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Full donor T-cell chimerism (FDTCC) after allogeneic stem cell transplant (allo-SCT) has been associated with improved outcomes in hematologic malignancy. We studied if donor human leukocyte antigen (HLA) mismatch improves achievement of FDTCC because mismatched HLA promotes donor T-cell proliferation where recipient T-cells had been impaired by previous treatment. Patients (N = 138) received allo-SCT with reduced-intensity conditioning (RIC) from 39 HLA mismatched donors (16 unrelated; 23 haploidentical) with post-transplant cyclophosphamide (PTCy) or 99 matched donors (21 siblings; 78 unrelated) with PTCy (N = 18) or non-PTCy (N = 81). Achievement of FDTCC by day 100 was higher with HLA mismatched donors than matched donors (82.1% vs. 27.3%, p 00,001), which was further improved with 200 cGy total body irradiation (87.9%) or lymphoid (versus myeloid) malignancy (93.8%). Since all mismatched transplants used PTCy, FDTCC was higher with PTCy than non-PTCy (68.4% vs. 25.7%, p 0.00001), but not in the matched transplant with PTCy (38.9%), negating PTCy as the primary driver. Lymphocyte recovery was delayed with PTCy than without (median on day + 30: 100 vs. 630/µL, p 0.0001). The benefit of FDTCC was not translated into survival outcomes, especially in myeloid malignancies, possibly due to the insufficient graft-versus-tumor effects from the delayed lymphocyte recovery. Further studies are necessary to improve lymphocyte count recovery in PTCy transplants.

OBJECTIVE Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS. In this multicenter study by the International Radiosurgery Research Foundation (IRRF), the authors aimed to evaluate radiation tolerance of structures surrounding pituitary adenomas and identify predictors of delayed hypopituitarism after SRS for these tumors. METHODS This is a retrospective review of patients with pituitary adenomas who underwent single-fraction SRS from 1997 to 2019 at 16 institutions within the IRRF. Dosimetric point measurements of 14 predefined neuroanatomical structures along the hypothalamus, pituitary stalk, and normal pituitary gland were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiographic, and endocrine outcomes. RESULTS The study cohort comprised 521 pituitary adenomas treated with SRS. Tumor control was achieved in 93.9% of patients over a median follow-up period of 60.1 months, and 22.5% of patients developed new loss of pituitary function with a median treatment volume of 3.2 cm3. Median maximal radiosurgical doses to the hypothalamus, pituitary stalk, and normal pituitary gland were 1.4, 7.2, and 11.3 Gy, respectively. Nonfunctioning adenoma status, younger age, higher margin dose, and higher doses to the pituitary stalk and normal pituitary gland were independent predictors of new or worsening hypopituitarism. Neither the dose to the hypothalamus nor the ratio between doses to the pituitary stalk and gland were significant predictors. The threshold of the median dose to the pituitary stalk for new endocrinopathy was 10.7 Gy in a single fraction (OR 1.77, 95% CI 1.17–2.68, p = 0.006). CONCLUSIONS SRS for the treatment of pituitary adenomas affords a high tumor control rate with an acceptable risk of new or worsening endocrinopathy. This evaluation of point dosimetry to adjacent neuroanatomical structures revealed that doses to the pituitary stalk, with a threshold of 10.7 Gy, and doses to the normal gland significantly increased the risk of post-SRS hypopituitarism. In patients with preserved pre-SRS neuroendocrine function, limiting the dose to the pituitary stalk and gland while still delivering an optimal dose to the tumor appears prudent.

OBJECTIVE Radiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs. METHODS From 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS. RESULTS Fifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm3, and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4–195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3–45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm3 predicted progression (HR 8.226, 95% CI 1.028–65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS. CONCLUSIONS SRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.

