The effect of treatment package time on locally advanced oral cavity cancer outcomes.

OBJECTIVE(S): To assess the influence of treatment package time (TPT) on overall survival (OS) and event free survival (EFS) in oral cavity cancer (OCC) patients treated with surgery and adjuvant radiation therapy (RT) with or without concurrent chemotherapy (CHT). MATERIALS/METHODS: 354 adult OCC patients treated at a single, high-volume center between 2012-2022 with various pathologic risk features were included. TPT was defined as days from surgery to RT completion. Kaplan-Meier estimates, log-rank p-values, univariable (UVA) and multivariable (MVA) Cox regression analyses were performed to determine the impact of TPT on OS and EFS, and the optimal TPT cutoff. RESULTS: The optimal TPT cutoff was 105 days. TPT < 105 days was significantly associated with improved OS and EFS (p = 0.002 and p = 0.027, respectively) compared to TPT ≥ 105 days. On UVA, factors significantly associated with OS were TPT < 105 days, former/current smoker status, pathologic stage IV, positive perineural invasion (PNI), and extranodal extension (ENE) (all p < 0.05). On MVA for OS, TPT < 105 days, former/current smoker status, pathologic stage IV, and positive PNI (all p < 0.05) remained significant. Factors significantly associated with EFS on UVA were TPT < 105 days, former/current smoker status, pathologic stage IV, positive PNI or ENE, and concurrent CHT (all p < 0.05). On MVA, TPT < 105 days, pathologic stage IV, and positive PNI (all p < 0.05) remained significant. CONCLUSIONS: In a large, homogenous cohort of OCCs, optimal TPT was <105 days, with TPT ≥ 105 days significantly associated with worse OS and EFS. Multidisciplinary coordination should analyze factors potentially contributing to treatment delay.

Health Equity in Patients Receiving Durvalumab for Unresectable Stage III Non-Small Cell Lung Cancer in the US Veterans Health Administration.

BACKGROUND: Real-world evidence is limited regarding the relationship between race and use of durvalumab, an immunotherapy approved for use in adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This study aimed to evaluate if durvalumab treatment patterns differed by race in patients with unresectable stage III NSCLC in a Veterans Health Administration (VHA) population. MATERIALS AND METHODS: This was a retrospective analysis of White and Black adults with unresectable stage III NSCLC treated with durvalumab presenting to any VHA facility in the US from January 1, 2017, to June 30, 2020. Data captured included baseline characteristics and durvalumab treatment patterns, including treatment initiation delay (TID), interruption (TI), and discontinuation (TD); defined as CRT completion to durvalumab initiation greater than 42 days, greater than 28 days between durvalumab infusions, and more than 28 days from the last durvalumab dose with no new durvalumab restarts, respectively. The number of doses, duration of therapy, and adverse events were also collected. RESULTS: A total of 924 patients were included in this study (White = 726; Black = 198). Race was not a significant factor in a multivariate logistic regression model for TID (OR, 1.39; 95% CI, 0.81-2.37), TI (OR, 1.58; 95% CI, 0.90-2.76), or TD (OR, 0.84; 95% CI, 0.50-1.38). There were also no significant differences in median (interquartile range [IQR]) number of doses (White: 15 [7-24], Black: 18 [7-25]; P = .25) or median (IQR) duration of therapy (White: 8.7 months [2.9-11.8], Black: 9.8 months [3.6-12.0]; P = .08), although Black patients were less likely to experience an immune-related adverse event (28% vs. 36%, P = .03) and less likely to experience pneumonitis (7% vs. 14%, P < .01). CONCLUSION: Race was not found to be linked with TID, TI, or TD in this real-world study of patients with unresectable stage III NSCLC treated with durvalumab at the VHA.

Long-term Locoregional Control With Unilateral Radiation for AJCC-7 T1-2N2b Tonsillar Cancer.

