A phase 1 study of concurrent cabozantinib and cetuximab in recurrent or metastatic head and neck squamous cell cancer.

OBJECTIVES: Epidermal growth factor receptor (EGFR) inhibition with cetuximab is a standard treatment for head and neck squamous cell carcinoma (HNSCC). Activation of the receptor tyrosine kinases AXL, MET and VEGFR can mediate resistance to cetuximab. Cabozantinib, a multikinase inhibitor (MKI) targeting AXL/MET/VEGFR, has demonstrated antitumor activity in preclinical models of HNSCC. This investigator- initiated phase I trial evaluated the safety and efficacy of cetuximab plus cabozantinib in patients with recurrent/metastatic (R/M) HNSCC. MATERIALS AND METHODS: Patients received cetuximab concurrently with cabozantinib daily on a 28-day cycle. Using a 3 + 3 dose-escalation design, the primary endpoint was to determine the maximally tolerated dose (MTD) of cabozantinib. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) RESULTS: Among the 20 patients enrolled, most had prior disease progression on immune checkpoint inhibitors (95 %), platinum-based chemotherapy (95 %), and cetuximab (80 %). No dose-limiting toxicities were recorded and the MTD for cabozantinib was established to be 60 mg. Grade ≥ 3 adverse events occurred in 65 % of patients (n = 13). ORR was 20 %, with 4 partial responses (PRs). Two PRs were observed in cetuximab-naïve patients (n = 4), with an ORR of 50 % in this subgroup. In the overall population, DCR was 75 %, median PFS was 3.4 months and median OS was 8.1 months. CONCLUSION: Cetuximab plus cabozantinib demonstrated a manageable toxicity profile and preliminary efficacy in patients with heavily treated R/M HNSCC. The combination of cetuximab with MKIs targeting the AXL/MET/VEGFR axis warrants further investigation, including in cetuximab-naïve patients.

Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.

PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Nivolumab plus ipilimumab in advanced salivary gland cancer: a phase 2 trial.

Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier: NCT03172624 .

Concurrent carboplatin and paclitaxel definitive radiation therapy for locally advanced head and neck cancer.

BACKGROUND: We report the outcomes of cisplatin-ineligible HNSCC patients treated with definitive chemoradiation and concurrent carboplatin and paclitaxel. MATERIALS AND METHODS: We included consecutive HNSCC patients treated from 2013 to 2021 that received definitive chemoradiation with carboplatin and paclitaxel. Locoregional recurrences (LRR) and distant metastases (DM) were estimated using cumulative incidence functions. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. RESULTS: Sixty-five patients were identified with median age of 71 years (range 44-85). Median radiation dose was 70 Gy and the median doses of carboplatin and paclitaxel were AUC 1 and 40 mg/m2 , respectively. At a median follow-up of 29 (range 5-91) months, the 2-year rates of LRR, DM, PFS, and OS were 8.8%, 9.4%, 72.2%, and 88.7%, respectively. In total, there were 5 LRR, 7 DM, and 12 deaths. CONCLUSIONS: Chemoradiation with carboplatin and paclitaxel is an excellent option for cisplatin-ineligible HNSCC patients.

Post-operative PET/CT improves the detection of early recurrence of squamous cell carcinomas of the oral cavity.

BACKGROUND: We evaluate the impact of post-operative 18-fluorodeoxyglucose positron emission tomography with computed tomography (PET/CT) for radiation planning on the detection of early recurrence (ER) and treatment outcomes in oral squamous cell carcinoma (OSCC). METHODS: We retrospectively reviewed the records of patients treated with post-operative radiation between 2005 and 2019 for OSCC at our institution. Extracapsular extension and positive surgical margins were classified as high risk features; pT3-4, node positivity, lymphovascular invasion, perineural invasion, tumor thickness >5 mm, and close surgical margins were considered intermediate risk features. Patients with ER were identified. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances between baseline characteristics. RESULTS: 391 patients with OSCC were treated with post-operative radiation. 237 (60.6%) patients underwent post-operative PET/CT planning vs. 154 (39.4%) who were planned with CT only. Patients screened with post-operative PET/CT were more likely to be diagnosed with ER than those planned with CT only (16.5 vs. 3.3%, p < 0.0001). Among patients with ER, those with intermediate features were more likely than those high risk features to undergo major treatment intensification, including re-operation, the addition of chemotherapy, or intensification of radiation by ≥ 10 Gy (91% vs. 9%, p < 0.0001). Post-operative PET/CT was associated with improved disease-free and overall survival for patients with intermediate risk features (IPTW log-rank p = 0.026 and p = 0.047, respectively) but not high risk features (IPTW log-rank p = 0.44 and p = 0.96). CONCLUSIONS: Use of post-operative PET/CT is associated with increased detection of early recurrence. Among patients with intermediate risk features, this may translate to improved disease-free survival.

