Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial.

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS). Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation. Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023. Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks. Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers. Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed. Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.

Radiotherapy Plus Cisplatin With or Without Lapatinib for Non-Human Papillomavirus Head and Neck Carcinoma: A Phase 2 Randomized Clinical Trial.

Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC. Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS). Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020. Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo). Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS. Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84). Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.

Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial.

BACKGROUND: Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population. METHODS: Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m2) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m2), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete. FINDINGS: The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group). INTERPRETATION: To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated. FUNDING: National Cancer Institute and Novartis.

A phase 2 trial of a topical antiseptic bundle in head and neck cancer surgery: Effects on surgical site infection and the oral microbiome.

BACKGROUND: Head and neck cancer (HNC) surgery remains an important component of management but is associated with a high rate of surgical site infection (SSI). We aimed to assess the safety and efficacy of a topical mucosal antiseptic bundle in preventing SSI and evaluate microbial predictors of infection through a genomic sequencing approach. METHODS: This study was an open-label, single-arm, single-center, phase 2 trial of a topical mucosal antiseptic bundle in patients with HNC undergoing aerodigestive tract resection and reconstruction. Patients underwent topical preparation of the oral mucosa with povidone-iodine (PI) and chlorhexidine gluconate (CHG) pre- and intra-operatively followed by oral tetracycline ointment every 6 hours for 2 days post-operatively. The primary outcome was change in bacterial bioburden at the oral surgical site. Secondary outcomes included safety, SSI, and microbial predictors of infection. FINDINGS: Of 27 patients screened between January 8, 2021, and May 14, 2021, 26 were enrolled and 25 completed the study. There were no antiseptic-related adverse events. The topical mucosal antiseptic bundle significantly decreased oral bacterial colony-forming units from pre-operative levels (log10 mean difference 4·03, 95%CI 3·13-4·;92). There were three SSI (12%) within 30 days. In correlative genomic studies, a distinct set of amplicon sequence variants in the post-operative microbiome was associated with SSI. Further, despite no instance of post-operative orocervical fistula, metagenomic sequence mapping revealed the oral cavity as the origin of the infectious organism in two of the three SSI. INTERPRETATION: The bacterial strains which subsequently caused SSI were frequently identified in the pre-operative oral cavity. Accordingly, a topical antiseptic bundle decreased oral bacterial bioburden throughout the peri-operative period and was associated with a low rate of SSI, supporting further study of topical antisepsis in HNC surgery. FUNDING: Alliance Oncology.

Pharmacokinetic Basis for Using Saliva Matrine Concentrations as a Clinical Compliance Monitoring in Antitumor B Chemoprevention Trials in Humans.

This study reports the first clinical evidence of significantly high secretion of matrine in a multi-component botanical (Antitumor B, ATB) into human saliva from the systemic circulation. This is of high clinical significance as matrine can be used as a monitoring tool during longitudinal clinical studies to overcome the key limitation of poor patient compliance often reported in cancer chemoprevention trials. Both matrine and dictamine were detected in the saliva and plasma samples but only matrine was quantifiable after the oral administration of ATB tablets (2400 mg) in 8 healthy volunteers. A significantly high saliva/plasma ratios for Cmax (6.5 ± 2.0) and AUC0-24 (4.8 ± 2.0) of matrine suggested an active secretion in saliva probably due to entero-salivary recycling as evident from the long half-lives (t1/2 plasma = 10.0 ± 2.8 h, t1/2 saliva = 13.4 ± 6.9 h). The correlation between saliva and plasma levels of matrine was established using a population compartmental pharmacokinetic co-model. Moreover, a species-relevant PBPK model was developed to adequately describe the pharmacokinetic profiles of matrine in mouse, rat, and human. In conclusion, matrine saliva concentrations can be used as an excellent marker compound for mechanistic studies of active secretion of drugs from plasma to saliva as well as monitor the patient's compliance to the treatment regimen in upcoming clinical trials of ATB.

Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer.

