Quad-shot-immunotherapy: quad-shot radiotherapy with pembrolizumab for advanced/recurrent head and neck cancer.

Effective treatments for advanced/recurrent head and neck squamous-cell carcinoma are limited. For cases not curable by conventional local therapies, the immune checkpoint inhibitor pembrolizumab shows modest response rates. Quad-shot, a hypofractionated palliative radiotherapy regimen (14.8 Gy in four twice-daily fractions), can provide symptomatic relief, contributes to local control and may potentiate the effects of immune checkpoint inhibitors. In this study, 15 patients with advanced/recurrent head and neck squamous-cell carcinoma will be treated with pembrolizumab combined with up to three administrations of quad-shot before cycles four, eight and 13. Outcomes include disease response, survival and treatment toxicity. Correlative multiomics analysis of blood and saliva will identify molecular biomarkers of response to immune checkpoint inhibitor and the immune-related impact of quad-shot. Clinical trial registration: This study (WFBCCC 60320) is registered on NCT04454489 (ClinicalTrials.gov).

Advanced and recurrent head and neck cancers are difficult to treat. Most patients receive systemic therapies, such as chemotherapy or immunotherapy, with modest rates of cancer control. We aim to test the effectiveness of an immunotherapy drug called pembrolizumab in combination with a type of low-dose radiation therapy called quad-shot. Patients will receive pembrolizumab every 3 weeks and will be treated with one to three low-dose radiation therapy courses targeted at their cancer in the head and neck approximately every 12 weeks. We plan to measure how well the cancer responds to treatment, how long this response lasts, how long patients survive and treatment side effects.

Survival and Swallowing Function after Primary Radiotherapy versus Transoral Robotic Surgery for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

INTRODUCTION: The aim of this study was to investigate the impact of primary transoral robotic surgery (TORS) versus radiotherapy (RT) on progression-free survival (PFS), overall survival (OS), and 1-year swallowing function for patients with early-stage HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Patients with stage I-II (AJCC 8th Ed.) HPV-associated OPSCC treated with TORS followed by risk-adapted adjuvant therapy or (chemo)radiotherapy between 2014 and 2019 were identified. PFS, OS, and swallowing outcomes including gastrostomy tube (GT) use/dependence, and Functional Oral Intake Scale (FOIS) change over 1 year were compared. RESULTS: One hundred sixty-seven patients were analyzed: 116 treated with TORS with or without adjuvant RT and 51 treated with RT (50 chemoRT). The RT group had more advanced tumor/nodal stage, higher comorbidity, and higher rates of concurrent chemotherapy. There were no differences in 3-year PFS (88% TORS vs. 75% RT) or OS (90% vs. 81%) between groups, which persisted after adjusting for stage, age, and comorbidity. GT use/dependence rates were higher in the RT group. Mean (SD) FOIS scores in the TORS group were 6.9 (0.4) at baseline and 6.4 (1.0) at 1 year, compared with 6.7 (0.6) and 5.6 (1.7) for the RT group. Only clinical nodal stage was found to be significantly associated with FOIS change from baseline to 1 year. CONCLUSION: There were no differences in PFS or OS between patients treated with primary TORS or RT for early-stage HPV-associated OPSCC. Clinical N2 status is associated with FOIS change at 1 year and may be the major factor affecting long-term swallowing function, irrespective of primary treatment modality.

Timing of radiotherapy and chemotherapy start for patients treated with definitive concurrent chemoradiation for head and neck cancer.

BACKGROUND: The ideal timing for the initiation of chemotherapy and radiation therapy (RT) in the use of definitive chemoradiation (CRT) for patients with head and neck cancer is not well established. We sought to evaluate the impact of the timing of initiating these two modalities on clinical outcomes. MATERIALS AND METHODS: Patients with squamous cell carcinoma of the head and neck who were treated using definitive chemoradiation from 2012 to 2018 were identified. Patients undergoing re-irradiation, post-op CRT, had recurrent or second primaries, or ECOG 3-4 were excluded. Outcomes including locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated and compared between subgroups of the cohort based on the timing in which chemotherapy or RT were initiated: chemotherapy first, same day start, within 24 h, or start on Monday/Tuesday/Wednesday. RESULTS: A total of 131 patients were included for analysis consisting of oropharynx (64%), larynx (22.9%), nasopharynx (6.9%), hypopharynx (3.1%), oral cavity (1.5%), and unknown primary (1.5%). Chemotherapy was administered as bolus cisplatin every 3 weeks in 40% of patients and weekly cisplatin in 60% with a median cumulative dose of 240 mg/m2. In the multivariable analysis (MVA), starting chemotherapy before RT was associated with improved LRC (HR 0.33, 95% CI: 0.11-0.99). Three-year LRC for patients starting chemotherapy first was 90.9% compared to 78.2% in those starting RT first. In the MVA, cisplatin regimen and cumulative cisplatin dose were associated with improved OS, while no factors were significantly associated with DC or PFS. CONCLUSION: Starting chemotherapy prior to radiation therapy improves LRC, but did not impact DC, PFS, or OS. Clinical outcomes were not different when stratifying by the other differences in the timing of initiating chemotherapy or RT.