OBJECTIVES: Unilateral radiation to cervical nodes has been used as a de-escalation strategy in well-lateralized tonsil cancers. The efficacy of this approach with multiple ipsilateral nodes is not established. The study hypothesis was that unilateral radiation for American Joint Committee on Cancer (AJCC)-7 T1-2N2b tonsillar cancer results in a low rate of contralateral nodal failure. MATERIALS AND METHODS: This study was a retrospective chart review of patients with AJCC-7 T1-2N2b tonsillar cancer from 2 academic institutions who were treated with unilateral radiation. The primary endpoint was the contralateral nodal failure rate. Locoregional control, overall survival, and the need for gastrostomy tube placement were additional endpoints. RESULTS: The study cohort included 66 patients treated between 2005 and 2016. The median follow-up time was 80.9 months; contralateral nodal failure occurred in 2/66 (3.0%) patients at 4.1 and 20.9 months, respectively. Both patients underwent salvage treatment with long-term subsequent survival. Overall locoregional control at both 2 and 5 years was 93.9% and the median duration of control was not reached. Overall survival at 5 years was 92.4%. CONCLUSIONS: The use of unilateral radiation for AJCC-7 T1-2N2b tonsillar cancer resulted in low rates of contralateral nodal failure. This outcome demonstrates the safety of considering unilateral radiation treatment in patients with a relatively high ipsilateral nodal burden.

A phase I/II trial of concurrent immunotherapy with chemoradiation in locally advanced larynx cancer.

Objectives: Cisplatin-based chemoradiation is an established organ-preserving strategy for locally advanced laryngeal cancer, but long-term survival remains suboptimal. Immunotherapy has been studied in the metastatic and unresectable recurrent settings. However, additional data are needed to assess its role in organ preservation for locally advanced laryngeal cancer. Methods: This trial was an open-label, single-arm, multi-institutional study with a Phase I run-in portion followed by a planned Phase II component, which closed early due to low accrual. Study patients had Stage III or IV (T2-3; N0-3; M0) laryngeal squamous cell carcinoma and were candidates for larynx preservation. Pembrolizumab was given 2-3 weeks prior to chemoradiation and then, q21 days concurrently with high-dose cisplatin and radiation prescribed to a total dose of 70 Gy. The primary endpoint of the trial was organ-preservation rate (OPR) at 18 months. Results: A total of nine patients were enrolled with a median follow-up of 30.1 months. No patient required laryngectomy, resulting in 100% OPR at 18 months. The 12-month overall survival (OS) rate was 77.8% and the median duration of OS was not reached. All acute Grade 4 (n = 3) toxicities occurred in a single patient with poorly controlled diabetes at baseline. One patient had late Grade 4 laryngeal edema requiring tracheostomy 8 months after chemoradiation, which self-resolved. Conclusion: UCCI-HN-15-02 demonstrated the safety of the addition of immunotherapy to definitive chemoradiation and the patient outcomes suggest the potential for improving long-term survival while minimizing negative impact from treatment. While results from this trial were promising, a randomized study with a larger number of patients and longer follow-up is warranted to verify this treatment approach prior to wider adoption. NCT #: NCT02759575.Level of evidence: 2b.

Radiation Therapy in the Treatment of Head and Neck Rhabdomyosarcoma.

The use of radiation therapy is an important part of multimodality treatment for rhabdomyosarcoma. The specific doses, treatment volumes, and techniques used in radiation therapy can vary dramatically based upon a number of factors including location, tumor size, and molecular characteristics, resulting in complex decisions in treatment planning. This article reviews the principles of evaluation and management for head and neck rhabdomyosarcoma including a summary of the historical studies upon which current management is based.

Hypothyroidism in Head and Neck Squamous Cell Carcinoma Patients Receiving Radiotherapy With or Without Immune Checkpoint Inhibitors.

OBJECTIVES/HYPOTHESIS: Hypothyroidism is a relatively common complication of head and neck squamous cell carcinoma (HNSCC) treatment. The objective of this study was to determine whether the addition of programmed death ligand-1 (PD-1) or programmed death ligand-1 (PD-L1) inhibition (anti-PD-1/PD-L1 therapy) to standard treatment increases the risk of hypothyroidism in HNSCC. STUDY DESIGN: Retrospective Cohort. METHODS: This is a retrospective, single institutional cohort study. Patients who received radiotherapy (RT) for HNSCC were identified in the electronic medical record. Patient factors collected include age, sex, body mass index (BMI), smoking status, alcohol use, Charlson comorbidity index, and HNSCC treatment records. The rate of hypothyroidism for patients with HNSCC receiving RT (+/- chemotherapy and surgery) (RT group, n = 101) was compared to that of HNSCC patients receiving RT (+/- chemotherapy and surgery) + anti-PD-1/PD-L1 therapy, either concurrently or after RT (RT + anti-PD-1/PD-L1 group, n = 38). RESULTS: There was no significant difference in the rate of clinical or subclinical hypothyroidism between the two groups. Multinomial logistic regression found no significant difference in hypothyroidism based on age, sex, or BMI. CONCLUSIONS: The addition of anti-PD-1/PD-L1 therapy to standard HNSCC treatment does not significantly increase the risk of developing hypothyroidism. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E2413-E2419, 2021.

