Establishing the minimal clinically important difference of the Brief Fatigue Inventory for brain or CNS cancer patients undergoing radiotherapy.

Background: Minimal clinically important differences (MCIDs) quantify the clinical relevance of quality of life results at the individual patient and group level. The aim of this study was to estimate the MCID for the Brief Fatigue Inventory (BFI) and the Worst and Usual Fatigue items in patients with brain or CNS cancer undergoing curative radiotherapy. Methods: Data from a multi-site prospective registry was used. The MCID was calculated using distribution-based and anchor-based approaches. For the anchor-based approach, the fatigue item from the PROMIS-10 served as the anchor to determine if a patient improved, deteriorated, or had no change from baseline to end of treatment (EOT). We compared the unadjusted means on the BFI for the 3 groups to calculate the MCID. For the distribution-based approaches, we calculated the MCID as 0.5 SD of the scores and as 1.96 times the standard error of measurement. Results: Three-hundred and fifty nine patients with brain or CNS tumors undergoing curative radiotherapy filled out the 9-item BFI at baseline and EOT. The MCID for the BFI was 1.33 (ranging from 0.99 to 1.70 across the approaches), 1.51 (ranging from 1.16 to 2.02) and 1.76 (ranging from 1.38 to 2.14) for the usual and worst fatigue items, respectively. Conclusions: This study provides the MCID ranges for the BFI and Worst and Usual fatigue items, which will allow clinically meaningful conclusions to be drawn from BFI scores. These results can be used to select optimal treatments for patients with brain or CNS cancer or to interpret BFI scores from clinical trials.

A Prospective Pilot Study of Pencil Beam Scanning Proton Radiation Therapy as a Component of Trimodality Therapy for Esophageal Cancer.

Purpose: To evaluate the safety and efficacy of pencil beam scanning (PBS) proton radiation therapy (RT) in trimodality therapy for esophageal cancer. Methods and Materials: This prospective pilot study was planned to accrue 30 patients with locally advanced esophageal or gastroesophageal junction carcinoma medically suitable for chemoradiation therapy (CRT) followed by esophagectomy. PBS proton RT consisted of 25 fractions, 50 Gy to tumor + 1 cm and 45 Gy to a 3.5 cm mucosal expansion and regional lymph nodes. Chemotherapy included weekly carboplatin (area under the curve, 2 mg/mL/min) and paclitaxel (50 mg/m2). At 4 to 8 weeks after CRT, patients underwent restaging and potential esophagectomy. The primary endpoint was acute grade 3+ adverse events (AEs) attributed to CRT. Overall survival and progression-free survival were assessed using the Kaplan-Meier methodology; local-regional recurrence and distant metastases rates were assessed using the cumulative incidence methodology. The Functional Assessment of Cancer Therapy-Esophagus assessed quality of life. Results: Thirty eligible patients were enrolled from June 2015 to April 2017. Median age was 68 years. Histology was adenocarcinoma in 87%, and location was distal esophagus/gastroesophageal junction in 90%. Stage was T3 to T4 in 87% and N1 to N3 in 80%. All patients completed the planned RT dose. Acute grade 3+ AEs occurred in 30%, most commonly leukopenia and neutropenia. Acute grade 3+ nonhematologic AEs occurred in 3%. Esophagectomy was performed in 90% of patients (R0 in 93%). Pathologic complete response rate was 40%. Major postoperative complications (Clavien-Dindo score, ≥3) occurred in 34%. Postoperative mortality at 30 days was 3.7%. Median follow-up was 5.2 years. Five-year outcome estimates were overall survival at 46%, progression-free survival at 39%, local-regional recurrence at 17%, and distant metastases at 40%. Functional Assessment of Cancer Therapy-Esophagus scores (medians) at baseline, at the end of CRT, before esophagectomy, at 12 months, and at 24 months were 145, 136 (p = .0002 vs baseline), 144, 146 and 157, respectively. Conclusions: PBS proton RT is feasible and safe as a component of trimodality therapy for esophageal cancer.

Integration of Telemedicine Consultation Into a Tertiary Radiation Oncology Department: Predictors of Use, Treatment Yield, and Effects on Patient Population.

