Search

Radiation induced lymphopenia (RIL) is common, but its clinical implications are not well defined. In this secondary analysis of a phase III randomized controlled trial evaluating chemoradiation strategies of intensity modulated proton therapy (IMPT) vs IMRT in patients with advanced stage OPSCC (NCT01893307), we evaluated predictors and clinical implications of RIL. This is a multi-center, randomized, Phase III non-inferiority trial including OPSCC AJCC 7th stage III-IVA, B, CRT, bilateral neck radiation, and ECOG <3. On-treatment absolute lymphocyte count (ALC) nadir was used to calculate the CTCAE v5 grade of lymphopenia. Covariates including patient characteristics, treatment modality - IMPT vs IMRT, and clinical features were assessed using ANOVA and linear regression with ALC as the dependent variable via per protocol analysis. Covariates demonstrating significant (p<0.05) associations with ALC nadir were selectively introduced in the multivariable analysis (MVA) after being assessed for multicollinearity. Three hundred ninety seven of 440 patients from 21 institutions initially assigned patients completed CRT, of whom 338 patients had ALC data evaluable for analysis. The majority experienced Grade 3 (n = 213, 63%) or Grade 4 (n = 75, 22%) lymphopenia. Lymphopenia grade was significantly associated with both ER visits (p<0.001) and hospital admission (p<0.001). Patients who developed Grade 4 lymphopenia presented to the ER 100% more frequently (0.78, 95% CI = 0.55-1.0 vs 0.38, 95% CI = 0.29-0.49, p<0.001) and were admitted 70% more frequently (0.51, 95% CI = 0.35-0.70 vs 0.30, 95% CI = 0.21-0.35 p = 0.001) than those who did not. At a median follow-up of 3.1 years, there was no statistically significant relationship between lymphopenia and 3-year PFS or OS. On univariate analysis, treatment with IMPT was associated with a 68% lower incidence of Grade 4 lymphopenia (11% vs 34%, p<0.001) and a 28% higher ALC nadir (0.32 vs 0.25, p<0.001). ALC nadir was also strongly correlated with baseline ALC (r2 = 0.44, p<0.001), and weakly correlated with CRT (r2 = 0.045, p = 0.032), body mean dose (r2 = 0.045, p<0.001), CTV70 (r2 = 0.041, p<0.001), and V5Gy (r2 = 0.062, p<0.001). MVA (p<0.001) confirmed significant effects of treatment modality (β1 = -0.091, p<0.001), baseline ALC (β2 = 0.14, p<0.001), and CRT with cetuximab (β4 = 0.12, pp = 0.011) and carboplatin (β5 = 0.10, p = 0.039). In patients with OPSCC treated with CRT, IMPT was associated with a reduced severity of RIL, while RIL was associated with increased rates of ER visits and HA. [ABSTRACT FROM AUTHOR]

Fast Neutron Radiotherapy (NRT) is a high linear energy transfer modality that can overcome tumor radioresistance to conventional radiotherapy (RT). This may be particularly beneficial in the palliative recurrent/metastatic setting. An ideal dose-fractionation in this setting is unknown. This study evaluates clinical and early toxicity outcomes of short course (2-4 fraction) palliative hypofractionated NRT (hNRT). Clinical characteristics, oncologic treatment history, clinical (tumor shrinkage and/or symptom response) and radiographic responses were reviewed in a single-institution, IRB-approved retrospective review of patients who received at least one palliative treatment course with 3D conformal hNRT from 11/2016 to 12/2022. Twenty-seven patients with Stage IV cancer received hNRT at median age of 79yr (range = 47–100) with median follow-up of 5.4mo (range = 0.1-75.6). Histology included squamous (n = 7), urothelial (n = 6), Merkel (n = 5), adenocarcinoma (n = 3), renal cell (n = 2), and other (n = 4). Median hNRT dose was 6 Gy in 3 fractions (range = 3.45-10 Gy, 2-4 fractions), equivalent to around 18-30 Gy of x-rays. There were 48 hNRT treatment courses across 32 unique anatomic sites, which included head-and-neck (HN) (n = 14), bone (n = 5), genitourinary (n = 4), non-HN lymph nodes (n = 7), and non-HN skin (n = 2). Twenty-three unique treatment sites (across 19 patients) received a single hNRT course, whereas nine sites (across 9 patients) received 2-4 successive courses (median 37d between courses). 16 patients (60%) were on concurrent systemic therapy and 8 sites (25%) were previously irradiated with photon RT. Median overall survival time from the end of the first hNRT course was 400d (95% CI = 221-not reached). Of treatment sites receiving one hNRT course, 18 (78%) of 23 had clinical response, and 11 of 13 (85%) sites with radiographic follow-up had radiographic response. Of sites receiving 2 or more successive courses, 9 (100%) of 9 had clinical response and 6 of 8 (75%) sites with radiographic follow-up had radiographic response. Of 8 sites previously irradiated with photon RT, 6 (75%) had a clinical response of which 4 (50%) had a concurrent radiographic response. Of 20 sites receiving hNRT for pain relief/bleeding, 3 (15%) had symptom stability and 17 (85%) had partial-to-full clinical response, 11 of which had symptom progression at a median of 145d post-response. Of 12 sites receiving hNRT to slow disease progression and/or stimulate an immune response (n = 11 on concurrent immunotherapy or ADT), 10 (83%) had partial-to-full clinical response with radiographically stable-to-improved disease and 1 had radiographic progression. Overall, RTOG Grade 2 (n = 1) or 3 (n = 2) side effects were uncommon. No patients experienced pain flares. Most patients treated with hNRT had symptom relief and radiographic response. None had pain flares and high-grade side effects were rare. Single or repeat-course hNRT may be a safe and effective method of palliation. [ABSTRACT FROM AUTHOR]

