Opioid therapy vs. multimodal analgesia in head and neck Cancer (OPTIMAL-HN): study protocol for a randomized clinical trial.

BACKGROUND: Radiation-induced mucositis (RIM) pain confers substantial morbidity for head and neck cancer (HNC) patients undergoing radiotherapy alone (RT) or chemoradiotherapy (CRT), often reducing treatment compliance. However, no standard currently exists for the treatment of RIM, and high dose opioid therapy, with its associated side effects and increased risk for chronic opioid use, remains the cornerstone of HNC pain management. The goal of this randomized clinical trial is to compare multimodal analgesia using analgesic medications with different mechanisms of action, to the institutional standard of opioid analgesia alone, in order to ascertain the optimal analgesic regimen for the management of RIM pain in HNC patients. METHODS: In this open-label, single-institution, non-inferiority, randomized clinical trial, sixty-two patients with mucosal head and neck malignancies treated with curative-intent radiation will be randomized in a 1:1 ratio, stratified by RT or CRT, between Arm 1: opioid analgesia alone as per the institutional standard, or Arm 2: multimodal analgesia using Pregabalin, Acetaminophen, and Naproxen, in addition to opioids, if required. The primary endpoint is the average 11-Numeric Rating Scale (11-NRS) score for pain during the last week of radiation treatment. Secondary endpoints include: average weekly opioid use, duration of opioid requirement, average daily 11-NRS score for pain, average weekly opioids dispensed, quality of life, hospitalizations for analgesic medication-induced complications, time to feeding tube insertion, weight loss, toxicity, treatment interruptions, and death within 3 months of completing RT treatment. Patients are eligible once analgesia is required for moderate 4/10 pain. DISCUSSION: This study will assess the efficacy and safety of multimodal analgesia and its impact on opioid requirements, clinical outcomes, and quality of life, as a potential new standard treatment for RIM pain in HNC patients undergoing definitive RT or CRT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04221165 . Date of registration: January 9, 2020. Appendix 2 reports the World Health Organization trial registration dataset.

Alert system for monitoring changes in patient anatomy during radiation therapy of head and neck cancer.

The purpose of this study is to validate a previously developed algorithm for alerting clinicians when to consider re-CT simulation due to changes in the patient's anatomy during radiation therapy of head and neck cancer. Cone beam computed tomography (CBCT) data were collected prospectively for 77 patients. Each CBCT was mathematically compared to a reference CBCT using the gamma index. We defined the match quality parameter (MQP) as an indicator of CBCT image similarity, where a negative MQP value indicates a poorer CBCT match than the match between the first two CBCT acquired during treatment. If three consecutive MQP values were below a chosen threshold, an "alert" is triggered to indicate action required, for example, possible re-CT simulation. The timing of image review requests made by the radiation therapists and any re-CT/re-plan decisions were documented for each patient's treatment course. The MQP for each patient (including any re-plans) was calculated in a manner that was blinded from the clinical process. The MQP as a function of fraction number was compared to actual clinical decisions in the treatment progress to evaluate alert system performance. There was a total of 93 plans (including re-plans) with 34 positives (action required) and 59 negatives (no action required). The sensitivity of the alert system was 0.76 and the false positive rate was 0.37. Only 1 case out of the 34 positive cases would have been missed by both the alert system and our clinical process. Despite the false negatives and false positives, analysis of the timing of alert triggers showed that the alert system could have resulted in seven fewer clinical misses. The alert system has the potential to be a valuable tool to complement human judgment and to provide a quality assurance safeguard to help improve the delivery of radiation treatment of head and neck cancer.

Is hypofractionated whole pelvis radiotherapy (WPRT) as well tolerated as conventionally fractionated WPRT in prostate cancer patients? The HOPE trial.