Background Radiation therapy (RT) is the cornerstone of management of malignant brain tumors, but its efficacy is limited in hypoxic tumors. Although numerous radiosensitizer compounds have been developed to enhance the effect of RT, progress has been stagnant. Through this systematic review, we provide an overview of radiosensitizers developed for malignant brain tumors, summarize their safety and efficacy, and evaluate areas for possible improvement. Methods Following PRISMA guidelines, PubMed, EMBASE, Cochrane, and Web of Science were searched using terminology pertaining to radiosensitizers for brain tumor RT. Articles reporting clinical evidence of nonantineoplastic radiosensitizers with RT for malignant central nervous system tumors were included. Data of interest were presumed mechanism of action, median overall survival (OS), progression-free survival (PFS), and adverse events. Results Twenty-two unique radiosensitizers were identified. Only 2/22 agents (fluosol with oxygen, and efaproxiral) showed improvement in OS in patients with glioblastoma and brain metastasis, respectively. A larger study was not able to confirm the latter. Improved PFS was reported with use of metronidazole, sodium glycididazole, and chloroquine. There was a wide range of toxicities, which prompted change of schedule or complete discontinuation of 9 agents. Conclusions Progress in radiosensitizers for malignant CNS tumors has been limited. Only 2 radiosensitizers have shown limited improvement in survival. Alternative strategies such as synthetic drug design, based on a mechanism of action that is independent of crossing the blood-brain barrier, may be necessary. Use of drug development strategies using new technologies to overcome past challenges is necessary.

Pancreatic cancer is a highly fatal malignancy for which surgery is currently considered to be the only curative treatment. However, less than a quarter of patients have disease amenable to definitive surgical resection. Local treatment with radiation therapy is a promising alternative to surgery for those patients with unresectable disease. However, conventional radiation techniques with computed tomography (CT)-guided therapy have yielded disappointing results due to the inability to deliver ablative doses of ionizing radiation, while sparing the radiosensitive adjacent organs at risk. Magnetic resonance-guided radiotherapy (MRgRT) has emerged as an alternative to CT-guided radiation treatment which allows for the delivery of higher doses of radiation with low toxicity to surrounding structures. Further study into the use of MRgRT and dose escalation for locally advanced unresectable pancreatic cancer is needed.

BackgroundPatients with bladder cancer (BC) who are cisplatin ineligible or have unresectable disease have limited treatment options. Previously, we showed targeting programmed death-ligand 1 (PD-L1) with durvalumab (durva) and radiation therapy (RT) combination was safe in BC. We now report results from a phase II study evaluating the toxicity and efficacy of durva and RT in localized BC.MethodsThis is a single-arm, multi-institutional phase II study; N=26. Enrolled patients had pure or mixed urothelial BC (T2-4 N0-2 M0) with unresectable tumors and were unfit for surgery or cisplatin ineligible. Patients received durva concurrently with RT ×7 weeks, followed by adjuvant durva × 1 year.Primary endpoints: (A) progression-free survival (PFS) at 1 year and (B) disease control rate (DCR) post adjuvant durva. Key secondary endpoints: (A) complete response (CR) post durvaRT (8 weeks), (B) overall survival (OS), (C) PFS and (D) toxicity. Correlative studies included evaluation of baseline tumor and blood (baseline, post durvaRT) for biomarkers.ResultsMedian follow-up was 27 months. Evaluable patients: 24/26 post durvaRT, 22/26 for DCR post adjuvant durva, all patients for PFS and OS. Post adjuvant durva, DCR was seen in 72.7%, CR of 54.5%. 1-year PFS was 71.5%, median PFS was 21.8 months. 1-year OS was 83.8%, median OS was 30.8 months. CR at 8 weeks post durvaRT was 62.5%. Node positive (N+) patients had similar median PFS and OS. DurvaRT was well tolerated. Grade ≥3 treatment-related adverse events: anemia, high lipase/amylase, immune-nephritis, transaminitis, dyspnea (grade 4-COPD/immune), fatigue, rash, diarrhea and scleritis. No difference in outcome was observed with PD-L1 status of baseline tumor. Patients with CR/PR or SD had an increase in naïve CD4 T cells, a decrease in PD-1+CD4 T cells at baseline and an increase in cytokine-producing CD8 T cells, including interferon gamma (IFNγ) producing cells, in the peripheral blood.ConclusionDurva with RT followed by adjuvant durva was safe with promising efficacy in localized BC patients with comorbidities, including N+ patients. Larger randomized studies, like S1806 and EA8185, are needed to evaluate the efficacy of combining immunotherapy and RT in BC.Trial registration numberNCT02891161.

