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Purpose: We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC)., Patients and Methods: We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis., Results: Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery., Conclusions: Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil., (©2021 The Authors; Published by the American Association for Cancer Research.)

Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination., Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m(2)) followed by 250 mg/m(2)/week and cisplatin 75 mg/m(2) q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival., Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%-61%]. Two-year overall survival (OS) was 66% (95% CI, 53%-77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV(+) patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively)., Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV(+) tumors., (©2014 American Association for Cancer Research.)

Purpose: The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo., Experimental Design: Patients with untreated, operable stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after seven to 14 days of treatment. The primary endpoint was change in Ki67 proliferation index. We hypothesized an ordering effect in Ki67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX2 signaling intermediates., Results: From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, P = 0.04). Wilcoxon pairwise contrasts confirmed greater Ki67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo, P = 0.043; erlotinib vs. placebo, P = 0.027). There was a significant trend in ordering of Ki67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, P = 0.0185). Low baseline pSrc correlated with greater Ki67 reduction (R(2) = 0.312, P = 0.024)., Conclusions: Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target., (©2014 American Association for Cancer Research.)

Background: p53 accumulation in head and neck squamous cell carcinoma (HNSCC) cells creates a targetable tumor antigen. Adjuvant dendritic cell (DC)-based vaccination against p53 was tested in a phase I clinical trial., Experimental Methods: Monocyte-derived DC from 16 patients were loaded with two modified HLA-class I p53 peptides (Arm 1), additional Th tetanus toxoid peptide (Arm 2), or additional Th wild-type (wt) p53-specific peptide (Arm 3). Vaccine DCs (vDC) were delivered to inguinal lymph nodes at three time points. vDC phenotype, circulating p53-specific T cells, and regulatory T cells (Treg) were serially monitored by flow cytometry and cytokine production by Luminex. vDC properties were compared with those of DC1 generated with an alternative maturation regimen., Results: No grade II-IV adverse events were observed. Two-year disease-free survival of 88% was favorable. p53-specific T-cell frequencies were increased postvaccination in 11 of 16 patients (69%), with IFN-γ secretion detected in four of 16 patients. Treg frequencies were consistently decreased (P = 0.006) relative to prevaccination values. The phenotype and function of DC1 were improved relative to vDC., Conclusion: Adjuvant p53-specific vaccination of patients with HNSCC was safe and associated with promising clinical outcome, decreased Treg levels, and modest vaccine-specific immunity. HNSCC patients' DC required stronger maturation stimuli to reverse immune suppression and improve vaccine efficacy., (©2014 AACR.)

Purpose: To assess the prognostic value of epidermal growth factor receptor (EGFR) molecular characteristics of head and neck squamous cell carcinoma (HNSCC)., Patients and Methods: HNSCC tumors from patients prospectively enrolled in either an Early Detection Research Network (EDRN) study and treated with surgery without an EGFR-targeted agent (N = 154) or enrolled in a chemoradiation trial involving the EGFR-targeted antibody cetuximab (N = 39) were evaluated for EGFR gene amplification by FISH and EGFR protein by immunohistochemical staining. Fresh-frozen tumors (EDRN) were also evaluated for EGFR protein and site-specific phosphorylation at Y992 and Y1068 using reverse-phase protein array (n = 67). Tumor (n = 50) EGFR and EGFRvIII mRNA levels were quantified using real-time PCR., Results: EGFR expression by immunohistochemistry (IHC) was significantly higher in the EDRN tumors with EGFR gene amplification (P < 0.001), and a similar trend was noted in the cetuximab-treated cohort. In the EDRN and cetuximab-treated cohorts elevated EGFR by IHC was associated with reduced survival (P = 0.019 and P = 0.06, respectively). Elevated expression of total EGFR and EGFR PY1068 were independently significantly associated with reduced progression-free survival in the EDRN cohort [HR = 2.75; 95% confidence interval (CI) = 1.26-6.00 and HR = 3.29; 95% CI = 1.34-8.14, respectively]., Conclusions: In two independent HNSCC cohorts treated with or without cetuximab, tumor EGFR levels were indicative of survival. Tumor EGFR PY1068 levels provided prognostic information independent of total EGFR., (©2012 AACR.)

Purpose: A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy., Experimental Design: Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m²) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1., Results: Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m², without dose-limiting toxicities; one patient treated at 1.3 mg/m² was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1., Conclusions: Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination., (©2011 AACR.)