BACKGROUND: Patients with high-risk prostate cancer are at increased risk of lymph node metastasis and are thought to benefit from whole pelvis radiotherapy (WPRT). There has been recent interest in the use of hypofractionated radiotherapy in treating prostate cancer. However, toxicity and cancer outcomes associated with hypofractionated WPRT are unclear at this time. This phase II study aims to investigate the impact in quality of life associated with hypofractionated WPRT compared to conventionally fractionated WPRT. METHODS: Fifty-eight patients with unfavourable intermediate-, high- or very high-risk prostate cancer will be randomized in a 1:1 ratio between high-dose-rate brachytherapy (HDR-BT) + conventionally fractionated (45 Gy in 25 fractions) WPRT vs. HDR-BT + hypofractionated (25 Gy in 5 fractions) WPRT. Randomization will be performed with a permuted block design without stratification. The primary endpoint is late bowel toxicity and the secondary endpoints include acute and late urinary and sexual toxicity, acute bowel toxicity, biochemical failure-, androgen deprivation therapy-, metastasis- and prostate cancer-free survival of the hypofractionated arm compared to the conventionally fractionated arm. DISCUSSION: To our knowledge, this is the first study to compare hypofractionated WPRT to conventionally fractionated WPRT with HDR-BT boost. Hypofractionated WPRT is a more attractive and convenient treatment approach, and may become the new standard of care if demonstrated to be well-tolerated and effective. TRIAL REGISTRATION: This trial was prospectively registered in ClinicalTrials.gov as NCT04197141 on December 12, 2019.

Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial.

BACKGROUND: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. METHODS: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. DISCUSSION: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial.

BACKGROUND: Transoral robotic surgery (TORS) with concurrent neck dissection has supplanted radiotherapy in the USA as the most common treatment for oropharyngeal squamous cell carcinoma (OPSCC), yet no randomised trials have compared these modalities. We aimed to evaluate differences in quality of life (QOL) 1 year after treatment. METHODS: The ORATOR trial was an investigator-initiated, multicentre, international, open-label, parallel-group, phase 2, randomised study. Patients were enrolled at six hospitals in Canada and Australia. We randomly assigned (1:1) patients aged 18 years or older, with Eastern Cooperative Oncology Group scores of 0-2, and with T1-T2, N0-2 (≤4 cm) OPSCC tumour types to radiotherapy (70 Gy, with chemotherapy if N1-2) or TORS plus neck dissection (with or without adjuvant chemoradiotherapy, based on pathology). Following stratification by p16 status, patients were randomly assigned using a computer-generated randomisation list with permuted blocks of four. The primary endpoint was swallowing-related QOL at 1 year as established using the MD Anderson Dysphagia Inventory (MDADI) score, powered to detect a 10-point improvement (a clinically meaningful change) in the TORS plus neck dissection group. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov (NCT01590355) and is active, but not currently recruiting. FINDINGS: 68 patients were randomly assigned (34 per group) between Aug 10, 2012, and June 9, 2017. Median follow-up was 25 months (IQR 20-33) for the radiotherapy group and 29 months (23-43) for the TORS plus neck dissection group. MDADI total scores at 1 year were mean 86·9 (SD 11·4) in the radiotherapy group versus 80·1 (13·0) in the TORS plus neck dissection group (p=0·042). There were more cases of neutropenia (six [18%] of 34 patients vs none of 34), hearing loss (13 [38%] vs five [15%]), and tinnitus (12 [35%] vs two [6%]) reported in the radiotherapy group than in the TORS plus neck dissection group, and more cases of trismus in the TORS plus neck dissection group (nine [26%] vs one [3%]). The most common adverse events in the radiotherapy group were dysphagia (n=6), hearing loss (n=6), and mucositis (n=4), all grade 3, and in the TORS plus neck dissection group, dysphagia (n=9, all grade 3) and there was one death caused by bleeding after TORS. INTERPRETATION: Patients treated with radiotherapy showed superior swallowing-related QOL scores 1 year after treatment, although the difference did not represent a clinically meaningful change. Toxicity patterns differed between the groups. Patients with OPSCC should be informed about both treatment options. FUNDING: Canadian Cancer Society Research Institute Grant (#701842), Ontario Institute for Cancer Research Clinician-Scientist research grant, and the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers grant.

