Intra-operative Radiation Therapy for Colorectal or Anal Cancer at Risk for Margin-Positive Resection: Initial Results of a Single-Institution Registry.

PURPOSE: Pelvic recurrence of rectal or anal cancers is associated with considerable morbidity and mortality. We report our initial experience with an aggressive intra-operative radiotherapy (IORT) program. METHODS: Patients with locally advanced or recurrent rectal or anal cancers considered to have a high likelihood of R1 or R2 resection after multi-disciplinary review underwent surgical excision and IORT using a high-dose-rate afterloader (Ir-192) and HAM applicator. Endpoints included local or distant recurrence, and acute and late toxicity graded using the American College of Surgeons (ACS) NSQIP and the LENT-SOMA scale. RESULTS: Twenty-one patients, largely with prior history of both pelvic external beam radiotherapy (EBRT, median 50.4 Gy) and surgical resection, underwent excision with IORT (median dose 12.5 Gy, range 10-15). Median follow-up was 20 months. Twelve (57%) patients had failure at the IORT site. Freedom from failure (FFF) within the IORT field was associated with resection status (FFF at 1 year 75% for R0 vs 15% for R1/2, p = 0.0065) but not re-irradiation EBRT or IORT dose (p > 0.05). Twelve, 5, and 13 patients experienced local, regional, and distant failure, respectively; 3 (14%) patients were disease-free at last follow-up. The most frequent acute toxicity was sepsis/abscess (24%). One patient (5%) required a ureteral stent; no patients developed neuropathy attributable to IORT. CONCLUSIONS: In patients treated with excision and IORT for locally recurrent cancer, R0 resection is a critical determinant of local control. For patients with R1/2 resection, poor disease-free outcomes warrant consideration of a different treatment strategy.

Hematuria following Post-Prostatectomy Radiotherapy: Incidence Increases with Long-Term Followup.

PURPOSE: Hematuria following post-prostatectomy radiotherapy (PPRT) is inadequately characterized. We performed a consecutive cohort study of patients treated with PPRT at our institution to characterize this complication including impact on patient-reported quality of life. MATERIALS AND METHODS: Patients with potential followup ≥4 years following PPRT were identified. Freedom from ≥grade 2 hematuria (FFG2H; macroscopic blood) was estimated using the Kaplan-Meier method. Predictors of ≥grade 2 hematuria (G2H) were assessed via log-rank tests and the Cox model. Urinary patient-reported quality of life by EPIC-26 (26-question Expanded Prostate Cancer Index Composite) was compared for patients with/without hematuria using mixed-effects regression. RESULTS: A total of 216 men received PPRT (median 68.4 Gy, IQR 68.0-68.4) from 2007 to 2016 at a median of 20 months (IQR 9-45) after prostatectomy. Median followup was 72 months (IQR 54-99). A total of 85 men developed hematuria, of whom 49 (58%) underwent cystoscopy, 13 (15%) required intervention and 26 (31%) experienced recurrent hematuria. Eight-year FFG2H was 55%. G2H was highest in men treated with anticoagulation/antiplatelet therapy (HR 3.24, p <0.001), men with bladder V65 Gy ≥43% (HR 1.97, p=0.004) and men with medication allergies (HR 1.73, p=0.049). Age <65 years (HR 0.81, p=0.374) and diabetes mellitus (HR 0.49, p=0.098) were not associated with G2H. Change in urinary continence (mean -3.5, 95% CI: 10.1, 3.1) and irritation/obstruction (mean -3.0, 95% CI: 5.8, -0.3) domain scores did not exceed the minimally clinically important difference for men with/without hematuria. CONCLUSIONS: Hematuria following PPRT is common, especially among men with medication allergies and those on anticoagulation/antiplatelet therapy; however, PPRT-related hematuria is typically self-limited. Limiting bladder V65 Gy may reduce PPRT-related hematuria.

A prospective clinical and transcriptomic feasibility study of oral-only hormonal therapy with radiation for unfavorable prostate cancer in men 70 years of age and older or with comorbidity.