Evaluation of Proton Therapy Reirradiation for Patients With Recurrent Head and Neck Squamous Cell Carcinoma.

Importance: Use of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret. Objective: To evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma. Design, Setting, and Participants: This retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and grade early and late toxic effects. Exposures: Proton therapy reirradiation. Main Outcomes and Measures: Follow-up was defined from the start of PT-ReRT. The Kaplan-Meier method was used for outcomes of interest, including local control (LC), locoregional control, distant metastatic control, progression-free survival, and overall survival (OS). Cox proportional hazards regression modeling was used to assess associations of covariates with OS. Results: A total of 242 patients (median [range] age, 63 [21-96] years; 183 [75.6%] male) were included. Of these patients, 231 (95.9%) had a Karnofsky performance status score of 70 or higher, and 145 (59.9%) had at least a 10-pack-year smoking history. Median (range) follow-up was 12.0 (5.8-26.0) months for all patients and 24.5 (13.8-37.8) months for living patients. A total of 206 patients (85.1%) had recurrent disease vs second primary or residual disease. The median (range) interval between radiation courses was 22 (1-669) months. Median PT-ReRT dose was 70 cobalt gray equivalents (CGE) for the fractionated cohort and 44.4 CGE for the quad shot cohort. For the fractionated cohort, the 1-year LC was 71.8% (95% CI, 62.8%-79.0%) and the 1-year OS was 66.6% (95% CI, 58.1%-73.8%). For the quad shot cohort, the 1-year LC was 61.6% (95% CI, 46.4%-73.6%) and the 1-year OS was 28.5% (95% CI, 19.4%-38.3%). Higher Karnofsky performance status scores (hazard ratio [HR], 0.50; 95% CI, 0.25-0.99; P = .046) and receipt of salvage surgery prior to PT-ReRT (HR, 0.57; 95% CI, 0.39-0.84; P = .005) were associated with improved OS, whereas receipt of quad shot (HR, 1.97; 95% CI, 1.36-2.86; P < .001) was associated with worse OS. There were a total of 73 grade 3 and 6 grade 4 early toxic effects. There were 79 potential grade 3, 4 grade 4, and 5 grade 5 late toxic effects. Conclusions and Relevance: The findings of this cohort study suggest that, compared with previous reports with photon-based reirradiation, patients are living longer with aggressive PT-ReRT; however, surviving patients remain at risk of early and late complications.

Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Oropharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy.