PURPOSE: The COVID-19 pandemic led to rapid expansion of telemedicine. The implications of telemedicine have not been rigorously studied in radiation oncology, a procedural specialty. This study aimed to evaluate the characteristics of in-person patients (IPPs) and virtual patients (VPs) who presented to a large cancer center before and during the pandemic and to understand variables affecting likelihood of receiving radiotherapy (yield) at our institution. METHODS: A total of 17,915 patients presenting for new consultation between 2019 and 2021 were included, stratified by prepandemic and pandemic periods starting March 24, 2020. Telemedicine visits included video and telephone calls. Area deprivation indices (ADIs) were also compared. RESULTS: The overall population was 56% male and 93% White with mean age of 63 years. During the pandemic, VPs accounted for 21% of visits, were on average younger than their in-person (IP) counterparts (63.3 years IP v 62.4 VP), and lived further away from clinic (215 miles IP v 402 VP). Among treated VPs, living closer to clinic was associated with higher yield (odds ratio [OR], 0.95; P < .001). This was also seen among IPPs who received treatment (OR, 0.96; P < .001); however, the average distance from clinic was significantly lower for IPPs than VPs (205 miles IP v 349 VP). Specialized radiotherapy (proton and brachytherapy) was used more in VPs. IPPs had higher ADI than VPs. Among VPs, those treated had higher ADI (P < .001). CONCLUSION: Patient characteristics and yield were significantly different between IPPs and VPs. Telemedicine increased reach to patients further away from clinic, including from rural or health care-deprived areas, allowing access to specialized radiation oncology care. Telemedicine has the potential to increase the reach of other technical and procedural specialties.

Assessment of minimum target dose as a predictor of local failure after spine SBRT.

OBJECTIVES: Metastasis-directed stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). We assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. METHODS: Spine SBRT treatments with imaging follow-up were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, delivering 20-24 Gy in 1 fraction to the gross tumor volume (GTV) and 16 Gy to the low dose volume (or 27-36 Gy and 21-24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. RESULTS: 522 eligible spine SBRT treatments (68 % single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95 % confidence interval: 34.3-54.4). The cumulative incidence of local failure was 10.5 % (7.4-13.4) at 1 year and 16.3 % (12.6-19.9) at 2 years. Local control was maximized at 15.3 Gy minimum dose for single-fraction treatment (HR = 0.31, 95 % CI: 0.17 - 0.56, p < 0.0001) and confirmed via multivariable analyses. Cumulative incidence of local failure was 6.1 % (2.6-9.4) vs. 14.2 % (8.3-19.8) at 1 year using this cut-off, with comparable findings for minimum 14 Gy. Additionally, epidural and soft tissue involvement were predictive of local failure (HR = 1.77 and 2.30). CONCLUSIONS: Spine SBRT offers favorable local control; however, minimum dose to the GTV has a strong association with local control. Achieving GTV minimum dose of 14-15.3 Gy with single fraction SBRT is recommended whenever possible.

Participant Evaluation of a Multi-disciplinary Oncology Preceptorship Training Program for Oncology Health Professionals from Kumasi, Ghana.

A critical shortage of skilled healthcare workers is a primary cause of disparate global cancer outcomes. We report participant evaluation of a multidisciplinary preceptorship program. In collaboration with the city of Kumasi, Ghana, Mayo Clinic and the City Cancer Challenge hosted a preceptorship program for comprehensive multidisciplinary breast and cervix cancer training. A total of 14 healthcare workers from Kumasi received two weeks of training at Mayo Clinic in November and December 2021. Each participant and preceptor were requested to complete an anonymous post-participation survey. Of the 14 trainee participants, 10 (71%) completed the survey. All respondents found the program "valuable and applicable to their clinical practice." Ninety percent reported they were able to "review effective and critical elements in the development and expansion of the multidisciplinary team" and able to "solve practical clinical cases as a team". General themes of satisfaction included: (1) organization and administration, (2) clinical observations and demonstrations, (3) guidelines development, and (4) recognizing the central importance of cultivating a team-based approach. Of the 40 preceptors, 16 (40%) completed the survey. All respondents reported they felt the training would meaningfully "influence patient care in Ghana", that participation "added value or joy to their clinical practice," and all wished to "participate in future preceptorship programs". After a focused two-week program, trainees reported high satisfaction, usefulness from observing specialized cancer care, and value in closely observing a multidisciplinary oncology team. Preceptors reported the experience added joy and perspective to their clinical practice and wished to participate in future programs.

