IMRT combined with planned GKRS conformal boost results in excellent LC with minimal additional toxicity. This paradigm represents a promising means of dose escalation for locally advanced HNC with extension to critical OAR.

Clinical outcomes for patients with early-stage (AJCC 8th Edition Stage I-II) HPV-associated oropharyngeal squamous cell carcinoma are excellent. Current upfront treatment options include radiotherapy (RT) or transoral robotic surgery (TORS) followed by risk-based adjuvant therapy. We aim to compare survival, disease control and long-term gastrostomy tube (GT) presence between the two approaches.

For patients with squamous cell carcinoma (SCC) involving the parotid gland, risk factors for recurrence after parotidectomy are not clearly established in the literature. We sought to evaluate the risk factors for failure after parotidectomy and predictors of overall survival (OS) for patients with Stage I-IVb SCC involving the parotid gland. We hypothesized that higher T stage, nodal disease, and margin status would predict for worse locoregional control. We retrospectively reviewed patients treated at our institution from 1998-2016 with SCC involving the parotid gland for baseline characteristics, extent of surgery, pathologic diagnosis, adjuvant treatment details, and patterns of failure. Risk factors and outcomes including OS, freedom from locoregional failure, and freedom from distant failure were analyzed using Kaplan-Meier estimates and Cox proportional hazard ratios. From 1998-2016, 45 patients with Stage I-IVb SCC involving the parotid were identified for review. The median age at diagnosis was 73. Median OS was 19.9 (95% CI 14.5-67.1) months and median follow up was 15.2 (94% CI 11.7-22.1) months. Sixteen patients died from SCC of the parotid. Three patients had a history of lymphoma, 7 were immunosuppressed and 23 had a known prior history of SCC of the skin. Forty patients (89%) underwent complete parotidectomy and 5 (11%) underwent a partial parotidectomy. Forty-three (95.6%) of patients underwent a neck dissection and 31 (70.5%) received postoperative RT. The distribution of stages were as follows: Stage I-II, 9 (20.5%), Stage III, 7 (16.7%), Stage IVA 22 (52.4%), and Stage IVb 4 (9.5%), 6 (12.5%) were unknown. Nineteen (43.2%) patients were pN0. Median OS for patients who received RT vs no RT was 56.2 vs 14.2 months (p=0.01). On univariate analysis, characteristics associated with worse OS included ECOG (HR 1.77 p=0.03), tumors ≥4 cm (HR 3.53, p<0.01), history of lymphoma (HR 4.86, p<0.02). Freedom from locoregional failure at 2 years for patients that received RT vs no RT was 76% vs 20% (p=0.01) and for tumors ≥4 cm vs <4 cm was 35% vs 74% (p=0.05). Other characteristics predicting for increased locoregional failure included ≥N2b or higher disease (HR 3.8, p=0.05), lymphovascular space invasion (LVSI) (HR 3.92, p=0.02) and a history of lymphoma (HR 11.26 p<0.01). Margin status, grade, extracapsular extension, facial nerve involvement, and perineural invasion were not statistically significant for increased rates of locoregional failure. Freedom from distant failure at two years for patients with tumors ≥4 cm vs <4 cm was 41% vs 96% (p<0.01). Patients who received RT had similar rates of distant failure (HR 0.34, p=0.12). For patients with SCC involving the parotid gland, tumor size ≥4 cm, ≥N2b disease, LVSI, and a history of lymphoma were associated with worse locoregional control. RT was associated with improved locoregional control and OS. Tumor size ≥4 cm predicted for worse freedom from distant failure.

Small cell carcinoma (SCC) is a rare variant of head and neck cancer characterized by a high-grade neuroendocrine cancer with similar features to small cell lung carcinoma (SCLC). Human papillomavirus (HPV) is an increasingly recognized cause of head and neck cancer but usually associated squamous cell carcinoma of the oropharynx. In this report, we present the clinical presentation, diagnosis, and management of a patient with HPV-related SCC of the oropharynx that responded favorably to chemotherapy with cisplatin plus etoposide and concomitant radiation therapy, a regimen typically used in SCLC.