Using gamma index to flag changes in anatomy during image-guided radiation therapy of head and neck cancer.

During radiation therapy of head and neck cancer, the decision to consider replanning a treatment because of anatomical changes has significant resource implications. We developed an algorithm that compares cone-beam computed tomography (CBCT) image pairs and provides an automatic alert as to when remedial action may be required. Retrospective CBCT data from ten head and neck cancer patients that were replanned during their treatment was used to train the algorithm on when to recommend a repeat CT simulation (re-CT). An additional 20 patients (replanned and not replanned) were used to validate the predictive power of the algorithm. CBCT images were compared in 3D using the gamma index, combining Hounsfield Unit (HU) difference with distance-to-agreement (DTA), where the CBCT study acquired on the first fraction is used as the reference. We defined the match quality parameter (MQPx ) as a difference between the xth percentiles of the failed-pixel histograms calculated from the reference gamma comparison and subsequent comparisons, where the reference gamma comparison is taken from the first two CBCT images acquired during treatment. The decision to consider re-CT was based on three consecutive MQP values being less than or equal to a threshold value, such that re-CT recommendations were within ±3 fractions of the actual re-CT order date for the training cases. Receiver-operator characteristic analysis showed that the best trade-off in sensitivity and specificity was achieved using gamma criteria of 3 mm DTA and 30 HU difference, and the 80th percentile of the failed-pixel histogram. A sensitivity of 82% and 100% was achieved in the training and validation cases, respectively, with a false positive rate of ~30%. We have demonstrated that gamma analysis of CBCT-acquired anatomy can be used to flag patients for possible replanning in a manner consistent with local clinical practice guidelines.

Early-stage squamous cell carcinoma of the oropharynx: radiotherapy vs. trans-oral robotic surgery (ORATOR)--study protocol for a randomized phase II trial.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased over the last three decades due to newly found associations with human papillomavirus (HPV) infection. Primary radiotherapy (RT) is the treatment of choice for OPSCC at most centers, and over the last decade, the addition of concurrent chemotherapy has led to a significant improvement in survival, but at the cost of increased acute and late toxicity. Transoral robotic surgery (TORS) has emerged as a promising alternative treatment, with preliminary case series demonstrating encouraging oncologic, functional, and quality of life (QOL) outcomes. However, comparisons of TORS and RT in a non-randomized fashion are susceptible to bias. The goal of this randomized phase II study is to compare QOL, functional outcomes, toxicity profiles, and survival following primary RT (± chemotherapy) vs. TORS (± adjuvant [chemo] RT) in patients with OPSCC. METHODS/DESIGN: The target patient population comprises OPSCC patients who would be unlikely to require chemotherapy post-resection: Tumor stage T1-T2 with likely negative margins at surgery; Nodal stage N0-2, ≤3 cm in size, with no evidence of extranodal extension on imaging. Participants will be randomized in a 1:1 ratio between Arm 1 (RT ± chemotherapy) and Arm 2 (TORS ± adjuvant [chemo] RT). In Arm 1, patients with N0 disease will receive RT alone, whereas N1-2 patients will receive concurrent chemoradiation. In Arm 2, patients will undergo TORS along with selective neck dissections, which may be staged. Pathologic high-risk features will be used to determine the requirement for adjuvant radiotherapy +/- chemotherapy. The primary endpoint is QOL score using the M.D. Anderson Dysphagia Inventory (MDADI), with secondary endpoints including survival, toxicity, other QOL outcomes, and swallowing function. A sample of 68 patients is required. DISCUSSION: This study, if successful, will provide a much-needed randomized comparison of the conventional strategy of primary RT vs. the novel strategy of primary TORS. The trial is designed to provide a definitive QOL comparison between the two arms, and to inform the design of an eventual phase III trial for survival outcomes. TRIAL REGISTRATION: NCT01590355.

