Prospective Evaluation of Limited-Stage Small Cell Lung Cancer Radiotherapy Fractionation Regimen Usage and Acute Toxicity in a Large Statewide Quality Collaborative.

PURPOSE: National guidelines on limited-stage small cell lung cancer (LS-SCLC) treatment give preference to a hyperfractionated regimen of 45 Gy in 30 fractions delivered twice daily; however, use of this regimen is uncommon compared with once-daily regimens. The purpose of this study was to characterize the LS-SCLC fractionation regimens used throughout a statewide collaborative, analyze patient and treatment factors associated with these regimens, and describe real-world acute toxicity profiles of once- and twice-daily radiation therapy (RT) regimens. METHODS AND MATERIALS: Demographic, clinical, and treatment data along with physician-assessed toxicity and patient-reported outcomes were prospectively collected by 29 institutions within the Michigan Radiation Oncology Quality Consortium between 2012 and 2021 for patients with LS-SCLC. We modeled the influence of RT fractionation and other patient-level variables clustered by treatment site on the odds of a treatment break specifically due to toxicity with multilevel logistic regression. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, incident grade 2 or worse toxicity was longitudinally compared between regimens. RESULTS: There were 78 patients (15.6% overall) treated with twice-daily RT and 421 patients treated with once-daily RT. Patients receiving twice-daily RT were more likely to be married or living with someone (65% vs 51%; P = .019) and to have no major comorbidities (24% vs 10%; P = .017). Once-daily RT fractionation toxicity peaked during RT, and twice-daily toxicity peaked within 1 month after RT. After stratifying by treatment site and adjusting for patient-level variables, once-daily treated patients had 4.11 (95% confidence interval, 1.31-12.87) higher odds of treatment break specifically due to toxicity than twice-daily treated patients. CONCLUSIONS: Hyperfractionation for LS-SCLC remains infrequently prescribed despite the lack of evidence demonstrating superior efficacy or lower toxicity of once-daily RT. With peak acute toxicity after RT and lower likelihood of a treatment break with twice-daily fractionation in real-word practice, providers may start using hyperfractionated RT more frequently.

Patterns of recurrence after intracranial stereotactic radiosurgery for brain-only metastases from non-small cell lung cancer and the impact of upfront thoracic therapy with synchronous presentation.

Background: We characterized long-term organ-specific patterns of recurrence, time to progression (TTP) and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) with brain-only metastases treated with single-fraction stereotactic radiosurgery (SRS) and analyzed the impact of upfront thoracic therapy (UTT) in those with synchronous presentation of primary NSCLC and brain metastases. Methods: The clinical records of 137 patients with brain metastases from NSCLC treated with intracranial SRS, and no other metastatic sites, were retrospectively reviewed. Patients with available follow-up imaging (n=124) were analyzed for patterns of recurrence; all were analyzed for OS. Results: The majority of first distant recurrences were in brain and thoracic sites, while extra-thoracic sites were relatively uncommon. After median follow-up of 16.0 months, 24.8% did not develop recurrence outside of brain and/or thoracic sites and 43.5% were free of distant extracranial recurrence. Whole brain radiotherapy (WBRT) and UTT, but not systemic therapy, altered patterns of recurrence and intracranial or extracranial TTP. Multivariable analysis revealed UTT, but not systemic therapy or WBRT, was associated with more favorable OS [hazard ratio (HR) 0.515, P=0.029] among 88 patients with synchronous presentation. Within the subgroup of thoracic stage III patients (n=69), those treated with UTT experienced remarkable median extracranial TTP and OS of 19.3 and 22.7 months, respectively. Conclusions: First and cumulative recurrences in patients treated with intracranial SRS for NSCLC metastases limited to brain are most often in the brain and thorax. Long-term survival is possible, regardless of thoracic stage, and is dependent on UTT among other factors.

Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer.

