Purpose/Objective(s) We aimed to conduct the most extensive and detailed meta-analysis to date, synthesizing data from existing randomized clinical trials (RCTs) to evaluate the effectiveness and safety of hypofractionated radiotherapy (HFRT) versus conventionally fractionated, dose-escalated radiotherapy (CFRT) in the treatment of localized prostate cancer. Materials/Methods We searched Medline and relevant conference proceedings for RCTs comparing the outcomes of HFRT (dose per fraction between 2.4 to 4.5 Gy) and CFRT (dose per fraction between 1.8 to 2.0 Gy) in patients with localized prostate cancer. RCTs were excluded if the CFRT dose was below 74 Gy or the HFRT dose had an equivalent dose in 2 Gy fractions (EQD2) of less than 74 Gy, rounded. The primary outcome was biochemical and/or clinical progression-free survival (BCPFS), with secondary outcomes including prostate-cancer-specific survival (PCSS), overall survival (OS), as well as acute and late genitourinary (GU) and gastrointestinal (GI) toxicities. Survival outcomes were analyzed using hazard ratios (HR), while odds ratios (OR) were employed for toxicity data. Depending on heterogeneity, analyses were conducted using either a random-effects (RE) or a fixed-effect model (FE). Results Ten RCTs comprising a total of 6,267 patients were analyzed. One three-arm trial had an arm with a lower dose HFRT (57 Gy in 19 fractions) and this arm was excluded due to its EQD2 being less than 74 Gy. Pooled analysis showed a statistically significant improvement in BCPFS for HFRT over CFRT (HR = 0.87; 95% CI = 0.77, 0.98, p = 0.02, FE). Available subgroup data was pooled and showed significant benefit in Gleason <6 (p = 0.03, FE), PSA between 10-20 (p = 0.03, FE) and age > 70 (p = 0.01, FE). There was a trend towards significance in intermediate risk ((p = 0.06, FE) and cT1-2 (p = 0.08, FE) disease. No significant differences were observed in PCSS (HR = 0.83; 95% CI = 0.52, 1.32, p = 0.43, FE) or OS (HR = 0.90; 95% CI = 0.77, 1.04, p = 0.15, FE). HFRT was associated with a significant increase in acute grade 2+ GI toxicity (25.7% vs. 18.2%, OR = 1.61, 95% CI = 1.40, 1.85, p<0.00001, FE) and a modest but statistically significant increase in grade 2+ late GU toxicity (21.4% vs. 19.5%, OR = 1.14, 95% CI = 0.997, 1.296, p = 0.0499, FE). There was no significant difference in acute grade 2+ GU toxicity (41.2% vs. 41.8%, p = 0.83, FE) or late grade 2+ GI toxicity (14.2% vs. 13.4%, p = 0.65, RE). Conclusion HFRT demonstrates a statistically significant improvement in BCPFS for patients with localized prostate cancer when compared to CFRT. No PCSS or OS differences were observed. The benefit in BCPFS is achieved at the cost of a slight increase in both acute GI and late GU toxicities. The findings support the consideration of HFRT as the preferred option for the treatment of localized prostate cancer, balancing improved biochemical control against a modest increase in toxicities.

Methionine is an essential amino acid critical for cell growth and survival. Preclinical evidence suggests a methionine restricted diet (MRD) sensitizes cancer to radiation therapy (RT), without significant adverse effects. However, this has never been evaluated in humans. The purpose of this pilot study was to evaluate the safety and feasibility of concurrent MRD with standard-of-care definitive RT in adults with any non-skin cancer malignancy. The MRD extended from 2 wk before RT initiation, through 2 wk beyond RT completion. The primary endpoint of safety was assessed as rate of grade 3 or higher acute and late toxicities. Feasibility was assessed with quantitative plasma amino acid panel every 2 wk during the MRD (target plasma methionine 13 mu M). Nine patients were accrued over a two-year period, with five able to complete the treatment course. The trial was closed due to slow accrual and subjects' difficulty maintaining the diet. No grade 3 or higher adverse events were observed. Subjects' average methionine level was 18.8 mu M during treatment, with average nadir 16.8 mu M. These findings suggest the safety of concurrent MRD with RT, with toxicities comparable to those expected with RT alone. However, the diet was challenging, and unacceptable to most patients.