IMPORTANCE: Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. OBJECTIVE: To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. DESIGN, SETTING, AND PARTICIPANTS: FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. INTERVENTIONS: SRS and WBRT for small cell lung cancer brain metastases. MAIN OUTCOMES AND MEASURES: Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score–matched analyses. RESULTS: In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score–matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P

Our purpose is to identify cancer patients at highest risk of suicide compared to the general population and other cancer patients. This is a retrospective, population-based study using nationally representative data from the Surveillance, Epidemiology, and End Results program, 1973-2014. Among 8,651,569 cancer patients, 13,311 committed suicide; the rate of suicide was 28.58/ 100,000-person years, and the standardized mortality ratio (SMR) of suicide was 4.44 (95% CI, 4.33, 4.55). The predominant patients who committed suicide were male (83%) and white (92%). Cancers of the lung, head and neck, testes, bladder, and Hodgkin lymphoma had the highest SMRs ( > 5-10) through the follow up period. Elderly, white, unmarried males with localized disease are at highest risk vs other cancer patients. Among those diagnosed at 50, from prostate, lung, and colorectal cancer patients., Cancer patients are at an increased risk of suicide: elderly, white, unmarried males with localized disease are at highest risk vs other cancer patients. Among those diagnosed at 50, from prostate, lung, and colorectal cancer patients.

398 Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, or locally advanced and unresectable have limited treatment options. DUART investigates if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. We recently reported that the combination was safe, tolerable and disease control rate (DCR) was 92% post durvaRT. Here we present interim efficacy data of our phase II study. Methods: Pts with pure or mixed urothelial bladder cancer (T2-4 N0-2 M0) were enrolled if their tumor was unresectable (35%), were unfit for surgery (50%) and/or cisplatin ineligible (89%). Primary endpoints: a) PFS at 1-yr b) DCR post adjuvant durva; Secondary endpoints: a) CR post durvaRT b) median PFS c) median OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy. Sample size was based on assumption that this regimen would increase 1 yr PFS by 25% compared to RT alone (50% to 75%); we assumed DCR of 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Twenty-six pts (19 males, 7 females) were enrolled, median age 74 yr (51-94). Sixty two percent of pts had >T2 disease, 31% had positive lymph nodes; 62% with unresectable tumor or were unfit for surgery due to comorbidities. At data cut off (9/30/2020) 20/26 pts were evaluable for DCR post adjuvant durva (3 pts with CR post durvaRT, did not get adjuvant therapy; 1 pt withdrew after 3 cycles for adjuvant durva and was on f/u with unconfirmed CR; 2 pts are still on adjuvant durva) and 25/26 for PFS and all 26 pts for OS. Post completion of adjuvant durva, DCR was seen in 70 % (14/20 with 10 CR; 3 PR; 1 SD; 6 PD). One-year probability of PFS was 73% (95% CI 56.4%, 94.4%), median PFS was 18.5 months. One-year OS probability was 83.8% (95% CI 70.4%, 99.7%) with two-year OS probability of 76.8 (95% CI 60.2%, 98%). Median OS has not been reached. We did not observe any correlation between clinical outcome and baseline tumor PD-L1 expression. Conclusions: DurvaRT followed by adjuvant durva demonstrated promising efficacy with 1-year PFS probability of 73%, 1- year OS probability of 83.8% and DCR of 70% in MIBC and locally advanced BC pts with comorbidities. Results will be updated prior to the final presentation. Efficacy was also seen in node (+) pts which led to the design of prospective randomized NCTN study. Induction chemo followed by chemo+durvaRT+ adjuvant durva vs. chemoRT combination is being evaluated in the ongoing EA8185 clinical trial (ECOG-ACRIN/NRG study) for node (+) BC pts. Clinical trial information: NCT02891161.

513 Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, unresectable have limited treatment options. In this study, we investigate if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. Our results from phase (ph) Ib suggested that the combination was safe. Here we present the response rate post durvaRT and updated treatment related adverse events (TRAEs) amongst our evaluable pts in ph II. Methods: This is a single arm ph Ib-II study for T2-4 N0-2 M0 pts. The ph II primary endpoints a) PFS rate at 1 yr b) disease control rate (DCR); secondary endpoints were a) CR post durvaRT b) PFS c) OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy post durvaRT. We anticipated that durvaRT followed by durva would increase PFS at 1 yr from 50% to 75% when compared to RT; we assumed DCR of about 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Total N = 26 patients (male 19; female 7, median age 74yr). At the time of data cut off, 21/26 pts were evaluable for response post durvaRT. Post completion of durvaRT time point, clinical CR was seen in 15/21 pts (71.4%); PR 1/21 pts (4.7%); SD 4/21 (19%); PD 1/21 (4.7%). DCR was seen in 20/21 pts (95%) post durvaRT. Median follow up from D1 to last follow up was 6.1 mos. Grade ≥ 3 TRAE amongst 26 pts: anemia (1/26), lipase/amylase (1/26), immune nephritis (1/26), dyspnea (gr 4, copd/immune), fatigue (1/26), lymphopenia (6/26). Other TRAEs: Fatigue was the most common TRAE (16/26); UTI (5/26); cystitis (3/26). No fatal TRAEs were observed. Conclusions: DurvaRT demonstrated promising efficacy with clinical CR of 71.4% and DCR of 95% in unresectable, cisplatin ineligible locally advanced BC. It was generally well tolerated. Ph II study has completed accrual and longer-term results will further our understanding of this regimen’s efficacy in locally advanced BC. Clinical trial information: NCT02891161.