Introduction: There is some evidence of a dose-response relationship for intravascular brachytherapy (IVBT) of native vessel or first-time in-stent restenosis (ISR). It has also been shown that in-field failure predominates following intravascular brachytherapy-treated lesions. Accordingly, it may be advantageous to increase the radiation dose(s) currently used. Given the rationale for escalation from currently doses, a scrutiny of the potential complications that have been reported seems timely., Methods: PubMed was searched from 1966 through November 21st, 2023, using the terms coronary and brachytherapy, yielding 1287 references. A 10/16/24 follow-up search of Embase, using the terms "coronary and brachytherapy and complications", yielding 511 articles. In total, 68 articles were identified as adverse event reports based on their title, or by scrutinizing articles that did not mention adverse events in their titles., Results: The best documented adverse IVBT-related event is the occurrence of late (> 1 month) thrombosis. Following identification of the risk, longer DAPT regimens were adopted, bringing the incidence to non-IVBT levels. A variety of other adverse events have been reported, including aneurysms, dissections, arterial spasm, "black holes" and vasomotor response inhibition. However, none of which were associated with adverse clinical outcomes., Conclusions: Nearly all reports regarding IVBT-related complications are retrospective analyses of a limited number of events, subject to reporting bias. Clinically important IVBT-related complications, at current doses, appear highly unlikely., (Copyright © 2024 American Brachytherapy Society. All rights reserved.)

Background: We previously reported in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs), pretreatment higher lactate dehydrogenase (LDH) and absolute (abx) neutrophils as well as lower percent (%) lymphocytes correlated with worse overall survival (OS). In this study we aimed to develop a prognostic signature for HNSCC treated with ICIs using these peripheral blood biomarkers (PBBMs)., Methods: Adults with R/M HNSCC treated with ICIs at our institution from 08/2012 to 03/2021 with pretreatment PBBMs were included. Follow-up continued until 02/15/2022. The cohort (n = 151) was randomly split into training (n = 100) and testing (n = 51) datasets. A prognostic score incorporating LDH, % lymphocytes, and abx neutrophils was developed from the training dataset using Cox proportional hazards regression. In the training dataset, a grid search identified the optimal cutpoints classifying patients into high, medium, and low-risk groups (trichotomized signature) as well as high vs. low-risk groups (dichotomized signature). The prognostic score, dichotomized and trichotomized signatures were then validated in the testing dataset., Results: Training and testing datasets showed no clinically meaningful differences in clinicodemographic characteristics or PBBMs. An OS prognostic model was developed from the training dataset: Risk score = 1.24*log10(LDH) - 1.95*log10(% lymphocytes) + 0.47*log10(abx neutrophils). Optimal risk score cutpoints for the dichotomized and trichotomized signatures were defined in the training dataset, and Kaplan-Meier curves for both dichotomized and trichotomized signatures showed good separation between risk groups. Risk scores were calculated in the testing dataset, where the trichotomized signature demonstrated overlap between low and medium-risk groups but good separation from the high-risk group while the dichotomized signature showed clear separation between low and high-risk groups. Higher risk score correlated with worse OS (HR 2.08, [95%CI 1.17-3.68], p = 0.012). Progression-free survival Kaplan-Meier curves likewise showed excellent separation between dichotomized risk groups in the training and testing datasets., Conclusions: We developed a prognostic signature for OS based on 3 previously identified PBBMs for HNSCC treated with ICIs and identified a high-risk group of patients least likely to have survival benefit from ICIs. This signature may improve ICI patient selection and warrants validation in an independent cohort as well as correlation with CPS., Competing Interests: Declarations Ethics approval and consent to participate This study was reviewed and approved by the Fred Hutchinson Cancer Research Institutional Review Board (IRB ID: STUDY00007717). The requirement to obtain informed consent was waived. Consent for publication Not applicable. Competing interests Conflict of Interest Disclosures: Dr. Futran reported educational consultancy role for Stryker Corporation. Dr. Rodriguez reported receipt of institutional research funding from AstraZeneca, Ayala, Bristol Myers Squibb, Ignyta, and Merck, and reported advisory board membership for Cue Biopharma. The other authors declare no potential conflicts of interest., (© 2024. The Author(s).)