BACKGROUND: Androgen deprivation therapy (ADT) improves outcomes in unfavorable-risk prostate cancer (PCa) treated with radiation therapy (RT). It was hypothesized that replacing luteinizing hormone-releasing hormone (LHRH) agonists with a 5-α-reductase inhibitor (5-ARI) would improve hormonal health-related quality of life (HRQOL) without differentially suppressing androgen-responsive (AR) gene expression. METHODS: Patients with localized unfavorable-risk PCa, aged ≥70 years or Charlson Comorbidity Index score ≥2 were treated with oral ADT (oADT), consisting of 4 months of bicalutamide, a 5-ARI, and RT at 78 Gy. The primary end point was Expanded Prostate Cancer Index Composite HRQOL at 6 months ≤30%, and improvement compared with a synchronous standard of care (SOC) cohort receiving 4 months of bicalutamide and long-term LHRH agonist with RT. RNA sequencing was performed from matched pre-/post-ADT prostate tumor biopsies in a subset of men. Differential gene and pathway expressional changes were examined using gene set enrichment. RESULTS: Between 2011 and 2018, 40 and 30 men were enrolled in the oADT and SOC cohorts, respectively. Median follow-up was 40 months. Those with ≤30% decline in hormonal HRQOL at 6 months was 97% (oADT) and 93% (SOC). The average 6-month hormonal decline was 1% (oADT) versus 12% (SOC; P = .04). The 4-year freedom from biochemical failure was 88% (oADT) versus 81% (SOC; P = .48). RNA sequencing (n = 9) showed similar numbers of downregulated and upregulated genes between the treatment groups (fold-change = 2; false-discovery rate-adjusted P ≤ .05). Both treatments comparably decreased the expression of 20 genes in canonical androgen receptor signaling. CONCLUSIONS: For men with PCa undergoing RT, oral versus standard ADT may improve 6-month QOL and appears to have a similar impact on androgen-responsive gene expression.

Goals of care discussions: perceptions of radiation and medical oncologists.

BACKGROUND: Goals of care discussions (GOCD) are essential when counseling patients with cancer. Respective roles of radiation oncologists (RO) and medical oncologists (MO) in GOCD can be unclear. This study aims to clarify the dynamics and barriers to GOCD. METHODS: Five hundred and fifty-four ROs and 1604 MOs at NCI-designated comprehensive cancer centers were sent an anonymous electronic survey regarding demographics, opinions, training in GOCD, GOCD frequency, and three vignettes. Response formats were Yes/No, Likert-type, and free response. Chi-square and Wilcoxon rank-sum tests were performed. Likert-type scores were reported as median [interquartile range]. RESULTS: There were 76 (13.7%) RO and 153 (9.5%) MO who completed surveys. Sixty-three percent of RO and 66% of MO reported GOCD with > 50% of patients (p = 0.90). GOCD were initiated for declining performance status (74%) and poor life expectancy (69%). More MO (42%) received formal GOCD training compared to RO (18%) (p < 0.01). MO were more comfortable conducting GOCD than RO (p < 0.01). RO-conducted GOCD were rated to be less important by MO compared to RO (p < 0.05). Thirty-six percent of MO reported being "not at all" or "somewhat" comfortable with RO-conducted GOCD. RO-initiated GOCD with new patients were rated less appropriate by RO compared to MO perceptions of RO-initiated GOCD (p < 0.01). CONCLUSIONS: While MO and RO conduct GOCD with similar frequency, MO are more comfortable conducting GOCD and are more likely to have formal training. MO rate importance of RO involvement lower than RO. Further research is needed to understand interdisciplinary dynamics that may impact GOCD and subsequent patient care outcomes.

Comfort Level of US Radiation Oncology Graduates: Assessment of Transition to Independent Clinical Practice.

