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Purpose:Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS).Patients and Methods:Patients with AST received SBRT (30–50 Gy in 3–5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray.Results:Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17–0.75; P = 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T-cell genes and irradiated tumor response.Conclusions:In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.

Stereotactic radiosurgery (SRS) is a standard of care for many patients with brain metastases. To optimize post-SRS surveillance, this study aimed to validate a previously published nomogram predicting post-SRS intracranial progression (IP). We identified consecutive patients completing an initial course of SRS across two institutions between July 2017 and December 2020. Patients were classified as low- or high-risk for post-SRS IP per a previously published nomogram. Overall survival (OS) and freedom from IP (FFIP) were assessed via the Kaplan–Meier method. Assessment of parameters impacting FFIP was performed with univariable and multivariable Cox proportional hazard models. Among 890 patients, median follow-up was 9.8 months (95% CI 9.1–11.2 months). In total, 47% had NSCLC primary tumors, and 47% had oligometastatic disease (defined as ≤5 metastastic foci) at the time of SRS. Per the IP nomogram, 53% of patients were deemed high-risk. For low- and high-risk patients, median FFIP was 13.9 months (95% CI 11.1–17.1 months) and 7.6 months (95% CI 6.4–9.3 months), respectively, and FFIP was superior in low-risk patients (p < 0.0001). This large multisite BM cohort supports the use of an IP nomogram as a quick and simple means of stratifying patients into low- and high-risk groups for post-SRS IP.

Purpose Data comparing moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) are lacking. We aim to compare late toxicity profiles of patients with early-stage prostate cancer treated with moderately hypofractionated PBT and IMRT. Methods and Materials This multi-institutional analysis included patients with low- or intermediate-risk biopsy-proven prostate adenocarcinoma from 7 tertiary referral centers treated from 1998 to 2018. All patients were treated with moderately hypofractionated radiation, defined as 250 to 300 cGy per daily fraction given for 4 to 6 weeks, and stratified by use of IMRT or PBT. Primary outcomes were late genitourinary (GU) and gastrointestinal (GI) toxicity. Adjusted toxicity rates were calculated using inverse probability of treatment weighting, accounting for race, National Comprehensive Cancer Network risk group, age, pretreatment International Prostate Symptom Score (GU only), and anticoagulant use (GI only). Results A total of 1850 patients were included: 1282 IMRT (median follow-up 80.0 months) and 568 PBT (median follow-up 43.9 months). Overall toxicity rates were low, with the majority of patients experiencing no late GU (56.6%, n = 1048) or late GI (74.4%, n = 1377) toxicity. No difference was seen in the rates of late toxicity between the groups, with late grade 3+ GU toxicity of 2.0% versus 3.9% (odds ratio [OR] 0.47; 95% confidence interval 0.17-1.28) and late grade 2+ GI toxicity of 14.6% versus 4.7% (OR 2.69; confidence interval 0.80-9.05) for the PBT and IMRT cohorts, respectively. On multivariable analysis, no factors were significantly predictive of GU toxicity, and only anticoagulant use was significantly predictive of GI toxicity (OR 1.90; P = .008). Conclusions In this large, multi-institutional analysis of 1850 patients with early-stage prostate cancer, treatment with moderately hypofractionated IMRT and PBT resulted in low rates of toxicity. No difference was seen in late GI and GU toxicity between the modalities during long-term follow-up. Both treatments are safe and well tolerated.

BACKGROUND: Moderately hypofractionated radiotherapy (MHRT) is an accepted treatment for localized prostate cancer; however, limited MHRT data address high-risk prostate cancer (HRPC) and/or African American patients. We report clinical outcomes and toxicity profiles for individuals with HRPC treated in an equal access system. METHODS: We identified patients with HRPC treated with MHRT at a US Department of Veterans Affairs referral center. Exclusion criteria included < 12 months follow-up and elective nodal irradiation. MHRT included 70 Gy over 28 fractions or 60 Gy over 20 fractions. Acute and late gastrointestinal (GI) and genitourinary (GU) toxicities were graded using Common Terminology Criteria for Adverse Events, version 5.0. Clinical endpoints, including biochemical recurrence-free survival (BRFS), distant metastases-free survival (DMFS), overall survival (OS), and prostate cancer–specific survival (PCSS) were estimated using Kaplan-Meier methods. Clinical outcomes, acute toxicity, and late toxicity-free survival were compared between African American and White patients with logistic regression and log-rank testing. RESULTS: Between November 2008 and August 2018, 143 patients with HRPC were treated with MHRT and followed for a median of 38.5 months; 82 (57%) were African American and 61 were White patients. Concurrent androgen deprivation therapy (ADT) was provided for 138 (97%) patients for a median duration of 24 months. No significant differences between African American and White patients were observed for 5-year OS (73% [95% CI, 58%–83%] vs 77% [95% CI, 60%–97%]; P = .55), PCSS (90% [95% CI, 79%–95%] vs 87% [95 % CI, 70%–95%]; P = .57), DMFS (91% [95% CI, 80%–96%] vs 81% [95% CI, 62%–91%]; P = .55), or BRFS (83% [95% CI, 70%–91%] vs 71% [95% CI, 53%–82%]; P = .57), respectively. Rates of acute grade 3+ GU and GI were low overall (4% and 1%, respectively). Late toxicities were similarly favorable with no significant differences by race. CONCLUSIONS: Individuals with HRPC treated with MHRT in an equal access setting demonstrated favorable clinical outcomes that did not differ by race, alongside acceptable rates of acute and late toxicities.