Background: Merkel cell carcinoma (MCC) is often treated with surgery and postoperative radiation therapy (PORT). The optimal time to initiate PORT (Time-to-PORT [ttPORT]) is unknown., Purpose: We assessed if delays in ttPORT were associated with inferior outcomes., Methods: Competing risk regression was used to evaluate associations between ttPORT and locoregional recurrence (LRR) for patients with stage I/II MCC in a prospective registry and adjust for covariates. Distant metastasis and death were competing risks., Results: The cohort included 124 patients with median ttPORT of 41 days (range: 8-125 days). Median follow-up was 55 months. 17 (14%) patients experienced a LRR, 14 (82%) of which arose outside the radiation field. LRR at 5 years was increased for ttPORT >8 weeks vs ≤ 8 weeks, 28.0% vs 9.2%, P = .006. There was an increase in the cumulative incidence of MCC-specific death with increasing ttPORT (HR = 1.14 per 1-week increase, P = .016)., Limitations: The relatively low number of LRRs limited the extent of our multivariable analyses., Conclusions: Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival., Competing Interests: Conflict of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Fast neutron therapy is a high linear energy transfer (LET) radiation treatment modality offering advantages over low LET radiations. Multileaf collimator technology reduces normal-tissue dose (toxicity) and makes neutron therapy more comparable to MV x-ray treatments. Published clinical-trial and other experiences with fast neutron therapy are reported. Early comparative studies failed to consider differences in target-dose spatial conformality between x-ray and neutron treatments, which is especially important for organs-at-risk close to tumor targets. Treatments planning systems (TPS) for high-energy neutrons lag behind TPS tools for MV x-rays, creating challenges for comparative studies of clinical outcomes. A previously published Monte Carlo model of the University of Washington (UW) Clinical Neutron Therapy System (CNTS) is refined and integrated with the RayStation TPS as an external dose planning/verification tool. The collapsed cone (CC) dose calculations in the TPS are based on measured dose profiles and output factors in water, with the absolute dose determined using a tissue-equivalent ionization chamber. For comparison, independent (external) Monte Carlo simulation computes dose on a voxel-by-voxel basis using an atlas that maps Hounsfield Unit (HU) numbers to elemental composition and density. Although the CC algorithm in the TPS accurately computes neutron dose to water compared to Monte Carlo calculations, calculated dose to water differs from bone or tissue depending largely on hydrogen content. Therefore, the elemental composition of tissue and bone, rather than the material or electron density, affects fast neutron dose. While the CC algorithm suffices for reproducible patient dosimetry in fast neutron therapy, adopting methods that consider tissue heterogeneity would enhance patient-specific neutron dose accuracy relative to national standards for other types of ionizing radiation. Corrections for tissue composition have a significant impact on absolute dose and the relative biological effectiveness (RBE) of neutron treatments compared to other radiation types (MV x-rays, protons, and carbon ions)., (© 2023 Institute of Physics and Engineering in Medicine.)

Background: Perineural invasion (PNI) in head and neck squamous cell carcinoma (HNSCC) portends poor prognosis. Extent of treatment of nerve pathways with varying degrees of PNI and patterns of failure following elective neural radiotherapy (RT) remain unclear., Methods: Retrospective review of HNSCC patients with high-risk (clinical/gross, large-nerve, extensive) or low-risk (microscopic/focal) PNI who underwent curative-intent treatment from 2010 to 2021., Results: Forty-four patients (mean follow-up 22 months; 59% high-risk, 41% low-risk PNI) were included. Recurrence following definitive treatment occurred in 31% high-risk and 17% low-risk PNI patients. Among high-risk patients, 69% underwent surgery with post-operative RT and 46% underwent elective neural RT. Local control (83% low-risk vs. 75% high-risk), disease-free, and overall survival did not differ between groups., Conclusions: High local control rates were achieved in high-risk PNI patients treated with adjuvant or primary RT, including treatment of both involved and uninvolved, communicating cranial nerves, with few failures in electively treated regions., (© 2023 Wiley Periodicals LLC.)

Purpose: The role of postoperative radiation therapy (PORT) in early stage Merkel cell carcinoma (MCC) is controversial. We analyzed the role of PORT in preventing local recurrences (LR) among patients with low-risk, pathologic stage I MCC based on the location of the primary tumors: head/neck (HN) versus non-HN sites., Methods and Materials: One hundred forty-seven patients with MCC were identified that had "low risk" disease (pathologic T1 primary tumor, negative microscopic margins, negative pathologic node status, no immunosuppression or prior systemic therapy). LR was defined as tumor recurrence within 2 cm of the primary surgical bed, and its frequency was estimated with the cumulative incidence method., Results: Seventy-nine patients received PORT (30 HN, 49 non-HN) with a median dose of 50 Gy (range, 8-64 Gy) and 68 patients were treated with surgery alone (30 HN, 38 non-HN). Overall, PORT was associated with a decreased risk of LR (5-year rate: 0% vs 9.5%; P  = .004) with 6 LRs observed in the surgery alone group. Although the addition of PORT significantly reduced LR rates among patients with HN MCC (0% vs. 21%; P  = .034), no LRs were observed in patients with non-HN MCC managed with surgery alone. There was no significant difference in MCC-specific survival comparing HN versus non-HN groups, with or without PORT., Conclusions: For low-risk, pathologic stage I MCC of the extremities and trunk, excellent local control rates were achieved with surgery, and PORT is not indicated. However, PORT was associated with a significant reduction in LRs among low-risk MCC of the HN., Competing Interests: Peter H. Goff reports research funding from Gilead Sciences, Inc, the Conquer Cancer Foundation of the American Society of Clinical Oncology, and the RSNA R&E Foundation not directly related to this work. Daniel S. Hippe reports research grants from GE Health care, Philips Health care, Canon Medical Systems USA, and Siemens Healthineers. Paul Nghiem reports research funding and personal fees from EMD-Serono and Merck & Co. All research funding and personal fees are unrelated to the submitted work., (© 2023 The Authors.)

