Development and Standardization of an Osteoradionecrosis Classification System in Head and Neck Cancer: Implementation of a Risk-Based Model.

PURPOSE: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. METHODS: Consecutive patients with head and neck cancer (HNC) treated with curative-intent intensity-modulated radiation therapy (IMRT) (≥45 Gy) from 2011 to 2017 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared with 15 existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). RESULTS: ORN was identified in 219 of 2,732 (8%) consecutive patients with HNC. Factors associated with high risk of ORN were oral cavity or oropharyngeal primaries, received IMRT dose ≥60 Gy, current/ex-smokers, and/or stage III to IV periodontal condition. The ORN rate for high-risk versus low-risk patients was 12.7% versus 3.1% (P < .001) with an AUC of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, ClinRad, was proposed on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. CONCLUSION: We identified risk factors for ORN and proposed a novel ORN classification system on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN and may facilitate clinical care and clinical trials.

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.

Development and Standardization of a Classification System for Osteoradionecrosis: Implementation of a Risk-Based Model.

Purpose: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. Methods: Consecutive head-and-neck cancer (HNC) patients treated with curative-intent IMRT (≥ 45Gy) in 2011-2018 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared to fifteen existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). Results: ORN was identified in 219 out of 2732 (8%) consecutive HNC patients. Factors associated with high-risk of ORN were: oral-cavity or oropharyngeal primaries, received IMRT dose ≥60Gy, current/ex-smokers, and/or stage III-IV periodontal disease. The ORN rate for high-risk vs low-risk patients was 12.7% vs 3.1% (p<0.001) with an area-under-the-receiver-operating-curve (AUC) of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, RadORN, was proposed based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. Conclusion: We identified risk factors for ORN, and proposed a novel ORN classification system based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN, and may facilitate clinical care and clinical trials.

Advances and Challenges in Trials of Local Therapy for Patients With Oligometastatic or Oligoprogressive Disease.

The paradigm of oligometastatic disease (OMD), characterized by a limited number of metastases potentially amenable to local therapies, presents unique opportunities and challenges in clinical trial design and implementation. Although local ablative therapies, such as stereotactic body radiation therapy, have shown promise in improving outcomes for patients with OMD, there is a lack of large-scale randomized phase III trials supporting their widespread use. This paper outlines the key challenges in trial design and implementation in the oligometastatic setting, including appropriate patient selection, the definition of the oligometastatic state, trial design considerations, endpoint selection, and logistical considerations related to enrollment and follow-up. We suggest potential strategies to address these challenges, emphasizing the importance of a comprehensive, patient-centric approach, and the integration of multidisciplinary teams in trial design and implementation. The aim is to encourage the design of well-structured clinical trials, ultimately refining best practices and enhancing patient outcomes in the management of OMD.

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.

Automated tracking of morphologic changes in weekly magnetic resonance imaging during head and neck radiotherapy.

BACKGROUND AND PURPOSE: Anatomic changes during head and neck radiotherapy can impact dose delivery, necessitate adaptive replanning, and indicate patient-specific response to treatment. We have developed an automated system to track these changes through longitudinal MRI scans to aid identification and clinical intervention. The purpose of this article is to describe this tracking system and present results from an initial cohort of patients. MATERIALS AND METHODS: The Automated Watchdog in Adaptive Radiotherapy Environment (AWARE) was developed to process longitudinal MRI data for radiotherapy patients. AWARE automatically identifies and collects weekly scans, propagates radiotherapy planning structures, computes structure changes over time, and reports important trends to the clinical team. AWARE also incorporates manual structure review and revision from clinical experts and dynamically updates tracking statistics when necessary. AWARE was applied to patients receiving weekly T2-weighted MRI scans during head and neck radiotherapy. Changes in nodal gross tumor volume (GTV) and parotid gland delineations were tracked over time to assess changes during treatment and identify early indicators of treatment response. RESULTS: N = 91 patients were tracked and analyzed in this study. Nodal GTVs and parotids both shrunk considerably throughout treatment (-9.7 ± 7.7% and -3.7 ± 3.3% per week, respectively). Ipsilateral parotids shrunk significantly faster than contralateral (-4.3 ± 3.1% vs. -2.9 ± 3.3% per week, p = 0.005) and increased in distance from GTVs over time (+2.7 ± 7.2% per week, p < 1 × 10-5 ). Automatic structure propagations agreed well with manual revisions (Dice = 0.88 ± 0.09 for parotids and 0.80 ± 0.15 for GTVs), but for GTVs the agreement degraded 4-5 weeks after the start of treatment. Changes in GTV volume observed by AWARE as early as one week into treatment were predictive of large changes later in the course (AUC = 0.79). CONCLUSION: AWARE automatically identified longitudinal changes in GTV and parotid volumes during radiotherapy. Results suggest that this system may be useful for identifying rapidly responding patients as early as one week into treatment.