Background. Head and neck cancer (HNC) patients are at an increased risk for developing second primary tumors (SPTs). Diets rich in fruits and vegetables (FVs) may lower HNC risk. FV concentrates may offer a potential alternative to increasing FV intake. Methods. We conducted a randomized, double-blind, placebo-controlled trial to evaluate whether Juice PLUS+ (JP; a commercial product with multiple FV concentrates) has an effect on p27 and Ki-67, biomarkers associated with the risk of SPTs. During 2004-2008, we randomized 134 HNC patients to 12 weeks of JP (n = 72) or placebo (n = 62). Oral cavity mucosal biopsies and whole blood were obtained at baseline and after 12 weeks. All participants were given the opportunity to receive JP for 5 years following the end of the intervention period, and they were followed yearly for the development of SPTs. Results. After 12 weeks, patients on JP had significantly higher serum α-carotene (P = .009), β-carotene (P < .0001), and lutein (P = .003) but did not differ significantly in p27 (P = .23) or Ki-67 (P = .95). JP use following the initial 12-week trial was not significantly associated with SPT prevention. Conclusions. Despite increased serum micronutrient levels, our results do not suggest a clinical benefit of JP in HNC patients. Future studies should focus on longer intervention periods and/or modified supplement formulations with demonstrated chemopreventive properties.

e17548 Background: Recurrent/Metastatic HNSCC is an immunosuppressive disease, especially in the group of patients with poor performance status. Recent studies have shown that low dose chemotherapy, which is much better tolerated than full dose cytotoxic chemotherapy, can increase the anti-tumor immune response and cause tumor regression. In this study we assessed the immune-effects of weekly cetuximab in combination with low dose weekly chemotherapy in HNSCC pts with poor PS by measuring saliva and plasma immune modulatory micro RNAs (miRs). Methods: Patients with recurrent/metastatic HNC with an ECOG PS of 2 or 3 were treated with low-dose weekly carboplatin (AUC 1) and paclitaxel (25 mg/m2) along with weekly cetuximab (400mg/m2 followed by 250 mg/m2). Seven immune modulatory miRs (146a, 155, 181, 20a, 223, 335, 125b) were measured in the saliva and plasma by quantitative PCR prior to treatment and at week 5. Results: Between 4/2016 and 1/2017, 30 patients were enrolled in this study. 24 patients were evaluable for response. Mean age was 69 years (range 51-89), Male/Female: 14/8. ECOG PS 2/3: 13/9. Site of disease: oral cavity 7, pharynx 9, larynx 4, para-nasal 2, unknown 2. Treatment was well tolerated. The most common dose limiting toxicity was skin rash in 10/24 pts (41.5%). Response: partial response 12 (50%); stable disease 4 (16.5%); progressive disease 8 (33.5%). Reduction in miR levels by week 5 were associated with clinical response. Reduction in saliva levels of miRs 146a and 181 correlated with clinical benefit (PR+SD). Pre-treatment saliva levels of miR 146a also showed to be a predictor of tumor response to therapy. Plasma levels of the immune modulatory miRs tested were not associated with response to therapy. Conclusions: The combination of cetuximab and low-dose chemotherapy is active and well tolerated in HNSCC patients with poor PS. Reduction in saliva levels of immune modulatory miRs 146a and 181 were associated with clinical benefit to therapy.