Purpose: Coronary stents reduce IVBT radiation dose with a single layer by 10-30%. However, the impact of multiple stent layers and stent expansion remains unexplored. Individualized dose adjustments considering variations in stent layers and expansion could improve radiation delivery effectiveness., Methods: EGSnrc was used to compute the delivered vessel wall dose in various IVBT scenarios. Stent effects were modeled for the stent density of 25%, 50%, and 75% with 1, 2, and 3 layers respectively. Doses were calculated at 1.75 to 5.00 mm away from the source center, normalized to 100% at 2 mm., Results: Dose fall-off increased with increasing stent density. With a single layer, the dose at 2 mm from source fell from 100% of prescription to 92%, 83% and 73% at 25%, 50% and 75% density, respectively. The computed dose to points with increasing radial distance from the source decreased progressively with increasing stent layers. With three layers, at 75% stent density, the dose at 2 mm from source center fell to 38%., Conclusions: A schema for image-guided IVBT dose adjustment is described. While it would be an improvement over current standard of care, myriad factors remain to be addressed in a comprehensive effort to optimize IVBT., (Copyright © 2023 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: Little is known regarding associations between peripheral blood biomarkers (PBBMs) and survival, response, and toxicity in recurrent/metastatic head and neck squamous cell carcinomas (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs)., Methods: In this single-institution retrospective cohort study, a dataset of patients with R/M HNSCC treated with ICIs between 08/2012-03/2021 was established, including demographic and clinicopathologic characteristics. Pretreatment PBBMs were collected and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv5, objective response (ORR) by RECIST 1.1, overall survival (OS), and progression-free survival (PFS). Multivariable models for each outcome were created using elastic net variable selection., Results: Our study included 186 patients, with 51 (27%) demonstrating complete or partial response to immunotherapy. Multivariable models adjusted for ECOG performance status (PS), p16, and smoking demonstrated that pretreatment higher LDH and absolute neutrophils, as well as lower percent lymphocytes correlated with worse OS and PFS. Higher LDH and lower % lymphocytes also correlated with worse ORR., Conclusions: In the largest study to date examining PBBMs in ICI-treated R/M HNSCCs, our variable selection method revealed PBBMs prognostic for survival and response to immunotherapy. These biomarkers warrant further investigation in a prospective study along with validation with CPS biomarker., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: None disclosed.

Purpose: Our goal is to develop a novel cobalt-compensator-based IMRT device for low- and middle-income countries that is reliable and cost-effective while delivering treatment plans of equal quality to those from linac-MLC devices. The present study examines the quality of treatment plans using this device., Methods: A commercial treatment planning system (TPS; RayStation v.8B) was commissioned for this device using Monte Carlo simulations from the Geant4 toolkit. Patient-specific compensators were created as regions-of-interest. Thirty clinical head & neck cases were planned and compared to clinical plans with a 6MV linac using IMRT. The mock head and neck plan from TG-119 was used for further validation., Results: PTV objectives were achieved in all 30 plans with PTV V95% >95 %. OAR sparing was similar to clinical plans. There were 14 cases where OAR dose limits exceeded the recommended QUANTEC limits in the clinical plan in order to achieve target coverage. OAR sparing was better in the cobalt compensator plan in 8 cases and worse in 3 cases, in the latter cases exceeding the clinical plan doses by an average of 8.22 % (0.0 %-13.5 %). Average field-by-field gamma pass-rate were 93.7 % (2 %/2mm). Estimated treatment times using the Co-60 compensator device were 1 min 27 s vs 1 min 2 s for the clinical system., Conclusion: This system is the first of its kind to allow for IMRT with a Co-60 device. Data here suggests that the delivery meets plan quality criteria while maintaining short treatment times which may offer a sustainable and cost-low option for IMRT on the global scale., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background: Associations between peripheral blood biomarkers and oncologic outcomes were explored in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HN) and salivary gland cancer (SGC) treated with pembrolizumab and vorinostat on a phase II trial (NCT02538510)., Experimental Design: Twenty-five HN and 25 SGCs were treated with pembrolizumab and vorinostat. Baseline peripheral blood was available in 21 HN and 20 SGCs and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv4, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS)., Results: Higher pretreatment neutrophil-to-lymphocyte ratio (NLR) and neutrophils, as well as lower pretreatment lymphocytes and T helper cells correlated with worse OS and PFS. Higher NLR further predicted increased rates of G ≥ 3AEs. No correlations with ORR were observed., Conclusions: In a prospectively evaluated cohort of HN and SGCs treated with pembrolizumab and vorinostat, we observed novel associations between peripheral blood biomarkers and oncologic outcomes and toxicities., (© 2022 Wiley Periodicals LLC.)

Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin cancer, has a high rate (20%) of distant metastasis. Within a prospective registry of 582 patients with metastatic MCC (mMCC) diagnosed between 2003-2021, we identified 9 (1.5%) patients who developed cardiac metastatic MCC (mMCC). We compared overall survival (OS) between patients with cardiac and non-cardiac metastases in a matched case-control study. Cardiac metastasis was a late event (median 925 days from initial MCC diagnosis). The right heart was predominantly involved (8 of 9; 89%). Among 7 patients treated with immunotherapy, 6 achieved a complete or partial response of the cardiac lesion. Among these 6 responders, 5 received concurrent cardiac radiotherapy (median 20 Gray) with immunotherapy; 4 of 5 did not have local disease progression or recurrence in the treated cardiac lesion. One-year OS was 44%, which was not significantly different from non-cardiac mMCC patients (45%, p = 0.96). Though it occurs relatively late in the disease course, cardiac mMCC responded to immunotherapy and/or radiotherapy and was not associated with worse prognosis compared to mMCC at other anatomic sites. These results are timely as cardiac mMCC may be increasingly encountered in the era of immunotherapy as patients with metastatic MCC live longer.

Introduction: One strategy to improve the effectiveness of intravascular brachytherapy (IVBT) is to study its failures. Previous investigations described mostly discrete, focal recurrences, typically at the proximal or distal edges of the irradiated segment after plain angioplasty or bare metal stents. We reviewed failure patterns of 30 unselected drug-eluting stent (DES) patients who had follow-up angiograms for recurrence within their IVBT-treated vessel., Methods: Records of 53 unselected IVBT patients treated between 2016 and 2021 were reviewed. Thirty of the 53 patients had at least one subsequent percutaneous intervention (PCI) for in-stent restenosis (ISR) after IVBT. Angiographic findings of those 30 patients with ISR within their previously irradiated vessel are reported here., Results: Of the 30 patients, 21 (70%) developed recurrent ISR within the irradiated segment. Six of the 21 patients who failed within the irradiated segment also experienced ISR proximal or distal to the irradiated segment. Only 15 patients (50%) failed exclusively within the irradiated segment. In nine patients (30%), restenosis occurred proximally and/or distally to the irradiated segment, but not inside of the irradiated segment itself., Conclusions: We have shown here that 50% of failures after coronary IVBT for DES ISR occur exclusively within the irradiated segment. An additional 20% of patients had failure within and outside of the irradiated segment. These percentages suggest that a higher radiation dose might improve the long-term patency rates, a conclusion that should be tempered by the lack of universal follow-up., (© 2022 Wiley Periodicals LLC.)

Background: Anti-PD1 checkpoint inhibitors (ICI) represent an established standard-of-care for patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC). Landmark studies excluded patients with ECOG performance status (PS) ≥2; the benefit of ICI in this population is therefore unknown., Methods: We retrospectively reviewed RMHNSCC patients who received 1+ dose of ICI at our institution between 2013 and 2019. Demographic and clinical data were obtained; the latter included objective response (ORR), toxicity, and any unplanned hospitalization (UH). Associations were explored using uni- and multivariate analysis. Overall survival (OS) was estimated using a Cox proportional hazards model; ORR, toxicity, and UH were evaluated with logistic regression., Results: Of the 152 patients, 29 (19%) had an ECOG PS ≥2. Sixty-six (44%) experienced toxicity; 54 (36%) had a UH. A multivariate model for OS containing PS, smoking status, and HPV status demonstrated a strong association between ECOG ≥2 and shorter OS (p < 0.001; HR = 3.30, CI = 2.01-5.41). An association between OS and former (vs. never) smoking was also seen (p < 0.001; HR = 2.17, CI = 1.41-3.35); current smoking did not reach statistical significance. On univariate analysis, poor PS was associated with inferior ORR (p = 0.03; OR = 0.25, CI = 0.06-0.77) and increased UH (p = 0.04; OR = 2.43, CI = 1.05-5.71). There was no significant association between toxicity and any patient characteristic., Conclusions: We observed inferior OS, ORR, and rates of UH among ICI-treated RMHNSCC patients with ECOG 2/3. Our findings help frame discussion of therapeutic options in this poor-risk population., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Despite reduction of xerostomia with intensity-modulated compared to conformal X-ray radiotherapy, radiation-induced dental complications continue to occur. Proton therapy is promising in head and neck cancers to further reduce radiation-induced side-effects, but the optimal dental management has not been defined., Material and Methods: Dental management before proton therapy was assessed compared to intensity-modulated radiotherapy based on a bicentric experience, a literature review and illustrative cases., Results: Preserved teeth frequently contain metallic dental restorations (amalgams, crowns, implants). Metals blur CT images, introducing errors in tumour and organ contour during radiotherapy planning. Due to their physical interactions with matter, protons are more sensitive than photons to tissue composition. The composition of restorative materials is rarely documented during radiotherapy planning, introducing dose errors. Manual artefact recontouring, metal artefact-reduction CT algorithms, dual or multi-energy CT and appropriate dose calculation algorithms insufficiently compensate for contour and dose errors during proton therapy. Physical uncertainties may be associated with lower tumour control probability and more side-effects after proton therapy. Metal-induced errors should be quantified and removal of metal restorations discussed on a case by case basis between dental care specialists, radiation oncologists and physicists. Metallic amalgams can be replaced with water-equivalent materials and crowns temporarily removed depending on rehabilitation potential, dental condition and cost. Implants might contraindicate proton therapy if they are in the proton beam path., Conclusion: Metallic restorations may more severely affect proton than photon radiotherapy quality. Personalized dental care prior to proton therapy requires multidisciplinary assessment of metal-induced errors before choice of conservation/removal of dental metals and optimal radiotherapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations stratifies patients with head and neck squamous cell carcinoma (HNSCC) bearing TP53 missense mutations as high-risk, associated with poor outcomes, or low-risk, with similar outcomes as TP53 wild-type, and has been validated as a reliable prognostic marker. We performed this study to further validate prior findings demonstrating that EAp53 is a prognostic marker for patients with locally advanced HNSCC and explored its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy., Methods and Materials: Eighty-one resection samples from patients treated surgically for stage III or IV human papillomavirus-negative HNSCC with high-risk pathologic features, who received either radiation therapy + cetuximab + cisplatin (cisplatin) or radiation therapy + cetuximab + docetaxel (docetaxel) as adjuvant treatment in a phase 2 study were subjected to TP53 targeted sequencing and EAp53 scoring to correlate with clinical outcomes. Due to the limited sample size, patients were combined into 2 EAp53 groups: (1) wild-type or low-risk; and (2) high-risk or other., Results: At a median follow-up of 9.8 years, there was a significant interaction between EAp53 group and treatment for overall survival ( P  = .008), disease-free survival ( P  = .05), and distant metastasis (DM; P  = .004). In wild-type or low-risk group, the docetaxel arm showed significantly better overall survival (hazard ratio [HR] 0.11, [0.03-0.36]), disease-free survival (HR 0.24, [0.09-0.61]), and less DM (HR 0.04, [0.01-0.31]) than the cisplatin arm. In high-risk or other group, differences between treatments were not statistically significant., Conclusions: The docetaxel arm was associated with better survival than the cisplatin arm for patients with wild-type or low-risk EAp53. These benefits appear to be largely driven by a reduction in DM., (© 2022 NRG Oncology.)