Practical Steps to Mitigate Cybersecurity Attacks on Radiation Oncology Practices.

Radiation oncology, as a technologically intensive discipline that requires communication between multiple and diverse computer systems, is vulnerable to cyberattack. Given the enormous amount of the loss of time, energy, and money that results from a cyberattack, it behooves radiation oncologists and their teams to minimize cybersecurity threats to their practices. In this article, we present practical steps that radiation oncologists can take to prevent, prepare for, and respond to a cyberattack.

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.

Consensuses, controversies, and future directions in treatment deintensification for human papillomavirus-associated oropharyngeal cancer.

The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long-term morbidities with chemoradiation and the favorable prognosis of HPV-positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head-and-neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de-escalation. National database studies estimate that up to one third of patients receive nonstandard de-escalated treatments, which have subspecialty-specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV-positive OPC de-escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de-escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy-based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de-escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real-time surveillance.

Participation of Patients From Racial and Ethnic Minority Groups in Phase 1 Early Cancer Drug Development Trials in the US, 2000-2018.

Importance: Despite federal initiatives encouraging the enrollment of individuals from racial and ethnic minority groups in US clinical trials, no studies to date have specifically examined demographic disparities among participants in phase 1 drug development trials for patients with metastatic cancer. Objective: To assess trends in the enrollment of patients from racial and ethnic minority groups in US phase 1 therapeutic drug trials for metastatic cancer from 2000 to 2018. Design, Setting, and Participants: In this cross-sectional study, ClinicalTrials.gov was queried in July 2021 to identify completed phase 1 drug trials for metastatic cancer in the US from January 1, 2000, to December 31, 2018, with published results, yielding 221 phase 1 trials with 8309 participants aged 18 years or older with metastatic solid tumors. Proportions of each racial and ethnic group of trial participants were compared with that from the North American Association of Central Cancer Registries' Cancer in North America (CiNA) database. Statistical analysis was performed from July 12, 2021, to March 15, 2022. Main Outcomes and Measures: For each racial and ethnic group, the difference between trial and CiNA proportions was examined using a 2-sample test for equality of proportions with continuity correction. Results: The 8309 phase 1 trial participants (4198 men [50.5%]; median age, 59 years) included 23 American Indian or Alaska Native participants (0.3%), 371 Asian or Pacific Islander participants (4.5%), 514 Black participants (6.2%), 401 of 5076 Hispanic or Latinx participants (7.9%), and 7154 White participants (86.1%). Industry funded 165 of the 221 trials (74.7%). White patients were overrepresented overall compared with the corresponding CiNA cohort (7154 of 8309 [86.1%] vs 4 113 096 of 4 891 486 [84.1%]; difference, 2.0 percentage points; P < .001). There was an increase in overrepresentation of White patients from 2000 to 2011 (trials, 2780 of 3245 [85.7%]; CiNA, 2 378 019 of 2 800 711 [84.9%]; difference, 0.8 percentage points; P = .23) to 2012-2018 (trials, 4374 of 5063 [86.4%]; CiNA, 1 735 077 of 2 090 775 [82.9%]; difference, 3.5 percentage points; P < .001) and corresponding worsening representation of American Indian or Alaska Native patients (2000-2011: trials, 10 of 3245 [0.3%]; CiNA, 10 905 of 2 800 711 [0.4%]; difference, -0.08 percentage points; 2012-2018: trials, 13 of 5063 [0.3%]; CiNA, 9484 of 2 090 775 [0.5%]; difference, -0.20 percentage points), Asian or Pacific Islander patients (2000-2011: trials, 121 of 3245 [3.7%]; CiNA, 75 033 of 2 800 711 [2.7%]; difference, 1.1 percentage points; 2012-2018: trials, 151 of 5063 [3.0%]; CiNA 70 535 of 2 090 775 [3.4%]; difference, -0.75 percentage points), Black patients (2000-2011: trials, 244 of 3245 [7.5%]; CiNA, 322 701 of 2 800 711 [11.5%]; difference, -4.0 percentage points; 2012-2018: trials, 270 of 5063 [5.3%]; CiNA, 255 625 of 2 090 775 [12.2%]; difference, -6.9 percentage points), and Hispanic or Latinx patients (2000-2011: trials, 161 of 1792 [9.0%]; CiNA, 169 297 of 2 800 711 [6.0%]; difference, 3.0 percentage points; 2012-2018: trials, 240 of 3295 [7.3%]; CiNA, 156 118 of 2 090 775 [7.5%]; difference, -0.2 percentage points). Similar disparities were observed when comparing industry-funded and academic center-sponsored trials. Conclusions and Relevance: In this cross-sectional study of participants in phase 1 clinical trials of drugs for metastatic cancer, worsening disparities were observed over time in the accrual of patients from racial and ethnic minority groups. These findings may represent widening inequalities in access to trial sites and worsening systemic biases. More efforts are needed to diversify phase 1 cancer drug trials to improve equity in access to new treatments and to ensure that safety and efficacy findings from early drug trials are generalizable across populations.

