However, in comparing the G+ and G- cohorts, the use of G did not significantly alter any survival outcome or pattern of failure in either the p16+ or p16- OPC pts. Conclusions: Although the retrospective nature of this analysis limits the strength of our conclusions, in the definitive management of LRA HNSCC, we could identify no effect of oral EGFR inhibition on any outcome. In subset analysis there was also no differential impact found in either the p16+ or p16- OPC pts. Clinical trial information: NCT00352105.

6035 Background: Excellent outcomes have been reported using both single and multiagent CCRT in LAHNSCC. This trial compares a 5FU/cisplatin regimen to single agent cisplatin CCRT. Methods: Patients (pts) with previously untreated stage III-IV, M0, LAHNSCC of the larynx, oropharynx (OP), oral cavity or hypopharynx received definitive once or twice daily radiation (70-74.4 Gy) and were randomized between concurrent chemotherapy with either Arm A: cisplatin 100mg/m2 on days 1, 22 and 43 or Arm B: cisplatin (20mg/m2/day) and 5-FU (1000mg/m2/day) as continuous 96 hour infusions weeks 1 and 4. ECOG performance status ≤ 1, and adequate renal, liver and marrow function were required for entry. The primary endpoint was recurrence free survival (RFS). Results: Between 2/2008 and 10/2011, 69 pts were enrolled. An accrual of 126 pts was planned in order to demonstrate an improvement in 2-year RFS from 55% to 75%. The study was closed prematurely when a scheduled interim analysis confirmed markedly better outcomes in both arms and the futility of further comparison. Pt and tumor characteristics were well balanced in both arms. OP cancer was diagnosed in 83% of pts; 86% of the OP cancers were HPV/p16+. With a median follow up of 29.4 months, 2 yr Kaplan-Meier outcome estimates were similar between arms (Table). Pts on Arm A experienced more nephrotoxicity (26% vs. 3%; p=0.007) and ototoxicity (11% vs. 0%; p=0.042), but less Grade ≥2 radiation dermatitis (43% vs. 68%; p=0.038), neutropenia <1000/mm3 (34% vs. 65%; p=0.012), and unplanned hospitalization (43% vs. 68% p=0.038). Treatment outcomes were inferior and feeding tube requirements greater in the HPV/p16 negative and actively smoking pts. Conclusions: Although these CCRT regimens produced similar outcomes, their toxicity profiles proved different and may serve to inform individual pt treatment. Tobacco use and HPV status had far greater impact on treatment outcomes than did the CCRT regimen. Clinical trial information: NCT00608205. [Table: see text]

Background Tumor human papillomavirus (HPV) status has emerged as one of the most powerful prognostic factors for disease control and survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). We reviewed our experience in patients with OPSCC and known tumor HPV status treated with definitive chemoradiotherapy (CRT). Methods Patients with stage III-IVb OPSCC and known tumor HPV status treated with CRT between 2006 and 2011 were identified from an IRB approved registry for this retrospective review. Outcomes were estimated using the Kaplan-Meier method and compared between HPV-positive and negative patients using the log-rank test. Results Of the 121 pts (89% male, 93% Caucasian) included in this study, median age was 57 (range: 40–73) and median follow-up was 21 months (range: 6–63). Ninety-seven (80%) patients were HPV-positive and 24 (20%) were HPV-negative. Primary site was base of tongue (55%), tonsil (44%), and oropharyngeal wall (2%). Two year rates of locoregional recurrence (3% vs. 26%; p = 0.002), disease free survival (93% vs. 64%; p = 0.001) and overall survival (94% vs 73%; p = 0.002) were superior in HPV-positive patients, while rates of distant recurrence were similar (3% vs. 5%; p = 0.98). While acute toxicities were similar between both groups, patients with HPV-positive disease were more likely to resume a normal diet (90% vs. 65%; p = 0.017) at last follow up. Also, no HPV-positive patient required a feeding tube beyond 6 months after treatment, compared with 24% of HPV-negative patients. Conclusions Definitive CRT produces excellent rates of disease control with minimal late toxicity for patients with HPV-positive OPSCC. Studies of OPSCC should account for tumor HPV status when identifying factors prognostic for outcome.