This study aims to characterize the pharmacokinetic (PK) profiles and identify important bioavailability barriers and pharmacological pathways of the key active components (KACs) of Antitumor B (ATB), a chemopreventive agent. KACs (matrine, dictamine, fraxinellone, and maackiain) of ATB were confirmed using the antiproliferative assay and COX-2 inhibition activities in oral cancer cells. The observed in vitro activities of KACs were consistent with their cell signaling pathways predicted using the in silico network pharmacology approach. The pharmacokinetics of KACs were determined after i.v., i.p., and p.o. delivery using ATB extract and a mixture of four KACs in mice. Despite good solubilities and permeabilities, poor oral bioavailabilities were estimated for all KACs, mostly because of first-pass metabolism in the liver (for all KACs) and intestines (for matrine and fraxinellone). Multiple-dose PK studies showed 23.2-fold and 8.5-fold accumulation of dictamine and maackiain in the blood, respectively. Moreover, saliva levels of dictamine and matrine were found significantly higher than their blood levels. In conclusion, the systemic bioavailabilities of ATB-KACs were low, but significant levels of dictamine and matrine were found in saliva upon repeated oral administration. Significant salivary concentrations of matrine justified its possible use as a drug-monitoring tool to track patient compliance during chemoprevention trials.

The impact of age on outcome in phase III NRG Oncology/RTOG trials of radiotherapy (XRT) +/- systemic therapy in locally advanced head and neck cancer.

PURPOSE: To examine the role age plays in the treatment and prognosis of locally advanced head and neck cancer (LAHNC) treated definitively with radiation alone or combined modality therapy. METHODS: A retrospective analysis was performed of three NRG/RTOG trials examining either radiation alone or combined radiation and systemic therapy for LAHNC. The effect of age (≥70 yrs.) on cause-specific survival (CSS), overall survival (OS), and toxicity was evaluated. RESULTS: A total of 2688 patients were analyzed, of whom 309 patients (11.5%) were ≥ 70. For all studies combined, the hazard ratio (HR) for CSS for patients age ≥ 70 vs. those <70 was 1.33 (95%CI: 1.14-1.55, p < 0.001). For OS, the HR for patients age ≥ 70 vs. those <70 for all studies combined was 1.55 (95% CI 1.35-1.77, p < 0.001). After adjustment for all covariates, age ≥ 70 was associated with worse OS regardless of adjustment for smoking and p16 status. The survival difference was more pronounced in those receiving combined radiation and systemic therapy. Hematologic and renal toxicities were increased in combined modality trials in patients ≥70 years old. CONCLUSIONS: Patients age ≥ 70 with LAHNC were underrepresented in these clinical trials. Their CSS and OS proved inferior to patients <70 years old.

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group.

BACKGROUND AND PURPOSE: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

De-Escalation After DE-ESCALATE and RTOG 1016: A Head and Neck Cancer InterGroup Framework for Future De-Escalation Studies.

Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is increasing rapidly. The younger age, significantly improved prognosis, and relative morbidity of the standard-of-care cisplatin and radiotherapy in this population have led to the popularization of the concept of treatment de-escalation. The recent results of the first 3 randomized de-escalation trials, however, have shown a clear detriment in survival when cisplatin is omitted or substituted. In view of these results, the Head and Neck Cancer International Group identified the need to issue guidance regarding future de-escalation studies for patients with HPV-positive head and neck cancer to avoid the possibility of patients being harmed. We review the current state of the literature regarding HPV de-escalation trials and present a framework and guidance on future and existing clinical trials for treatment de-escalation of HPV-positive OPC. De-escalation paradigms of HPV-positive OPC should be evaluated in phase II studies, and results should be awaited before proceeding to phase III studies. Implementation into clinical practice before high-level evidence is available should not be undertaken in this context. Finally, harm-minimization techniques should also be evaluated as an alternative to de-escalation of treatment in these patient groups.

Nomogram to Predict the Benefit of Intensive Treatment for Locoregionally Advanced Head and Neck Cancer.

PURPOSE: Previous studies indicate that the benefit of therapy depends on patients' risk for cancer recurrence relative to noncancer mortality (ω ratio). We sought to test the hypothesis that patients with head and neck cancer (HNC) with a higher ω ratio selectively benefit from intensive therapy. EXPERIMENTAL DESIGN: We analyzed 2,688 patients with stage III-IVB HNC undergoing primary radiotherapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score on the basis of tumor, demographic, and health factors. Analysis was by intention to treat. RESULTS: Decreasing age, improved performance status, higher body mass index, node-positive status, P16-negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥0.80 were more likely to benefit from intensive treatment [5-year overall survival (OS), 70.0% vs. 56.6%; HR of 0.73, 95% confidence interval (CI): 0.57-0.94; P = 0.016] than those with ω score <0.80 (5-year OS, 46.7% vs. 45.3%; HR of 1.02, 95% CI: 0.92-1.14; P = 0.69; P = 0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression. CONCLUSIONS: Patients with HNC with a higher ω score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.

Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non-Small Cell Lung Cancer: A Long-term Update of the NRG Oncology/RTOG 0214 Phase 3 Randomized Clinical Trial.

IMPORTANCE: Brain metastasis (BM) rates are high in locally advanced non-small cell lung cancer (LA-NSCLC), approaching rates seen in small cell lung cancer, where prophylactic cranial irradiation (PCI) is standard of care. Although PCI decreases the incidence of BM in LA-NSCLC, a survival advantage has not yet been shown. OBJECTIVE: To determine if PCI improves survival in LA-NSCLC. DESIGN, SETTING, AND PARTICIPANTS: Radiation Therapy Oncology Group (RTOG) 0214 was a randomized phase 3 clinical trial in stage III NSCLC stratified by stage (IIIA vs IIIB), histologic characteristics (nonsquamous vs squamous) and therapy (no surgery vs surgery). The study took place at 291 institutions in the United States, Canada, and internationally. Of 356 patients with stage III NSCLC entered onto this study, 16 were ineligible; therefore, 340 patients were randomized. INTERVENTION FOR CLINICAL TRIALS: Observation vs PCI. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS). The secondary end points were disease-free survival (DFS) and incidence of BM. RESULTS: Of the 340 total participants, mean (SD) age was 61 years; 213 of the participants were men and 127 were women. The median follow-up time was 2.1 years for all patients, and 9.2 years for living patients. The OS for PCI was not significantly better than observation (hazard ratio [HR], 0.82; 95% CI, 0.63-1.06; P = .12; 5- and 10-year rates, 24.7% and 17.6% vs 26.0% and 13.3%, respectively), while the DFS (HR, 0.76; 95% CI, 0.59-0.97; P = .03; 5- and 10-year rates, 19.0% and 12.6% vs 16.1% and 7.5% for PCI vs observation) and BM (HR, 0.43; 95% CI, 0.24-0.77; P = .003; 5- and 10-year rates, 16.7% vs 28.3% for PCI vs observation) were significantly different. Patients in the PCI arm were 57% less likely to develop BM than those in the observation arm. Younger patients (<60 years) and patients with nonsquamous disease developed more BM. On multivariable analysis, PCI was associated with decreased BM and improved DFS, but not improved OS. Multivariable analysis within the nonsurgical arm suggests that PCI effectively prolongs OS, DFS, and BM. CONCLUSIONS AND RELEVANCE: In patients with stage III LA-NSCLC without progression of disease after therapy, PCI decreased the 5- and 10-year rate of BM and improved 5- and 10-year DFS, but did not improve OS. Although this study did not meet its primary end point, the long-term results reveal many important findings that will benefit future trials. Identifying the appropriate patient population and a safe intervention is critical. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00048997.

Validation of NRG oncology/RTOG-0129 risk groups for HPV-positive and HPV-negative oropharyngeal squamous cell cancer: Implications for risk-based therapeutic intensity trials.

BACKGROUND: Radiation Therapy Oncology Group (RTOG)-0129 recursive partitioning analysis was the basis for risk-based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors' knowledge, the question of whether RTOG-0129 overall survival (OS) estimates for low-risk, intermediate-risk, and high-risk groups are similar in other data sets or applicable to progression-free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG-0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups. METHODS: Prospective randomized clinical trials were analyzed retrospectively. RTOG-0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG-0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible. RESULTS: There was a total of 260 patients and 287 patients, respectively, from RTOG-0129 and RTOG-0522, with median follow-ups for surviving patients of 7.9 years (range, 1.7-9.9 years) and 4.7 years (range, 0.1-7.0 years), respectively. Previous OS differences in RTOG-0129 persisted at 5 years. In RTOG-0522, the 5-year OS rates for the low-risk, intermediate-risk, and high-risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5-year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG-0522 among a subgroup of patients considered to be at very good risk (p16-positive disease, smoking history of ≤10 pack-years, and classified with T1-T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5-year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group. CONCLUSIONS: RTOG-0129 risk groups persisted at 5 years and were reproducible in RTOG-0522. However, there was variability in the estimates. These data underscore the importance of long-term follow-up and appropriate patient selection in therapeutic deintensification trials.