Stereotactic body radiotherapy for synchronous early stage non-small cell lung cancer.

INTRODUCTION: In patients with non-small cell lung cancer (NSCLC) who present with multiple pulmonary nodules, it is often difficult to distinguish metastatic disease from synchronous primary lung cancers (SPLC). We sought to evaluate clinical outcomes after stereotactic body radiotherapy (SBRT) alone to synchronous primary lesions. MATERIAL AND METHODS: Patients with synchronous AJCC 8th Edition Stage IA-IIA NSCLC and treated with stereotactic body radiation therapy (SBRT) to all lesions between 2009-2018 were reviewed. SPLC was defined as patients having received two courses of SBRT within 180 days for treatment of separate early stage tumors. In total, 36 patients with 73 lesions were included. Overall survival (OS), progression-free survival (PFS), cumulative incidence of local failure (LF), and regional/distant failure (R/DF) were estimated and compared with a control cohort of solitary early stage NSCLC patients. RESULTS: Median PFS was 38.8 months (95% CI 14.3-not reached [NR]); 3-year PFS rates were 50.6% (35.6-72.1). Median OS was 45.9 months (95% CI: 35.9-NR); 3-year OS was 63.0% (47.4-83.8). Three-year cumulative incidence of LF and R/DF was 6.6% (3.7-13.9) and 35.7% (19.3-52.1), respectively. Patients with SPLC were compared to a control group (n = 272) of patients treated for a solitary early stage NSCLC. There was no statistically significant difference in PFS (p = .91) or OS (p = .43). Evaluation of the patterns of failure showed a trend for worse cumulative incidence of R/DF in SPLC patients as compared to solitary early stage NSCLC (p = .06). CONCLUSION: SBRT alone to multiple lung tumors with SPLC results in comparable PFS, OS, and LF rates to a cohort of patients treated for solitary early stage NSCLC. Those with SPLC had non-significantly higher R/DF. Patients with SPLC should be followed closely for failure and possible salvage therapy.

Impact of brain metastasis velocity on neurologic death for brain metastasis patients experiencing distant brain failure after initial stereotactic radiosurgery.

PURPOSE: Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS). METHODS: From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment. RESULTS: Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p < 0.01), and 31% vs 48% (p < 0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01). CONCLUSION: Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.

Initial brain metastasis velocity: does the rate at which cancers first seed the brain affect outcomes?

PURPOSE/OBJECTIVE(S): Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactic radiosurgery (SRS). A limitation in the application of BMV is it cannot be applied until time of first BM failure after SRS. We developed initial BM velocity (iBMV), a new metric that accounts for the number of BM at first SRS and the time since initial cancer diagnosis. MATERIALS/METHODS: We reviewed patients with BM treated at our institution with upfront SRS without WBRT. iBMV was calculated as the number of BM at initial SRS divided by time (years) from initial cancer diagnosis to first SRS. We performed a linear regression to correlate BMV as a continuous variable and with low, intermediate, and high BMV risk groups. Kaplan-Meier estimation of OS was calculated from time of first SRS to death. iBMV was not calculated for patients who presented with BM at initial cancer diagnosis. RESULTS: 994 patients were treated with upfront SRS without WBRT between 2000 and 2017. Median OS was 8.5 mos. 595 (60%) patients developed BM after cancer diagnosis and median time to first SRS from time of initial diagnosis was 2.2 years. Median iBMV was 0.79 BM/year. iBMV correlated with BMV (ß = 1.57 p = 0.021) and independently predicted for mortality [Cox proportional hazard ratio (HR) 1.11, p = 0.036] after accounting for histology, number of initial brain metastases (HR 1.03, p = 0.32), time from cancer diagnosis to SRS (HR 0.98, p = 0.157) in a multivariate model. CONCLUSION: iBMV correlates with BMV and OS. With further validation, iBMV could serve as a metric to risk stratify patients for WBRT or SRS at time of first BM presentation.