OBJECTIVES: The addition of adjuvant durvalumab improves overall survival in locally advanced nonsmall-cell lung cancer (NSCLC) patients treated with definitive chemoradiation, but the real-world uptake of adjuvant durvalumab is unknown. MATERIALS AND METHODS: We identified patients with stage III NSCLC treated with definitive concurrent chemoradiation from January 2018 to October 2020 from a statewide radiation oncology quality consortium, representing a mix of community (n=22 centers) and academic (n=5) across the state of Michigan. Use of adjuvant durvalumab was ascertained at the time of routine 3-month or 6-month follow-up after completion of chemoradiation. RESULTS: Of 421 patients with stage III NSCLC who completed chemoradiation, 322 (76.5%) initiated adjuvant durvalumab. The percentage of patients initiating adjuvant durvalumab increased over time from 66% early in the study period to 92% at the end of the study period. There was substantial heterogeneity by treatment center, ranging from 53% to 90%. In multivariable logistic regression, independent predictors of durvalumab initiation included more recent month (odds ratio [OR]: 1.05 per month, 95% confidence interval [CI]: 1.02-1.08, P=0.003), lower Eastern Cooperative Oncology Group score (OR: 4.02 for ECOG 0 vs. 2+, 95% CI: 1.67-9.64, P=0.002), and a trend toward significance for female sex (OR: 1.66, 95% CI: 0.98-2.82, P=0.06). CONCLUSION: Adjuvant durvalumab for stage III NSCLC treated with definitive chemoradiation was rapidly and successfully incorporated into clinical care across a range of community and academic settings in the state of Michigan, with over 90% of potentially eligible patients starting durvalumab in more recent months.

Racial Differences in Treatments and Toxicity in Patients With Non-Small-Cell Lung Cancer Treated With Thoracic Radiation Therapy.

PURPOSE: Historical racial disparities in lung cancer surgery rates resulted in lower survival in Black patients. Our objective was to examine racial differences in thoracic radiation treatments and toxicities in patients with non-small-cell lung cancer. METHODS AND MATERIALS: A large institutional review board-approved statewide patient-level database of patients with stage II-III non-small-cell lung cancer who received definitive thoracic radiation from March 2012 to November 2019 was analyzed to assess associations between race and other variables. Race (White or Black) was defined by patient self-report. Provider-reported toxicity was defined by Common Terminology Criteria for Adverse Events version 4.0. Patient-reported toxicity was determined by the Functional Assessment of Cancer Therapy-Lung quality-of-life instrument. Univariable and multivariable regression models were fitted to assess relationships between race and variables of interest. Spearman rank-correlation coefficients were calculated between provider-reported toxicity and similar patient-reported outcomes. RESULTS: One thousand four hundred forty-one patients from 24 institutions with mean age 68 years (range, 38-94 years) were evaluated. Race was not significantly associated with radiation or chemotherapy approach. There was significantly increased patient-reported general pain in Black patients at the preradiation and end-of-radiation time points. Black patients were significantly less likely to have provider-reported grade 2+ pneumonitis (odds ratio 0.36, P = .03), even after controlling for known patient and treatment factors. Correlation coefficients between provider- and patient-reported toxicities were generally similar across race groups except for a stronger correlation between patient- and provider-reported esophagitis in White patients. CONCLUSION: In this large multi-institutional study, we found no evidence of racial differences in radiation treatment or chemotherapy approaches. We did, however, unexpectedly find that Black race was associated with lower odds of provider-reported grade 2+ radiation pneumonitis. The stronger correlation between patient- and provider-reported esophagitis and swallowing symptoms for White patients also suggests possible under-recognition of symptoms in Black patients. Further research is needed to study the implications for Black patients.

Single-Fraction Radiosurgery Using Conservative Doses for Brain Metastases: Durable Responses in Select Primaries With Limited Toxicity.