Comparison of Hounsfield units and vertebral bone quality score for the prediction of time to pathologic fracture in mobile spine metastases treated with radiotherapy.

OBJECTIVE: Spine metastases are commonly treated with radiotherapy for local tumor control; pathologic fracture is a potential complication of spinal radiotherapy. Both Hounsfield units (HUs) on CT and vertebral bone quality (VBQ) on MRI have been argued to predict stability as measured by odds of pathologic fracture, although it is unclear if there is a difference in the predictive power between the two methodologies. The objective of the present study was to examine whether one methodology is a better predictor of pathologic fracture following radiotherapy for mobile spine metastases. METHODS: Patients who underwent radiotherapy (conventional external-beam radiation therapy, stereotactic body radiation therapy, or intensity-modulated radiation therapy) for mobile spine (C1-L5) metastases at a tertiary care center were retrospectively identified. Details regarding underlying pathology, patient demographics, and tumor morphology were collected. Vertebral involvement was assessed using the Weinstein-Boriani-Biagini (WBB) system. Bone quality of the non-tumor-involved bone was assessed on both pretreatment CT and MRI. Univariable analyses were conducted to identify independent predictors of fracture, and Kaplan-Meier analyses were used to identify significant predictors of time to pathologic fracture. Stepwise Cox regression analysis was used to determine independent predictors of time to fracture. RESULTS: One hundred patients were included (mean age 62.7 ± 11.9 years; 61% male), of whom 35 experienced postradiotherapy pathologic fractures. The most common histologies were lung (22%), prostate (21%), breast (14%), and renal cell (13%). On univariable analysis, the mean HUs of the vertebrae adjacent to the fractured vertebra were significantly lower among those experiencing fracture; VBQ was not significantly associated with fracture odds. Survival analysis showed that average HUs ≤ 132, nonprostate pathology, involvement of ≥ 3 vertebral body segments on the WBB system, Spine Instability Neoplastic Score (SINS) ≥ 7, and the presence of axial pain all predicted increased odds of fracture (all p < 0.001). Cox regression found that HUs ≤ 132 (OR 2.533, 95% CI 1.257-5.103; p = 0.009), ≥ 3 WBB vertebral body segments involved (OR 2.376, 95% CI 1.132-4.987; p = 0.022), and axial pain (OR 2.036, 95% CI 0.916-4.526; p = 0.081) predicted increased fracture odds, while prostate pathology predicted decreased odds (OR 0.076, 95% CI 0.009-0.613; p = 0.016). Sensitivity analysis suggested that an HU threshold of ≤ 132 and a SINS of ≥ 7 identified patients at increased risk of fracture. CONCLUSIONS: The present results suggest that bone density surrogates as measured on CT, but not MRI, can be used to predict the risk of pathologic fracture following radiotherapy for mobile spine metastases. More extensive vertebral body involvement and the presence of mechanical axial pain additionally predict increased fracture odds.

Sublobar Resection, Stereotactic Body Radiation Therapy, and Percutaneous Ablation Provide Comparable Outcomes for Lung Metastasis-Directed Therapy.

BACKGROUND: Prolonged survival of patients with metastatic disease has furthered interest in metastasis-directed therapy (MDT). RESEARCH QUESTION: There is a paucity of data comparing lung MDT modalities. Do outcomes among sublobar resection (SLR), stereotactic body radiation therapy (SBRT), and percutaneous ablation (PA) for lung metastases vary in terms of local control and survival? STUDY DESIGN AND METHODS: Medical records of patients undergoing lung MDT at a single cancer center between January 2015 and December 2020 were reviewed. Overall survival, local progression, and toxicity outcomes were collected. Patient and lesion characteristics were used to generate multivariable models with propensity weighted analysis. RESULTS: Lung MDT courses (644 total: 243 SLR, 274 SBRT, 127 PA) delivered to 511 patients were included with a median follow-up of 22 months. There were 47 local progression events in 45 patients, and 159 patients died. Two-year overall survival and local progression were 80.3% and 63.3%, 83.8% and 9.6%, and 4.1% and 11.7% for SLR, SBRT, and PA, respectively. Lesion size per 1 cm was associated with worse overall survival (hazard ratio, 1.24; P = .003) and LP (hazard ratio, 1.50; P < .001). There was no difference in overall survival by modality. Relative to SLR, there was no difference in risk of local progression with PA; however, SBRT was associated with a decreased risk (hazard ratio, 0.26; P = .023). Rates of severe toxicity were low (2.1%-2.6%) and not different among groups. INTERPRETATION: This study performs a propensity weighted analysis of SLR, SBRT, and PA and shows no impact of lung MDT modality on overall survival. Given excellent local control across MDT options, a multidisciplinary approach is beneficial for patient triage and longitudinal management.