Importance: Patients with oropharyngeal carcinoma (OPC) treated with radiotherapy often experience substantial toxic effects, even with modern techniques such as intensity-modulated radiation therapy (IMRT). Intensity-modulated proton therapy (IMPT) has a potential advantage over IMRT due to reduced dose to the surrounding organs at risk; however, data are scarce given the limited availability and use of IMPT. Objective: To compare toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic OPC treated with IMPT vs IMRT with or without chemotherapy. Design, Setting, and Participants: This retrospective cohort study included patients aged 18 years or older with newly diagnosed nonmetastatic OPC who received curative-intent radiotherapy with IMPT or IMRT at a single-institution tertiary academic cancer center from January 1, 2018, to December 31, 2021, with follow-up through December 31, 2021. Exposures: IMPT or IMRT with or without chemotherapy. Main Outcomes and Measures: The main outcomes were the incidence of acute and chronic (present after ≥6 months) treatment-related adverse events (AEs) and oncologic outcomes, including locoregional recurrence (LRR), progression-free survival (PFS), and overall survival (OS). Fisher exact tests and χ2 tests were used to evaluate associations between toxic effects and treatment modality (IMPT vs IMRT), and the Kaplan-Meier method was used to compare LRR, PFS, and OS between the 2 groups. Results: The study included 292 patients with OPC (272 [93%] with human papillomavirus [HPV]-p16-positive tumors); 254 (87%) were men, 38 (13%) were women, and the median age was 64 years (IQR, 58-71 years). Fifty-eight patients (20%) were treated with IMPT, and 234 (80%) were treated with IMRT. Median follow-up was 26 months (IQR, 17-36 months). Most patients (283 [97%]) received a dose to the primary tumor of 70 Gy. Fifty-seven of the patients treated with IMPT (98%) and 215 of those treated with IMRT (92%) had HPV-p16-positive disease. There were no significant differences in 3-year OS (97% IMPT vs 91% IMRT; P = .18), PFS (82% IMPT vs 85% IMRT; P = .62), or LRR (5% IMPT vs 4% IMRT; P = .59). The incidence of acute toxic effects was significantly higher for IMRT compared with IMPT for oral pain of grade 2 or greater (42 [72%] IMPT vs 217 [93%] IMRT; P < .001), xerostomia of grade 2 or greater (12 [21%] IMPT vs 68 [29%] IMRT; P < .001), dysgeusia of grade 2 or greater (16 [28%] IMPT vs 134 [57%] IMRT; P < .001), grade 3 dysphagia (4 [7%] IMPT vs 29 [12%] IMRT; P < .001), mucositis of grade 3 or greater (10 [53%] IMPT vs 13 [70%] IMRT; P = .003), nausea of grade 2 or greater (0 [0%] IMPT vs 18 [8%] IMRT; P = .04), and weight loss of grade 2 or greater (22 [37%] IMPT vs 138 [59%] IMRT; P < .001). There were no significant differences in chronic toxic effects of grade 3 or greater, although there was a significant difference for chronic xerostomia of grade 2 or greater (6 IMPT [11%] vs 22 IMRT [10%]; P < .001). Four patients receiving IMRT (2%) vs 0 receiving IMPT had a percutaneous endoscopic gastrostomy tube for longer than 6 months. Conclusions and Relevance: In this study, curative-intent radiotherapy with IMPT for nonmetastatic OPC was associated with a significantly reduced acute toxicity burden compared with IMRT, with few chronic toxic effects and favorable oncologic outcomes, including locoregional recurrence of only 5% at 2 years. Prospective randomized clinical trials comparing these 2 technologies and of patient-reported outcomes are warranted.

Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Nasopharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy.