To define the toxicity and feasibility of concurrent pemetrexed and dose escalated erlotinib with radiation followed by maintenance erlotinib in the reirradiation setting. Fourteen unresectable/medically inoperable non-metastatic patients with measurable disease by CT and biopsy confirmed recurrence following primary chemoradiation therapy underwent concurrent chemotherapy with 2 cycles of pemetrexed 500 mg/m2 q 3 wks and dose escalated erlotinib (100/125/150 mg) daily for 6 weeks starting day 1 of reirradiation. Sixty Gy and 54 Gy in 30 fractions were delivered to gross disease and high risk occult sites respectively using an IMRT technique. Serial imaging and PET/CT were used to delineate the radiation treatment volume. The spinal cord was constrained to < 54 Gy to the 0.1 cc volume on the composite plan. Following concurrent chemotherapy and re-irradiation the patients were offered maintenance treatment with erlotinib (Non-smoker: 150 mg, Smoker: 300 mg) for two years or until tumor progression. The median follow-up at review was 18 months. No dose limiting toxicity was encountered at 100 and 125 mg of dose escalated erlotinib concurrent with radiation. One patient went off protocol due to progression during concurrent chemoradiation. Two of three patients at 150 mg erlotinib experienced dose limiting toxicities (DLT) and discontinued protocol therapy due to grade 3 transaminitis, mesenteric ischemia, sepsis, and/or death. At 150 mg dose level of erlotinib two patients discontinued protocol treatment: one secondary to sepsis (which developed at treatment day 2), and one due to sudden death. Both prior mentioned toxicities were found to be unrelated to treatment. Subsequently, 3 more patients were enrolled at 125 mg daily erlotinib with no DLTs. Grade ≥ 3 hematologic toxicity was encountered in 4 of 9 patients. Grade 1-2 acneiform rash was observed in 6 of 9 patients and was not exacerbated by concurrent radiation. No late radiation associated grade 3-4 toxicities have been observed. Out of 12 patients treated, five patients obtained CR and five patients PR at the end of CRT. Eight patients received maintenance treatment with erlotinib. Two patients have completed two years of maintenance treatment without tumor recurrence. Six of the 8 patients who completed therapy were free of local progression at last follow-up. Three of 12 patients were alive at the last follow-up. Concurrent chemoradiation with pemetrexed and dose escalated erlotinib are well tolerated and show promising efficacy in the completed phase 1 study. The phase 2 portion will continue with the recommended dose of 125 mg concurrent erlotinib with pemetrexed and re-irradiation.

Objectives: The standard concurrent radiotherapy and chemotherapy regimens for patients with oropharyngeal cancer are highly toxic. Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has recently emerged as a distinct biological and clinical entity with improved response to treatment and prognosis. A tailored therapeutic approach is needed to optimize patient care. The aim of our study was to investigate the impact of HPV and smoking status on early toxicities (primarily mucositis) associated with concurrent chemotherapy and radiotherapy in patients with OPSCC.Materials and methods: We retrospectively evaluated 72 consecutive patients with OPSCC and known HPV status treated with concurrent radiotherapy and chemotherapy at our institution. Treatment-related toxicities were stratified by smoking and HPV status and compared using univariate and multivariate logistic regression.Results: HPV-positive patients had a 6.86-fold increase in the risk of having severe, grade 3-4 mucositis. This effect was preserved after adjusting for patient smoking status, nodal stage, radiotherapy technique and radiotherapy maximum dose. Additionally, HPV status had significant effect on the objective weight loss during treatment and at three months after treatment. Consistently, non-smokers had a significant 2.70-fold increase in the risk of developing severe mucositis.Conclusion: Risk factors for OPSCC modify the incidence of treatment-related early toxicities, with HPV-positive and non-smoking status correlating with increased risk of high grade mucositis and associated outcomes. Retrospective single-institution studies need to be interpreted cautiously. However, this finding is important to consider when designing therapeutic strategies for HPV-positive patients and merits further investigation in prospective clinical trials. (C) 2014 Elsevier Ltd. All rights reserved.