Non-small-cell lung cancer (NSCLC) causes significant mortality each year. After successful resection of disease stage IB (>4 cm) to IIIA (per AJCC 7), adjuvant platinum-based chemotherapy improves median overall survival and is the standard of care, but many patients still experience recurrence of disease. An adjuvant regimen with greater efficacy could substantially improve outcomes. Pembrolizumab, a programmed cell death-1 inhibitor, has become an important option in the treatment of metastatic NSCLC. ALCHEMIST is a clinical trial platform of the National Cancer Institute that includes biomarker analysis for resected NSCLC and supports therapeutic trials including A081801 (ACCIO), a three-arm study that will evaluate both concurrent chemotherapy plus pembrolizumab and sequential chemotherapy followed by pembrolizumab to standard of care adjuvant platinum-based chemotherapy. Clinical trial registration: NCT04267848 (ClinicalTrials.gov), Tweetable abstract Non-small-cell lung cancer adjuvant platinum-based therapy is standard of care (SOC). Including pembrolizumab may improve efficacy. A081801 (ACCIO) is a three-arm study: SOC versus sequential chemotherapy–pembrolizumab versus concurrent chemotherapy + pembrolizumab.

PURPOSE: Stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) is a standard of care for medically inoperable patients. Our aim was to compare Common Terminology Criteria for Adverse Events (CTCAE) thoracic grade 3 or higher adverse events (AEs) of 30 Gy in one fraction (arm 1) vs. 60 Gy in 3 fractions (arm 2). METHODS: This was a randomized multi-institutional, phase II, two-arm, clinical trial. Medically inoperable patients with biopsy-proven peripheral T1/T2N0M0 NSCLC tumors were enrolled. Patients were randomized to arm 1 or arm 2 and stratified by performance status. The primary endpoint was CTCAE thoracic grade 3 or higher AEs. Secondary end points were local control (LC), progression-free survival (PFS), overall survival (OS), and quality of life (QOL). RESULTS: Between September, 2008 and April, 2015, 98 patients were randomized. Median follow-up was 53.8 months. 10 patients were lost to follow-up; 1 in arm 1 and 9 in arm 2. Thoracic grade 3 AEs were experienced by 8 (16%) patients on arm 1 and 6 (12%) patients on arm 2 there were no grade 4 or 5 AEs.. There were no differences in LC, PFS or OS (p= 0.68, 0.86 and 0.94, respectively). Arm 1 reported better social functioning (p=0.006) with less dyspnea (p=0.016) in follow-up at 6 months. CONCLUSIONS: This randomized phase II study demonstrated 30 Gy in one fraction was equivalent to 60 Gy in three fractions in terms of toxicity, LC, PFS and OS. QOL measures of social functioning and dyspnea favored single fraction SBRT.

BACKGROUND: Combining radiotherapy (RT) and immunotherapy (IT) may enhance outcomes for metastatic non-small cell lung cancer (mNSCLC). However, data on the immunomodulatory effects of extracranial RT remains limited. This retrospective database analysis examined real-world practice patterns, predictors of survival, and comparative effectiveness of extracranial radioimmunotherapy (RT + IT) versus early-incorporation immunotherapy (eIT) in patients with mNSCLC. METHODS: Patients diagnosed with mNSCLC between 2004–2016 treated with eIT or RT + IT were identified in the National Cancer Database. Practice patterns were assessed using Cochrane-Armitrage trend test. Cox proportional hazards and Kaplan-Meier method were used to analyze overall survival (OS). Propensity score matching was performed to account for baseline imbalances. Biologically effective doses (BED) were stratified based on the median (39 Gy(10)). Stereotactic body radiotherapy (SBRT) was defined as above median BED in ≤5 fractions. RESULTS: eIT utilization increased from 0.3% in 2010 to 13.2% in 2016 (P

Purpose: Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS). Patients and Methods: Patients with AST received SBRT (30–50 Gy in 3–5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray. Results: Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17–0.75; P = 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T-cell genes and irradiated tumor response. Conclusions: In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.