Importance: Patients with nonmetastatic nasopharyngeal carcinoma (NPC) are primarily treated by radiotherapy with curative intent with or without chemotherapy and often experience substantial treatment-related toxic effects even with modern radiation techniques, such as intensity-modulated radiation therapy (IMRT). Intensity-modulated proton therapy (IMPT) may improve the toxicity profile; however, there is a paucity of data given the limited availability of IMPT in regions with endemic NPC. Objective: To compare toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic NPC when treated with IMPT vs IMRT with or without chemotherapy. Design, Setting, and Participants: This retrospective cohort study included 77 patients with newly diagnosed nonmetastatic NPC who received curative-intent radiotherapy with IMPT or IMRT at a tertiary academic cancer center from January 1, 2016, to December 31, 2019. Forty-eight patients with Epstein-Barr virus (EBV)-positive tumors were included in a 1:1 propensity score-matched analysis for survival outcomes. The end of the follow-up period was March 31, 2021. Exposures: IMPT vs IMRT with or without chemotherapy. Main Outcomes and Measures: The main outcomes were the incidence of acute and chronic treatment-related adverse events (AEs) and oncologic outcomes, including locoregional failure-free survival (LRFS), progression-free survival (PFS), and overall survival (OS). Results: We identified 77 patients (25 [32.5%] women; 52 [67.5%] men; median [interquartile range] age, 48.7 [42.2-60.3] years), among whom 28 (36.4%) were treated with IMPT and 49 (63.6%) were treated with IMRT. Median (interquartile range) follow-up was 30.3 (17.9-41.5) months. On multivariable logistic regression analyses, IMPT was associated with lower likelihood of developing grade 2 or higher acute AEs compared with IMRT (odds ratio [OR], 0.15; 95% CI, 0.03-0.60; P = .01). Only 1 case (3.8%) of a chronic grade 3 or higher AE occurred in the IMPT group compared with 8 cases (16.3%) in the IMRT group (OR, 0.21; 95% CI, 0.01-1.21; P = .15). Propensity score matching generated a balanced cohort of 48 patients (24 IMPT vs 24 IMRT) and found similar PFS in the IMPT and IMRT groups (2-year PFS, 95.7% [95% CI, 87.7%-100%] vs 76.7% [95% CI, 60.7%-97.0%]; hazard ratio [HR], 0.31; 95% CI, 0.07-1.47; P = .14). No locoregional recurrence or death was observed in the IMPT group from the matched cohort. Two-year LRFS was 100% (95% CI, 100%-100%) in the IMPT group and 86.2% (95% CI, 72.8%-100%) in the IMRT group (P = .08). Three-year OS was 100% (95% CI, 100%-100%) in the IMPT group and 94.1% (95% CI, 83.6%-100%) in the IMRT group (P = .42). Smoking history was the only clinical factor significantly associated with both poor LRFS (HR, 63.37; 95% CI, 3.25-1236.13; P = .006) and poor PFS (HR, 6.33; 95% CI, 1.16-34.57; P = .03) on multivariable analyses. Conclusions and Relevance: In this study, curative-intent radiotherapy with IMPT for nonmetastatic NPC was associated with significantly reduced acute toxicity burden in comparison with IMRT, with rare late complications and excellent oncologic outcomes, including 100% locoregional control at 2 years. Prospective trials are warranted to direct the optimal patient selection for IMPT as the primary radiotherapy modality for nonmetastatic NPC.

Any day, split halfway: Flexibility in scheduling high-dose cisplatin-A large retrospective review from a high-volume cancer center.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m2 × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m2 × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.

Randomized Phase II Trial of Nivolumab With Stereotactic Body Radiotherapy Versus Nivolumab Alone in Metastatic Head and Neck Squamous Cell Carcinoma.

PURPOSE: The objective response rate (ORR) for single-agent anti-programmed death receptor 1 (anti-PD-1) therapy is modest in patients with metastatic or recurrent head and neck squamous cell carcinoma (HNSCC). We aimed to test whether radiotherapy may act synergistically with anti-PD-1 therapy to improve response through the abscopal effect. PATIENTS AND METHODS: We conducted a single-center, randomized, phase II trial of nivolumab (anti-PD-1 therapy) versus nivolumab plus stereotactic body radiotherapy (SBRT) in patients with metastatic HNSCC. Patients had at least two metastatic lesions: one that could be safely irradiated and one measurable by RECIST version 1.1. Patients were randomly assigned (1:1), stratified by human papillomavirus status, to nivolumab (3 mg/kg intravenously every 2 weeks) or nivolumab (same dose) plus SBRT (9 Gy × 3) to 1 lesion. The primary end point was ORR in nonirradiated lesions, which was assessed by RECIST in patients with at least one available set of on-treatment images; safety was assessed in a per-protocol population. RESULTS: Between March 11, 2016, and June 22, 2018, 62 patients were randomly assigned to nivolumab (n = 30) or nivolumab plus SBRT (n = 32). There was no statistically significant ORR difference between arms (34.5% [95% CI, 19.9% to 52.7%] v 29.0% [95% CI, 16.1% to 46.6%]; P = .86). There was no significant difference in overall survival (P = .75), progression-free survival (P = .79), or response duration (P = .26). Grade 3-5 toxicities were similar (13.3% v 9.7%; P = .70). CONCLUSION: We found no improvement in response and no evidence of an abscopal effect with the addition of SBRT to nivolumab in unselected patients with metastatic HNSCC.

Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial.

PURPOSE: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC. PATIENTS AND METHODS: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%-49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684). RESULTS: Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%-41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients. CONCLUSIONS: Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical.

Temporal Lobe Necrosis in Head and Neck Cancer Patients after Proton Therapy to the Skull Base.

PURPOSE: To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base. MATERIALS AND METHODS: Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with <3 months of follow-up, receiving <45 GyRBE or nonconventional fractionation, and/or no follow-up magnetic resonance imaging (MRI) were excluded. TLN was determined using MRI and graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Clinical (gender, age, comorbidities, concurrent chemotherapy, smoking, radiation techniques) and dose-volume parameters were analyzed for TLN correlation. The receiver operating characteristic curve and area under the curve (AUC) were performed to determine the cutoff points of significant dose-volume parameters. RESULTS: Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2-69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 showed maximum specificity and sensitivity. CONCLUSION: The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm3, D2cm3 ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.

Last-line local treatment with the Quad Shot regimen for previously irradiated head and neck cancers.

OBJECTIVES: Patients with prior irradiated head and neck cancer (HNC) who are ineligible for definitive retreatment have limited local palliative options. We report the largest series of the use of the Quad Shot (QS) regimen as a last-line local palliative therapy. MATERIALS AND METHODS: We identified 166 patients with prior HN radiation therapy (RT) treated with QS regimen (3.7 Gy twice daily over 2 consecutive days at 4 weeks intervals per cycle, up to 4 cycles). Palliative response defined by symptom(s) relief or radiographic tumor reduction, locoregional progression free survival (LPFS), overall survival (OS) and radiation-related toxicity were assessed. RESULTS: Median age was 66 years. Median follow-up for all patients was 6.0 months and 9.7 months for living patients. Overall palliative response rate was 66% and symptoms improved in 60% of all patients. Predictors of palliative response were > 2 year interval from prior RT and 3-4 QS cycles. Median LPFS was 5.1 months with 1-year LPFS 17.7%, and median OS was 6.4 months with 1-year OS 25.3%. On multivariate analysis, proton RT, KPS > 70, presence of palliative response and 3-4 QS cycles were associated with improved LPFS and improved OS. The overall Grade 3 toxicity rate was 10.8% (n = 18). No Grade 4-5 toxicities were observed. CONCLUSION: Palliative QS is an effective last-line local therapy with minimal toxicity in patients with previously irradiated HNC. The administration of 3-4 QS cycles predicts palliative response, improved PFS, and improved OS. KPS > 70 and proton therapy are associated with survival improvements.

Outcomes and toxicities of definitive radiotherapy and reirradiation using 3-dimensional conformal or intensity-modulated (pencil beam) proton therapy for patients with nasal cavity and paranasal sinus malignancies.

BACKGROUND: Proton therapy (PT) improves outcomes in patients with nasal cavity (NC) and paranasal sinus (PNS) cancers. Herein, the authors have reported to their knowledge the largest series to date using intensity-modulated proton therapy (IMPT) in the treatment of these patients. METHODS: Between 2013 and 2018, a total of 86 consecutive patients (68 of whom were radiation-naive and 18 of whom were reirradiated) received PT to median doses of 70 grays and 67 grays relative biological effectiveness, respectively. Approximately 53% received IMPT. RESULTS: The median follow-up was 23.4 months (range, 1.7-69.3 months) for all patients and 28.1 months (range, 2.3-69.3 months) for surviving patients. The 2-year local control (LC), distant control, disease-free survival, and overall survival rates were 83%, 84%, 74%, and 81%, respectively, for radiation-naive patients and 77%, 80%, 54%, and 66%, respectively for reirradiated patients. Among radiation-naive patients, when compared with 3-dimensional conformal proton technique, IMPT significantly improved LC (91% vs 72%; P < .01) and independently predicted LC (hazard ratio, 0.14; P = .01). Sixteen radiation-naive patients (24%) experienced acute grade 3 toxicities; 4 (6%) experienced late grade 3 toxicities (osteoradionecrosis, vision loss, soft-tissue necrosis, and soft tissue fibrosis) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 5.0]). Slightly inferior LC was noted for patients undergoing reirradiation with higher complications: 11% experienced late grade 3 toxicities (facial pain and brain necrosis). Patients treated with reirradiation had more grade 1 to 2 radionecrosis than radiation-naive patients (brain: 33% vs 7% and osteoradionecrosis: 17% vs 3%). CONCLUSIONS: PT achieved remarkable LC for patients with nasal cavity and paranasal sinus cancers with lower grade 3 toxicities relative to historical reports. IMPT has the potential to improve the therapeutic ratio in these malignancies and is worthy of further investigation.