Risk Factors for Poor Survival Outcomes in Parotid Metastatic Cutaneous Squamous Cell Carcinoma.

OBJECTIVE: We aimed to analyze risk factors associated with poor survival outcomes for metastatic cutaneous head-and-neck SCC to the parotid. METHODS: All patients undergoing surgery for metastatic cutaneous SCC to the parotid with curative intent between 2011 and 2018, were reviewed. Demographic and clinical characteristics were evaluated. Histopathological data including tumor size and histology, tumor grade, TNM stage, resection margins, lymphovascular invasion, and perineural invasion, were analyzed. Overall survival (OS), disease-specific survival (DSS), and freedom from locoregional recurrence (LRR) were assessed. RESULTS: Ninety patients were included (mean age, 77 years; 75 men [83.3%]). A total parotidectomy was performed in 48 patients (53.3%), and 42 (46.7%) underwent a superficial parotidectomy. Seventy patients (77.8%) underwent adjuvant RT. The median follow-up was 31 months (20-39 months). Tumor volume ≥ 50 cm3 and a shorter RT duration (<20 days) were associated with reduced OS (p = 0.002 and p = 0.01, p = 0.02 and p = 0.009, respectively), and DSS (p = 0.004 and p = 0.02, p = 0.04 and p = 0.02, respectively) on univariable and multivariable analysis, respectively. Only a shorter RT duration was associated with worse freedom from LRR on univariable and multivariable analysis, (p = 0.04 and p < 0.001, respectively). However, with death as a competing risk, a shorter duration of RT was not significantly associated with freedom from LRR. CONCLUSION: A shorter duration of adjuvant RT, and excised tumor volume ≥50 cm3 were predictive factors of reduced OS and DSS, and a shorter duration of RT was also associated with reduced freedom from LRR in patients with metastatic SCC to the parotid gland. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1163-1168, 2023.

Randomized Trial of Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Long-Term Results of the ORATOR Trial.

PURPOSE: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has risen rapidly, because of an epidemic of human papillomavirus infection. The optimal management of early-stage OPSCC with surgery or radiation continues to be a clinical controversy. Long-term randomized data comparing these paradigms are lacking. METHODS: We randomly assigned patients with T1-T2, N0-2 (≤ 4 cm) OPSCC to radiotherapy (RT) (with chemotherapy if N1-2) versus transoral robotic surgery plus neck dissection (TORS + ND) (with or without adjuvant therapy). The primary end point was swallowing quality of life (QOL) at 1-year using the MD Anderson Dysphagia Inventory. Secondary end points included adverse events, other QOL outcomes, overall survival, and progression-free survival. All analyses were intention-to-treat. Herein, we present long-term outcomes from the trial. RESULTS: Sixty-eight patients were randomly assigned (n = 34 per arm) between August 10, 2012, and June 9, 2017. Median follow-up was 45 months. Longitudinal MD Anderson Dysphagia Inventory analyses demonstrated statistical superiority of RT arm over time (P = .049), although the differences beyond 1 year were of smaller magnitude than at the 1-year timepoint (year 2: 86.0 ± 13.5 in the RT arm v 84.8 ± 12.5 in the TORS + ND arm, P = .74; year 3: 88.9 ± 11.3 v 83.3 ± 13.9, P = .12). These differences did not meet the threshold to qualify as a clinically meaningful change at any timepoint. Certain differences in QOL concerns including more pain and dental concerns in the TORS + ND arm seen at 1 year resolved at 2 and 3 years; however, TORS patients started to use more nutritional supplements at 3 years (P = .015). Dry mouth scores were higher in RT patients over time (P = .041). CONCLUSION: On longitudinal analysis, the swallowing QOL difference between primary RT and TORS + ND approaches persists but decreases over time. Patients with OPSCC should be informed about the pros and cons of both treatment options (ClinicalTrials.gov identifier: NCT01590355).

Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: The ORATOR2 Phase 2 Randomized Clinical Trial.