Conventional versus hypofractionated postmastectomy proton radiotherapy in the USA (MC1631): a randomised phase 2 trial.

BACKGROUND: Proton therapy is under investigation in breast cancer as a strategy to reduce radiation exposure to the heart and lungs. So far, studies investigating proton postmastectomy radiotherapy (PMRT) have used conventional fractionation over 25-28 days, but whether hypofractionated proton PMRT is feasible is unclear. We aimed to compare conventional fractionation and hypofractionation in patients with indications for PMRT, including those with immediate breast reconstruction. METHODS: We did a randomised phase 2 trial (MC1631) at Mayo Clinic in Rochester (MN, USA) and Mayo Clinic in Arizona (Phoenix, AZ, USA) comparing conventional fractionated (50 Gy in 25 fractions of 2 Gy [relative biological effectiveness of 1·1]) and hypofractionated (40·05 Gy in 15 fractions of 2·67 Gy [relative biological effectiveness of 1·1]) proton PMRT. All patients were treated with pencil-beam scanning. Eligibility criteria included age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, and breast cancer resected by mastectomy with or without immediate reconstruction with indications for PMRT. Patients were randomly assigned (1:1) to either conventional fractionation or hypofractionation, with presence of immediate reconstruction (yes vs no) as a stratification factor, using a biased-coin minimisation algorithm. Any patient who received at least one fraction of protocol treatment was evaluable for the primary endpoint and safety analyses. The primary endpoint was 24-month complication rate from the date of first radiotherapy, defined as grade 3 or worse adverse events occurring from 90 days after last radiotherapy or unplanned surgical interventions in patients with immediate reconstruction. The inferiority of hypofractionation would not be ruled out if the upper bound of the one-sided 95% CI for the difference in 24-month complication rate between the two groups was greater than 10%. This trial is registered with ClinicalTrials.gov, NCT02783690, and is closed to accrual. FINDINGS: Between June 2, 2016, and Aug 23, 2018, 88 patients were randomly assigned (44 to each group), of whom 82 received protocol treatment (41 in the conventional fractionation group and 41 in the hypofractionation group; median age of 52 years [IQR 44-64], 79 [96%] patients were White, two [2%] were Black or African American, one [1%] was Asian, and 79 [96%] were not of Hispanic ethnicity). As of data cutoff (Jan 30, 2023), the median follow-up was 39·3 months (IQR 37·5-61·2). The median mean heart dose was 0·54 Gy (IQR 0·30-0·72) for the conventional fractionation group and 0·49 Gy (0·25-0·64) for the hypofractionation group. Within 24 months of first radiotherapy, 14 protocol-defined complications occurred in six (15%) patients in the conventional fractionation group and in eight (20%) patients in the hypofractionation group (absolute difference 4·9% [one-sided 95% CI 18·5], p=0·27). The complications in the conventionally fractionated group were contracture (five [12%] of 41 patients]) and fat necrosis (one [2%] patient) requiring surgical intervention. All eight protocol-defined complications in the hypofractionation group were due to infections, three of which were acute infections that required surgical intervention, and five were late infections, four of which required surgical intervention. All 14 complications were in patients with immediate expander or implant-based reconstruction. INTERPRETATION: After a median follow-up of 39·3 months, non-inferiority of the hypofractionation group could not be established. However, given similar tolerability, hypofractionated proton PMRT appears to be worthy of further study in patients with and without immediate reconstruction. FUNDING: The Department of Radiation Oncology, Mayo Clinic, Rochester, MN, the Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA, and the US National Cancer Institute.