e15000 Background: The role of epidermal growth factor receptor (EGFR) inhibition in resectable E/GEJ cancer is uncertain. We update and retrospectively compare results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery; the second study differing only by the addition of gefitinib (G) to the treatment regimen. Methods: Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma (ACA), with an endoscopic ultrasound stage of at least T3, N1, or M1a (AJCC 6th). Patients (pts) in both trials received 5-FU (1000mg/m2/d) and cisplatin (20mg/m2/d) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250mg/d, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Results: Clinical characteristics were similar between the 80 pts on the G trial (2003-2006) and the 93 pts on the no-G trial (1999-2003): median age (58 vs. 59 years), male gender (91% vs. 86%), ACA (94% vs. 83%), and HER2 positivity (28% vs. 18%). Minimum follow-up for all pts was 5 years. Multivariable Cox analyses comparing the G vs. no-G pts and adjusting for statistically significant covariates demonstrated improved overall survival (HR 0.62, 95% CI 0.44-0.88, p=0.008), relapse-free survival (RFS) (HR 0.59, 95% CI 0.41-0.84, p=0.003), and distant metastatic recurrence (HR 0.64, 95% CI 0.43-0.96, p=0.03), but not locoregional recurrence. Further subgroup analyses demonstrated improved RFS with G in pts not experiencing a pathologic response (HR=0.59, 95% CI 0.38-0.92, p=0.021), with T4 or M1a disease at surgery (HR=0.33, 95% CI 0.13-0.87, p=0.024), or with HER2-negative tumors (HR=0.65, 95% CI 0.42-0.99, p=0.048). Conclusions: Although this retrospective comparison can only be considered exploratory, it suggests that gefitinib may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer. Clinical benefit may be greatest in pts with a poor response to preoperative chemoradiation, and in those with HER2-negative tumors. Clinical trial information: NCT00258323.

e14611 Background: Multiagent concurrent chemoradiation (CRT) and surgery is a standard curative-intent approach for patients (pts) with LRA ACA of the E/GEJ. This single institution retrospective analysis examined whether toxicities occurring during induction chemoradiation (ICRT) were independently prognostic for outcome. Methods: Between 11/99 and 7/06, 152 pts with T3, N1 or M1a ACA of the E/GEJ were entered onto one of two Cleveland Clinic trials. ICRT with 96 hour infusions of cisplatin (20mg/m2/d) and fluorouracil (1000mg/m2/d) beginning on day 1 of radiation (30Gy@1.5Gy bid), was followed by surgery and identical post-operative CRT. 75 pts also received 2 years of oral gefitinib. Multivariable Cox analysis was used to identify prognostic factors for overall survival (OS), freedom from recurrence (FFR), locoregional (LRC) and distant metastatic control (DMC). Both clinical features (including demographics, tumor characteristics, symptomatic and pathologic response), and ICRT- related toxicities (including nausea/vomiting, mucositis/dysphagia, neutropenia, thrombocytopenia, neutropenic fever and any unplanned hospitalization) were analyzed. Results: Of the 152 pts enrolled, resection proved possible in 138 (91%). With a median follow-up of 90 (range 57-126) months, the 5-year Kaplan-Meier projected OS is 22%, FFR 24%, DMC 27% and LRC 69%. As expected, in multivariable analysis, earlier clinical stage disease and a pathologic and symptomatic response to ICRT all proved favorable for treatment outcomes. In addition, the development of grade 3-4 (vs. grade 0-2) mucositis and/or dysphagia during ICRT was a significant risk factor for distant recurrence [HR 2.62 (1.34-5.12), p=0.005]; any recurrence [HR 2.08 (1.08-4.00), p=0.027] and death [HR 2.00 (1.07-3.74), p=0.031]. Neutropenic fever was also correlated with distant recurrence [HR 1.82 (1.03-3.22, p=0.039] and any recurrence [HR 2.19 (1.23-3.90) p=0.007]. Conclusions: Neutropenic fever and the development of grade 3-4 mucositis and/or dysphagia during ICRT are independently associated with worse outcomes after multimodality therapy for E/GEJ ACA.