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown. Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC. Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up. Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings). Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects. Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively). Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes. Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

Cross validation of the prostate cancer radiotherapy late toxicity (PCRT) questionnaire with the expanded prostate cancer index composite (EPIC) instrument.

INTRODUCTION: A 29-item prostate cancer radiotherapy (PCRT) questionnaire with genitourinary (GU), gastrointestinal (GI), and sexual (S) domains has been previously validated for the assessment of late toxicity health-related quality of life (HRQoL) effects. The study objective was to cross-validate the PCRT domains versus the expanded prostate cancer index composite (EPIC) questionnaire urinary (U), bowel (B), hormonal (H), and S subscales. METHODS AND MATERIALS: A single-institution cross-sectional PCRT patient cohort was surveyed. Descriptive and intra- and inter-class correlation coefficient statistics for the various EPIC and PCRT HRQoL domain scores were generated. Univariable and multivariable Cox and logistic regressions were performed depending on the HRQoL endpoint being assessed. RESULTS: A total of 189/276 patients (68%) completed questionnaires with EPIC and PCRT missing data rates of 9% and 4%, respectively. Mean age was 75.8 years (SD 5.5) and the mean time of questionnaire completion after radiotherapy was 852 days (range 212-1454 days). Mean EPIC urinary (85.1 SD 12.9), bowel (84.1 SD 15.8), sexual (21.8 SD 20.7), and hormonal (85.3 SD 13.7) as well as PCRT genitourinary (66.1 SD 15.3), gastrointestinal (83.6 SD 14.3), and sexual (39.4 SD 21.6) domain scores were calculated. Intraclass correlation coefficients comparing corresponding EPIC/PCRT domains ranged from 0.50-0.88. Interclass correlation coefficients for non-corresponding EPIC/PCRT domains ranged from 0.16-0.43 and 0.23-0.30, respectively. EPIC B/U, PCRT GI/GU and PCRT S required arcsin square root transformation and EPIC S/H domains required dichotomous transformations prior to univariable/multivariable analyses. Multivariable analysis demonstrated novel associations between predictive variables and HRQoL domains including between the PTV-bladder overlap volume and PCRT GU score. CONCLUSIONS: The PCRT is a compact, valid, and HRQoL instrument with very high questionnaire compliance rates and similar statistical properties to the EPIC instrument. However, dichotomization of the PRCT S data was not required which suggests some potential statistical advantage to the PCRT.

Evaluation of tomotherapy MVCT image enhancement program for tumor volume delineation.

The aims of this study were to investigate the variability between physicians in delineation of head and neck tumors on original tomotherapy megavoltage CT (MVCT) studies and corresponding software enhanced MVCT images, and to establish an optimal approach for evaluation of image improvement. Five physicians contoured the gross tumor volume (GTV) for three head and neck cancer patients on 34 original and enhanced MVCT studies. Variation between original and enhanced MVCT studies was quantified by DICE coefficient and the coefficient of variance. Based on volume of agreement between physicians, higher correlation in terms of average DICE coefficients was observed in GTV delineation for enhanced MVCT for patients 1, 2, and 3 by 15%, 3%, and 7%, respectively, while delineation variance among physicians was reduced using enhanced MVCT for 12 of 17 weekly image studies. Enhanced MVCT provides advantages in reduction of variance among physicians in delineation of the GTV. Agreement on contouring by the same physician on both original and enhanced MVCT was equally high.