Purpose: We previously reported on the clinical outcomes of treating oligometastases with radiation using an elective simultaneous integrated boost technique (SIB), delivering higher doses to known metastases and reduced doses to adjacent bone or nodal basins. Here we compare outcomes of oligometastases receiving radiation targeting metastases alone (MA) versus those treated via an SIB. Methods: Oligometastatic patients with ≤5 active metastases treated with either SIB or MA radiation at two institutions from 2013 to 2019 were analyzed retrospectively for treatment-related toxicity, pain control, and recurrence patterns. Tumor metastasis control (TMC) was defined as an absence of progression in the high dose planning target volume (PTV). Marginal recurrence (MR) was defined as recurrence outside the elective PTV but within the adjacent bone or nodal basin. Distant recurrence (DR) was defined as any recurrence that is not within the PTV or surrounding bone or nodal basin. The outcome rates were estimated using the Kaplan–Meier method and compared between the two techniques using the log-rank test. Results: 101 patients were treated via an SIB to 90 sites (58% nodal and 42% osseous) and via MA radiation to 46 sites (22% nodal and 78% osseous). The median follow-up among surviving patients was 24.6 months (range 1.4–71.0). Of the patients treated to MA, the doses ranged from 18 Gy in one fraction (22%) to 50 Gy in 10 fractions (50%). Most patients treated with an SIB received 50 Gy to the treated metastases and 30 Gy to the elective PTV in 10 fractions (88%). No acute grade ≥3 toxicities occurred in either cohort. Late grade ≥3 toxicity occurred in 3 SIB patients (vocal cord paralysis and two vertebral body compression), all related to the high dose PTV and not the elective volume. There was similar crude pain relief between cohorts. The MR-free survival rate at 2 years was 87% (95% CI: 70%, 95%) in the MA group and 98% (95% CI: 87%, 99%) in the SIB group (p = 0.07). The crude TMC was 89% (41/46) in the MA group and 94% (85/90) in the SIB group. There were no significant differences in DR-free survival (65% (95% CI: 55–74%; p = 0.24)), disease-free survival (60% (95% CI: 40–75%; p = 0.40)), or overall survival (88% (95% CI: 73–95%; p = 0.26)), between the MA and SIB cohorts. Conclusion: Both SIB and MA irradiation of oligometastases achieved high rates of TMC and similar pain control, with a trend towards improved MR-free survival for oligometastases treated with an SIB. Further investigation of this technique with prospective trials is warranted.

Background: Adjuvant chemotherapy (AC) after chemoradiation (CRT) and surgery for locoregionally advanced rectal cancer (LARC) is a standard of care in the United States. This study examined the role, optimal regimen, and duration of AC using data from the largest integrated health system in the United States. Patients and Methods: Using the Veterans Affairs Central Cancer Registry, patients with stage II–III rectal cancer diagnosed in 2001 through 2011 who received neoadjuvant CRT and surgery with or without AC were identified. Kaplan-Meier analysis, log-rank tests, and propensity score (PS) adjustment analysis were used to assess survival. Results: A total of 866 patients were identified; 417 received AC and 449 did not (observation [OBS] group). Median follow-up was 109 months. Median disease-specific survival (DSS) was not reached. Six-year DSS was 73.7%; 79.5% for the AC group versus 68.0% for the OBS group. PS-matched analysis for DSS favored AC (P=.0002). Median overall survival (OS) was 90.8 months. Six-year OS was 56.7%; 64.3% for AC versus 49.6% for OBS. In PS-matched analysis, median OS was 117.4 months for AC and 74.3 months for OBS (PP=.023). No difference in DSS or OS was seen with single-agent versus multiagent AC. Conclusions: In this population of patients with LARC treated with neoadjuvant CRT and surgery, OS and DSS were improved among those treated with AC versus OBS. DSS benefits were seen with ≥4 months of AC. No additional benefit was observed with multiagent therapy. In the absence of phase III data, these findings support the use of AC for LARC.

INTRODUCTION: Treatment of advanced stage non-small cell lung cancer (NSCLC) has changed dramatically due to immunotherapy. However, patients without Programmed Death-Ligand 1 (PD-L1) protein expression often benefit less from immunotherapy. This trial is designed to test if stereotactic body radiation therapy (SBRT) to a single tumor site can significantly enhance the outcome of patients with advanced stage PD-L1(−) NSCLC when added to systemic therapy including immunotherapy. MATERIALS AND METHODS: Alliance A082002 is based on subgroup analysis from the randomized phase II PEMBRO-RT trial., PEMBRO-RT compared pembrolizumab alone or with SBRT and revealed improved progression-free and overall survival (PFS and OS, respectively) in PD-L1(−) patients when adding SBRT (8 Gy x 3 fractions). In A082002, patients without PD-L1 expression will be randomized to SBRT (8 Gy x3) plus systemic therapy versus systemic therapy alone. The primary endpoint of the phase II portion of the trial is PFS and will require 100 patients. The primary endpoint of the phase III portion of the trial is OS and will require an additional 284 patients. This trial will clarify whether adding SBRT to systemic therapy can improve PFS and OS in a larger multi-institutional cohort. Several systemic treatment options are allowed including either immunotherapy alone or chemo-immunotherapy. CONCLUSIONS: This phase II/III Alliance trial A082002 will test whether the addition of SBRT to a single tumor site will enhance the anti-tumor activity of systemic immunotherapy or chemo-immunotherapy in patients with stage IV PD-L1(−) NSCLC. It is now open in the National Clinical Trials Network (NCTN).

The Oncotype DX Genomic Prostate Score (GPS) assay has been validated as a strong prognostic indicator of adverse pathology, biochemical recurrence, distant metastasis (DM), and prostate cancer (PCa)-related death (PCD) in men with localized PCa after radical prostatectomy. However, it has yet to be tested in men undergoing external beam radiation therapy (EBRT), for whom assessing PCa progression risk could inform decisions on treatment intensity. We analyzed whether GPS results are associated with time to biochemical failure (BCF), DM, and PCD after EBRT in men with localized PCa and whether the association is modified by race.We conducted a retrospective study of men with localized PCa treated with EBRT at the VA Health Care System in Durham, NC from 2000 to 2016. Study endpoints were time to BCF per the Phoenix criteria, DM, and PCD. The association of GPS results, per 20-unit increase or dichotomous variable (0-40 vs 41-100), was evaluated with each endpoint using univariable and multivariable Cox proportional hazards models. Results were then stratified by race.A total of 238 patients (69% Black) met the eligibility criteria. Median follow-up for patients who did not experience BCF was 7.6 years. GPS results per 20-unit increase were significantly associated with BCF (hazard ratio [HR], 3.62; 95% confidence interval [CI], 2.59-5.02), DM (HR, 4.48; 95% CI, 2.75-7.38), and PCD (HR, 5.36; 95% CI, 3.06-9.76) in univariable analysis. GPS results remained significant in multivariable models adjusted for baseline clinical and pathological factors, with HRs being similar to the univariable analysis. There was no significant interaction between the GPS assay and race (P = .923). HRs for BCF were similar in Black men (HR, 3.88; 95% CI, 2.40-6.24) versus non-Black men (HR, 4.01; 95% CI, 2.42-6.45).Among men treated with EBRT, the GPS assay is a strong, independent prognostic indicator of time to BCF, DM, and PCD, and performs similarly in Black and non-Black men.