Radiation training programs are designed to prepare graduates for independent practice, with metrics in place to assess appropriateness of clinical decision-making. Here, we investigated the self-assessed preparedness of US graduates during the transition to independent practice.An anonymous, Internet-based survey was distributed to recent graduates of radiation oncology residencies (2016-2017). A Likert scale was used to assess comfort with various aspects of practice, as well as "time" to development of comfort in independent practice.Responses were obtained from 70/210 (33%), the majority reported training in programs with 5-8 residents (n = 35). Most (77%) reported designing between 500 and 900 treatment plans during training (n = 54). Only 41% of respondents reported the opportunity to review treatment plans and make decisions about safety/adequacy without attending input > 50% of the time (n = 29). Thirty percent of residents reported being responsible for seeing/managing on-treatment visits (OTVs) ≤ 75% of the time. Aspects with which practitioners reported the least comfort were understanding of billing/application to practice (2.43, IQR 2-3), orthovoltage (superficial radiation) setup and field design (2.57, IQR 1-4), and planning/delivery of prostate implants (2.82, IQR 2-4). Increased mean comfort levels were reported by those designing > 700 treatment plans in training as well as those reporting an opportunity to evaluate plans and make clinical decisions prior to attending input > 50% of the time during residency. Comfort with the delivery of stereotactic body radiation (SBRT) correlated with caseload for liver, spine, prostate, and CNS disease sites but not lung.Variations in training experiences exist across institutions. Here, a lower than expected number of residents reported seeing/managing OTVs as well as reviewing treatment plans prior to attending input during training. Overall comfort was correlated with case volume and opportunities to independently review treatment plans prior to attending input. These data highlight areas of opportunity for improving resident education with implications for ease of transition to independent clinical practice.

Utilizing the TrueBeam Advanced Imaging Package to monitor intrafraction motion with periodic kV imaging and automatic marker detection during VMAT prostate treatments.

BACKGROUND: Fiducial markers are frequently used before treatment for image-guided patient setup in radiation therapy (RT), but can also be used during treatment for image-guided intrafraction motion detection. This report describes our implementation of automatic marker detection with periodic kV imaging (TrueBeam v2.5) to monitor and correct intrafraction motion during prostate RT. METHODS: We evaluated the reproducibility and accuracy of software fiducial detection using a phantom with 3 implanted fiducial markers. Clinical implementation for patients with intraprostatic fiducials receiving volumetric modulated arc therapy (VMAT) utilized periodic on-board kV imaging with 10 s intervals during treatment delivery. For each image, the software automatically identified fiducial locations and determined whether their distance relative to planned locations were within a 3 mm tolerance. Motion was corrected if either ≥2 fiducials in a single image or ≥1 fiducial in sequential images were out of tolerance. RESULTS: Phantom studies demonstrated poorer performance of linear fiducials compared to collapsible fiducials, and wide variability to accurately detect fiducials across eight software settings. For any given setting, results were relatively reproducible and precise to ~0.5 mm. Across 17 patients treated with a median of 20 fractions, the software recommended a shift in 44% of fractions, and a shift was actually implemented after visual confirmation of movement greater than the 3 mm threshold in 20% of fractions. Adjustment of our approach led to improved accuracy for the latter (n = 7) patient subset. On average, table repositioning added 3.0 ± 0.3 min to patient time on table. Periodic kV imaging increased skin dose by an estimated 1 cGy per treatment arc. CONCLUSIONS: Periodic kV imaging with automatic detection of motion during VMAT prostate treatments is commercially available, and can be successfully implemented to mitigate effects of intrafraction motion with careful attention to software settings.

Diagnosis and Treatment of Early Stage Testicular Cancer: AUA Guideline.

PURPOSE: Testis cancer is the most common solid malignancy in young males. The purpose of this guideline is to provide a useful reference on the effective evidence-based treatment of early stage testicular cancer. METHODS: The systematic review utilized to inform this guideline was conducted by a methodology team at the Johns Hopkins University Evidence-based Practice Center. The methodology team searched using PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1980 through August 2018. The evidence review team also reviewed relevant systematic reviews and references provided by the panel to identify articles that may have been missed by the database searches. RESULTS: When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low). Such evidence-based statements are provided as Strong, Moderate, or Conditional Recommendations. In instances of insufficient evidence, additional guidance is provided as Clinical Principles and Expert Opinions. CONCLUSIONS: This guideline attempts to improve a clinician's ability to evaluate and treat patients with testicular cancer, but higher quality evidence in future trials will be essential to improve level of care for these patients.