Risk of Chronic Opioid Use After Radiation for Head and Neck Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Opioid addiction is a major public health concern. Chronic opioid use (COU) patterns after radiation for head and neck cancer (HNC) remain poorly understood. The aim of this study was to estimate the prevalence of COU and to identify its risk factors in patients with HNC undergoing curative-intent radiation therapy (RT) or chemoradiotherapy (CRT). METHODS AND MATERIALS: We performed a systematic review and meta-analysis using the PubMed (Medline), EMBASE, and Cochrane Library databases, queried from dates of inception until January 2020. COU was defined as persistent use of opioids ≥ 3 months after treatment completion. Meta-analyses were performed using random effects models. Heterogeneity was assessed using the I2 value. RESULTS: Seven retrospective studies, reporting on 1841 patients, met the inclusion criteria. Median age was 59.4 (range: 56.0-62.0) years with 1343 (72.9%) men and 498 (27.1%) women. Primary tumor locations included oropharynx (n = 891, 48.4%), oral cavity (n = 533, 29.0%), larynx (n = 93, 5.1%), hypopharynx (n = 32, 1.7%), and nasopharynx (n = 29, 1.6%). Eight hundred fifty-four (46.0%) patients had stage I/II and 952 (50.3%) had stage III-IV disease. Three hundred one (16.3%) patients had RT alone, 738 (40.1%) received CRT, and 594 (32.3%) underwent surgery followed by adjuvant RT/CRT. The proportion of patients with HNC who developed COU post-RT/CRT was 40.7% at 3 months (95% confidence interval [CI]: 22.6%-61.7%; I2 = 97.1%) and 15.5% at 6 months (95% CI: 7.3%-29.7%; I2 = 94.3%). Oropharyngeal malignancies had the highest rate of COU based on primary tumor location (46.6%; 95% CI: 30.8%-63.1%; P < .0001). High proportions of COU were found in patients with a history of psychiatric disorder(s) (61.7%), former/current alcohol abuse (53.9%), and opioid requirements before radiation treatment (51.6%; P = .035). CONCLUSIONS: A significant proportion of patients who undergo RT for HNC suffer from COU. High-risk factors for COU include an oropharyngeal primary, history of psychiatric disorder, former/current alcohol abuse, and pre-treatment opioid use. New strategies to mitigate COU are needed.

Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer.

BACKGROUND: A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy. METHODS: We randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation) to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week. The primary end point was overall survival. RESULTS: With a minimum of 2 years of follow-up (> or =3 years for 69% of patients), significantly more patients survived in the TPF group than in the PF group (hazard ratio for death, 0.70; P=0.006). Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group; the median overall survival was 71 months and 30 months, respectively (P=0.006). There was better locoregional control in the TPF group than in the PF group (P=0.04), but the incidence of distant metastases in the two groups did not differ significantly (P=0.14). Rates of neutropenia and febrile neutropenia were higher in the TPF group; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group. CONCLUSIONS: Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy. (ClinicalTrials.gov number, NCT00273546 [ClinicalTrials.gov].).

Preservation of swallowing in resected oral cavity squamous cell carcinoma: examining radiation volume effects (PRESERVE): study protocol for a randomized phase II trial.

BACKGROUND: Patients with resected oral cavity squamous cell carcinoma (OCSCC) are often treated with adjuvant radiation (RT) ± concomitant chemotherapy based on pathological findings. Standard RT volumes include all surgically dissected areas, including the tumour bed and dissected neck. RT has significant acute and long-term toxicities including odynophagia, dysphagia, dermatitis and fibrosis. The goal of this study is to assess the rate of regional failure with omission of radiation to the surgically dissected pathologically node negative (pN0) hemi-neck(s) compared to historical control, and to compare oncologic outcomes, toxicity, and quality of life (QoL) profiles between standard RT volumes and omission of RT to the pN0 neck. METHODS: This is a multicentre phase II study randomizing 90 patients with T1-4 N0-2 OCSCC with at least one pN0 hemi-neck in a 1:2 ratio between standard RT volumes and omission of RT to the pN0 hemi-neck(s). Patients will be stratified based on overall nodal status (nodal involvement vs. no nodal involvement) and use of concurrent chemotherapy. The primary endpoint is regional failure in the pN0 hemi-neck(s); we hypothesize that a 2-year regional recurrence of 20% or less will be achieved. Secondary endpoints include overall and progression-free survival, local recurrence, rate of salvage therapy, toxicity and QoL. DISCUSSION: This study will provide an assessment of omission of RT to the dissected pN0 hemi-neck(s) on oncologic outcomes, QoL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03997643 . Date of registration: June 25, 2019, Current version: 2.0 on July 11 2020.