In 2017, the American Society for Radiation Oncology (ASTRO) incorporated diversity into its core mission. Accelerated by the tumultuous tragedies of 2020 with the murder of George Floyd and the stark health inequities illuminated by the COVID-19 pandemic, renewed efforts toward supporting diversity, inclusion, and health equity have culminated in a new Health Equity, Diversity, and Inclusion (HEDI) Council with new positions on the Board of Directors (BOD). Indeed, with these positions and the newly elected vice chair of the Education Council, as well as more than 40% of board positions currently occupied by women including the board's chair, this board represents the most diverse BOD in ASTRO's history of more than 60 years. ASTRO has committed to promoting a culture of inclusion and belonging that goes well beyond all-too-common virtue signaling. To this end, a cultural audit is currently underway, with findings from the external consultant anticipated this year.

e15087 Background: Methionine is an amino acid necessary for cell growth and survival. Normal cells can tolerate methionine deficiency, but most cancer cells are methionine auxotrophs, requiring dietary intake since they cannot synthesize it. In vitro, methionine deficiency causes cancer cells to undergo cell cycle arrest and cell death, and in vivo a methionine restricted diet (MRD) enhances radiosensitization without significant adverse effects. Combining a MRD and radiation therapy (RT) for human malignancies has never been evaluated. The hypothesis of this Phase I study was that a MRD would be safe, and feasible to administer concurrently with curative-intent RT. Methods: Eligible patients included adults with any non-skin cancer malignancy undergoing standard RT without concurrent cytotoxic chemotherapy. The MRD consisted of low-protein cereals, grains, and breads; fruits; vegetables; margarines and oils; and simple carbohydrates. A clinical dietician developed a personalized meal plan with each subject to reduce methionine consumption to 5-10 mg/kg body weight/day, while maintaining adequate protein and caloric intake. An unlimited supply of a commercially available methionine-free protein supplement was provided to minimize hunger and weight loss. The MRD extended from 2 weeks before initiation of RT, through 2 weeks beyond completion of RT. The primary endpoint for safety was the rate of grade 3 or higher acute and late toxicities per CTCAE, over 12 months follow-up. Feasibility was assessed with a biweekly quantitative plasma amino acid panel during the MRD. The target accrual was 15 subjects. Results: Over two years, 53 patients were offered enrollment, 9 subjects enrolled, 5 completed the MRD and RT, and 4 withdrew during the MRD. The table summarizes subjects’ characteristics and outcomes. There was no grade 3 or higher adverse events attributable to the MRD. Methionine plasma levels varied over the course of treatment, and while no subject achieved the target of 13 μM, two nadired at 14 μM. The trial was closed early due to slow accrual and subjects’ difficulty maintaining the diet. Clinical trial information: NCT03574194 .Conclusions: This study suggests a MRD is safe with thoracic or abdominopelvic RT, with toxicities comparable to those expected with RT alone. However, the diet was challenging, and unacceptable to most patients with cancer. [Table: see text]

Daily Tamoxifen was the best prophylactic treatment choice, significantly better than RT, weekly Tamoxifen and Anastrozole. RT, weekly Tamoxifen and Anastrozole were significantly better than No Treatment/Placebo, but not daily Tamoxifen, in terms of prevention of treatment-induced gynecomastia in patients with prostate cancer.

The American Brachytherapy Society (ABS), American Radium Society® (ARS), Society of Chairs of Academic Radiation Oncology Programs (SCAROP), and the Radiosurgery Society (RSS) endorse this editorial.