Objective. The purpose of this study was to investigate whether, compared with traditional criteria, the modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapeutics (iRECIST) improves prediction of local tumor control and survival in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT). Materials and Methods. Fifty-one HCC lesions (mean size, 3.1 cm) treated with SBRT in 41 patients (mean age, 67 years) were retrospectively included. Each patient underwent CT or MRI before SBRT and at least once after SBRT. Best overall response was categorized using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), iRECIST, World Health Organization (WHO) criteria, modified Response Evaluation Criteria in Solid Tumors (mRECIST), and European Association for the Study of the Liver (EASL) criteria. Lesions were then classified as local tumor control (i.e., stable disease, partial response, or complete response) or local treatment failure (i.e., progressive disease) by each tumor response criteria. Proportions of local tumor control were compared using the McNemar exact test. The 1-year overall survival was estimated using the Kaplan-Meier method. Results. The median follow-up after SBRT was 21.0 months. The local tumor control rate was 94.1% (48/51) by iRECIST, 88.2% (45/51) by RECIST 1.1, 72.5% (37/51) by WHO criteria, 80.4% (41/51) by mRECIST, and 72.5% (37/51) by EASL criteria. The local tumor control rate was significantly higher according to iRECIST compared with WHO (p = 0.0010) and EASL (p = 0.0225) criteria. The 1-year survival rate for patients with local tumor control according to iRECIST (86.4%) was higher (although not statistically significant) compared with the 1-year survival rate for patients with local tumor control according to the other response criteria. Conclusion. iRECIST may provide more robust interpretation of HCC response after SBRT, yielding improved prediction of local tumor control and 1-year survival rates compared with traditional criteria.

Standard therapy for locally advanced rectal cancer includes neoadjuvant chemoradiation and surgery. Complete response (CR) rates after chemoradiation can be as high as 29%, suggesting that nonoperative management (NOM) may be reasonable with appropriately selected patients. We sought to identify potential NOM candidates.Using the Veterans Administration Central Cancer Registry, patients with stage II to III rectal cancer receiving chemoradiation with or without subsequent surgery were identified. Clinical CR (cCR) was assessed by physical examination, endoscopy, or imaging. Kaplan-Meier and log-rank tests were used to assess survival; multivariate analysis was performed using Cox proportional hazards.A total of 1313 patients were identified. Of these, 313 received chemoradiation alone (CRT cohort); 1000 received chemoradiation followed by surgery (CRT + S cohort). Median follow-up was 67.2 months. Median overall survival (OS) was 68.5 months. Median OS was 30.6 months for CRT and 89.3 months for CRT + S (P .001). Median disease-specific survival (DSS) was 44.8 months for CRT and not reached (NR) for CRT + S (P .001). Sixty-five CRT patients (20.8%) had a cCR. Median OS for CRT cCR patients was 73.5 months (P = .128 vs CRT + S); median DSS was NR (P = .161 vs CRT + S). One hundred thirty-seven (10.5%) CRT + S patients had a pathologic CR (pCR). Median OS with pCR was 133.7 months (P .001 vs CRT cCR), and median DSS was NR (P = .276 vs CRT cCR).CRT patients with cCR had similar OS and DSS versus CRT + S patients and similar DSS versus CRT + S patients with a pCR. This suggests that patients with locally advanced rectal cancer with a cCR to CRT have an excellent prognosis and may be candidates for organ preservation.

Purpose: To evaluate the effect of prostate volume on outcomes after moderately hypofractionated radiation therapy (mHFRT) for prostate cancer. Methods and Materials: Prostate cancer patients treated with mHFRT at a Veteran's Affairs Medical Center from August 20, 2008, to January 31, 2018, were identified. Patients were placed into a large prostate planning target volume (LPTV) cohort if their prostate PTV was in the highest quartile. Acute/late genitourinary (GU) and gastrointestinal toxicity events among patients with and without LPTV were compared. Multivariable analyses estimated the effect of factors on toxicity. Overall survival, biochemical recurrence-free survival, and freedom from late GU/gastrointestinal toxicity of patients with and without LPTV were estimated via Kaplan-Meier. Results: Four hundred and seventy-two patients were included. Ninety-three percent received 70 Gy in 2.5 Gy fractions; 75% received androgen deprivation therapy. Median follow-up was 69 months. Patients with LPTV (PTV >138.4 cm3) had a higher late 2 + GU toxicity compared with those without (59% vs 48%, P = .03). Earlier time to late 2 + GU toxicity was associated with LPTV (hazard ratio 1.36; 95% confidence interval [CI], 1.00-1.86; P = .047), androgen deprivation therapy use (hazard ratio 1.60; 95% CI, 1.13-2.27; P = .01), and higher baseline American Urologic Association symptom score (odds ratio 1.03; 95% CI, 1.02-1.05; P < .001). At 2 years, freedom from late 2 + GU toxicity was 46% (95% CI, 47%-54%) for those with LPTV versus 61% (95% CI, 55%-65%) for those without (P = .04). Late grade 3 GU toxicity was 7% for those with LPTV and 4% for those without. No differences in overall survival or biochemical recurrence-free survival were observed between patients with or without LPTV. Conclusions: LPTV did not affect efficacy of mHFRT for prostate cancer; however, it was associated with increased risk and earlier onset of late grade 2 + GU toxicity.