Prognostication methods for patients treated with palliative radiotherapy: a narrative review.

BACKGROUND AND OBJECTIVE: Palliative radiotherapy (PRT) practice patterns among radiation oncologists are heterogeneous. Appropriate selection of PRT regimen must balance symptom/disease control with patient quality of life. The aim of this review is to summarize prognostic scoring systems for PRT in order to help guide clinical decision making and selection of appropriate PRT regimens. METHODS: A PubMed search was conducted for articles published between 01/2000 and 07/2023. Standardized search terms including "palliative", "radiotherapy" and "survival" were used. Only English-language, peer-reviewed articles that presented a prognostic scoring system of PRT were included in this review. KEY CONTENT AND FINDINGS: In this study, we review the published literature on prognostic scoring systems for patients treated with PRT. Multiple models have been developed and each pertains to a specific patient population or primary tumor type. While they are specific to a particular patient population, all models incorporate patients' clinical characteristics such as primary site, performance status, location of metastatic disease, and indication for PRT to estimate overall survival (OS) after PRT. For each model, the salient points of the scoring system are described. Based on survival estimates from each prognostic system, different PRT regimens are recommended. CONCLUSIONS: PRT scoring systems can be used to help clinicians assess patient prognosis. With the information provided by the included studies, radiation oncologists will be better prepared to formulate an optimal, individualized treatment plan for patients to be treated with PRT.

Histology-driven hypofractionated radiation therapy schemes for early-stage lung adenocarcinoma and squamous cell carcinoma.

BACKGROUND AND PURPOSE: Histology was found to be an important prognostic factor for local tumor control probability (TCP) after stereotactic body radiotherapy (SBRT) of early-stage non-small-cell lung cancer (NSCLC). A histology-driven SBRT approach has not been explored in routine clinical practice and histology-dependent fractionation schemes remain unknown. Here, we analyzed pooled histologic TCP data as a function of biologically effective dose (BED) to determine histology-driven fractionation schemes for SBRT and hypofractionated radiotherapy of two predominant early-stage NSCLC histologic subtypes adenocarcinoma (ADC) and squamous cell carcinoma (SCC). MATERIAL AND METHODS: The least-χ2 method was used to fit the collected histologic TCP data of 8510 early-stage NSCLC patients to determine parameters for a well-developed radiobiological model per the Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative. RESULTS: A fit to the histologic TCP data yielded independent radiobiological parameter sets for radiotherapy of early-stage lung ADC and SCC. TCP increases steeply with BED and reaches an asymptotic maximal plateau, allowing us to determine model-independent optimal fractionation schemes of least doses in 1-30 fractions to achieve maximal tumor control for early-stage lung ADC and SCC, e.g., 30, 44, 48, and 51 Gy for ADC, and 32, 48, 54, and 58 Gy for SCC in 1, 3, 4, and 5 fractions, respectively. CONCLUSION: We presented the first determination of histology-dependent radiobiological parameters and model-independent histology-driven optimal SBRT and hypofractionated radiation therapy schemes for early-stage lung ADC and SCC. SCC requires substantially higher radiation doses to maximize tumor control than ADC, plausibly attributed to tumor genetic diversity and microenvironment. The determined optimal SBRT schemes agree well with clinical practice for early-stage lung ADC. These proposed optimal fractionation schemes provide first insights for histology-based personalized radiotherapy of two predominant early-stage NSCLC subtypes ADC and SCC, which require further validation with large-scale histologic TCP data.

Clinical outcomes of oropharyngeal squamous cell carcinoma stratified by human papillomavirus subtype: A systematic review and meta-analysis.