EDITORIAL article Front. Oncol., 24 February 2021Sec. Radiation Oncology Volume 11 - 2021 | https://doi.org/10.3389/fonc.2021.645615

Despite the continued controversy over defining an optimal delivery mechanism, the critical role of adjuvant radiation in the management of surgically resected primary and metastatic brain tumors remains one of the universally accepted standards in neuro-oncology. Local disease control still ranks as a significant predictor of survival in both high-grade glioma and treated intracranial metastases with radiation treatment being essential in maximizing tumor control. As with the emergence and eventual acceptance of cranial stereotactic radiosurgery (SRS) following an era dominated by traditional radiotherapy, evidence to support the use of intraoperative radiotherapy (IORT) in brain tumors requiring surgical intervention continues to accumulate. While the clinical trial strategies in treating glioblastoma with IORT involve delivery of a boost of cavitary radiation prior to the planned standard external beam radiation, the use of IORT in metastatic disease offers the potential for dose escalation to the level needed for definitive adjuvant radiation, eliminating the need for additional episodes of care while providing local control equal or superior to that achieved with SRS in a single fraction. In this review, we explore the contemporary clinical data on IORT in the treatment of brain tumors along with a discussion of the unique dosimetric and radiobiological factors inherent in IORT that could account for favorable outcome data beyond those seen in other techniques.

Granulosa cell tumors (GCTs) of the ovary are rare, comprising less than 5% of all malignant ovarian neoplasms. While generally considered indolent, GCTs have a tendency for metastasis and delayed relapse, with recurrence developing in 20%-50%. Recurrent or metastatic disease is associated with aggressive behavior and a poor prognosis, as nearly 70% of patients developing recurrence will eventually succumb to their disease. The optimal management of relapsed disease is controversial. Initial salvage therapy typically involves surgical debulking followed by cisplatin-based chemotherapy. Unfortunately, tumor responses are durable for less than half of patients treated with this regimen. Radiation therapy is an attractive option for providing rapid palliation and improving local control without the morbidity of additional surgery or chemotherapy. Here we describe a case of multiply recurrent, rapidly growing intraperitoneal GCT refractory to repeated surgical debulking and several lines of systemic therapy. The patient was treated with two courses of palliative radiotherapy and achieved rapid symptomatic relief, achieving over a 90% reduction in tumor volume. Serum concentration of inhibin B, often inappropriately elevated in patients with GCT, decreased by 98% following irradiation with no interim systemic therapy. At one-year follow-up, the patient has no evidence of radiographic or biochemical recurrence.

Patients receiving chemo-RT for H&N cancer were significantly more likely to have EDV/HA resulting in longer overall RT courses. Other treatment factors and patient specific factors were not associated with increased EDV/HA. Proactive management of the most common presenting symptoms in this cohort could minimize hospital encounters and improve outcomes.

This single-arm prospective trial enrolled 35 patients to assess whether radiation therapy can be added safely to CPI immunotherapy (with or without chemotherapy) in patients with metastatic non-small cell lung cancer. No grade 3 to 5 radiation-induced toxicities were observed, and a preliminary assessment of efficacy suggests that radiation may be particularly valuable for patients with high PD-L1 expression who receive CPI without chemotherapy. Introduction/Background: This study assessed the safety and systemic (abscopal) response from the addition of local stereotactic body radiation therapy (SBRT) to checkpoint inhibitor (CPI) immunotherapy in patients with metastatic non-small cell lung cancer. Patients/Methods: Thirty-five patients with at least 2 sites of measurable disease on PET/CT received standard-of-care CPI immunotherapy alone (n = 19), or in combination with 4 cycles doublet carboplatin/pemetrexed chemotherapy (n = 16), and 3 to 5 fractions SBRT to a single extracranial target lesion between cycles 1 to 2 of the systemic therapy. Adverse events were assessed using CTCAE version 5.0. Best systemic objective response rate (ORR) was assessed using iRECIST criteria, excluding any irradiated lesion(s). Additional SBRT to a different target lesion was offered to patients who continued on immunotherapy with unconfirmed progressive disease or mixed response. Results: Fifteen patients (44%) experienced 22 grade 1 to 2 toxicities potentially attributable to radiation, most commonly pneumonitis (n = 9) and fatigue (n = 6), and no grade 3 to 5 radiation-induced toxicities. Patients undergoing combined CPI-chemotherapy received a lower median biologically effective dose of SBRT than those undergoing CPI monotherapy (43.2 vs. 60Gy), but had a higher rate of radiation-induced toxicity (56% vs. 32%, P < .01). The best systemic ORR was 53%, with 20.5% stable disease and 26.5% progressive disease. Fifteen patients underwent a subsequent course of SBRT based on their response, among which 3 (20%) had progression-free intervals of 12, 16, and 10 months thereafter. Conclusions: Addition of SBRT to CPI immunotherapy (with/without chemotherapy) is safe. The favorable systemic response observed warrants further assessment with a randomized trial.