5568 Background: Strategies for early detection of cellular response to EGFR inhibitors are critical to personalizing therapy for SCCHN. The glycolytic enzymes responsible for uptake of the positron emission tomography (PET) tracer [18F] 2- fluoro-2-deoxy-d-glucose (FDG) are regulated by intermediates of the EGFR pathway such as AKT, mTOR and MAPK. It was hypothesized that the inhibition of these EGFR pathway markers could be read by the 18[F]-FDG uptake by tumor. It is also possible that the EGFR pathway is aberrantly activated in some cancers and that glycolysis and downstream effects are not always linked. Previous in vitro and in vivo studies showed that 18[F]-FDG uptake changes very early in SCCHN tumor models responsive to EGFR inhibition. We developed a pilot clinical protocol to investigate this further in patients with SCCHN.METHODSPatients with operable SCCHN with a window of at least 15 days between the time of initial biopsy and established surgery will receive E 150 mg/day or 300 mg/day if the patient is actively smoking. Smokers metabolize E rapidly with an MTD that is twice that of non-smokers. Patients must have additional biopsy tissue for laboratory research studies. 18[F]-FDG PET scan and neck CT with contrast are performed before treatment, 4-6 days through treatment and at the end of E administration.RESULTS11 patients have been treated to date with an average of 18.6 days of treatment. Of the 10 evaluable patients, 7 showed partial response (PR) and 3 patients showed stable disease (SD). 8 patients received E 300 mg. No grade 3 or 4 toxicities. Early (4-6 days)18[F]-FDG PET scans showed a decrease in SUV max to 93.25% +/- 18% in patients with SD and to 51% +/- 22% in patients with PR (defined as at least 20% reduction in maximum diameter). This pilot trial will continue to enroll patients to address the primary laboratory research correlative aim. Pre-and post-treatment tumor tissue is available in all patients.CONCLUSIONSShort course treatment with E in a dose adjusted per smoking status is very active in previously untreated patients with SCCHN. Early changes in the 18[F]-FDG PET scan uptake can be used as a marker predictive of response to EGFR inhibition.

OBJECTIVE:To report the rate of pathological complete response after induction chemotherapy with the docetaxel, cisplatin, and fluorouracil (TPF) combination.DESIGN:Retrospective cohort analysis.SETTING:Tertiary care academic cancer center, between June 1999 and May 2004.PATIENTS:Seventy-two patients with newly diagnosed squamous cell carcinoma of the head and neck; 68 (95%) of the patients had stage IV, locally advanced disease.INTERVENTIONS:Three cycles of induction chemotherapy followed by a biopsy of the primary site. All patients subsequently underwent chemotherapy with 3 cycles of TPF.MAIN OUTCOME MEASURE:Rate of pathological complete response at the primary site after induction chemotherapy with 3 cycles of TPF.RESULTS:Biopsy results were negative for cancer in 64 patients (89%) and positive in 8 patients (11%). The median follow-up was 2 years. In the positive biopsy result group, 2 (25%) of 8 patients died of disease vs 3 (4%) of 64 patients in the negative biopsy result group. Twenty-nine neck dissections were performed; results were positive in 7 patients (all alive with no evidence of disease) and negative in 22 patients (21 alive with no evidence of disease). The overall 2- and 5-year progression-free survival is currently projected at 85% and 85%, respectively; the overall 2- and 5-year survival, at 95% and 90%, respectively. Importantly, T4 presentation did not predict a positive biopsy result at the primary site or a positive neck dissection result (P = .60 and P = .56, respectively). N3 presentation (12 patients) did not predict a positive biopsy result at the primary site (P = .87) but did correlate with positive neck dissection results in 6 of 12 patients (P<.001).CONCLUSIONS:Induction chemotherapy with the TPF regimen results in a high pathological complete response rate (89%). This rate is higher than with the cisplatin plus fluorouracil combination therapy, which was reported to be between 25% and 50% in previous studies. Chemoradiotherapy is currently an accepted standard of care, but induction chemotherapy continues to be investigated. Based on recent phase 3 trial results and the data presented herein, we propose that the 3-drug combination be used as the new platform when administering induction chemotherapy.