A Phase 1b Study of Cetuximab and BYL719 (Alpelisib) Concurrent with Intensity Modulated Radiation Therapy in Stage III-IVB Head and Neck Squamous Cell Carcinoma.

PURPOSE: Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. METHODS AND MATERIALS: This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design. RESULTS: Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans. CONCLUSIONS: The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.

Cisplatin exposure causes c-Myc-dependent resistance to CDK4/6 inhibition in HPV-negative head and neck squamous cell carcinoma.

The loss of p16 is a signature event in Human Papilloma Virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) that leads to increased Cyclin Dependent Kinase 4/6 (CDK) signaling. Palbociclib, a CDK4/6 inhibitor, is active for the treatment of a subset of HNSCC. In this study, we analyzed patient response data from a phase I clinical trial of palbociclib in HNSCC and observed an association between prior cisplatin exposure and CDK inhibitor resistance. We studied the effects of palbociclib on cisplatin-sensitive and -resistant HNSCC cell lines. We found that while palbociclib is highly effective against chemo-naive HNSCC cell lines and tumor xenografts, prior cisplatin exposure induces intrinsic resistance to palbociclib in vivo, a relationship that was not observed in vitro. Mechanistically, in the course of provoking a DNA damage-resistance phenotype, cisplatin exposure upregulates both c-Myc and cyclin E, and combination treatment with palbociclib and the c-Myc bromodomain inhibitor JQ1 exerts a synergistic anti-growth effect in cisplatin-resistant cells. These data show the benefit of exploiting the inherent resistance mechanisms of HNSCC to overcome cisplatin- and palbociclib resistance through the use of c-Myc inhibition.

Trends and Disparities of Proton Therapy Use among Patients with Head and Neck Cancer: Analysis from the National Cancer Database (2005-14).

PURPOSE: The purpose of this study was to analyze national trends and disparities in proton therapy use among patients with head and neck cancer receiving radiotherapy to primary disease sites. PATIENTS AND METHODS: Using the National Cancer Database, we identified patients diagnosed with any nonmetastatic head and neck primary malignancy between 2005 and 2014 who were treated with radiation therapy or proton therapy directed specifically at the primary disease site. Distributions of patient and clinical factors between the two groups were evaluated. Multivariable logistic regression was used to correlate factors associated with proton therapy use compared with other modalities of radiation therapy. RESULTS: There were 220 491 patients who received any radiation therapy as part of their initial treatment course, only 417 (0.2%) of whom received proton therapy. The use of protons underwent a small increase from 0.13% in 2005-06 to 0.41% by 2013-14 (P < .001). The most common primary sites treated with proton therapy were the nasal cavity/nasopharynx (n = 151, 36.2%) and the oral cavity (n = 98, 23.5%). Most patients had T4 disease (n = 94, 31.0%). On multivariable logistic regression, all primary sites compared with hypopharynx/larynx sites (odds ratio [OR], 2.53-10.53; P < .001), treatment at an academic facility (OR, 2.54; P < .001), ≥ 13-mile distance from the treating facility (OR, 1.94; P < .001), and highest median household income quartile (> $63 000; OR, 2.52; P = .002) were associated with an increased likelihood of receiving proton therapy. CONCLUSION: Proton use has undergone an incremental increase in the United States but remains an uncommon modality for the treatment of primary head and neck cancer.