BACKGROUND:Intraoperative radiation therapy (IORT) is an alternate accelerated form of radiation following breast-conserving surgery (BCS). Lack of data regarding long-term outcomes has limited adoption. We report our experience with IORT in patients undergoing BCS versus whole breast radiation therapy (WBRT).METHODS:Retrospective review of patients undergoing BCS with IORT versus WBRT (2012-2017). Inclusion: low grade, T1-2N0M0, estrogen receptor/progesterone receptor positive, and Her2-negative infiltrating ductal carcinomas. IORT was delivered as a single fraction of radiation (20 Gy) intraoperatively. Outcomes were compared using Fisher's test for discrete variables or Wilcoxon signed-rank test for continuous variables. Kaplan-Meier method was used to estimate disease-free survival (DFS).RESULTS:Fifty-one patients (44%) received IORT, and 66 (56%) received WBRT. There was no difference in age, tumor size, receptor status, or in-breast recurrence (1.9% vs 0%, all P > .05). Length of follow-up was longer in the WBRT group due to time to inception of IORT (mean ± SD: 44 ± 8.1 vs 73 ± 13 months, P < .001). There was no difference in DFS between the 2 groups (HR 2.5; P = .44). IORT patients experienced delay to BCS (mean ± SD: 38 ± 12.7 vs 27 ± 12.2 days, P < .001) likely due to coordination of care. Analysis demonstrated IORT patients would have traveled a mean distance of 20 miles to the closest WBRT center (range 1-70, miles) for a mean travel time of 31 minutes (range 4-90, minutes) per WBRT treatment.DISCUSSION:IORT produces noninferior oncologic outcomes and decreased skin toxicity compared with WBRT. It can be convenient for patients in rural regions with limited health care access.

: Radiation has been relegated to a palliative role in the management of epithelial ovarian cancer (EOC). Contemporary radiation techniques, including intensity modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and image-guided radiation therapy, enable conformal treatment that controls local disease with minimal morbidity. Recent studies from multiple institutions support the role of radiation in the ablative treatment of oligometastatic disease and control of locally recurrent and metastatic disease. Effective local treatment with radiation complements the role of systemic therapy in the management of EOC; reduces symptoms and disease burden, and may contribute to a prolonged drug free interval.