Purpose: Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC)., Experimental Design: Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms (SNP) in the XPF gene by using a custom array. The primary endpoint was progression-free survival (PFS)., Results: XPF expression was higher in tumors from the oral cavity than from the other sites (P < 0.01). High XPF expression correlated with early time to progression both by univariate (HR = 1.87, P = 0.03) and multivariate analysis (HR = 1.83, P = 0.05). The one year PFS for high expressers was 47% (95% CI = 31-62) compared with 72% (95% CI = 55-83) for low expressers. In addition, we identified four XPF SNPs that showed marginal association with treatment failure., Conclusions: Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next generation personalized cancer therapy., (©2011 AACR.)

Purpose: Epidermal growth factor receptor (EGFR) overexpression is correlated with decreased survival in head and neck cancer (HNC) where the addition of EGFR inhibition to standard chemoradiation approaches has improved treatment responses. However, the basis for the limited efficacy of EGFR inhibitors in HNC is incompletely understood. G-protein-coupled receptors (GPCR) have been shown to be overexpressed in HNC where GPCR activation induces HNC growth via both EGFR-dependent and -independent pathways. We hypothesized that targeting GPCR-induced EGFR-independent signaling would improve the efficacy of EGFR inhibition., Experimental Design: Using a high-throughput phosphoproteome array, we identified proteins that were phosphorylated in HNC cells where EGFR expression was downmodulated by RNA interference (RNAi) in the presence or absence of a GPCR ligand. We confirmed the findings from the array by Western blotting followed by in vitro and in vivo phenotypic assays., Results: p70S6K phosphorylation was elevated approximately sixfold in EGFR siRNA-transfected cells treated with a GPCR ligand. In addition to RNAi-mediated EGFR downmodulation, GPCR-mediated phosphorylation of p70S6K was modestly increased by EGFR inhibitor cetuximab approved by the Food and Drug Administration. Biopsies from cetuximab-treated patients also displayed increased phospho-p70S6K staining compared with pretreatment biopsies. HNC cells were growth inhibited by both genetic and pharmacologic p70S6K targeting strategies. Furthermore, p70S6K targeting in combination with cetuximab resulted in enhanced antitumor effects in both in vitro and in vivo HNC models., Conclusions: These results indicate that increased phosphorylation of p70S6K in cetuximab-treated patients may be due to increased GPCR signaling. Therefore, the addition of p70S6K targeting strategies may improve treatment responses to EGFR inhibition., (©2011 AACR.)

Purpose: Mammalian target of rapamycin (mTOR) is a promising target in small cell lung cancer (SCLC). We designed a phase II study of everolimus, an mTOR inhibitor, in previously treated, relapsed SCLC., Experimental Design: Patients were treated with everolimus 10 mg orally daily until disease progression. The primary endpoint was disease control rate (DCR) at 6 weeks. PI3K/Akt signaling pathway biomarkers were evaluated on baseline tumor tissue., Results: A total of 40 patients were treated: 23 had 1 prior regimen/sensitive relapse, 4 had 1 prior regimen/refractory, and 13 had 2 prior regimens. Twenty-eight patients received 2 or more cycles of everolimus, 7 received 1 cycle, and 5 did not complete the first cycle. Best response in 35 evaluable patients: 1 (3%) partial response (in sensitive relapse), 8 (23%) stable disease, and 26 (74%) progression; DCR at 6 weeks was 26% (95% CI = 11-40). Median survival was 6.7 months and median time to progression was 1.3 months. Grade 3 toxicities included thrombocytopenia (n = 2), neutropenia (n = 2), infection (n = 2), pneumonitis (n = 1), fatigue (n = 1), elevated transaminases (n = 1), diarrhea (n = 2), and acute renal failure (n = 1). High phosphorylated AKT expression was modestly associated with overall survival (HR = 2.07; 95% CI = 0.97-4.43). Baseline S6 kinase protein expression was significantly higher in patients with disease control versus patients with progression (P = 0.0093)., Conclusions: Everolimus was well tolerated but had limited single-agent antitumor activity in unselected previously treated patients with relapsed SCLC. Further evaluation in combination regimens for patients with sensitive relapse may be considered., (©2010 AACR.)