BACKGROUND: Optimal doses for single-fraction stereotactic radiosurgery (SRS) in the treatment of brain metastases are not well established. Our institution utilized conservative dosing compared to maximum-tolerated doses from the Radiation Therapy Oncology Group 90-05 Phase I study. OBJECTIVE: To report individual lesion control (LC) from conservative single-fraction doses and determine factors affecting LC. METHODS: From 2003 to 2015, patients who underwent linear accelerator-based single-fraction SRS for cerebral/cerebellar metastases and receiving at least 1 follow-up magnetic resonance imaging (MRI) were identified. Lesion response was assessed by a size-based rating system and modified "Response Assessment in Neuro-Oncology Brain Metastases" (RANO-BM) criteria. RESULTS: Among 188 patients with 519 lesions, median survival was 13.1 mo; median follow-up time with MRI was 9.6 mo per course. Median tumor-periphery dose was 15 Gy (range: 7.5-20.7). Median lesion volume was 0.5 cc and diameter was 9 mm (range: 2-45). Concordance between RANO-BM and size-based system was 93%. Crude 1-yr LC was 80%, 73%, 56%, and 38% for lesions 1 to 10, 11 to 20, 21 to 30, >31 mm, respectively. On multivariate analysis, increased size, melanoma and colorectal histology, and progression after whole brain radiation therapy predicted worse LC. When excluding lesions treated as a boost, dose was a significant predictor of LC in multivariate models (hazard ratio 0.89, P = .01). Symptomatic radiation necrosis occurred in 10 lesions in 10 patients. CONCLUSION: Histology predicts LC after conservative SRS doses with evidence of a dose-response relationship. Conservative single-fraction SRS doses confer minimal toxicity and acceptable control in certain subgroups (breast cancer, <5 mm), with suboptimal control in larger lesions and in combination with whole brain radiation therapy.

Radiotherapy for Oligometastatic Lung Cancer.

Non-small cell lung cancer (NSCLC) typically presents at an advanced stage, which is often felt to be incurable, and such patients are usually treated with a palliative approach. Accumulating retrospective and prospective clinical evidence, including a recently completed randomized trial, support the existence of an oligometastatic disease state wherein select individuals with advanced NSCLC may experience historically unprecedented prolonged survival with aggressive local treatments, consisting of radiotherapy and/or surgery, to limited sites of metastatic disease. This is reflected in the most recent AJCC staging subcategorizing metastatic disease into intra-thoracic (M1a), a single extra thoracic site (M1b), and more diffuse metastases (M1c). In the field of radiation oncology, recent technological advances have allowed for the delivery of very high, potentially ablative, doses of radiotherapy to both intra- and extra-cranial disease sites, referred to as stereotactic radiosurgery and stereotactic body radiotherapy (or SABR), in much shorter time periods compared to conventional radiation and with minimal associated toxicity. At the same time, significant improvements in systemic therapy, including platinum-based doublet chemotherapy, molecular agents targeting oncogene-addicted NSCLC, and immunotherapy in the form of checkpoint inhibitors, have led to improved control of micro-metastatic disease and extended survival sparking newfound interest in combining these agents with ablative local therapies to provide additive, and in the case of radiation and immunotherapy, potentially synergistic, effects in order to further improve progression-free and overall survival. Currently, despite the tantalizing potential associated with aggressive local therapy in the setting of oligometastatic NSCLC, well-designed prospective randomized controlled trials sufficiently powered to detect and measure the possible added benefit afforded by this approach are desperately needed.

The evolving role of radiotherapy in treatment of oligometastatic NSCLC.

Non-small cell lung cancer (NSCLC) patients with metastases limited in site and number, termed oligometastases, may represent a unique subpopulation of advanced NSCLC with improved prognosis. The optimal management of these patients remains unclear with the treatment approach currently undergoing a paradigm shift. The potential benefit of aggressive metastasis directed local treatment with surgery and/or radiotherapy (RT) in combination with systemic therapy is bolstered predominantly by retrospective analyses but also by a growing number of non-randomized prospective studies regarding the use of ablative RT techniques including stereotactic body radiotherapy (SBRT), alternatively termed stereotactic ablative radiotherapy (SABR), directed at the primary tumor (if present) and all metastatic sites. Long-term survival is possible in a subset of patients treated aggressively in this manner. The challenge for the clinical oncology community moving forward is appropriately selecting patients for this treatment approach based on clinical, imaging, and molecular features and increasing enrollment of patients to prospective clinical trials to more definitively determine the added benefit and appropriate timing of aggressive metastasis directed therapy in the oligometastatic setting.