Comparing Oncologic Outcomes and Toxicity for Combined Modality Therapy vs. Carbon-Ion Radiotherapy for Previously Irradiated Locally Recurrent Rectal Cancer.

No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six at Institution B with CMT (30 Gy/15 fx chemoradiation, resection, intraoperative electron radiotherapy (IOERT)) between 2006 and 2019 were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), distant metastasis (DM), or any disease progression (DP) were analyzed with the Kaplan-Meier model, with outcomes compared using the Cox proportional hazards model. Acute and late toxicities were compared, as was the 2-year cost. The median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 and 2.6 years, respectively (p ≤ 0.01). No difference was seen in the cumulative incidence of PR (p = 0.17), DM (p = 0.39), or DP (p = 0.19). Lower acute grade ≥ 2 skin and GI/GU toxicity and lower late grade ≥ 2 GU toxicities were associated with CIRT. Higher 2-year cumulative costs were associated with CMT. Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT, and CIRT was associated with longer OS. Prospective comparative studies are needed.

Early Impact of Proton Beam Therapy on Electrophysiological Characteristics in a Porcine Model.

BACKGROUND: Particle therapy is a noninvasive, catheter-free modality for cardiac ablation. We previously demonstrated the efficacy for creating ablation lesions in the porcine heart. Despite several earlier studies, the exact mechanism of early biophysical effects of proton and photon beam delivery on the myocardium remain incompletely resolved. METHODS: Ten normal and 9 infarcted in situ porcine hearts received proton beam irradiation (40 Gy) delivered to the left ventricular myocardium with follow-up for 8 weeks. High-resolution electroanatomical mapping of the left ventricular was performed at baseline and follow-up. Bipolar voltage amplitude, conduction velocity, and connexin-43 were determined within the irradiated and nonirradiated areas. RESULTS: The irradiated area in normal hearts showed a significant reduction of bipolar voltage amplitude (10.1±4.9 mV versus 5.7±3.2, P<0.0001) and conduction velocity (85±26 versus 55±13 cm/s, P=0.03) beginning at 4 weeks after irradiation. In infarcted myocardium after irradiation, bipolar voltage amplitude of the infarct scar (2.0±2.9 versus 0.8±0.7 mV, P=0.008) was significantly reduced as well as the conduction velocity in the infarcted heart (43.7±15.7 versus 26.3±11.4 cm/s, P=0.02). There were no significant changes in bipolar voltage amplitude and conduction velocity in nonirradiated myocardium. Myocytolysis, capillary hyperplasia, and dilation were seen in the irradiated myocardium 8 weeks after irradiation. Active caspase-3 and reduction of connexin-43 expression began in irradiated myocardium 1 week after irradiation and decreased over 8 weeks. CONCLUSIONS: Irradiation of the myocardium with proton beams reduce connexin-43 expression, conduction velocity, and bipolar conducted electrogram amplitude in a large porcine model. The changes in biomarkers preceded electrophysiological changes after proton beam therapy.

Risk stratification of postoperative cardiopulmonary toxicity after trimodality therapy for esophageal cancer.

Purpose/objective: Postoperative toxicity for esophageal cancer impacts patient quality of life and potentially overall survival (OS). We studied whether patient and toxicity parameters post-chemoradiation therapy predict for post-surgical cardiopulmonary total toxicity burden (CPTTB) and whether CPTTB was associated with short and long-term outcomes. Materials/methods: Patients had biopsy-proven esophageal cancer treated with neoadjuvant chemoradiation and esophagectomy. CPTTB was derived from total perioperative toxicity burden (Lin et al. JCO 2020). To develop a CPTTB risk score predictive for major CPTTB, recursive partitioning analysis was used. Results: From 3 institutions, 571 patients were included. Patients were treated with 3D (37%), IMRT (44%), and proton therapy (19%). 61 patients had major CPTTB (score ≥ 70). Increasing CPTTB was predictive of decreased OS (p<0.001), lengthier post-esophagectomy length of stay (LOS, p<0.001), and death or readmission within 60 days of surgery (DR60, p<0.001). Major CPTTB was also predictive of decreased OS (hazard ratio = 1.70, 95% confidence interval: 1.17-2.47, p=0.005). The RPA-based risk score included: age ≥ 65, grade ≥ 2 nausea or esophagitis attributed to chemoradiation, and grade ≥ 3 hematologic toxicity attributed to chemoradiation. Patients treated with 3D radiotherapy had inferior OS (p=0.010) and increased major CPTTB (18.5% vs. 6.1%, p<0.001). Conclusion: CPTTB predicts for OS, LOS, and DR60. Patients with 3D radiotherapy or age ≥ 65 years and chemoradiation toxicity are at highest risk for major CPTTB, predicting for higher short and long-term morbidity and mortality. Strategies to optimize medical management and reduce toxicity from chemoradiation should be strongly considered.