Modern treatment outcomes for early T-stage oropharyngeal cancer treated with intensity-modulated radiation therapy at a tertiary care institution.

BACKGROUND: Transoral surgery (TOS), particularly transoral robotic surgery (TORS) has become the preferred modality in the United States for the treatment of early stage oropharyngeal cancer, largely due to assumptions of fewer toxicities and improved quality of life compared to primary radiotherapy (RT). However, these assumptions are based on retrospective analysis, a subset of which utilize primary RT groups not limited to T1-2 stage tumors for which transoral robotic surgery is FDA approved. Thus, there is potential for underestimating survival and overestimating toxicity, including treatment related mortality, in primary RT. METHODS: Consecutive cases of early T-stage (T1-T2) oropharyngeal cancer presenting to the London Health Sciences Centre between 2014 and 2018 treated with RT or chemoradiation (CRT) were reviewed. Patient demographics, treatment details, survival outcomes and toxicity were collected. Toxicities were retrospectively graded using the Common Terminology Criteria for Adverse Events criteria. RESULTS: A total of 198 patients were identified, of which 82% were male and 73% were HPV-positive. Sixty-eight percent of patients experienced a grade 2 toxicity, 48% a grade 3 and 4% a grade 4. The most frequent toxicities were dysphagia, neutropenia and ototoxicity. The rates of gastrostomy tube dependence at 1 and 2 years were 2.5% and 1% respectively. There were no grade 5 (fatal) toxicities. HPV-positive patients experienced improved 5-year overall survival (86% vs 64%, p = 0.0026). CONCLUSIONS: Primary RT or CRT provides outstanding survival for early T-stage disease, with low rates of severe toxicity and feeding tube dependence. This study provides a reference for comparison for patients treated with primary transoral surgery.

Does 5 + 5 Equal Better Radiation Treatment Plans in Head and Neck Cancers?

PURPOSE: Accurate contouring in head and neck cancer (HNC) is critical. International consensus guidelines recommend the 5 + 5 mm rule for expansions around the primary tumor, wherein high- and low-dose clinical target volumes (CTV-P1 and CTV-P2, respectively) are created using successive 5 mm expansions on the gross tumor volume. To our knowledge, the necessity of a low-dose CTV-P2 has never been assessed; therefore, we evaluated the dosimetric impact of adding a CTV-P2 expansion using the 5 + 5 mm rule compared with contouring with a high-dose CTV-P1 alone. METHODS AND MATERIALS: A retrospective study of clinically delivered (chemo)radiation therapy treatment plans for HNC was conducted. All patients were treated with 70 Gy in 35 fractions using volumetric modulated arc therapy in a single phase. CTV-P2 was retrospectively contoured per guidelines as a 5 mm expansion on CTV-P1 from the clinical plan, carving off specified barriers to spread. We used a 5 mm planning target volume (PTV) expansion. Our primary outcome was whether 95% of the volume of the PTV for the CTV-P2 contour (ie, PTV-P2) received at least 56 Gy. To assess dose falloff, the coverage of a PTV ring structure was created by subtracting PTV-P1 from PTV-P2. RESULTS: Twenty-seven patients from 4 HNC subsites (base of tongue, tonsil, hypopharynx, and supraglottic larynx) were included. In all 108 treatment plans, at least 95% of the PTV-P2 structure received at least 56 Gy. The minimum volume of the PTV-P2 structure receiving at least 56 Gy was 97.4%. Eight of 108 treatment plans had borderline coverage of the PTV ring substructure alone. CONCLUSIONS: Adding a CTV-P2 structure using the 5 + 5 mm rule had no dosimetric impact, adds contouring time, adds treatment planning complexity, and could potentially introduce errors. The 5 + 5 mm rule may have value in other settings, such as when smaller PTV margins are used, and warrants further evaluation with prospective or randomized studies.