Long-Term Survival of a Patient with Metastatic Small-Cell Carcinoma of the Stomach Treated with Radiation Therapy.

Small-cell carcinoma (SCC), or high-grade neuroendocrine carcinoma of the stomach, is a rare subtype of extra-pulmonary SCC which is almost invariably lethal. Gastric SCC often presents with local symptoms indistinguishable from other primary stomach cancers; however, both regional and distant spread are common at the initial presentation. Depending on symptoms and patient performance status, treatment typically consists of chemotherapy or resection followed by adjuvant chemotherapy, as even patients with limited stage gastric SCC likely have micrometastatic disease at the time of diagnosis. In this case report, we describe the long-term survival of a 75-year-old male with recurrent oligometastatic high-grade neuroendocrine carcinoma of the stomach treated with radiation therapy (RT) alone. He presented with abdominal pain and dyspepsia and was found to have a 6 cm locally invasive node-positive gastric SCC initially treated with extensive surgical resection. He was not a candidate for adjuvant chemotherapy, and surveillance imaging subsequently confirmed metachronous liver and local recurrences within 1 year after surgery, which were managed with stereotactic body RT and conventional radiation, respectively. An additional para-aortic nodal recurrence was treated with intensity-modulated radiotherapy 7 years after surgery with good response. He tolerated all RT courses without notable radiation-related toxicity and remains in complete remission 11 years after initial diagnosis.

Bladder cancer in the elderly patient: challenges and solutions.

Bladder cancer (BC) is an age-associated malignancy with increased prevalence in the elderly population. Elderly patients are a vulnerable population at increased risk for treatment-related toxicity secondary to medical comorbidities and geriatric syndromes. As a result, this population has been historically undertreated and suffers worse disease-specific outcomes than younger patients with BC. Recognition of this disparity has led to efforts to individualize treatment decisions based on functional status rather than chronologic age in an effort to optimize the use of curative therapies for the fit elderly and modify treatments to reduce the risk of toxicity and disease-related morbidity in vulnerable or frail patients. The comprehensive geriatric assessment is a decision framework that helps to balance underlying health considerations and risks of therapy with aggressiveness of the cancer. Development of systemic therapies with increased efficacy against BC and reduced toxicity are eagerly awaited, as are techniques and interventions to reduce the morbidity from surgery and radiation for patients with BC.

The Role of Lung Lobes in Radiation Pneumonitis and Radiation-Induced Inflammation in the Lung: A Retrospective Study.

OBJECTIVE: We examined the relative response to radiation of the upper lung lobes (UL) versus lower lung lobes (LL) of normal lung tissue using normalized [18F]-fluorodeoxyglucose (FDG) uptake per radiation dose received per lung voxel in patients treated with either photons or protons and tested for correlation of the radiation response with clinical pneumonitis. METHODS: Seventy-five patients (photon (n = 51) or proton (n = 24)) treated for esophageal cancer from November 1, 2003 to May 15, 2011 who received restaging FDG-positron emission tomography (PET) imaging 1 to 3 months after chemoradiation were selected. UL and LL were contoured using the major fissure as the boundary, with the right middle lobe being included in the right UL structure. Pneumonitis toxicity was scored using the Common Terminology Criteria for Adverse Events, version 4.0 based on the consensus of 5 clinicians. RESULTS: LL had a higher mean dose (15.6 Gy vs. 10.4 Gy, p<0.001), higher mean standard uptake value (SUV) (0.78 vs. 0.56, p=0.001) and SUV in low dose regions (0.80 vs. 0.66 for 10 to 20 Gy, p=0.001), and lower mean dose response (0.015 vs. 0.019, p=0.003) compared to the UL. The mean dose ratio of UL vs. LL (p < 0.001), and SUV in the region of lung receiving 0-10 Gy (p=0.04), but not the dose response ratio of UL vs. LL (p=0.53) correlated with symptomatic pneumonitis. CONCLUSION: Upper lung lobes had a greater pulmonary metabolic radiation response than lower lung lobes. Greater dose to UL relative to LL and higher SUV in the low dose region (10-20 Gy) on post-treatment PET correlated with symptomatic pneumonitis.