Development and validation of a recursive partitioning analysis-based pretreatment decision-making tool identifying ideal candidates for spine stereotactic body radiation therapy.

BACKGROUND: This study was aimed at developing and validating a decision-making tool predictive of overall survival (OS) for patients receiving stereotactic body radiation therapy (SBRT) for spinal metastases. METHODS: Three hundred sixty-one patients at one institution were used for the training set, and 182 at a second institution were used for external validation. Treatments most commonly involved one or three fractions of spine SBRT. Exclusion criteria included proton therapy and benign histologies. RESULTS: The final model consisted of the following variables and scores: Spinal Instability Neoplastic Score (SINS) ≥ 6 (1), time from primary diagnosis < 21 months (1), Eastern Cooperative Oncology Group (ECOG) performance status = 1 (1) or ECOG performance status > 1 (2), and >1 organ system involved (1). Each variable was an independent predictor of OS (p < .001), and each 1-point increase in the score was associated with a hazard ratio of 2.01 (95% confidence interval [CI], 1.79-2.25; p < .0001). The concordance value was 0.75 (95% CI, 0.71-0.78). The scores were discretized into three groups-favorable (score = 0-1), intermediate (score = 2), and poor survival (score = 3-5)-with 2-year OS rates of 84% (95% CI, 79%-90%), 46% (95% CI, 36%-59%), and 21% (95% CI, 14%-32%), respectively (p < .0001 for each). In the external validation set (182 patients), the score was also predictive of OS (p < .0001). Increasing SINS was predictive of decreased OS as a continuous variable (p < .0001). CONCLUSIONS: This novel score is proposed as a decision-making tool to help to optimize patient selection for spine SBRT. SINS may be an independent predictor of OS.

Preoperative stereotactic radiosurgery in the management of brain metastases and gliomas.

Stereotactic radiosurgery (SRS) is the delivery of a high dose ionizing radiation in a highly conformal manner, which allows for significant sparing of nearby healthy tissues. It is typically delivered in 1-5 sessions and has demonstrated safety and efficacy across multiple intracranial neoplasms and functional disorders. In the setting of brain metastases, postoperative and definitive SRS has demonstrated favorable rates of tumor control and improved cognitive preservation compared to conventional whole brain radiation therapy. However, the risk of local failure and treatment-related complications (e.g. radiation necrosis) markedly increases with larger postoperative treatment volumes. Additionally, the risk of leptomeningeal disease is significantly higher in patients treated with postoperative SRS. In the setting of high grade glioma, preclinical reports have suggested that preoperative SRS may enhance anti-tumor immunity as compared to postoperative radiotherapy. In addition to potentially permitting smaller target volumes, tissue analysis may permit characterization of DNA repair pathways and tumor microenvironment changes in response to SRS, which may be used to further tailor therapy and identify novel therapeutic targets. Building on the work from preoperative SRS for brain metastases and preclinical work for high grade gliomas, further exploration of this treatment paradigm in the latter is warranted. Presently, there are prospective early phase clinical trials underway investigating the role of preoperative SRS in the management of high grade gliomas. In the forthcoming sections, we review the biologic rationale for preoperative SRS, as well as pertinent preclinical and clinical data, including ongoing and planned prospective clinical trials.

Single and Multifraction Spine Stereotactic Body Radiation Therapy and the Risk of Radiation Induced Myelopathy.