Purpose: Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, potentiates antitumor effects of erlotinib in preclinical studies, and COX-2 is frequently expressed in non-small cell lung cancer (NSCLC). With these observations, we designed a phase II trial to evaluate the efficacy and safety of erlotinib plus celecoxib in advanced NSCLC., Experimental Design: Previously treated stage IIIB/IV NSCLC patients were given celecoxib at 400 mg orally twice daily and erlotinib at 150 mg orally daily until disease progression. Planned accrual was 40 patients. Tissue was collected for epidermal growth factor receptor (EGFR) analysis and COX-2 immunohistochemistry., Results: Twenty-six patients were enrolled (17 men, 9 women; median age, 66 years). Eighteen and 21 patients had tissue available for EGFR analysis and COX-2 immunohistochemistry, respectively. The median progression-free survival (PFS) and overall survival were 2.0 and 9.2 months, respectively. Eleven of 21 patients tested had increased tumor COX-2 expression, which was strongly associated with prolonged PFS (P=0.048). Four patients on anticoagulation or with a history of peptic ulcer disease had grade 3/grade 4 upper gastrointestinal bleeding (GIB), prompting early study closure. Three patients with GIB had endoscopy that found peptic ulcers., Conclusions: The combination of erlotinib and celecoxib does not seem superior to erlotinib alone in unselected patients. However, longer PFS with high-tumor COX-2 expression suggests that trials of EGFR and COX-2 inhibitors may be warranted in this patient subset. GIB observed in our trial supports excluding patients with a history of peptic ulcer disease or those requiring therapeutic anticoagulation from future EGFR and COX-2 inhibitor studies.

Purpose: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel., Experimental Design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxel were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized., Results: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non-dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25 patients evaluable for response, partial responses occurred in 11 (10 non-small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics., Conclusions: Both schedules of vorinostat (400 mg oral qd x 14 days or 300 mg bd x 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL x min) and paclitaxel (200 mg/m(2)). Encouraging anticancer activity was noted in patients with previously untreated non-small cell lung cancer.

Purpose: We previously demonstrated high locoregional control, in patients with poor-prognosis head and neck cancer (HNC), using paclitaxel, 5-fluorouracil, hydroxyurea, and concomitant hyperfractionated radiotherapy. In the present phase I trial, gemcitabine, a novel antimetabolite with strong radiation-enhancing activity, replaces hydroxyurea. We sought to determine the recommended phase II dose and clinical efficacy in poor-prognosis HNC patients., Experimental Design: Seventy-two patients enrolled. Eligibility criteria included recurrent or second primary HNC, metastases or expected 2-year survival <20%. Chemoradiotherapy consisted of 5-fluorouracil, 600 mg/m(2)/d, for 5 days; paclitaxel, 100 mg/m(2) on Day 1; and concurrent 1.5 Gy twice-daily radiation for 5 days. Gemcitabine was dose escalated, 50-300 mg/m(2) on day 1. Cycles repeated every 14 days until the completion of chemoradiation. Dose-limiting toxicities (DLTs) included: neutropenic fever; grade > or =4 neutropenia or thrombocytopenia for >4 days; grade > or =4 mucositis or dermatitis for >7 days; or grade 3 toxicity necessitating chemotherapy dose reductions. Non-DLT dose reductions in 5-fluorouracil and/or paclitaxel were allowed., Results: Seventy-nine percent of assessable patients experienced a clinical response. Five-year actuarial survival is 33.0%, and locoregional control is 61.4%. The recommended phase II dose of gemcitabine in this regimen is 100 mg/m(2) during cycles 1-5 (1 of 7 patients with DLT) or 200 mg/m(2) delivered only during cycles 3-5 (3 of 19 with DLT). Grades 3 and 4 mucositis (56 and 21%, respectively) and dermatitis (25 and 21%, respectively) were common., Conclusions: Gemcitabine, 5-fluorouracil, paclitaxel, and twice-daily radiation, delivered on alternating weeks, is active in patients with poor-prognosis HNC, although severe mucositis limits the clinical applicability of this regimen. Refinements in radiotherapy, including intensity-modulated radiation therapy, may improve the tolerance for this regimen.