Background/Objective: End-of-life health care utilization (EOLHCU) is largely uncharacterized among patients with recurrent/metastatic head and neck squamous cell carcinomas (RMHNSCC), particularly now that immune checkpoint inhibitors (ICI) have been introduced to the treatment landscape. We examined this in a single-institution, retrospective study. Design/Settings: We utilized a database of deceased, ICI-treated RMHNSCC patients to obtain demographic and EOLHCU data, the latter of which included advanced care plan documentation (ACPD) and systemic therapy or emergency room (ER)/hospital/intensive care unit (ICU) admission within 30 days of death (DOD). This was compared with a cohort of deceased thoracic malignancy (TM) patients in an exploratory analysis. Multivariate analysis was performed to examine for association between patient factors (such as age, Eastern Cooperative Oncology Group (ECOG) performance status, or smoking status) and overall survival (OS); associations between the said patient factors and EOLHCU were also evaluated. This study was conducted at an academic, tertiary center in the United States. Results: The RMHNSCC patients ( n  = 74) were more likely to have ACPD ( p  < 0.01), an emergency department visit ( p  < 0.01), and/or hospital admission ( p  < 0.01) within 30 DOD relative to the TM group. There was no difference in ICU admissions, ICU deaths, or systemic therapy at end of life (EOL). The OS declined in association with ECOG performance status (PS) and smoking. No association was observed between patient factors and any EOLHCU metric. Conclusions: At our center, patients with ICI-treated RMHNSCC have higher rates of both ACPD and EOLHCU, suggesting high symptom burden and representing opportunities for further study into supportive care augmentation.