Purpose: This study reports on the risk of radiation-induced myelitis (RM) of the spinal cord from a large single-institutional experience with 1 to 5 fraction stereotactic body radiation therapy (SBRT) to the spine. Methods and Materials: A retrospective review of patients who received spine SBRT to a radiation naïve level at or above the conus medullaris between 2007 and 2019 was performed. Local failure determination was based on SPIne response assessment in Neuro-Oncology criteria. RM was defined as neurologic symptoms consistent with the segment of cord irradiated in the absence of neoplastic disease recurrence and graded by Common Toxicity Criteria for Adverse Events, version 4.0. Rates of adverse events were estimated and dose-volume statistics from delivered treatment plans were extracted for the planning target volumes and spinal cord. Results: A total of 353 lesions in 277 patients were identified that met the specified criteria, for which 270, 70, and 13 lesions received 1-, 3-, and 5-fraction treatments, respectively, with a median follow-up of 46 months (95% confidence interval [CI], 41-52 months) for all surviving patients. The median overall survival was 33.0 months (95% CI, 29-43). The median D0.03cc to the spinal cord was 11.7 Gy (interquartile range [IQR], 10.5-12.4), 16.7 Gy (IQR, 12.8-20.6), and 26.0 Gy (IQR, 24.1-28.1), for 1-, 3-, 5-fractions. Using an a/b = 2Gy for the spinal cord, the median single-fraction equivalent-dose (SFED2) was 11.7 Gy (IQR, 10.2-12.5 Gy) and the normalized biological equivalent dose (nBED2/2) was 19.9 Gy (IQR, 15.4-22.8 Gy). One patient experienced grade 2 RM after a single-fraction treatment. The cumulative probability of RM was 0.3% (95% CI, 0%-2%). Conclusions: Spine SBRT is safe while limiting the spinal cord (as defined on treatment planning magnetic resonance imaging or computed tomography myelogram) D0.03cc to less than 14 Gy, 21.9 Gy, and 30 Gy, for 1, 3, and 5-fractions, consistent with standard guidelines.

FDG-PET Predicts Neoadjuvant Therapy Response and Survival in Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma.

BACKGROUND: Neoadjuvant therapy (NAT) is used in borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). Anatomic imaging (CT/MRI) poorly predicts response, and biochemical (CA 19-9) markers are not useful (nonsecretors/nonelevated) in many patients. Pathologic response highly predicts survival post-NAT, but is only known postoperatively. Because metabolic imaging (FDG-PET) reveals primary tumor viability, this study aimed to evaluate our experience with preoperative FDG-PET in patients with BR/LA PDAC in predicting NAT response and survival. METHODS: We reviewed all patients with resected BR/LA PDAC who underwent NAT with FDG-PET within 60 days of resection. Pre- and post-NAT metabolic (FDG-PET) and biochemical (CA 19-9) responses were dichotomized in addition to pathologic responses. We compared post-NAT metabolic and biochemical responses as preoperative predictors of pathologic responses and recurrence-free survival (RFS) and overall survival (OS). RESULTS: We identified 202 eligible patients. Post-NAT, 58% of patients had optimization of CA 19-9 levels. Major metabolic and pathologic responses were present in 51% and 38% of patients, respectively. Median RFS and OS times were 21 and 48.7 months, respectively. Metabolic response was superior to biochemical response in predicting pathologic response (area under the curve, 0.86 vs 0.75; P<.001). Metabolic response was the only univariate preoperative predictor of OS (odds ratio, 0.25; 95% CI, 0.13-0.40), and was highly correlated (P=.001) with pathologic response as opposed to biochemical response alone. After multivariate adjustment, metabolic response was the single largest independent preoperative predictor (P<.001) for pathologic response (odds ratio, 43.2; 95% CI, 16.9-153.2), RFS (hazard ratio, 0.37; 95% CI, 0.2-0.6), and OS (hazard ratio, 0.21; 95% CI, 0.1-0.4). CONCLUSIONS: Among patients with post-NAT resected BR/LA PDAC, FDG-PET highly predicts pathologic response and survival, superior to biochemical responses alone. Given the poor ability of anatomic imaging or biochemical markers to assess NAT responses in these patients, FDG-PET is a preoperative metric of NAT efficacy, thereby allowing potential therapeutic alterations and surgical treatment decisions. We suggest that FDG-PET should be an adjunct and recommended modality during the NAT phase of care for these patients.