This prospective phase II clinical trial assessed our hypothesis that stereotactic body radiation therapy (SBRT) administered concurrently with checkpoint inhibitor immunotherapy will improve the systemic response for patients with metastatic non-small cell lung cancer (NSCLC). Thirty-four enrolled patients with at least two sites of measurable disease on PET/CT received standard-of-care checkpoint inhibitor immunotherapy alone (56%) or in combination with 4 cycles Carboplatin/Pemetrexed chemotherapy (44%), as well as 3-5 fractions SBRT to a single extracranial target lesion between cycles 1-2 of systemic therapy. The primary endpoint was best systemic overall response rate (ORR) as assessed using iRECIST criteria, excluding any irradiated lesion(s). Secondary endpoints included progression free survival (PFS), overall survival (OS) and time-to-progression (TTP) using the Kaplan-Meier method, and toxicity using CTCAE. Patient, tumor and treatment-related variables were correlated with outcomes using the Fisher's exact, Wilcoxon rank-sum, and log-rank tests. The median RT biologically effective dose (BED) was 48 Gy (interquartile range 43 – 60 Gy), and RT targeted the primary tumor 65% of the time. Sixty-four percent of patients had PD-L1 tumor proportion score ≥50%, 27% had PD-L1 of 1-50%, and 9% had PD-L1 of 0%. At a median follow-up of 7 months, the best systemic ORR was 47% (28% also had stable disease). Median OS was 12.0 months, median TTP 8.5 months, and median PFS 6.1 months. There were no grade 3 or higher toxicities related to the RT. On subgroup analysis, improved response was associated with RT to the primary tumor (vs. a metastasis, p < 0.01) and PD-L1 ≥ 50% (vs. < 50%, p = 0.06). Primary tumor RT and PD-L1 ≥ 50% were also associated with significantly longer TTP and PFS (p < 0.01). The use of chemotherapy, higher BED, and size of tumor irradiated did not significantly impact ORR, TTP or PFS. Initial progressive disease was associated with significantly higher peripheral blood regulatory T-cells (27.6% vs. 0.6%, p = 0.02) and inflammatory monocytes/macrophages (1.2% vs. 0.1%, p = 0.04), and lower cytotoxic:regulatory T-cell ratio (0.26 vs. 21.3, p = 0.05). These findings compare favorably to historical standards for metastatic NSCLC evaluating immunotherapy alone (ORR 19-25%, median PFS 4 months) or in combination with chemotherapy (ORR 46%, PFS 13 months), supporting further evaluation in a Phase III study. SBRT may be particularly valuable for patients who are not candidates for chemotherapy, and when the primary tumor is amenable to RT. Peripheral blood leukocyte counts may also be a useful predictive biomarker for systemic response.

The improved preservation of neurocognition associated with post-operative stereotactic radiosurgery (SRS) over whole brain irradiation following resection of large brain metastases comes at a cost of higher rates of local failure. Intra-operative radiotherapy (IORT) is an emerging alternative which consolidates local therapy thereby reducing the burden-of-care and ameliorating challenges in defining the post-operative radiotherapy target. Here-in we report our clinical experience with IORT following resection of large brain metastases.

Bicalutamide-induced gynecomastia is a side-effect that can severely limit quality of life and use of this agent. Several prophylactic strategies exist for this potential side-effect including hormone therapy and radiotherapy. We performed a network meta-analysis(NMA) to compare all regimens simultaneously, to determine which therapy has the best results. A systematic review was performed through MEDLINE, Cochrane Central Register of Controlled Trials and meeting abstracts to identify RCTs testing treatments for Bicalutamide-induced gynecomastia. Treatments included radiotherapy(RT) and hormone therapy with either Anastrazole(ANZ) or Tamoxifen(TMX) compared to no treatment/placebo(NoTx). The primary endpoint was number of breast-events for gynecomastia development. Odds Ratio(OR) was the effect size of choice. A frequentist NMA was used to compare treatments; random–effects model was used. All test were 2-sided with an alpha = 0.05. 6 studies involving 1066 patients were identified (Boccardo 2005, Fradet 2007, Perdona 2005, Saltzein 2005, Tyrell 2005, Widmark 2003), with 4 distinct treatments: RT (n=277), ANZ (n=90), TMX (n=280) and NoTx (n=419). Gynecomastia occurred in 84% (352/419) of patients with NoTx, 66% (59/90) with ANZ, 43% (119/277) with RT, and 18% (50/280) with TMX. TMX was significantly better than RT (OR 5.48 [1.68, 17.83]), ANZ (OR 7.19 [2.32, 22.24]) and NoTx (OR 25.40 [10.29, 62.72]). RT were significantly better than NoTx (OR 4.64 [1.88, 11.47]), but did not reach significance compared to ANZ (OR 1.31 [0.30, 5.74]). ANZ was significantly better than NoTx (OR 3.54[1.03,12.11]). RT and ANZ were significantly worse compared to TMX in terms of gynecomastia development. TMX was the best prophylactic treatment choice, significantly better than RT and ANZ, which were all significantly better than NoTx in terms of prevention of Bicalutamide-induced gynecomastia.