Purpose: The purpose of this retrospective analysis was to evaluate the emergence of second primary malignancies and the contribution of different causes of death to the outcome of patients with locoregionally advanced head and cancer receiving primary chemoradiotherapy., Experimental Design: We studied 324 patients with stage IV squamous cell head and neck cancer who were enrolled on five consecutive multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T-FHX). The cumulative incidence of second primary tumors or death from any cause was estimated using methods of competing risk analysis., Results: Median follow-up of surviving patients was 5.2 years (2-10.6 years). The 5-year overall survival and progression-free survival of the cohort were 46% and 65%, respectively. Causes of death and median time of occurrence were as follows: disease (n = 88; 1.5 years), treatment-associated acute or late complications (n = 30; 4 months), second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second primary tumor at a median time of 2.8 years (4 months to 10 years). The cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10 years, respectively. The most frequent site of second primaries was the lung (n = 13), followed by the esophagus (n = 3) and head and neck (n = 2), Conclusions: Patients with locoregionally advanced head and neck cancer treated with concurrent chemoradiotherapy are potentially curable but face significant risks of mortality from causes other than disease progression. Ameliorating toxicity, and implementing secondary screening and chemoprevention strategies are major goals in the management of head and neck cancer.

Purpose: HER-2/neu and estrogen receptor (ER) are critical in the biology of breast carcinoma, and both are validated therapeutic targets. Extensive interactions between the signaling pathways of these receptors have been demonstrated. This suggests that targeting both receptors simultaneously may have a dramatic effect on the biology of breast cancer. This hypothesis was tested in cell culture experiments., Experimental Design: ER-positive, HER-2/neu-overexpressing BT-474 human breast carcinoma cells were cultured in the presence of the anti-HER-2/neu therapeutic antibody trastuzumab (Herceptin), the antiestrogen tamoxifen, or both. The effects on cell growth, cell cycle distribution, clonogenicity, survival, and the level and activity of HER-2/neu were examined., Results: The combination of tamoxifen and Herceptin resulted in synergistic growth inhibition and enhancement of cell accumulation in the G(0)-G(1) phase of the cell cycle, with a decrease in cells in S phase. Clonogenicity was inhibited in the presence of each drug and more so by the combination, although prior exposure to drugs did not affect subsequent clonogenicity in drug-free media, and neither drug nor the combination induced apoptosis. Herceptin, but not tamoxifen, inhibited signaling by HER-2/neu., Conclusions: The combination of tamoxifen and Herceptin is formally demonstrated to result in synergistic growth inhibition and enhancement of G(0)-G(1) cell cycle accumulation. In vitro, the individual drugs or combination produces a cytostatic effect. These results suggest that combined inhibition of ER and HER-2/neu signaling may represent a powerful approach to the treatment of breast cancer.

Purpose: Induction chemotherapy with carboplatin and paclitaxel followed by concomitant TFHX (paclitaxel, infusional 5-fluorouracil, hydroxyurea, and twice-daily radiation therapy administered every other week) has resulted in 70% 3-year survival in stage IV patients. Locoregional and distant control rates were 94 and 93%, respectively. In an attempt to decrease toxicity without compromising local control, a second cohort of patients was treated with a lower dose of radiation to sites of potential microscopic disease., Experimental Design: Sixty-four patients were entered on study. Patients received six weekly doses of carboplatin (area under the curve 2) and paclitaxel (135 mg/m2) followed by five cycles of TFHX. The radiation dose to gross disease was 75 Gy as in the previous trial. The radiation dose to high-risk microscopic disease was reduced from 60 to 54 Gy, and the dose to low-risk microscopic disease was reduced from 45 to 39 Gy., Results: Ninety-seven percent of patients had stage IV disease. The response rate to induction chemotherapy was 82% with a complete response rate of 42%. At the completion of therapy the clinical complete response rate rose to 100% with a median follow-up of 29 months. The actuarial 2 and 3-year survival was 77 and 70%, respectively. Five patients developed progressive disease for an overall 3-year progression-free survival of 90%. Two patients failed in locoregional sites alone, resulting in a 3-year locoregional control of 97%. The 3-year systemic control was 95%. Four patients were completely feeding tube dependent at the time of analysis. Only 1 of these patients had normal swallowing function before treatment., Conclusions: In this second trial, induction chemotherapy with carboplatin and paclitaxel followed by TFHX chemoradiotherapy results in high survival and progression-free survival. The reduction in radiation dose did not compromise survival or disease control compared with our prior study using higher radiation doses. Data continues to support definitive evaluation of this approach.