HPV is a powerful independent prognostic factor in LA-HNC. We reviewed our long term patterns of failure and survival outcomes for larynx (L) and hypopharynx (HP) cancer treated with CRT and compared them to a more recent cohort of HPV- oropharynx (OP) cancer. Patients (pts) with stage III-IVb SCC of the L, HP and OP treated with CRT were identified in an IRB approved registry. All pts with L and HP treated between 1990 and 2011 were included as they were assumed to be HPV negative without being routinely tested. OP pts treated between 2006 and 2011 who were known to be HPV negative after being tested by in situ hybridization were included as well. Treatment consisted of once or twice daily RT prescribed to a total dose of 70-74.4 Gy. Concurrent chemotherapy was administered either as 96 hour infusions of cisplatin (20mg/m2/day) and 5-fluorouracil (1,000mg/m2/day) given during the first and four weeks of RT (C/F), or 3 cycles of cisplatin (C) at 100 mg/m2 q3 weeks. Pts who demonstrated locoregionally persistent or recurrent disease were salvaged surgically when possible. Kaplan Meier analysis was used to determine disease free (DFS) and overall survival (OS). Survival outcomes for L/HP cancers were compared to those of HPV- OP using the log rank test. Univariate (UVA) and multivariate (MVA) analysis was performed using Cox proportional hazards regression to identify pt, tumor, and treatment related variables associated with DFS and OS. In this study of 158 pts (77% male, 86% white), the median age was 59 (range: 41-78), median KPS 80 and median follow-up 36.3 months (range: 1-241). 87% of pts had a smoking history and 27% had heavy alcohol use. Primary sites consisted of L, HP and OP in 54%, 31% and 15% of pts. Stage III, IVa and IVb comprised 33%, 57% and 10% of the cohort, respectively. 74% of patients had T3/4 tumors. 90% of pts received C/F, while 10% received C. Local recurrence (LR), regional recurrence (RR) and distant failure (DF) occurred in 16%, 15% and 14% of pts overall. 40% of pts with a LRR were successfully salvaged. Among L and HP pts, 78% achieved local control with an intact larynx. Actuarial 3yr OS and DFS were 76% and 57%, respectively. Rates of LRR (p=0.76), DF (p=0.32), DFS (p=0.95) and OS (p=0.21) were statistically similar between L/H cancers and HPV - OP cancers. MVA revealed that heavy alcohol use was associated with inferior DFS (HR 1.76; p=0.02), while higher radiation doses conferred a DFS (HR 0.64; p<0.001) and OS advantage (HR 0.51; p<0.001). Definitive CRT, with surgical salvage reserved for recurrent disease, yields high rates of LRC and organ preservation even in HPV-unrelated LA-HNC. HPV - OP cancer appears to behave similarly to L and HP cancer. Radiation dose escalation may further improve outcomes in this patient population.

Purpose To report our 20 yr experience of definitive radiotherapy for early glottic squamous cell carcinoma (SCC). Methods and materials Radiation records of 141 patients were retrospectively evaluated for patient, tumor, and treatment characteristics. Cox proportional hazard models were used to perform univariate (UVA) and multivariate analyses (MVA). Cause specific survival (CSS) and overall survival (OS) were plotted using cumulative incidence and Kaplan-Meir curves, respectively. Results Of the 91% patients that presented with impaired voice, 73% noted significant improvement. Chronic laryngeal edema and dysphagia were noted in 18% and 7%, respectively. The five year LC was 94% (T1a), 83% (T1b), 87% (T2a), 65% (T2b); the ten year LC was 89% (T1a), 83% (T1b), 87% (T2a), and 53% (T2b). The cumulative incidence of death due to larynx cancer at 10 yrs was 5.5%, respectively. On MVA, T-stage, heavy alcohol consumption during treatment, and used of weighted fields were predictive for poor outcome (p < 0.05). The five year CSS and OS was 95.9% and 76.8%, respectively. Conclusions Definitive radiotherapy provides excellent LC and CSS for early glottis carcinoma, with excellent voice preservation and minimal long term toxicity. Alternative management strategies should be pursued for T2b glottis carcinomas.

e14665 Background: Retrospective studies in breast, colon, and head and neck cancer have suggested that delays in administration of adjuvant chemotherapy result in inferior outcomes. We explore this question in patients with LRA E/GEJ ACA. Methods: From 11/99 to 7/06, 152 patients with cT3, N1, or M1a disease were enrolled on one of two clinical trials at the Cleveland Clinic. Two courses of CCRT consisting of 30Gy radiation (@1.5Gy BID) with continuous infusion cisplatin (20mg/m2/day x 4 days) and 5Fu (1000mg/m2/d x 4 days) were given both before and after surgical resection. In the second trial, 75 patients also received gefitinib during the 4 week induction and for a total of two years postoperatively. Using recursive partitioning analysis (RPA), we retrospectively explored the relationship between treatment duration and loco-regional control (LRC), distant metastatic control (DMC), freedom from recurrence (FFR), and overall survival (OS) in the 115 patients (76%) who completed all treatment. Outcomes were estimated using the Kaplan-Meier method and compared among groups using the log-rank test. Results: RPA analysis identified three groups of patients: 19 patients in whom resection occurred ≤45 days from the start of CCRT to resection (short treatment), 63 patients who underwent resection >45 days from the start of CCRT and required <50 days to complete treatment after surgery (intermediate treatment), and 33 patients who underwent resection >45 days from the start of CCRT but required ≥50 days to complete treatment after surgery (prolonged treatment). With a median follow-up of 90 (range 57-126) months, we found that patients with shorter treatment times had better 5 year DMC [64% (short) v 26% (intermediate) v 16% (prolonged); p=0.004], FFR [57% (short) v 23% (intermediate) v 16% (prolonged); p=0.015)], and OS [42% (short) v 30% (intermediate) v 12% (prolonged); p=0.08]. LRC was not different between the groups. Conclusions: Treatment delays in patients receiving multimodality therapy for LRA E/GEJ ACA may result in a greater risk of recurrence and decreased survival.