Purpose/objective(s) Management of HCC without surgical resection or transplantation is poorly defined with no standard. Stereotactic body radiation therapy (SBRT) or hypofractionated image-guided radiotherapy (HIGRT), is an evolving, non-invasive, therapeutic option for patients with HCC delivering ablative doses with modest toxicity. Materials/methods We retrospectively identified all patients with unresectable, non-metastatic HCC treated with SBRT/HIGRT who presented to our University and Veterans Affairs (VA) radiation oncology departments from 2013 to 2019. Primary study endpoints included freedom from local progression, progression free survival, overall survival, and treatment-related toxicity. Results 149 patients were included in our analysis with median delivered radiation dose of 50 Gy in 5 fractions. This included a total of 172 treatment courses, as 21 patients received more than one course (19 patients received 2 courses; 2 patients received 3 courses). Twenty-two of the re-treatment courses were to previously unirradiated lesions, while one course was delivered to a previously treated lesion exhibiting local progression. Sixty-nine percent (69%) of patients were Child-Pugh A and 89% had a baseline ALBI grade of 1-2 prior to treatment. A majority of patients (59%) had a single lesion with a median size of 2.70 cm (Q1 2.00, Q3 3.95). Fifty-seven percent (57%) of patients received a biologically effective dose (BEDα/β = 10) of at least 75 Gy and 48% of patients had undergone prior liver-directed therapy. All patients completed their intended treatment course with 1 patient (0.7%) experiencing Grade 3+ acute and 4 patients (2.6%) experiencing Grade 3+ late toxicities. Fifteen treatment courses (8.7%) resulted in non-classical radiation-induced liver disease (RILD), defined as an increase of 2 or more points in Child-Pugh score following radiation. With median follow up of 40 months, median overall survival was 25 months (95% CI 18-30 months). The 2-year freedom from local progression was 75% (95% CI 65-83%) overall, 64% (95% CI 48-77%) among patients who received BED ≤75 Gy and 86% (95% CI 72-93%) among those who received BED > 75 Gy. Median progression free survival was not reached. During the study period, 8.1% of patients developed regional nodal progression and 18.8% developed distant metastatic disease (42.9% osseous, 50.0% lung, 46.4% soft tissue/peritoneal/other involvement; multiple patients with more than one site of metastatic involvement). Conclusion SBRT/HIGRT results in high rates of local control with minimal treatment related toxicities. Randomized, prospective trials should seek to establish SBRT/HIGRT as a standard local therapeutic option for patients with unresectable, non-metastatic HCC.

To develop and validate a nomogram that predicts overall survival (OS) for patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR) vs. observation.Adults with biopsy-proven T1-T2N0 NCSLC treated with SABR (30-70 Gy in 1-10 fractions with biologically effective dose ≥100 GyA total of 22,073 adults met inclusion criteria and 4418 matched pairs (total n = 8836) were identified for nomogram development. The factors most strongly associated with improved OS on multivariable analysis included younger age (HR 0.82 by decade, P.001), female sex (HR 0.81, P.001), lower comorbidity index (HR 0.65 for 0 vs. ≥3, P.001), smaller tumor size (HR 0.60 for ≤3 cm vs. 5.1-7 cm, P.001), adenocarcinoma histology (P.001), and receipt of SABR (P.001). Interaction between SABR and histology was significantly associated with OS (P = .017). Relative to adenocarcinoma, patients with squamous cell carcinoma who were observed (HR 1.44, 95% CI 1.33-1.56) or treated with SABR (HR 1.24, 95% CI 1.14-1.35) had significantly worse OS. The nomogram demonstrated fair accuracy for predicting OS, with an integrated time-dependent AUC of 0.694 over the entire follow-up period.This nomogram estimates OS at 2 and 5 years based on whether medically inoperable early-stage NSCLC patients receive SABR or elect for observation. Incorporation of other variables not captured within the NCDB may improve the model accuracy.

Objectives Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). Materials and methods Patients received veliparib orally twice daily (BID) in escalating doses (60–240 mg, Day –3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120–240 mg BID, Days –2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. Results Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7–32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0–not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0–not reached). Conclusions When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.