The treatment of head and neck cancer continues to evolve. The recent use of aggressive chemoradiotherapy protocols has resulted in significant morbidity involving mucositis, dysphagia, and a higher rate of feeding tube dependency. We have initiated a randomized phase II study with concomitant chemoradiotherapy with or without subcutaneous amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD). This article presents a detailed background, rationale, and endpoints for this study and discusses future directions in the treatment of head and neck cancer.

Haddad, Robert MD; Mahadevan, Anand MD; Posner, Marshall R. MD; Sullivan, Christopher Author Information

5511 Background: Sequential chemoradiotherapy using induction chemotherapy (IC) followed by chemoradiotherapy (CRT) is often used in patients with SCCHN. Two recent large phase III studies have shown that adding a taxane to standard PF induction regimen improves outcome and is better tolerated than PF (Hitt et al ASCO 2003, Vermorken et al. ASCO 2004). It is our standard practice to biopsy the primary site after IC before CRT. We report the rate of complete pathological response (pCR) after IC with TPF. Material and Methods: All patients received three cycles of IC with TPF followed by CRT. Chemoradiotherapy consisted of weekly carboplatin/ paclitaxel or docetaxel with standard or concomitant boost XRT. All patients were biopsied after IC, before starting CRT. Neck dissection (ND) was performed 6–12 weeks after CRT for N3 patients and incomplete responders to CRT. Results: Between June 1999 and May 2004, 72 patients underwent biopsy of the primary site after IC. Stage IV: 95%, Oropharynx 75%: Biopsy was negative in 64 patients (89%) and positive in 8 patients (11%). Median follow up is two years. In the positive biopsy group 2/8 (25%) died of disease vs. 3/64 (4%) in the negative biopsy group. Twenty-nine ND were performed: Seven positive (all alive NED) and 22 Negative (21 Alive, NED). The overall 2 and 5- year progression-free survival currently projects at 85% and 85% respectively and the overall 2-year and 5-year survival at 95% and 90% respectively. Importantly, T4 presentation did not predict a positive biopsy at primary site or a positive ND (p =0.6031 and p=0.5557 respectively). N3 presentation (12 patients) did not predict a positive biopsy (p=0.8668), but did correlate with positive ND: 6/12 (p<0.001). Conclusion: TPF induction chemotherapy results in high rate of pCR (89%). This rate is higher than PF, reported in previous studies to be between 25–50%. Chemoradiotherapy is currently an accepted standard of care but IC continues to be investigated. Based on the recent phase III results and the data presented here, we propose that the three-drug combination be used as the new platform when using IC. No significant financial relationships to disclose.

Cisplatin plus 5-fluorouracil (5-FU) (PF regimen) induction chemotherapy (IC) has been studied over the last two decades and has proven to be a durable and effective therapy for patients with locally advanced squamous cell cancer of the head and neck (SCCHN). Although randomized trials and meta-analyses have demonstrated that PF-based IC improves survival, reduces systemic metastases, and permits organ preservation, the effect on overall survival has been less robust than the results seen with cisplatin-based chemoradiotherapy (CRT) regimens. Differences in trial design, scheduling, and surgical interventions account for some of the variation in results. As studies have evolved, it has become evident that there are advantages to both approaches. This perception has led to the concept of sequential therapy (ST), the combination of IC, CRT, and surgery. ST programs are being studied intently in many centers. Phase II and III trials of ST regimens have reported unprecedented survival results in patients with locally advanced disease. In addition, the hypothesis that PF plus a taxane may result in an improved survival, compared to PF alone, for patients with locally advanced SCCHN on ST treatments is being tested in phase III trials. Although ST has not been compared head to head with CRT, early results support the use of this treatment paradigm in patients with poor prognosis SCCHN and should lead to definitive phase III trials in the near future. ST may represent the cutting edge of therapy for patients with curable, locally advanced SCCHN.