Purpose/Objective(s)Chemoradiation therapy (ChRT) for head and neck cancer is an effective organ preserving treatment that improves survival over radiation alone. However, ChRT carries a high incidence of acute grade 3 dysphagia and xerostomia. While intensity modulated radiation therapy (IMRT) has been shown to effectively decrease the incidence of treatment related xerostomia, its impact on acute dysphagia is not well studied. This study updates our previous findings and compares radiation doses delivered to critical structures associated with swallowing by IMRT and conventional radiation therapy (CRT) and their relationship to acute grade 3 dysphagia and the resolution of xerostomia after completion of ChRT.Materials/MethodsWe retrospectively reviewed patients with oropharyngeal cancer treated definitively with ChRT between January 2007 and June 2011 with either IMRT or CRT and at least 12 months of follow up. IMRT and CRT plans were compared specifically for doses to the supraglottis, glottic larynx, superior, middle, and inferior constrictors, parotid, submandibular glands, and oral cavity. Wilcoxon rank tests were performed for comparative analysis. Dysphagia and xerostomia toxicity grading is defined per CTCAE v4.0.ResultsNinety-two patients (IMRT 40; CRT 52) were included in this IRB approved study. All patients received platinum based chemotherapy and 5-FU was administered to 61% and 55% in the IMRT and CRT groups respectively (p=ns). Mean dose to parotids (31 vs 64 Gy; p<0.01), submandibular glands (57 vs 72 Gy; p<0.01), superior constrictors (61 vs 68 Gy; p<0.01), and middle constrictors (55 vs 61 Gy; p<0.01) were all significantly lower in the IMRT plans, while mean dose to the glottic larynx (41 vs 22 Gy; p<0.01) and inferior constrictors (44 vs 31 Gy; p<0.01) were all significantly higher for IMRT plans. Mean dose to the supraglottic larynx (53 vs 56 Gy; p=0.17) was not significantly different between the two groups. The incidence of grade 3 dysphagia was 48.7% with IMRT and 61.5% with CRT (p=0.22). Of the patients who developed grade 3 dysphagia, the duration of this grade 3 dysphagia (5.1 vs 7.3 weeks; p=0.01) was statistically significant. The time of onset (5.4 vs 4.6 weeks; p=0.12) was not significant. All patients developed acute xerostomia and significantly, at least 6 months after treatment xerostomia resolved in 19.5% of IMRT patients and 5.8% of CRT patients (p=0.04).ConclusionsGrade 3 dysphagia occurred less in patients who received IMRT compared to CRT. The use of IMRT compared to CRT significantly decreased the duration of feeding tube by over 2 weeks and patients had more resolution of xerostomia after treatment. Additional dosimetric study is needed to identify possible predictors for treatment related toxicity. Purpose/Objective(s)Chemoradiation therapy (ChRT) for head and neck cancer is an effective organ preserving treatment that improves survival over radiation alone. However, ChRT carries a high incidence of acute grade 3 dysphagia and xerostomia. While intensity modulated radiation therapy (IMRT) has been shown to effectively decrease the incidence of treatment related xerostomia, its impact on acute dysphagia is not well studied. This study updates our previous findings and compares radiation doses delivered to critical structures associated with swallowing by IMRT and conventional radiation therapy (CRT) and their relationship to acute grade 3 dysphagia and the resolution of xerostomia after completion of ChRT. Chemoradiation therapy (ChRT) for head and neck cancer is an effective organ preserving treatment that improves survival over radiation alone. However, ChRT carries a high incidence of acute grade 3 dysphagia and xerostomia. While intensity modulated radiation therapy (IMRT) has been shown to effectively decrease the incidence of treatment related xerostomia, its impact on acute dysphagia is not well studied. This study updates our previous findings and compares radiation doses delivered to critical structures associated with swallowing by IMRT and conventional radiation therapy (CRT) and their relationship to acute grade 3 dysphagia and the