There is a need to foster future generations of radiation oncology physician scientists, but the number of radiation oncologists with sufficient education, training, and funding to make transformative discoveries is relatively small. A large number of MD/PhD graduates have entered he field of radiation oncology over the past 2 decades, but this has not led to a significant cohort of externally funded physician scientists. Because radiation oncologists leading independent research labs have the potential to make transformative discoveries that advance our field and positively affect patients with cancer, we created the Duke Radiation Oncology Research Scholar (RORS) Program. In crafting this program, we sought to eliminate barriers preventing radiation oncology trainees from becoming independent physician scientists. The RORS program integrates the existing American Board of Radiology Holman Pathway with a 2-year post-graduate medical education instructor position with 80% research effort at the same institution. We use a separate match for RORS and traditional residency pathways, which we hope will increase the diversity of our residency program. Since the inception of the RORS program, we have matched 2 trainees into our program. We encourage other radiation oncology residency programs at peer institutions to consider this training pathway as a means to foster the development of independent physician scientists and a diverse workforce in radiation oncology.

Background: Osteolytic lesions are present in 75% of patients with multiple myeloma (MM) and frequently require palliation with radiation therapy (RT). Prior case series of patients with MM with bone pain undergoing palliative RT suggests doses ≥12 Gy (equivalent dose in 2Gy fractions, EQD2) provide excellent bone pain relief. However, recent advances in care and novel biologic agents have significantly improved overall survival and quality of life for patients with MM. We hypothesized that lower-dose RT (LDRT, EQD2

BACKGROUND: Fat distribution varies between individuals of similar body mass index (BMI). We hypothesized that visceral obesity is more strongly associated with poor prostate cancer outcomes than overall obesity defined by BMI.MATERIALS AND METHODS: We quantified abdominal visceral and subcutaneous fat area (VFA and SFA), and pelvic periprostatic adipose tissue area (PPAT), using computed tomography scans from radiation-treated prostate cancer patients at the Durham North Carolina Veterans Administration Hospital. Multivariable-adjusted Cox regression examined associations between each adiposity measure and risk of recurrence, overall and stratified by race and receipt of androgen deprivation therapy (ADT).RESULTS: Of 401 patients (59% black) treated from 2005 to 2011, 84 (21%) experienced recurrence during 9.3 years median follow-up. Overall, obesity defined by BMI was not associated with recurrence risk overall or stratified by race or ADT, nor was any measure of fat distribution related to the risk of recurrence overall or by race. However, higher VFA was associated with increased risk of recurrence in men who received radiation only (hazard ratio [HR], 1.79; 95% confidence interval [CI], 0.87-3.66), but inversely associated with recurrence risk in men treated with radiation and ADT (HR, 0.49; 95% CI, 0.24-1.03; P-interaction = .002), though neither association reached statistical significance. Similar patterns of ADT-stratified associations were observed for PPAT and SFA.CONCLUSIONS: Associations between abdominal and pelvic adiposity measures and recurrence risk differed significantly by ADT receipt, with positive directions of association observed only in men not receiving ADT. If confirmed, our findings suggest that obesity may have varying effects on prostate cancer progression risk dependent on the hormonal state of the individual.

Metastatic breast cancer has traditionally been considered incurable, with treatments focused on systemic therapies and palliative local treatment. However, evidence is emerging that in some patients with limited metastatic disease, or "oligometastatic disease," often defined as five or fewer metastases diagnosed on imaging, aggressive metastasis-directed therapy (MDT) with surgery and/or hypofractionated image-guided radiation therapy (HIGRT) improves outcomes and may even be curative. This practice is becoming more common as evidence has grown to support the approach and as technology has made it more feasible. Treatment of certain oligometastatic breast cancers in particular (i.e., hormone receptor positive and bone-only metastases) may be especially useful given the long natural history of the disease in some of these patients. Recently, high quality data supporting ablative MDT in patients with oligometastatic disease has emerged from randomized trials for specific sites such as non-small cell lung cancer and prostate cancer, as well as from histology agnostic studies (i.e., SABR-COMET). However, randomized data in breast cancer specifically is currently lacking. Retrospective series and subgroup analysis from prospective trials have demonstrated improved outcomes with MDT for oligometastatic breast cancer. The ongoing phase II/III NRG BR002 trial seeks to provide the first randomized data to determine whether MDT in oligometastatic breast cancer improves outcomes. This may be especially important as improved systemic therapies such as targeted agents and immunotherapy prolong the disease course. Alternatively, if improved systemic therapies render patients disease free, MDT may not be necessary and only adds toxicity. However, MDT may also provide non-curative benefits for patients such as palliation of symptoms and extended time off systemic therapy. For now, aggressive MDT for certain favorable subgroups of oligometastatic breast cancer such as those with few metastases, hormone positive disease, and/or bone-only metastases is reasonable and may improve outcomes. We eagerly anticipate the results of NRG BR002 to further clarify the role of ablative therapy to all sites of disease in these patients.

Fiberoptic laryngoscopy (FOL) is a critical tool for the diagnosis, staging, assessment of treatment response, and detection of recurrence for head and neck (HN) malignancies. No standardized recommendations exist for procedural FOL education in radiation oncology. We therefore implemented a pilot simulation workshop to train radiation oncology residents in pertinent HN anatomy and FOL technique.A 2-phase workshop and simulation session was designed. Residents initially received a lecture on HN anatomy and the logistics of the FOL examination. Subsequently, residents had a practical session in which they performed FOL in 2 simulated environments: a computerized FOL program and mannequin-based practice. Site-specific attending physicians were present to provide real-time guidance and education. Pre- and postworkshop surveys were administered to the participants to determine the impact of the workshop. Subsequently, postgraduate year (PGY)-2 residents were required to complete 6 supervised FOL examinations in clinic and were provided immediate feedback.Annual workshops were performed in 2017 to 2019. The survey completion rate was 14 of 18 (78%). Participants ranged from fourth-year medical students to PGY-2 to PGY-5 residents. All PGY-2 residents completed their 6 supervised FOL examinations. On a 5-point Likert scale, mean HN anatomy knowledge increased from 2.4 to 3.7 (standard deviation = 0.6, P.0001). Similarly, mean FOL procedural skill confidence increased from 2.2 to 3.3 (standard deviation = 0.7, P.0001). These effects were limited to novice (fourth-year medical students to PGY-2) participants. All participants found the exercise clinically informative.A simulation-based workshop for teaching FOL procedural skills increased confidence and procedural expertise of new radiation oncology residents and translated directly to supervised clinical encounters. Adoption of this type of program may help to improve resident training in HN cancer.