PURPOSE: We aim to determine if there is a survival difference between patients with oropharyngeal squamous cell carcinoma (OPSCC) associated with human papillomavirus (HPV) 16 versus HPV-non16 subtypes. PATIENT AND METHODS: Databases were queried for full length, peer-reviewed, English language, articles published between 01/01/1980 and 06/08/2022. Studies reporting clinical outcomes of OPSCC associated with HPV16 and HPV-non16 subtypes with at least 10 patients were included. Primary outcome was the overall survival (OS) of patients with HPV16- versus HPV-non16-associated OPSCC. Secondary outcomes were recurrence-free survival (RFS) and pooled rate of p16 positivity by immunohistochemistry (IHC). RESULTS: A total of 9 studies met inclusion criteria and included 1,310 patients with HPV16 and 219 with HPV-non16 subtypes of OPSCC. The prevalence of HPV-non16 was 14.3 %. The pooled 5-year OS rates for patients with HPV16 and HPV-non16 were 83.4 %(95 % CI 77.8-89.0 %) and 69.3 %(95 % CI 58.5-80.1 %), respectively. OS at 5 years was significantly worse for HPV-non16 subtype, compared to HPV16 (log odds ratio [OR] -0.54, p = 0.008). There was a trend towards worse 5-year RFS with HPV-non16 compared to HPV16 (log OR -0.55, p = 0.063). Patients with HPV-non16 disease were less likely to be p16 positive by IHC (log OR -0.91, p = 0.02). CONCLUSION: Patients with HPV-non16OPSCC may experience worse OS and were less likely to be p16 positive compared to patients with HPV16 disease. While future prospective validation is warranted, routine assessment of both p16 IHC and HPV subtype could be considered prior to pursuing treatment de-escalation for HPV-associated OPSCC.

Randomized Pilot Study of a Keratin-based Topical Cream for Radiation Dermatitis in Breast Cancer Patients.

Purpose: Radiotherapy (RT) is commonly used in the treatment of breast cancer and often, despite advances in fractionated dosing schedules, produces undesirable skin toxicity. The purpose of this study was to evaluate the feasibility of using a keratin-based topical cream, KeraStat® Cream (KC; KeraNetics, Inc., Winston Salem, NC, USA) to manage the symptoms of radiation dermatitis (RD) in breast cancer patients undergoing RT. Materials and Methods: A total of 24 subjects were enrolled on this single-center, randomized, open-label study. Participants were randomly assigned to KC or standard of care (SOC, patient's choice of a variety of readily available creams or moisturizers). Patients were asked to apply the assigned treatment to the irradiated area twice daily, beginning with day 1 of RT, through 30 days post-RT. The primary outcome was compliance of use. Secondary outcomes included safety and tolerability of KC, as well as RD severity assessed using the Radiation Therapy Oncology Group (RTOG) scale and the patient-reported Dermatology Life Quality Index (DLQI). Results: All subjects in the KC group were assessed as compliant with no adverse events. The rate of RTOG Grade 2 RD was lower in the KC group (30.8%) compared to the SOC group (54.5%, P = .408). At the final RT visit, the mean RTOG RD score was lower in the KC group (1.0) versus the SOC group (1.4). Similarly, patient-reported quality of life measured by the DLQI at the end of RT was improved in the KC group (mean 4.25, small effect) versus the SOC group (mean 6.18, moderate effect, P = .412). Conclusions: KC was safe and well tolerated with no adverse events. Though efficacy measures were not powered to draw definitive conclusions, trends and clinical assessments suggest that there is a benefit of using KC compared to SOC for breast cancer patients treated with RT, and a larger powered study for efficacy is warranted. Trial Registry: This clinical trial is registered as NCT03374995 titled KeraStat(R) Cream for Radiation Dermatitis.

Radiotherapy for Advanced Hodgkin Lymphoma with Initial Bulk: A Combined Analysis of Two Randomized Trials.

Purpose: The role of consolidative radiation therapy (RT) in patients with advanced Hodgkin lymphoma with initial bulk is unclear. GITIL/FIL HD0607 and FIL HD0801, 2 randomized controlled trials with similar design and methodologies, did not identify a benefit to consolidative RT after a metabolic complete response to 6 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine. However, their limited sample sizes reduced statistical power to detect a small but clinically meaningful benefit to RT. Methods and Materials: In a secondary analysis of these 2 phase 3 trials, reconstructed patient data were used to compare outcomes for early and complete responders randomized to no RT or RT to the site(s) of initial bulk. Estimates of progression-free survival (PFS) in the intent-to-treat (ITT) and per-protocol (PP) analyses were generated using the combined data and compared between groups using the log-rank test. Results: A total of 412 patients were included in the ITT analysis, and 373 patients were included in the PP analysis. Median age was 30 to 32 years, 42% of patients were stage IIB, and 73% of bulky sites were located in the mediastinum. For the no RT versus RT groups, 5-year ITT PFS estimates were 90.1% versus 90.1%, respectively (P = .81). Five-year PP PFS rates were 90.9% versus 92.9%, respectively (P = .31). There was no observed difference between no RT and RT groups in subgroups according to size of bulky disease: 5 to 7 cm (P = .78), 7 to 10 cm (P = .25), and >10 cm (P = .69). Conclusions: In this combined analysis of 2 randomized phase 3 clinical trials, consolidative RT to initial sites of bulky nodal involvement was not associated with a PFS benefit in patients with advanced Hodgkin lymphoma in metabolic complete response after 2 and 6 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine.