E3611-A Randomized Phase II Study of Ipilimumab at 3 or 10 mg/kg Alone or in Combination with High-Dose Interferon-α2b in Advanced Melanoma.

PURPOSE: Interferon-α favors a Th1 shift in immunity, and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects, leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-α (HDI) showed promising efficacy, supporting this hypothesis. PATIENTS AND METHODS: E3611 followed a 2-by-2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipilimumab doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression-free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3. RESULTS: For eligible and treated patients (N = 81) at a median follow-up time of 29.8 months, median PFS was 4.4 months [95% confidence interval (CI), 2.7-8.2] when ipilimumab was used alone and 7.5 months (95% CI, 5.1-11.0) when HDI was added. Median PFS was 3.8 months (95% CI, 2.6-7.5) with 3 mg/kg ipilimumab and 6.5 months (95% CI, 5.1-13.5) with 10 mg/kg. By study arm, median PFS was 8.0 months (95% CI, 2.8-20.2) in arm A, 6.2 months (95% CI, 2.7-25.7) in B, 5.7 months (95% CI, 1.5-11.1) in C, and 2.8 months (95% CI, 2.6-5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10. CONCLUSIONS: Although PFS was increased, the differences resulting from adding interferon-α or a higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.

Development and Validation of Nomograms Predictive of Overall and Progression-Free Survival in Patients With Oropharyngeal Cancer.

Purpose Treatment of oropharyngeal squamous cell carcinoma (OPSCC) is evolving toward risk-based modification of therapeutic intensity, which requires patient-specific estimates of overall survival (OS) and progression-free survival (PFS). Methods To develop and validate nomograms for OS and PFS, we used a derivation cohort of 493 patients with OPSCC with known p16 tumor status (surrogate of human papillomavirus) and cigarette smoking history (pack-years) randomly assigned to clinical trials using platinum-based chemoradiotherapy (NRG Oncology Radiation Therapy Oncology Group [RTOG] 0129 and 0522). Nomograms were created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index. Nomograms were externally validated in a cohort of 153 patients with OPSCC randomly assigned to a third trial, NRG Oncology RTOG 9003. Results Both models included age, Zubrod performance status, pack-years, education, p16 status, and T and N stage; the OS model also included anemia and age × pack-years interaction; and the PFS model also included marital status, weight loss, and p16 × Zubrod interaction. Predictions correlated well with observed 2-year and 5-year outcomes. The uncorrected concordance index was 0.76 (95% CI, 0.72 to 0.80) for OS and 0.70 (95% CI, 0.66 to 0.74) for PFS, and bias-corrected indices were similar. In the validation set, OS and PFS models were well calibrated, and OS and PFS were significantly different across tertiles of nomogram scores (log-rank P = .003;< .001). Conclusion The validated nomograms provided useful prediction of OS and PFS for patients with OPSCC treated with primary radiation-based therapy.

Locoregional Recurrent or Second Primary Head and Neck Cancer: Management Strategies and Challenges.

Treatment of patients with locoregional recurrent or second primary head and neck squamous cell cancer (HNSCC) has been guided by well-reasoned principles and informed by carefully tested chemotherapy and radiation regimens. However, clinical decision making for this population is complicated by many factors. Although surgery is generally considered the treatment of choice for patients with HNSCC with recurrent disease or new second primary disease in a previously irradiated field, operability of cases is not always straightforward. Postoperative treatment is frequently warranted but carries significant risk. In addition, the rapid rise in the incidence of HPV-associated HNSCC raises the question of whether established treatment paradigms should be re-examined in this population of patients with a much better prognosis than the non-HPV population. Furthermore, new radiation techniques and new systemic agents show early promising results in recent clinical studies, suggesting potential for practice-changing effects in the future management of this disease. This article examines each of the treatment modalities used in the care of patients with HNSCC with recurrent or new second primary disease and provides a perspective to aid clinicians in the management of this disease.