Oligometastases represent the clinical state where metastases are limited in number and extent, and potentially amenable to definitive metastases-directed (i.e., surgical or ablative) treatment (1). Systemic therapy is the standard treatment for metastatic cancer, though over the past decade, emerging data have supported the role of surgery or radical irradiation for oligometastatic patients (2,3). The notion that metastasis-directed therapy could improve cancer control and survival outcomes date back decades (4-6), with Hellman and Weichselbaum initially coining the term “oligometastases” and formulating and refining the hypothesis in 1995 (7).

Metastatic lung cancer has long been considered incurable, with the goal of treatment being palliation. However, a clinically meaningful number of these patients with limited metastases (approximately 25%) are living long term after definitive treatment to all sites of active disease. These patients with so-called oligometastatic disease likely represent a distinct clinical group who may possess a more indolent biology compared with their more widely metastatic counterparts. Hellman and Weichselbaum proposed the existence of the oligometastatic state, on the basis of the spectrum theory of cancer spread. The literature suggests that an oligometastatic state exists in patients with non–small-cell lung cancer (NSCLC). This observation in the setting of rapidly evolving systemic therapies, including immune checkpoint inhibitors and an increasing number of targeted therapies, represents a unique clinical opportunity. Metastasis-directed therapies to address sites of disease include surgery (metastasectomy) and/or radiation therapy. Available evidence suggests that treating patients with limited or oligometastases may improve outcomes in a meaningful way; however, the majority of the randomized data includes patients with intracranial metastatic disease, and there are limited robust, randomized data available in the setting of NSCLC with only extracranial sites of metastatic disease. Ongoing randomized trials, including NRG-LU002 and the UK Conventional Care Versus Radioablation (Stereotactic Body Radiotherapy) for Extracranial Oligometastases trial, are aimed at evaluating this question further. One of the current limitations of aggressive treatment of oligometastatic NSCLC is the inability to accurately identify these patients before therapy, yet molecular markers, including microRNA profiles, are being investigated as a promising way to identify these patients.

Introduction The combined impact of advances in diagnosis and treatment of stage I NSCLC has not been assessed comprehensively. To define the survival impact of modern staging and treatment techniques for clinical stage I NSCLC, the Veterans Administration Central Cancer Registry, a database of U.S. veterans in whom the disease was diagnosed in the Veteran's Health Administration, was queried. From this database, patients who had stage I NSCLC diagnosed from 2001 to 2010 and were treated with either surgery or radiation were identified. Methods Overall survival (OS) and lung cancer–specific survival were determined. Propensity score matching and Cox multivariate analysis were used to adjust for baseline patient characteristics. Results A total of 11,997 patients were identified. The 4-year OS rate increased from 38.9% to 53.2% from 2001 to 2010 for all patients. Positron emission tomography and endobronchial ultrasound did not improve OS. Survival of radiated patients improved from 12.7% to 28.5%. The introduction of stereotactic body radiation therapy (SBRT) significantly improved OS (hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.54–0.68) and lung cancer–specific survival (HR = 0.39, 95% CI: 0.32–0.46) compared with conventionally fractionated radiation. The 4-year OS rate also improved after surgery (from 51.5% to 66.5%). This increase was associated with use of adjuvant chemotherapy, increased use of video-assisted thoracoscopic surgical procedures, and decreased pneumonectomy rates, with similar survival between open and video-assisted thoracoscopic surgical procedures. OS after lobectomy was superior to that after sublobar resection (HR = 0.82, 95% CI: 0.75–0.89). In the era of available SBRT (2008–2010), 4-year OS was not significantly different after sublobar resection or lobectomy for medically unfit patients (Charlson comorbidity index = 2) (55.4% and 58.1%, respectively; p = 0.69) but was significantly worse for fit patients (Charlson comorbidity index = 0–1) undergoing sublobar resection (55.5% and 68.0%, respectively; p OS (HR = 0.36, 95% CI: 0.35–0.38) and lung cancer–specific survival (HR = 0.31, 95% CI: 0.29–0.33) were improved after surgery as compared with after radiation, with the improvement maintained on matched comparison of lobectomy and SBRT. Conclusions OS increased in veterans with a diagnosis of stage I NSCLC from 2001 to 2010; the increase was coincident with improved radiation and surgical techniques.