Secretory factors released from high dose radiation-activated osteoclasts increase the expression level of pain-associated neuropeptides in sensory neuronal cultures.

Stereotactic Body Radiation Therapy for lung tumors near the chest wall often causes significant chest wall pain (CWP), negatively impacting patients' quality of life. The mechanisms behind SBRT-induced CWP remain unclear and may involve multiple factors. We investigated the potential crosstalk between radiation-activated osteoclasts and sensory neurons, focusing on osteoclast-derived factors in CWP. Using the murine pre-osteoclast cell line Raw264.7, we induced differentiation with RANKL, followed by 10Gy gamma-irradiation. Conditioned media from these irradiated osteoclasts was used to treat sensory neuronal cultures from mouse dorsal root ganglia. Neuronal cultures were also directly exposed to 10Gy radiation, with and without osteoclast co-culture. Analysis of osteoclast markers and pain-associated neuropeptides was conducted using RT-qPCR and histochemical staining. Osteoclast differentiation and activity were inhibited using Osteoprotegerin and risedronate. Results showed that high-dose radiation significantly increased osteoclast size, resorption pit size, and activity biomarkers. Neurons treated with CM from irradiated osteoclasts showed increased expression of pain-associated neuropeptides CGRP and Substance P, which was mitigated by osteoprotegerin and risedronate. This study suggests that high-dose radiation enhances osteoclast activity, upregulating pain-associated neuropeptides in sensory neurons, and that inhibitors like osteoprotegerin and risedronate may offer therapeutic strategies for managing radiation-induced pain.

Association of Unilateral Radiotherapy With Contralateral Lymph Node Failure Among Patients With Squamous Cell Carcinoma of the Tonsil: A Systematic Review and Meta-analysis.

Importance: Ipsilateral neck radiotherapy (RT) is controversial in some patients with tonsil cancer due to concern for nodal failure within the contralateral nonirradiated neck (hereinafter referred to as contralateral neck failure [CNF]). Objective: To determine the rate of CNF following ipsilateral neck RT in patients with tonsil cancer. Data Sources: Databases including PubMed, Embase, Web of Science, and Cochrane Library were queried for peer-reviewed, English language articles published between January 1, 1980, and December 31, 2021. Study Selection: Studies reporting rates of CNF from at least 20 patients treated with ipsilateral neck RT. Studies were excluded if they lacked full text, reported results from databases or systematic reviews, or did not provide RT details. Data Extraction and Synthesis: Data were extracted following the PRISMA reporting guideline. Study quality was assessed using criteria from a methodological index for nonrandomized studies. Pooled outcomes were estimated using random-effects models. Main Outcomes and Measures: Primary outcome was the pooled rate of CNF following ipsilateral neck RT. Secondary outcomes were the pooled rates of CNF by tumor and nodal staging categories from the 7th edition of the AJCC Cancer Staging Manual and rates of toxic effects. Results: A total of 17 studies (16 retrospective and 1 prospective) including 1487 unique patients were identified. The pooled risk of CNF was 1.9% (95% CI, 1.2%-2.6%). The rate of CNF by tumor (T) category was as follows: 1.3% (95% CI, 0.3%-2.3%) for T1; 3.0% (95% CI, 1.6%-4.4%) for T2; 11.3% (95% CI, 3.3%-19.2%) for T3; and 16.0% (95% CI, -7.8% to 39.8%) for T4. Patients with T3 to T4 tumors had a significantly higher rate of CNF than those with T1 to T2 tumors (11.5% [95% CI, 3.9%-19.1%] vs 1.8% [95% CI, 1.0%-2.6%]; P < .001). The rate of CNF by nodal (N) category was 1.2% (95% CI, 0.1%-2.2%) for N0; 4.8% (95% CI, 2.4%-7.2%) for N1; 3.1% (95% CI, 0.4%-5.8%) for N2a; 3.1% (95% CI, 1.2%-4.9%) for N2b; and 0 (95% CI, not applicable) for N3. Rates of CNF were similar for patients with N2b to N3 and N0 to N2a disease (3.0% [95% CI, 1.2%-4.7%] vs 1.7% [95% CI, 0.6%-2.8%], respectively; P = .07). Compared with bilateral RT, ipsilateral RT was associated with increased risk of CNF (log odds ratio, 1.29 [95% CI, 0.09-2.48]; P = .04). The crude rates of xerostomia of grade 3 or greater and feeding tube use were 0.9% (95% CI, -0.2% to 1.9%) and 13.3% (95% CI, 8.3%-18.3%), respectively. Conclusions and Relevance: In this systematic review and meta-analysis, ipsilateral neck RT was associated with a low rate of CNF in patients with small, lateralized tonsil cancers. Bilateral neck RT was associated with lower risk of CNF compared with ipsilateral neck RT. Patients with tumors of a higher T category were at increased risk for CNF following ipsilateral neck RT, and advanced nodal stage was not associated with CNF. Rates of toxic effects appeared favorable in patients treated with ipsilateral neck RT.