Objectives: Timely administration of postoperative radiation therapy (PORT) impacts oncologic outcomes in resected squamous cell carcinomas of the head and neck. Salivary gland cancers (SGCs) are uncommon, and timing of PORT has not been extensively explored. We aimed to determine if the interval between surgery and PORT impacts outcomes in SGCs., Materials and Methods: This is a retrospective study of patients with SGCs who underwent curative intent surgical resection followed by adjuvant PORT. Locoregional recurrence free survival (LRFS), disease free survival (DFS), and overall survival (OS) were estimated using the Kaplan Meier method. A multivariate analysis explored the association between demographics, tumor characteristics, and PORT timing with oncologic outcomes using a stepwise Cox proportional hazards model., Results: 180 eligible patients were identified. The median time to PORT start was 61 (range 8-121) days. 169 (93.5%) of patients received neutron radiation. With a median follow up of 8.2 years in surviving patients, the 10-year OS and LRFS estimates were 61% and 53%. In a multivariate analysis, nodal involvement, histologic grade, and age at diagnosis were associated with OS, while nodal involvement, tumor size, and age at diagnosis were associated with LRFS and DFS. Time to PORT start or completion was not statistically associated with survival outcomes., Conclusion: SGC patients who underwent surgery in our tertiary institution received PORT within a median of 61 days after surgery. With long term follow up, PORT timing in this retrospective series was not associated with worse oncologic outcomes, and support timely administration of PORT., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Coronary artery disease leads to stenosis of the major cardiac vessels, resulting in ischemia and infarction. Percutaneous intervention (PCI) with balloon angioplasty can re-open stenosed vessels. Drug eluting stents (DES) and intravascular brachytherapy (IVBT) and drug-coated balloons (DCBs) are proven to decrease the likelihood of another restenosis after PCI, but neither is completely effective. Due to the limited long-term effectiveness of IVBT or DCB used separately for salvage PCI, we combined the two in some poor prognosis patients., Methods: Combined IVBT+DCB was intended for a total of 36 patients from 2015-2020. PCI with some combination of ballooning, laser and directional/rotational atherectomy was used to maximally open the stenotic region prior to IVBT+DCB. Beta-radiation brachytherapy for all patients was done with a Novoste Beta-Cath. Lutonix 4.0 x 40 mm paclitaxel-coated balloons (Bard, Murray Hill, NJ) were employed., Results: Overall survival at two years was 88%. Nine patients had follow-up angiograms, all for cardiac symptoms. Time from IVBT+DCB to follow-up angiography ranged from 4 to 33 months. The average months PCI-free interval before brachy therapy was 11.1 mos (95% CI 1.03-23.25) versus 23.3 mos after VBT (23.3 95% CI 12.3-32.3). The mean difference was 11.2 mos (95% CI 1.06-21.4, p < 0.031). None of the follow-up angiographic procedures displayed evidence of what could be interpreted as radiation damage., Conclusions: In this uncontrolled series, IVBT plus DCB appeared to lengthen the ISR-free interval relative to what had been achieved prior to the combined intervention. We view these results as mildly encouraging, worthy of further study., (Published by Elsevier Inc.)

Purpose: Neutron therapy is a high linear energy transfer modality that is useful for the treatment of radioresistant head and neck (H&N) cancers. It has been limited to 3-dimensioanal conformal-based fast-neutron therapy (3DCNT), but recent technical advances have enabled the clinical implementation of intensity-modulated neutron therapy (IMNT). This study evaluated the comparative dosimetry of IMNT and 3DCNT plans for the treatment of H&N cancers., Materials and Methods: Seven H&N IMNT plans were retrospectively created for patients previously treated with 3DCNT at the University of Washington (Seattle). A custom RayStation model with neutron-specific scattering kernels was used for inverse planning. Organ-at-risk (OAR) objectives from the original 3DCNT plan were initially used and were then systematically reduced to investigate the feasibility of improving a therapeutic ratio, defined as the ratio of the mean tumor to OAR dose. The IMNT and 3DCNT plan quality was evaluated using the therapeutic ratio, isodose contours, and dose volume histograms., Results: When compared with the 3DCNT plans, IMNT reduces the OAR dose for the equivalent tumor coverage. Moreover, IMNT is most advantageous for OARs in close spatial proximity to the target. For the 7 patients with H&N cancers examined, the therapeutic ratio for IMNT increased by an average of 56% when compared with the 3DCNT. The maximum OAR dose was reduced by an average of 20.5% and 20.7% for the spinal cord and temporal lobe, respectively. The mean dose to the larynx decreased by an average of 80%., Conclusion: The IMNT significantly decreases the OAR doses compared with 3DCNT and provides comparable tumor coverage. Improvements in the therapeutic ratio with IMNT are especially significant for dose-limiting OARs near tumor targets. Moreover, IMNT provides superior sparing of healthy tissues and creates significant new opportunities to improve the care of patients with H&N cancers treated with neutron therapy., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Introduction: Head and neck reconstructive surgery using a flap is increasingly common. Best practices and outcomes for postoperative radiotherapy (poRT) with flaps have not been specified. We aimed to provide consensus recommendations to assist clinical decision-making highlighting areas of uncertainty in the presence of flaps., Material and Methods: Radiation, medical, and surgical oncologists were assembled from GORTEC and internationally with the Head and Neck Cancer International Group (HNCIG). The consensus-building approach covered 59 topics across four domains: (1) identification of postoperative tissue changes on imaging for flap delineation, (2) understanding of tumor relapse risks and target volume definitions, (3) functional radiation-induced deterioration, (4) feasibility of flap avoidance., Results: Across the 4 domains, international consensus (median score ≥ 7/9) was achieved only for functional deterioration (73.3%); other consensus rates were 55.6% for poRT avoidance of flap structures, 41.2% for flap definition and 11.1% for tumor spread patterns. Radiation-induced flap fibrosis or atrophy and their functional impact was well recognized while flap necrosis was not, suggesting dose-volume adaptation for the former. Flap avoidance was recommended to minimize bone flap osteoradionecrosis but not soft-tissue toxicity. The need for identification (CT planning, fiducials, accurate operative report) and targeting of the junction area at risk between native tissues and flap was well recognized. Experts variably considered flaps as prone to tumor dissemination or not. Discrepancies in rating of 11 items among international reviewing participants are shown., Conclusion: International GORTEC and HNCIG-endorsed recommendations were generated for the management of flaps in head and neck radiotherapy. Considerable knowledge gaps hinder further consensus, in particular with respect to tumor spread patterns., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Radiation therapy is a standard modality in the treatment for cancers of the head and neck, but is associated with significant short- and long-term side effects. Proton therapy, with its unique physical characteristics, can deliver less dose to normal tissues, resulting in fewer side effects. Proton therapy is currently being used for the treatment of head and neck cancer, with increasing clinical evidence supporting its use. However, barriers to wider adoption include access, cost, and the need for higher-level evidence., Methods: The clinical evidence for the use of proton therapy in the treatment of head and neck cancer are reviewed here, including indications, advantages, and challenges., Results: The Particle Therapy Cooperative Group Head and Neck Subcommittee task group provides consensus guidelines for the use of proton therapy for head and neck cancer., Conclusion: This report can be used as a guide for clinical use, to understand clinical trials, and to inform future research efforts., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. The authors have no other relevant conflicts of interest to disclose., (©Copyright 2021 The Author(s) 2020.)