5548 Background: We have previously reported the results of Sequential Therapy (ST) with IC followed by weekly D and concurrent daily XRT (Cancer, 2002). In this Phase I/II trial, we investigated concurrent weekly D and the more dose intensive CBR radiation schedule after IC in patients with locally advanced SCCHN. Methods: All patients (AJCC Stage III -7% or IV -93%) were treated with IC (90% 3 cycles; 10% 1 or 2) using cisplatin/5-FU (PF), carboplatinum-F or DPF. Chemoradiotherapy (CRT) consisted of 4 weekly doses of D @ 20 or 25mg/M2 (15 patients/dose level) concurrently with the first 4 weeks of CBR (1.8 Gy qD X 18, 1.8/1.5 Gy bid X 12). Results: 31 patients were enrolled and 30 are evaluable. Median follow up is 21 months, (range of 6–40). Primary sites were: oropharynx 19, oral cavity 2, larynx/hypopharynx 5, unknown primary 4. 87% of patients had N2/N3 disease, 60% had T3/T4 disease. Only 20% of patients had a CR to IC and 50% had a CR to ST (IC, CRT, and Surgery) with 2 PD and 13 PRs. The 2 patients with PD died at 6 and 9 months. A total of 5 patients progressed (2 local, 1 local + distant, 2 distant) and died; another patient died of long-term toxicity. 19 of 26 patients presenting with neck disease had neck dissections. 7 did not; 5 were CRs, 1 had PD and one was inoperable. 7 of 19 (37%) dissections were positive and of these, two are dead of disease. Overall, 24 patients (80%) are alive, NED. No acute DLT was observed at either dose of D, but additional patients were added at 20 mg/M2 because of concerns regarding duration of PEG dependence at 25 mg/M2 and one patient dying late from respiratory arrest associated with severe fibrosis. Conclusions: This intensive ST regimen with concurrent D/CBR as CRT yields good local-regional control and survival in poor prognosis patients. Short term mucositis and late fibrosis are significant but may be justified by long term survival. Study accrual is complete and results of long term toxicity will be presented with additional follow up. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis

BACKGROUND:The authors conducted a series of four Phase I-II trials of high-dose and intermediate-dose docetaxel, cisplatin, and 5-fluorouracil (TPF)-based induction chemotherapy for patients with advanced squamous cell carcinoma of the head and neck (SCCHN). The chemotherapy regimens and response rates for each trial were published previously. In the current analysis, the authors report the data on long-term survival, patterns of failure, and morbidity among the patients who were treated at their institution.METHODS:A total of 101 patients with previously untreated, locally advanced, curable SCCHN were entered onto the studies. Overall, 68 patients (67%) had N2-N3 disease, and 86 patients (85%) had Stage IV disease. Patients were treated with combinations of TPF with or without leucovorin. Cycles were repeated every 21-28 days for a total of 3 cycles followed by hyperfractionated radiotherapy.RESULTS:After a median follow-up of 49 months, 65 patients (64%) remain alive with no evidence of disease (NED), and 3 patients remain alive with disease, for an overall survival rate of 67% (68 patients). Twenty-six patients had locoregional recurrences (LRR), and 5 patients had both LRR and distant metastasis (DM). Only five patients had DM as the sole site of failure. Four patients underwent salvage surgery at the primary site and remain alive with NED. Excluding 17 patients with nasopharyngeal carcinoma, of 84 patients, 55 patients remain alive with NED (65%). Notably, 43 of 84 patients (51%) had oropharyngeal primary tumors, and 30 of those patients remain alive with NED (70%). Significant morbidity was low, with two treatment-related deaths. All but two of the surviving patients are able to swallow and had their feeding tubes removed.CONCLUSIONS:These data suggest that docetaxel adds incrementally to the efficacy of cisplatin and fluorouracil. Local-regional failures continue to be the major impediment to cure in these patients. Given the increase in local-regional dose intensity with chemoradiation, sequential treatment plans that integrate induction chemotherapy and chemoradiotherapy seem to be the logical next step.