Cardiopulmonary Toxicity Following Intensity-Modulated Proton Therapy (IMPT) Versus Intensity-Modulated Radiation Therapy (IMRT) for Stage III Non-Small Cell Lung Cancer.

INTRODUCTION: Intensity-modulated proton therapy (IMPT) has the potential to reduce radiation dose to normal organs when compared to intensity-modulated radiation therapy (IMRT). We hypothesized that IMPT is associated with a reduced rate of cardiopulmonary toxicities in patients with Stage III NSCLC when compared with IMRT. METHODS: We analyzed 163 consecutively treated patients with biopsy-proven, stage III NSCLC who received IMPT (n = 35, 21%) or IMRT (n = 128, 79%). Patient, tumor, and treatment characteristics were analyzed. Overall survival (OS), freedom-from distant metastasis (FFDM), freedom-from locoregional relapse (FFLR), and cardiopulmonary toxicities (CTCAE v5.0) were calculated using the Kaplan-Meier estimate. Univariate cox regressions were conducted for the final model. RESULTS: Median follow-up of surviving patients was 25.5 (range, 4.6-58.1) months. Median RT dose was 60 (range, 45-72) Gy [RBE]. OS, FFDM, and FFLR were not different based on RT modality. IMPT provided significant dosimetric pulmonary and cardiac sparing when compared to IMRT. IMPT was associated with a reduced rate of grade more than or equal to 3 pneumonitis (HR 0.25, P = .04) and grade more than or equal to 3 cardiac events (HR 0.33, P = .08). Pre-treatment predicted diffusing capacity for carbon monoxide less than equal to 57% (HR 2.8, P = .04) and forced expiratory volume in the first second less than equal to 61% (HR 3.1, P = .03) were associated with an increased rate of grade more than or equal to 3 pneumonitis. CONCLUSIONS: IMPT is associated with a reduced risk of clinically significant pneumonitis and cardiac events when compared with IMRT without compromising tumor control in stage III NSCLC. IMPT may provide a safer treatment option, particularly for high-risk patients with poor pretreatment pulmonary function.

A Phase II prospective study of hypofractionated proton therapy of prostate and pelvic lymph nodes: Acute effects on patient-reported quality of life.

BACKGROUND: The objective of this study was to report acute changes in patient-reported quality of life (PRQOL) using the 26-item Expanded Prostate Index Composite (EPIC-26) questionnaire in a prospective study using hypofractionated intensity-modulated proton beam therapy (H-IMPT) targeting the prostate and the pelvic lymph nodes for high-risk or unfavorable intermediate-risk prostate cancer. METHODS: Fifty-five patients were enrolled. H-IMPT consisted of 45 GyE to the pelvic lymph nodes and 67.5 GyE to the prostate and seminal vesicles in 25 fractions. PRQOL was assessed with the urinary incontinence (UI), urinary irritative/obstructive symptoms (UO), and bowel function (BF) domains of EPIC-26 questionnaire. Mean changes in domain scores were analyzed from pretreatment to the end of treatment and 3 months posttreatment. A clinically meaningful change (or minimum important change) was defined as a score change > 50% of the baseline standard deviation. RESULTS: The mean scores of UO, UI, and BF at baseline were 84.6, 91.1, and 95.3, respectively. At the end of treatment, there were statistically significant and clinically meaningful declines in UO and BF scores (-13.5 and -2.3, respectively), while the decline in UI score was statistically significant but not clinically meaningful (-13.7). A clinically meaningful decline in UO, UI, and BF scores occurred in 53.5%, 22.7%, and 73.2% of the patients, respectively. At 3 months posttreatment, all three mean scores showed an improvement, with fewer patients having a clinically meaningful decline in UO, UI, and BF scores (18.4%, 20.5%, and 45.0%, respectively). There was no significant reduction in the mean UO and UI scores compared to baseline, although the mean BF score remained lower than baseline and the difference was clinically meaningful. CONCLUSIONS: UO, UI, and BF scores of PRQOL declined at the end of H-IMPT. UO and UI scores showed improvement at 3 months posttreatment and were similar to the baseline scores. However, BF score remained lower at 3 months posttreatment with a clinically meaningful decline.