resolution of xerostomia after completion of ChRT. Materials/MethodsWe retrospectively reviewed patients with oropharyngeal cancer treated definitively with ChRT between January 2007 and June 2011 with either IMRT or CRT and at least 12 months of follow up. IMRT and CRT plans were compared specifically for doses to the supraglottis, glottic larynx, superior, middle, and inferior constrictors, parotid, submandibular glands, and oral cavity. Wilcoxon rank tests were performed for comparative analysis. Dysphagia and xerostomia toxicity grading is defined per CTCAE v4.0. We retrospectively reviewed patients with oropharyngeal cancer treated definitively with ChRT between January 2007 and June 2011 with either IMRT or CRT and at least 12 months of follow up. IMRT and CRT plans were compared specifically for doses to the supraglottis, glottic larynx, superior, middle, and inferior constrictors, parotid, submandibular glands, and oral cavity. Wilcoxon rank tests were performed for comparative analysis. Dysphagia and xerostomia toxicity grading is defined per CTCAE v4.0. ResultsNinety-two patients (IMRT 40; CRT 52) were included in this IRB approved study. All patients received platinum based chemotherapy and 5-FU was administered to 61% and 55% in the IMRT and CRT groups respectively (p=ns). Mean dose to parotids (31 vs 64 Gy; p<0.01), submandibular glands (57 vs 72 Gy; p<0.01), superior constrictors (61 vs 68 Gy; p<0.01), and middle constrictors (55 vs 61 Gy; p<0.01) were all significantly lower in the IMRT plans, while mean dose to the glottic larynx (41 vs 22 Gy; p<0.01) and inferior constrictors (44 vs 31 Gy; p<0.01) were all significantly higher for IMRT plans. Mean dose to the supraglottic larynx (53 vs 56 Gy; p=0.17) was not significantly different between the two groups. The incidence of grade 3 dysphagia was 48.7% with IMRT and 61.5% with CRT (p=0.22). Of the patients who developed grade 3 dysphagia, the duration of this grade 3 dysphagia (5.1 vs 7.3 weeks; p=0.01) was statistically significant. The time of onset (5.4 vs 4.6 weeks; p=0.12) was not significant. All patients developed acute xerostomia and significantly, at least 6 months after treatment xerostomia resolved in 19.5% of IMRT patients and 5.8% of CRT patients (p=0.04). Ninety-two patients (IMRT 40; CRT 52) were included in this IRB approved study. All patients received platinum based chemotherapy and 5-FU was administered to 61% and 55% in the IMRT and CRT groups respectively (p=ns). Mean dose to parotids (31 vs 64 Gy; p<0.01), submandibular glands (57 vs 72 Gy; p<0.01), superior constrictors (61 vs 68 Gy; p<0.01), and middle constrictors (55 vs 61 Gy; p<0.01) were all significantly lower in the IMRT plans, while mean dose to the glottic larynx (41 vs 22 Gy; p<0.01) and inferior constrictors (44 vs 31 Gy; p<0.01) were all significantly higher for IMRT plans. Mean dose to the supraglottic larynx (53 vs 56 Gy; p=0.17) was not significantly different between the two groups. The incidence of grade 3 dysphagia was 48.7% with IMRT and 61.5% with CRT (p=0.22). Of the patients who developed grade 3 dysphagia, the duration of this grade 3 dysphagia (5.1 vs 7.3 weeks; p=0.01) was statistically significant. The time of onset (5.4 vs 4.6 weeks; p=0.12) was not significant. All patients developed acute xerostomia and significantly, at least 6 months after treatment xerostomia resolved in 19.5% of IMRT patients and 5.8% of CRT patients (p=0.04). ConclusionsGrade 3 dysphagia occurred less in patients who received IMRT compared to CRT. The use of IMRT compared to CRT significantly decreased the duration of feeding tube by over 2 weeks and patients had more resolution of xerostomia after treatment. Additional dosimetric study is needed to identify possible predictors for treatment related toxicity. Grade 3 dysphagia occurred less in patients who received IMRT compared to CRT. The use of IMRT compared to CRT significantly decreased the duration of feeding tube by over 2 weeks and patients had more resolution of xerostomia after treatment. Additional dosimetric study is needed to identify possible predictors for treatment related toxicity.