Association of ipsilateral radiation therapy with contralateral lymph node failure in patients with squamous cell carcinoma of the oral cavity: A systematic review and meta-analysis.

BACKGROUND: Ipsilateral neck radiotherapy (INRT) is controversial in some patients with oral cavity cancer due to concern for contralateral neck failure (CNF). METHODS: A systematic review was performed and data were extracted following PRISMA guidelines. Outcomes were the rate of CNF following INRT and the rates of CNF by AJCC 7th ed. tumor and nodal staging. RESULTS: Fifteen studies consisting of 1825 patients were identified. Among the 805 patients treated with INRT, the rate of CNF was 5.7%. Patients with T4 tumors constituted 56% of all CNF cases. The rate of CNF increased by N stage (N0: 1.2%; N1: 3.8%; N2-N3: 17.4%) and was significantly higher for patients with N2-N3 than N0-N1 disease (p < 0.001). DISCUSSION: INRT is associated with an overall low risk of CNF in well-selected patients with N0-N1 disease. Patients with N2-3 and/or T4 disease should receive bilateral RT due to increased risk of CNF following INRT.

Intensity-Modulated Radiation Therapy for Early-Stage Squamous Cell Carcinoma of the Glottic Larynx: A Systematic Review and Meta-Analysis.

PURPOSE: Early-stage squamous cell carcinoma of the glottic larynx is commonly treated with 2-dimensional or 3-dimensional conventional radiation therapy (CRT). Despite its use in other head and neck cancers, intensity-modulated radiation therapy (IMRT) remains controversial in this patient population. METHODS AND MATERIALS: A systematic review was performed by querying 3 databases (Pubmed, Embase, Web of Science) for articles published between December 1, 2000 and September 2, 2022. Included studies reported outcomes in at least 10 patients treated with IMRT for early-stage glottic cancer. Data were extracted and reported following PRISMA standards. Pooled outcomes were estimated using random-effects models. Primary outcome was the rate of local failure (LF) following IMRT. Secondary outcomes included rates of regional failure (RF) following IMRT and rates of LF and RF following CRT. RESULTS: A total of 15 studies (14 retrospective, 1 prospective) consisting of 2083 patients were identified. IMRT was used in 873 patients (64% T1, 28% T2). Multiple treatment (partial larynx, single vocal cord carotid sparing) and image-guided radiation therapy techniques were used. The pooled crude rate of LF was 7.6% (95% confidence inverval [CI], 3.6%-11.5%) and actuarial LF rates at 3 and 5 years were 6.3% (95% CI, 2.2%-10.3%) and 9.0% (95% CI, 4.4%-13.5%), respectively. The pooled crude rate of RF after IMRT was 1.5% (95% CI, 0.5%-2.5%). On metaregression analysis, increased rate of LF was significantly associated with T2 disease (P < .001) and grade 2 to 3 histology (P < .001). Treatment with CRT was reported in 738 patients (76% T1, 22% T2). Among the studies reporting outcomes of both modalities, there was no significant difference in LF (log odds ratio; P = .12) or RF (log odds ratio; P = .58) between IMRT or CRT. CONCLUSIONS: In patients with early-stage glottic cancer, retrospective data suggests local and regional control are similar for patients treated with IMRT and CRT. Additional prospective studies with uniform methods of volume delineation and image guidance are needed to confirm the efficacy of IMRT.