PURPOSE:Several retrospective series have reported that patients with collagen vascular disease (CVD) are at increased risk of radiation (RT) toxicity. However, the evidence is mixed, and many series lack control groups. We performed a meta-analysis including only case-cohort or randomized studies that examined the risk of RT toxicity for patients with CVD compared with controls.METHODS AND MATERIALS:Meta-analysis of Observational Studies in Epidemiology guidelines were used to perform a comprehensive search identifying case-control or randomized studies reporting RT toxicity outcomes for patients with CVD versus controls. Data were synthesized from studies reporting grade 2 to 3 or more (G2/3 +) acute and late RT toxicities. Results were analyzed with fixed effects meta-analysis on the random-effects model for between-study heterogeneity; otherwise, the fixed-effects model was used. Hazard ratio or odds ratio (OR) were the effect-size estimators, as appropriate.RESULTS:Ten studies were included, with 4028 patients (CVD: 406, control: 3622). Patients with CVD had higher rates of acute G2/3 + toxicity (26.2% vs 16.5%, OR [odds ratio] 2.01; P < .001) and late G2/3 + toxicity (18.4% vs 10.1%, OR 2.37; P < .001). Higher rates of late G2/3 + toxicity were observed for CVD patients with systemic lupus erythematous (21% vs 9.7%; OR 2.55, P = .03), systemic scleroderma (31.8% vs 9.7%, OR 3.85; P = .03), rheumatoid arthritis (11.7% vs 8.4%, OR = 2.56; P = .008), and those irradiated to the pelvis/abdomen (32.2% vs 11.9%, OR 3.29; P = .001), breast (14.7% vs 4.4%, OR 3.51; P = .003), thorax (12.5% vs 8.7%, OR 3.46; P < .001), and skin (14.6% vs 5.2%, OR 2.59; P = .02). Late grade 5 toxicities were significantly higher for patients with CVD, although absolute rates were low (3.9% vs 0.6%, OR = 7.81; P = .01).CONCLUSIONS:Moderate and severe toxicities are more likely in patients with CVD, with variable risk depending on toxicity grade, CVD subtype, treatment site, and dose. Severe toxicities are uncommon. These factors should be considered when informing patients of treatment-related risks and monitoring for morbid treatment sequelae.

114 Background: The optimal use of adjuvant radiation following surgical resection of large brain metastases (BM) remains undetermined. Time to initiation following surgery and target delineation both impact local control (LC). Intraoperative radiotherapy (IORT) allows for elimination of lag time between surgery and radiation, direct cavity targeting, and safe dose escalation beyond traditional stereotactic radiosurgery (SRS). The current study provides an analysis of local disease control and dosimetric parameters related to intracranial IORT. Methods: Retrospective data was collected on patients treated with IORT immediately following surgical resection of BMs at three institutions according to the approval of individual IRBs. All patients were treated with the Zeiss Intrabeam device (Carl Zeiss Meditech, Germany) using spherical applicators ranging from 1.5 to 4.0cm with 50kV output. Statistical analyses were performed using SPSS (IBM) with endpoints of LC and incidence of RN, with p < 0.05 considered significant. Dosimetric comparisons between IORT and SRS were made based on V10, V12, and dose homogeneity based on percent of GTV receiving greater than 20Gy or 30Gy. Results: 54 patients were treated with IORT with a median age of 64 years. The most common primary diagnosis was non-small cell lung cancer (40%) with the most common location in the frontal lobe (38%). Median follow-up was 7.2 months and 1-year LC rate was 88% with radiation necrosis (RN) present in 4 patients (7%). The dosimetric comparison of a single IORT case revealed non-target V10 and V12 volumes as 24.75cm3 and 14.76cm3, respectively, for the SRS treatment plan of 16Gy to the margin. The V10 and V12 for the IORT treatment plan were 20.83cm3 and 9.93cm3 with a surface dose of 30Gy. The volumes exceeding 20Gy and 30Gy in the SRS plan were 14.73cm3 and 0.328cm3, respectively, while the corresponding volumes in the IORT plan were 9.8cm3 and 0cm3. Conclusions: IORT is a safe and effective means of delivering adjuvant radiation to the BM resection cavities with a high rate of LC, low incidence of RN, increased homogeneity of target dose and ability to escalate dose beyond traditional SRS plans.