Assessing the Reliability and Positive Predictive Value of p16 as a Surrogate for Human Papillomavirus-Mediated E6/7 mRNA Expression in Squamous Cell Carcinoma of the Anal Canal.

BACKGROUND: Human papillomavirus has been implicated in the carcinogenesis of squamous cell carcinoma of the anal canal. p16 expression and the presence of human papillomavirus DNA have been used to define human papillomavirus-positive patients, but neither approach has been validated against the standard of human papillomavirus E6/7 mRNA expression at this disease site. OBJECTIVE: This study aimed to evaluate the acceptability of p16 immunohistochemistry as a surrogate to E6/7 mRNA expression in identifying human papillomavirus-mediated squamous cell carcinoma of the anal canal. DESIGN: This was a retrospective analysis of a previously constructed tissue microarray. SETTINGS: This study was conducted at a tertiary academic center. PATIENTS: Biopsies and resection specimens from patients diagnosed with squamous cell carcinoma of the anal canal at the study institution from 2005 to 2015 were reviewed for sample adequacy. MAIN OUTCOME MEASURES: Concordance between p16 positivity by immunohistochemistry and E6/7 mRNA expression by in situ hybridization was evaluated. Sensitivity, specificity, and positive predictive value were assessed. RESULTS: Among the 25 patients evaluated, p16 and E6/7 mRNA results were concordant in 24 of 25 specimens (96%). Of the 24 concordant samples, there were 23 true positives (p16+ and E6/7+) and 1 true negative (p16- and E6/7-). One specimen was discordant (p16- and E6/7+) between p16 and E6/7 mRNA (4%). This resulted in a sensitivity of 96% and a specificity of 100%. Positive predictive value of p16 immunohistochemistry for E6/7 mRNA expression was 100%. LIMITATIONS: This study was limited by its retrospective nature and small sample size. It only assessed diagnostic parameters rather than prognostic implications. CONCLUSIONS: In this study, the clinically prevalent method of p16 immunohistochemistry showed excellent concordance with the standard of E6/7 mRNA expression and demonstrated its potential to serve as a surrogate for identifying human papillomavirus-induced squamous cell carcinoma of the anal canal. See Video Abstract at http://links.lww.com/DCR/B448. EVALUANDO LA CONFIABILIDAD Y EL VALOR PREDICTIVO POSITIVO DE P, COMO SUSTITUTO DE LA EXPRESIN DE ARNM DE E / , MEDIADA POR EL VIRUS DEL PAPILOMA HUMANO, EN CARCINOMA DE CLULAS ESCAMOSAS DEL CANAL ANAL: ANTECEDENTES:El virus del papiloma humano se ha relacionado en la carcinogénesis del carcinoma de células escamosas del canal anal. La expresión de p16 y la presencia de ADN del virus del papiloma humano, se han utilizado para definir a los pacientes positivos al virus del papiloma humano. Pero ninguno de estos enfoques, han sido validados frente al estándar de oro de la expresión del ARNm del virus del papiloma humano E6 / 7, en este sitio de la enfermedad.OBJETIVO:El estudio tuvo como objetivo, evaluar la aceptabilidad de la inmunohistoquímica del p16, como sustituto de la expresión de ARNm de E6 / 7, en la identificación del carcinoma de células escamosas del canal anal, mediada por virus del papiloma humano.DISEÑO:Fue un análisis retrospectivo de un microarreglo de tejido previamente construido.AJUSTE:El estudio se realizó en un centro académico terciario.PACIENTES:Se revisaron biopsias y muestras de resección de pacientes diagnosticados con carcinoma de células escamosas del canal anal, en la institución del estudio, entre 2005 y 2015 para determinar la idoneidad de la muestra.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluó la concordancia entre la positividad de p16 por inmunohistoquímica y la expresión de ARNm de E6 / 7 por hibridación in situ. Se evaluaron la sensibilidad, especificidad y valor predictivo positivo.RESULTADOS:Entre los 25 pacientes evaluados, los resultados del ARNm de p16 y E6 / 7 fueron concordantes en 24/25 muestras (96%). De las 24 muestras concordantes, hubo 23 positivos verdaderos (p16 + y E6 / 7 +) y un negativo verdadero (p16- y E6 / 7-). Una muestra fue discordante (p16- y E6 / 7 +) entre p16 y ARNm de E6 / 7 (4%). Esto resultó en una sensibilidad del 96% y una especificidad del 100%. El valor predictivo positivo de la inmunohistoquímica de p16 para la expresión de ARNm de E6 / 7 fue del 100%.LIMITACIONES:El estudio estuvo limitado por su naturaleza retrospectiva y por el tamaño pequeño de la muestra. Solamente evaluó los parámetros de diagnóstico, en lugar de las implicaciones pronosticas.CONCLUSIONES:En este estudio, el método clínico prevalente de inmunohistoquímica p16, mostró una excelente concordancia con el estándar de oro de la expresión de ARNm de E6 / 7 y demostró su potencial para servir, como sustituto para identificar el carcinoma de células escamosas del canal anal, inducido por el virus del papiloma humano. Consulte Video Resumen en http://links.lww.com/DCR/B448.