Response and local control in patients treated with low-dose radiotherapy for tumoral mycosis fungoides.

Low-dose radiotherapy (LDRT), defined in this study as 2 fractions of 4 Gy delivered on consecutive days, is an effective option for local palliation of mycosis fungoides (MF), but its efficacy for tumoral lesions (TL) needs investigation. We assessed response and local control (LC) rates for patients treated with LDRT for MF and compared these outcomes between TL and non-TL. A total of 73 lesions in 18 patients treated with LDRT between 2013-2020 were analyzed. Response was defined as complete response (CR), partial response (PR), or no response (NR). In the non-TL versus TL groups, CR was observed in 16.7% v. 4.0%, PR in 81.2% v. 80.0%, NR in 2.1% v. 16.0%, respectively. 2-year LC was 100% for non-TL and 61% for TLs (p < 0.01). LDRT yields excellent response and lesion control for non-TLs and is associated with lower response rates and LC for TLs.

Low-dose radiation therapy yields excellent response and lesion control for non-tumoral lesions.

Palliative Appropriateness Criteria: A Pragmatic Method to Evaluate the Suitability of Palliative Radiotherapy Fractionation.

Purpose: To describe a novel metric to aid clinical decision making between shorter versus longer palliative radiotherapy (PRT) regimens using objective patient factors. Materials and Methods: Patients receiving PRT at a single institution between 2014 and 2018 were reviewed. The time between PRT start and finish was calculated and divided by overall survival (in days from start of PRT) to generate the percent of remaining life (PRL). This value was compared across various clinical factors using the Kruskal-Wallis test. Factors identified with a significance level p < 0.01 were included in a novel Palliative Appropriateness Criteria Score (PACS) and were included in an online risk assessment tool to assist clinicians in patient-specific fractionation decisions. Results: Totally 1027 courses of PRT were analyzed. Median age was 64 years; Eastern Cooperative Oncology Group (ECOG) performance status was 3-4 in 22%. Primary malignancies included were lung (38%), breast (13.8%), prostate (9.3%), and other (39%). The indication for PRT was pain (61%), neurological (21%), or other (18%). Palliative regimens included 199 (19.4%) receiving single fraction, 176 (17.1%) receiving 2-5 fractions, and 652 (63.5%) receiving 10 fractions. Median follow-up was 83 days overall and 437 days for patients alive at last follow-up. Factors significantly associated with increased PRL (and included in the PACS) were male gender, ECOG 3-4, lung or "other" primary diagnosis (vs. breast or prostate), PRT indication (neurological dysfunction vs. pain/other), inpatient status, and extraosseous sites treatment. Death within 30 days was significantly associated with high-risk PACS categorization, regardless of fractionation scheme (p < 0.001). Conclusions: The PACS is a novel metric for evaluating the utility of PRT regimens to improve clinical decision making. Single fraction is associated with low PRL. When considering multifraction PRT regimens, the PACS identifies patients who may benefit from shorter courses of PRT and alternatively, low-risk patients for whom a more protracted course is reasonable. Prospective external validation is warranted.

Brain Metastasis Incidence and Patterns of Presentation After Definitive Treatment of Locally Advanced Non-Small Cell Lung Cancer: A Potential Argument for Brain Magnetic Resonance Imaging Surveillance.