Time Interval to Biochemical Failure as a Surrogate End Point in Locally Advanced Prostate Cancer: Analysis of Randomized Trial NRG/RTOG 9202.

BACKGROUND: In prostate cancer, end points that reliably portend prognosis and treatment benefit (surrogate end points) can accelerate therapy development. Although surrogate end point candidates have been evaluated in the context of radiotherapy and short-term androgen deprivation (AD), potential surrogates under long-term (24 month) AD, a proven therapy in high-risk localized disease, have not been investigated. MATERIALS AND METHODS: In the NRG/RTOG 9202 randomized trial (N = 1,520) of short-term AD (4 months) versus long-term AD (LTAD; 28 months), the time interval free of biochemical failure (IBF) was evaluated in relation to clinical end points of prostate cancer-specific survival (PCSS) and overall survival (OS). Survival modeling and landmark analysis methods were applied to evaluate LTAD benefit on IBF and clinical end points, association between IBF and clinical end points, and the mediating effect of IBF on LTAD clinical end point benefits. RESULTS: LTAD was superior to short-term AD for both biochemical failure (BF) and the clinical end points. Men remaining free of BF for 3 years had relative risk reductions of 39% for OS and 73% for PCSS. Accounting for 3-year IBF status reduced the LTAD OS benefit from 12% (hazard ratio [HR], 0.88; 95% CI, 0.79 to 0.98) to 6% (HR, 0.94; 95% CI, 0.83 to 1.07). For PCSS, the LTAD benefit was reduced from 30% (HR, 0.70; 95% CI, 0.52 to 0.82) to 6% (HR, 0.94; 95% CI, 0.72 to 1.22). Among men with BF, by 3 years, 50% of subsequent deaths were attributed to prostate cancer, compared with 19% among men free of BF through 3 years. CONCLUSION: The IBF satisfied surrogacy criteria and identified the benefit of LTAD on disease-specific survival and OS. The IBF may serve as a valid end point in clinical trials and may also aid in risk monitoring after initial treatment.

Bcl-2 and Bax expression predict prostate cancer outcome in men treated with androgen deprivation and radiotherapy on radiation therapy oncology group protocol 92-02.

PURPOSE: Bcl-2 is antiapoptotic, and its overexpression has been associated with resistance to androgen deprivation and poor outcome in some patients treated with radiotherapy. Bax is proapoptotic, regulating Bcl-2 through heterodimer formation. In a prior study, Bcl-2 and Bax were not related to outcome in locally advanced patients treated with radiotherapy or short-term androgen deprivation + radiotherapy (STAD+RT) on another Radiation Therapy Oncology Group trial (86-10). A follow-up investigation was carried out here in more contemporary high-risk men treated on Radiation Therapy Oncology Group 92-02 with STAD+RT or long-term AD+RT (LTAD+RT). EXPERIMENTAL DESIGN: Adequate tissue was available to be analyzed immunohistochemically in 502 patients for Bcl-2 and 343 patients for Bax. Univariate and multivariate analyses by Cox proportional hazards models were applied to end points of failure. RESULTS: Bcl-2 was positive in 45.6% cases, and Bax expression altered in 53.9% cases. Abnormal Bcl-2 was not related to any of the failure end points tested. Altered Bax expression was significantly associated with any failure (P = 0.023) and marginally with biochemical failure (P = 0.085). The combination of negative Bcl-2/normal Bax expression seemed more robust, being significantly related to reduced biochemical failure (P = 0.036) and any failure (P = 0.046). The predictive value of negative Bcl-2/normal Bax was most pronounced in those who received STAD+RT, as opposed to LTAD+RT. CONCLUSIONS: Normal Bax expression was associated with significantly more favorable outcome. The combination of negative Bcl-2 and normal Bax was more consistently significant, particularly when STAD+RT was the treatment administered. These data suggest that LTAD+RT should be used when either Bcl-2 or Bax is abnormally expressed.