Osteoradionecrosis: Exposing the Evidence Not the Bone.

Osteoradionecrosis is a relatively rare but potentially morbid and costly complication of radiation therapy for head and neck cancer. Multidisciplinary diagnosis and treatment are essential. Despite evidence guiding individual aspects of care for osteoradionecrosis, there is a lack of broad consensus on the overall diagnosis and management of this condition. This study comprehensively reviews the literature, with a focus on the past 10 years, to guide evaluation and treatment.

The impact of proton therapy on cardiotoxicity following radiation treatment.

Cardiac disease following radiation therapy represents a major consideration in the treatment of a variety of malignancies. Damage to the heart can manifest in a variety of pathologies including ischemic cardiac disease, cardiomyopathy, valvular dysfunction, arrhythmias, and pericarditis. This damage has been shown to directly relate to cardiac radiation dose and to stem from a range of cellular pathways that are often related to fibrosis. The importance of minimizing radiation dose to the heart is especially critical in the pediatric population and when treating disease sites adjacent to the heart. Proton therapy represents a promising approach to minimize dose to normal tissues such as the heart. The cardiac dosimetry reductions due to proton therapy have been demonstrated in multiple cancers and further long-term follow-up will determine the clinical significance of these reductions to cardiac structures. Future approaches using advanced techniques such as FLASH therapy could provide even further benefit by reducing post-radiation fibrosis.

Comparison of spinal and general anesthesia approaches for MRI-guided brachytherapy for cervical cancer.

PURPOSE: To evaluate the impact of general versus spinal anesthesia on postprocedure narcotic use and of extradepartmental planning MRI on treatment time in high-dose-rate brachytherapy for cervical cancer. METHODS AND MATERIALS: Twenty-five patients (10 general anesthesia and 15 spinal anesthesia) who collectively received 96 brachytherapy fractions (39 general and 57 spinal) for cervical cancer between February 2015 and April 2017 were retrospectively reviewed. Over this time, institutional practice shifted from operating room-based general anesthesia to intradepartmental spinal anesthesia for tandem and ring placement. In some cases, extradepartmental planning MRI was performed. Administrations of narcotics after tandem and ring placement were recorded, and dosages were converted to intravenous (IV) morphine equivalents. Total treatment times for fractions using spinal anesthesia were documented. RESULTS: The general anesthesia group included a significantly higher proportion of fractions using postprocedure narcotics (100.0% vs. 31.6%, p < 0.0001). The general and spinal anesthesia groups required an average of 16.9 mg (range: 2.0-59.2) and 1.4 mg (range: 0.0-17.5) IV morphine equivalents per fraction, respectively (p < 0.0001). When using spinal anesthesia, the average total treatment time with MRI was 311.0 min (range: 218-379) versus 306.6 min (range: 177-429) without MRI (p = 0.810). CONCLUSION: Intradepartmental spinal anesthesia results in significant decreases in postprocedure narcotic usage compared with operating room-based general anesthesia. When using spinal anesthesia, addition of extradepartmental MRI does not increase treatment time. This workflow avoids transporting patients under general anesthesia, minimizes the need for MRI-compatible monitoring, allows treatment of multiple patients per day, and provides adequate analgesia.