PURPOSE/OBJECTIVE(S) Limited published data address modifiable risk factors for significant toxicity complicating moderately hypofractionated schedules of intensity-modulated radiation therapy (IMRT) and proton-beam therapy (PBT) in patients with early-stage prostate cancer (PC). This study explored dosimetric predictors of Grade 3+ gastrointestinal (GI) and genitourinary (GU) toxicity following IMRT or PBT in this patient population. MATERIALS/METHODS The study population included patients from five tertiary referral centers treated from 2002-2018 for low- or intermediate-risk biopsy-proven prostate adenocarcinoma. All patients were treated with moderately hypofractionated radiation defined as 250-300 cGY per daily fraction given over 4-6 weeks. Primary outcomes were late GI and GU toxicity as defined by CTCAE v4.0. Dosimetric variables included PTV max dose, PTV volume, bladder V31 Gy, bladder V50 Gy, bladder V70 Gy, bladder max dose, rectum V31 Gy, rectum V50 Gy, rectum V70 Gy, rectum max dose, penile bulb V10 Gy, penile bulb V15 Gy, and the left and right femoral head V40 Gy. The association of dosimetric variables with treatment toxicity was assessed with the Wilcoxon signed-rank test. RESULTS Dosimetric data were obtained for 1139 patients, including 667 treated with IMRT and 472 treated with PBT. Median follow-up for the two groups was 46.0 and 48.5 months, respectively. Late toxicity rates for the total population were 4.7% for Grade 3+ GU toxicity and 1.5% for Grade 3+ GI toxicity. Grade 3+ GU toxicity was associated with prostate volume, bladder V31 Gy and bladder V50 Gy (P = 0.016, P = 0.018, P = 0.028), but not with bladder V70 Gy or maximum dose to the bladder. Grade 3+ GI toxicity was not associated with any of the dosimetric variables. When analyzed by treatment group, Grade 3+ GU toxicity was observed in 3% of the IMRT cohort and 1.7% of the PBT cohort. Grade 3+ GI toxicity was seen only in PBT and was observed in 1.5% of patients. Proton plans were associated with less radiation exposure of rectum and bladder at lower doses (rectum V31 Gy: 13% vs 16%, P < 0.001; bladder V31 Gy: 18% vs 26%, P < 0.001), while IMRT was associated with less radiation exposure of rectum and bladder at higher doses (rectum V70 Gy: 0.4% vs 2%, P < 0.001; bladder V70 Gy: 1% vs 3%, P < 0.001). Photon plans yielded superior V40 Gy to the femoral heads, and superior V10 Gy and V15 Gy to the penile bulb (P < 0.001, P < 0.003, P < 0.002). CONCLUSION In this multi-institutional analysis of 1139 early-stage PC patients treated with moderately hypofractionated IMRT or PBT, risk of serious late GU and GI complications was low for both treatment groups. Analysis of the dosimetric variables identified an association of Grade 3+ GU toxicity with low-dose radiation exposure of the bladder. Grade 3+ GI toxicity was unrelated to dosimetric variables. PBT plans yielded less exposure of non-target organs to lower-dose radiation while IMRT plans yielded less exposure of non-target organs to higher-dose radiation.

Purpose/Objective(s) To date there is no clear standard non-surgical therapeutic option for HCC patients. Ablative radiation therapy (SBRT/HIGRT) is an emerging non-invasive treatment for patients with HCC. However, there is concern about the risk for radiation-induced liver toxicity following radiation in patients with decompensated liver function (Child-Pugh B/C). Materials/Methods We retrospectively identified all patients with unresectable, non-metastatic HCC treated with SBRT/HIGRT and underlying Child-Pugh B or C liver function prior to radiation therapy at our University and Veterans Affairs (VA) radiation oncology departments from 2014 to 2019. Primary endpoints included treatment-related toxicity, as well as, evaluation of dosimetric parameters for OAR. Results 38 patients (39 treatment courses) were included. Most patients (97%) had Child-Pugh B7-B9 (62% CP B7, 21% CP B8, 15% CP B9) or ALBI grade 2-3 (69% ALBI grade 2, 31% ALBI grade 3) liver disease prior to radiation therapy. A single patient had Child-Pugh C10 liver function. The most commonly utilized regimens include 50 Gy in either 5 or 10 fractions. The median delivered dose was 50 Gy (range 30-50) in an average of 7.5 fractions (range 5-10). Most patients had a single lesion (63%) with a median lesion size of 3.2 cm (range 1.10-7.40 cm). The mean liver dose was 9.40 Gy (range 3.38-23.94) with a liver D800cc of 4.14 Gy (range 0.35-17.31). All patients completed their intended treatment course with a median follow up of 43 months. Four (10.3%) treatment courses resulted in non-classical radiation-induced liver disease (RILD) (defined as an increase of 2 or more points in Child-Pugh score), compared to 8.3% for patients with Child-Pugh A liver function treated during a similar time period. Otherwise, one patient (2.6%) experienced acute grade 3+ (non-RILD) hepatobiliary toxicity (transient transaminitis). Two-year freedom from local progression was 73% (95% CI 37-90%), median overall survival 12 months (95% CI 5-25 months), and median progression free-survival was not reached. Conclusion Ablative radiation therapy as definitive management for patients with unresectable, non-metastatic HCC appears to be reasonably well tolerated in patients with decompensated liver function at baseline (Child-Pugh B7-B9), with low rates of RILD and encouraging local control. With careful selection, these patients appear to be reasonable candidates for consideration of SBRT/HIGRT. Our analysis did not include enough patients with Child-Pugh C10+ disease to draw meaningful conclusions.