Background: T1 and T2 tonsillar squamous cell cancer with limited neck disease can be managed with single-modality radiation or surgery. Over 11 years, 17 patients underwent radical tonsillectomies; and 33 patients underwent radiation-based treatments for T1 and T2 and N0 to N2a tonsil cancer. Patients were intended to receive single-modality treatment based on presentation; however, some ultimately received adjuvant treatments.Methods: A retrospective chart review to compare overall survival (OS), disease-specific survival (DSS), and locoregional control (LRC) between the groups was used.Results: In surgical group, of 17 patients, 11 underwent surgery alone, 3 underwent surgery and radiation, and 3 underwent surgery with concurrent chemoradiation. Five-year OS for the surgical and radiation groups was 93% and 72%, respectively (no significance achieved). Five-year DSS rates (93% and 80%) and LRC (69% and 89%) similarly did not yield any significant difference.Conclusion: Surgery remains a viable option in the management of T1 and T2 tonsillar cancers with comparable LRC, OS, and DSS. (C) 2012 Elsevier Inc. All rights reserved.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 21% of gastric and 33% of gastroesophageal junction (GEJ) adenocarcinomas. Trastuzumab has been approved for metastatic HER2-positive gastric/GEJ cancer in combination with chemotherapy. This retrospective analysis was undertaken to better define the clinicopathologic features, treatment outcomes, and prognosis in patients with HER2-positive adenocarcinoma of the esophagus/GEJ. Pathologic specimens from 156 patients with adenocarcinoma of the esophagus/GEJ treated on clinical trials with chemoradiation and surgery were tested for HER2. Seventy-six patients also received 2 years of gefitinib. Baseline characteristics and treatment outcomes of the HER2-positive and negative patients were compared both in aggregate and separately for each of the two trials. Of 156 patients, 135 had sufficient pathologic material available for HER2 assessment. HER2 positivity was found in 23%; 28% with GEJ primaries and 15% with esophageal primaries (P= 0.10). There was no statistical difference in clinicopathologic features between HER2-positive and negative patients except HER2-negative tumors were more likely to be poorly differentiated (P < 0.001). Locoregional recurrence, distant metastatic recurrence, any recurrence, and overall survival were also statistically similar between the HER2-positive and the HER2-negative groups, in both the entire cohort and in the gefitinib-treated subset. Except for tumor differentiation, HER2-positive and negative patients with adenocarcinoma of the esophagus and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2-positive gastric cancer and the similar incidence of HER2 overexpression in esophageal/GEJ adenocarcinoma, further evaluation of HER2-directed therapy in this disease seems indicated.

Background: Current treatment protocols for locoregionally advanced esophageal cancer add concurrent chemoradiotherapy to surgical resection in an effort to improve curative potential. These approaches are intensive and toxic. This retrospective review was undertaken to identify clinical features after concurrent chemoradiotherapy that might predict for treatment failure. Methods: 155 patients with locoregionally advanced adenocarcinoma of the esophagus/gastroesophageal junction were treated with concurrent chemoradiation with 96 hour infusions of cisplatin (20mg/m 2 /day) and fluorouracil (1,000mg/m 2 /day) beginning on day 1 of radiation (30 Gy @ 1.5 Gy bid). Surgery followed in 4-6 weeks with identical concurrent chemotherapy planned post-operatively. 75 patients also received 2 years of oral gefitinib Pretreatment staging evaluation was obtained in all patients which included a medical history, physical examination, complete blood count, serum chemistries, chest radiograph, computed tomographic scans of the chest and abdomen, pulmonary function studies, esophagogastroduodenoscopy (EGD) with biopsy, endoscopic ultrasound (EUS), and bronchoscopy if indicated by symptomatology, or by the extent or location of the primary lesion. This also included assessment of symptomatic dysphagia. Approximately 3 weeks after completing induction chemoradiation, all patients underwent restaging evaluation. Using this pretreatment and posttreatment staging information, prognostic factors for freedom from recurrence and overall survival were identified. Results: The 36 months freedom from recurrence was 31% and overall survival 32%. Post-induction change in EGD tumor length and EUS TNM stage did not correlate with outcome. Resolution of symptomatic dysphagia, which occurred in 86%, was the strongest predictor for freedom from recurrence (p<0.001) and overall survival (p<0.001).