468 Background: Small cell bladder carcinoma (SCBC) is an uncommon neuroendocrine tumor with poor prognosis. Treatment has largely been derived from data for small cell lung carcinoma and typically includes a multimodality approach with chemotherapy (chemo) serving as the backbone along with radical cystectomy (RC), and radiation (RT). Prior studies have demonstrated conflicting results regarding survival benefit. Methods: We performed a retrospective chart review of patients with SCBC between 2003 and 2017. We compared baseline patient characteristics and patient outcomes. OS was measured from time of initial diagnosis to death or last follow-up. Subgroup analyses were performed between patients treated with chemoRT vs. chemoRC using Fisher’s exact test for categorical variables, and nonparametric Wilcoxon Rank-Sum test for quantitative variables. Kaplan-Meier analyses were done on OS and RFS. All tests were two-sided and statistical significance level of 0.05 was used. Results: We identified a total of 31 patients with SCBC; 28 were non-metastatic and 3 were metastatic. Of the non-metastatic, 14 received chemoRT and 4 received chemoRC. The median age was 70; M:F ratio was 17:1. The median RFS in chemoRT patients was 3.05 yrs, and in chemoRC, RFS was not reached (p = 0.18). The median OS in chemoRT and chemoRC were 10.1 and 10.7 yrs respectively (p = 0.38). The overall median OS for SCBC was 2.45 yrs. Conclusions: There were no statistically significant differences in regards to median RFS or OS between the chemoRT and chemoRC patients, but this analysis was limited by the small sample size. However, the median OS in non-metastatic SCBC patients who received treatment with curative intent (chemoRT or chemoRC) was noticeably longer than that of all SCBC patients. This median OS is also longer than anticipated with small cell lung cancer and suggests that SCBC has a different natural history. These findings warrant further investigation.

455 Background: There is a significant variation in the treatment of locally advanced unresectable (T2-4 N0-2 M0) or cisplatin-ineligible (non-cis) bladder cancer (BC) patients (pts). The advent of immunotherapy (IO) in non-cis stage IV BC has been promising (response rate [RR] 23%; median survival 16 mo) but we are still in need of novel combinations for locally advanced unresectable BC. Durvalumab (Durva) is a human monoclonal antibody that inhibits the binding of PD-L1 to PD-1 on T-cell receptors. It has shown efficacy in platinum refractory BC with RR of 17%. Radiation (RT) is also effective in BC and can upregulate pro-inflammatory signals allowing for improved antitumor activity of IO. We report the safety data from phase Ib trial of combining RT with Durva (DurvaRT) in locally advanced BC. Methods: Treatment (Rx) naïve or post neoadjuvant chemotherapy pts with T3-4, N0-2, M0 who were either unresectable or unfit for surgery were treated with DurvaRT followed by Durva. Rx naïve locally advanced non-cis pts were also included in the study. DurvaRT: Durva 1500mg D1, D28 plus concurrent RT, 64.8Gy given in 36 fractions over 7weeks starting D1. These patients then started adjuvant Q4 weekly Durva after 4 weeks for 12 months. Primary end point for Ph Ib was safety of combining Durva with RT during 7-weeks period. Results: We enrolled 6 pts on phase Ib. 5/6 pts had completed the DurvaRT phase and none of them had any dose limiting toxicity. The table below summarizes the treatment related adverse events (TRAE). Post DurvaRT 3/4 pts have ongoing ORR; 1 pt. had progression; Rx response evaluation in 2 pts is ongoing. Clinical trial information: NCT02891161. Conclusions: DurvaRT was tolerable in pts with locally advanced unresectable BC, where there is a dearth for good Rx options. No grade 3 immune related AEs were observed during DurvaRT. Further investigation with DurvaRT is ongoing to evaluate the efficacy in this subset of pts (Clinical trial # NCT02891161).[Table: see text]