Effect of preradiation dental intervention on incidence of osteoradionecrosis in patients with head and neck cancer: A systematic review and meta-analysis.

BACKGROUND: The purpose of this systematic review was to examine whether dental intervention involving bone or soft-tissue manipulation preradiotherapy (pre-RT) is associated with lower rates of osteoradionecrosis of the jaw (ORNJ) in patients with head and neck cancer (HNC). TYPES OF STUDIES REVIEWED: The authors included relevant studies from MEDLINE, Embase, and Cochrane Library, including observational studies published from 2007 through 2021 and involving adults who underwent dental intervention pre-RT for HNC. Authors assessed evidence certainty by using the Grading of Recommendations Assessment, Development, and Evaluation approach. Random-effects models were used to calculate pooled relative risk estimates and hazard ratios. When meta-analysis was not possible, study-level measures of association and narrative summaries of the evidence were reported. RESULTS: Twenty-two studies were included. From the pooled, unadjusted analysis, patients undergoing pre-RT extractions may have a 55% increased risk of experiencing ORNJ (relative risk, 1.55; 95% CI, 0.85 to 2.86; very low certainty); the unadjusted pooled hazard ratio was 3.19 (95% CI, 0.99 to 10.31; very low certainty), corresponding to a possible increased hazard of developing ORNJ (very low certainty). Findings for other pre-RT procedures manipulating bone or tissue relied on limited, observational studies with low or very low certainty evidence. CONCLUSIONS: Mostly very low certainty evidence suggests that patients with HNC who need pre-RT dental intervention may have an increased risk of developing ORNJ compared with those who do not. PRACTICAL IMPLICATIONS: Maintaining optimal oral health may help reduce the need for urgent pre-RT dental treatment, potentially reducing ORNJ risk and minimizing delay of oncologic treatment in patients with HNC.

Peer Review of Head and Neck Cancer Planning Target Volumes in Radiation Oncology.

Purpose: Radiation treatment plans undergo peer review during chart rounds, but changes to treatment volumes would require replanning. Our group implemented weekly head and neck cancer "volume rounds" to peer review all target volumes for head and neck cancer before radiation therapy (RT) planning and chart rounds. Methods and Materials: We analyzed modifications made to planning target volumes (PTVs) at volume rounds for consecutive nonproton head and neck cancer cases from May 2020 to May 2021. Nine head and neck radiation oncologists participated in weekly volume rounds during this time. Recommendations were categorized as no changes, minor changes, major changes, additional workup (eg, biopsy or imaging), and consultation or tumor board discussion needed before the start of RT. Minor changes to PTVs generally did not require a second review before treatment planning while major changes did. Results: PTVs for 511 cases involving 432 patients underwent peer review and 298 (58.3%) of these cases did not require any modifications before treatment planning. Minor and major changes were recommended in 75 (14.7%) and 86 (16.8%) cases, respectively. Forty-five (8.8%) cases were recommended to have additional workup and 23 (4.5%) required additional consultation with nonradiation surgeons or medical oncologists. Of the 45 cases that were recommended for additional workup, 40 underwent biopsy or imaging. Positive findings on imaging or biopsy occurred in 13 patients, leading to a significant change in management, including 4 patients who underwent additional surgery after positive findings before the start of RT. Conclusions: Prospective peer review during head and neck cancer volume rounds led to frequent minor and major alterations to PTVs. Significant changes in the overall treatment plan, such as additional surgery before start of RT, occurred in a minority of patients.