Purpose: Brain metastases (BMs) are a common source of morbidity and mortality. Guidelines do not advise brain surveillance for locally advanced non-small cell lung cancer (LA-NSCLC). We describe the incidence, time to development, presentation, and management of BMs after definitive chemoradiotherapy (CRT). Methods and Materials: We reviewed records of patients with LA-NSCLC treated with CRT within the period from 2013 to 2020. Descriptive statistics were used to characterize the population and the Kaplan-Meier method was used to estimate time to BM. Fisher exact tests and Wilcoxon rank-sum tests were used to compare outcomes between symptomatic and asymptomatic patients. Results: A total of 219 patients were reviewed including 96 with squamous cell carcinoma, 88 with adenocarcinoma, and 35 with large cell/not otherwise specified (LC/NOS). Thirty-nine patients (17.8%) developed BMs: 35 (90%) symptomatic and 4 (10%) asymptomatic. The rate of BM was highest in LC/NOS (34.3%) and adenocarcinoma (23.9%). Ninety percent of BMs occurred within 2 years. All asymptomatic patients underwent stereotactic radiosurgery alone, compared with 40% of symptomatic patients (P = .04). Symptomatic patients were more likely to require hospitalization (65.7% vs 0%, P = .02), craniotomy (25.7% vs 0%, not significant), and steroids (91.4% vs 0%, P < .001). Cumulative BM volume was higher for symptomatic patients (4 vs 0.24 cm3, P < .001) as was median greatest axial dimension (2.18 vs 0.52 cm, P < .001). Conclusions: We identified a high rate of BMs, particularly in LC/NOS and adenocarcinoma histology NSCLC. The majority were symptomatic. These results provide rationale for post-CRT magnetic resonance imaging brain surveillance for patients at high risk of BM.

Collagen deposition within brain metastases is associated with leptomeningeal failure after cavity-directed radiosurgery.

Background: Leptomeningeal failure (LMF) represents a devastating progression of disease following resection of brain metastases (BrM). We sought to identify a biomarker at time of BrM resection that predicts for LMF using mass spectrometry-based proteomic analysis of resected BrM and to translate this finding with histochemical assays. Methods: We retrospectively reviewed 39 patients with proteomic data available from resected BrM. We performed an unsupervised analysis with false discovery rate adjustment (FDR) to compare proteomic signature of BrM from patients that developed LMF versus those that did not. Based on proteomic analysis, we applied trichrome stain to a total of 55 patients who specifically underwent resection and adjuvant radiosurgery. We used competing risks regression to assess predictors of LMF. Results: Of 39 patients with proteomic data, FDR revealed type I collagen-alpha-1 (COL1A1, P = .045) was associated with LMF. The degree of trichrome stain in each block correlated with COL1A1 expression (ß = 1.849, P = .001). In a cohort of 55 patients, a higher degree of trichrome staining was associated with an increased hazard of LMF in resected BrM (Hazard Ratio 1.58, 95% CI 1.11-2.26, P = .01). Conclusion: The degree of trichrome staining correlated with COL1A1 and portended a higher risk of LMF in patients with resected brain metastases treated with adjuvant radiosurgery. Collagen deposition and degree of fibrosis may be able to serve as a biomarker for LMF.

Bridging the Communication Gaps: A Prospective Single-Arm Pilot Study Testing the Feasibility of Interdisciplinary Radiotherapy Planning in Locally Advanced Lung Cancer.

RATIONALE AND OBJECTIVES: The treatment of locally advanced lung cancer (LALC) with radiotherapy (RT) can be challenging. Multidisciplinary collaboration between radiologists and radiation oncologists (ROs) may optimize RT planning, reduce uncertainty in follow-up imaging interpretation, and improve outcomes. MATERIALS AND METHODS: In this prospective clinical treatment trial (clinicaltrials.gov NCT04844736), 37 patients receiving definitive RT for LALC, six attending ROs, and three thoracic radiologists were consented and enrolled across four treatment centers. Prior to RT plan finalization, representative computed tomography (CT) slices with overlaid outlines of preliminary irradiation targets were shared with the team of radiologists. The primary endpoint was to assess feasibility of receiving feedback no later than 4 business days of RT simulation on at least 50% of plans. RESULTS: Thirty-seven patients with lung cancer were enrolled, and 35 of 37 RT plans were reviewed. Of the 35 patients reviewed, mean age was 69 years. For 27 of 37 plans (73%), feedback was received within 4 or fewer days (interquartile range 3-4 days). Thirteen of 35 cases (37%) received feedback that the delineated target potentially did not include all sites suspicious for tumor involvement. In total, changes to the RT plan were recommended for over- or undercoverage in 16 of 35 cases (46%) and implemented in all cases. Radiology review resulted in no treatment delays and substantial changes to irradiated volumes: gross tumor volume, -1.9 to +96.1%; planning target volume, -37.5 to +116.5%. CONCLUSION: Interdisciplinary collaborative RT planning using a simplified workflow was feasible, produced no treatment delays, and prompted substantial changes in RT targets.