Background and objective  Fast neutron radiotherapy (NRT) is a high linear energy transfer (LET) particle therapy that offers a local control (LC) advantage over low-LET X-rays in the treatment of advanced and unresectable salivary gland malignancies. However, in tumors approximating the base of skull (BOS), target volumes may be underdosed to minimize toxicity to the central nervous system (CNS). In this setting, a proton beam boost to the underdosed part of the tumor may improve LC. We report our early experience with a hybrid neutron-proton approach in patients with BOS involvement. Materials and methods We retrospectively reviewed 29 patients with locally advanced and unresectable salivary gland tumors involving the BOS between 2014-2018. The median age of the patients was 56 years, with the majority of them having adenoid cystic carcinomas (ACC) (79%) with advanced T4a/b disease (86%), pathologic perineural invasion (PNI) (55.2%), and orbital invasion (34.5%). Five patients (17.2%) were cases of re-irradiation. Surgical resection was attempted in 15 patients (51.7%), of which none achieved negative margins. The median neutron dose was 18.4 neutron Gray (nGy) with a sequential proton boost (PB) with a median dose of 25 Gy [relative biological effectiveness (RBE)] (range: 16-45 Gy). Toxicity was graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Descriptive statistics and the Kaplan-Meier method were used. Results At a median follow-up of 18.9 months [interquartile range (IQR): 6.1-32.5], the entire cohort's overall survival (OS) was 93.1%, progression-free survival (PFS) was 79.3%, and LC was 89.7%. Among patients who were not re-irradiated (n=24), the most commonly recorded acute grade 3 toxicities were mucositis (50%) and dermatitis (37.5%). There was no documented acute grade 4/5 events. Late grade 3/4 events included trismus (n=1), hearing loss (n=2), visual loss (n=6), and bone necrosis (n=1). There were no reported late grade 5 events in de novo patients. Conclusion In this challenging cohort with a poor prognosis, early outcomes for a hybrid neutron-proton approach were found to be promising. Further studies involving longer follow-ups with a larger cohort of patients are required to validate our findings., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Aljabab et al.)

Purpose: Advances in radiotherapy have improved tumor control and reduced toxicity in the management of nasopharyngeal carcinoma (NPC). Local failure remains a problem for some patients with advanced primary tumors, and toxicities are significant given the large treatment volume and tumor proximity to critical structures, even with modern photon-based radiotherapy. Proton therapy has unique dosimetric advantages, and recent technological advances now allow delivery of intensity-modulated proton therapy (IMPT), which can potentially improve the therapeutic ratio in NPC. We report our 2-year clinical outcomes with IMPT for NPC., Materials and Methods: We retrospectively reviewed treatment records of patients with NPC treated with IMPT at our center. Demographics, dosimetry, tumor response, local regional control (LRC), distant metastasis, overall survival, and acute and late toxicity outcomes were reviewed. Analyses were performed with descriptive statistics and Kaplan-Meier method. Toxicity was graded per Common Terminology Criteria for Adverse Events (version 4.0)., Results: Twenty-six patients were treated from 2015 to 2020. Median age was 48 years (range, 19-73 years), 62% (n = 16) had T3-T4 disease, 92% (n = 24) were node positive, 92% (n = 24) had stage III-IV disease, and 69% (n = 18) had positive results for Epstein-Barr virus. Dose-painted pencil-beam IMPT was used. Most patients (85%; 22 of 26) were treated with 70 Gy(RBE) in 33 fractions once daily; 4 (15%) underwent hyperfractionated accelerated treatment twice daily. All received concurrent cisplatin chemotherapy; 7 (27%) also received induction chemotherapy. All patients (100%) completed the planned radiotherapy, and no acute or late grade 4 or 5 toxicities were observed. At median follow-up of 25 months (range, 4-60), there were 2 local regional failures (8%) and 3 distant metastases (12%). The Kaplan-Meier 2-year LRC, freedom from distant metastasis, and overall survival were 92%, 87%, and 85% respectively., Conclusion: IMPT is feasible in locally advanced NPC with early outcomes demonstrating excellent LRC and favorable toxicity profile. Our data add to the growing body of evidence supporting the clinical use of IMPT for NPC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to disclose., (©Copyright 2021 The Author(s).)