Long term control and preservation of renal function after multiple courses of stereotactic body radiation therapy for renal cell carcinoma.

Renal cell carcinoma (RCC) is usually treated with surgery, with or without systemic therapy. For select patients, stereotactic body radiation therapy (SBRT) may be a suitable alternative. Although many reports exist on the successful use of SBRT, very few have described long term outcomes with regard to disease progression and renal function. We report a rare case of a single patient with primary, metastatic, and locally recurrent renal cell carcinoma who was successfully treated with SBRT. The patient has been disease-free for 8 years since treatment, with stable renal function even after two courses of SBRT to her solitary functioning kidney.

The use of Hormonal Therapy to Augment Radiation Therapy in Prostate Cancer: An Update.

PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) is an important adjunctive therapy to external beam radiation therapy (RT) for the definitive management of prostate cancer. The role of ADT is well-established for locally advanced or high-risk disease in conjunction with standard doses of RT, but less defined for intermediate-risk disease or with dose-escalated RT. The goal of this review is to summarize evidence evaluating the combination of ADT/RT, focusing on recent trials and current controversies as they pertain to the practicing clinician. RECENT FINDINGS: The benefit of ADT on biochemical control is maintained with dose-escalated RT according to recently reported phase III studies. Furthermore, there is now prospective, randomized evidence to support the addition of ADT to RT in the post-prostatectomy setting. ADT continues to play an important role for prostate cancer patients receiving dose-escalated RT. Future research is needed to identify subgroups most likely to benefit from this combination.

Hormonal Therapy and Radiation Therapy in Prostate Cancer: 5-Year Outcomes From a Trial Evaluating Combined Androgen Blockade With 5-Alpha Reductase Inhibitors as an Alternative to Gonadotropin Releasing Hormone Agonists.

BACKGROUND: We previously reported that for men undergoing combined androgen deprivation therapy (ADT) and radiation therapy (RT) for prostate cancer, substitution of LHRH-agonists with 5-α- reductase inhibitors (5-ARIs) led to improved preservation of 6-month hormonal quality of life (hQOL). With longer term follow-up, we evaluated disease control. METHODS: In this non-randomized trial, men with unfavorable intermediate or high-risk prostate cancer, aged ≥70 years or with Charlson Comorbidity Index ≥2, were treated with RT (78-79.2 Gy in 39-44 fractions) and either oral ADT (oADT; 5-ARI with antiandrogen) or standard of care ADT (SOC; leuprolide with antiandrogen) for up to 28 months. The primary endpoint was EPIC hQOL; secondary endpoints included biochemical control and survival as well as changes in cholesterol and hemoglobin levels. RESULTS: Between 2011 and 2018, 70 men were enrolled (40 in oADT; 30 in SOC). Median follow-up was 65 months [IQR 36-94]. Five-year freedom from biochemical failure for oADT and SOC was 89% versus 86%, disease free survival was 62% versus 69%, cancer-specific survival was 100% versus 96%, and overall survival was 70% versus 81% (all P>.1). Testosterone (2 mo through 3 yr) and hemoglobin levels (2 mo through 2 yr) were higher, and cholesterol levels (1 yr) were lower in the oADT groups (all P < .05). CONCLUSIONS: In this non-randomized study, men treated with combined RT and oADT had better preservation of hQOL and comparable 5-year disease outcomes to men treated with SOC. Eugonadal testosterone with this approach may yield measurable benefits in cholesterol and hemoglobin levels.

Monitoring Intrafraction Motion of the Prostate During Radiation Therapy: Suggested Practice Points From a Focused Review.

PURPOSE: External beam radiation therapy to the prostate is typically delivered after verification of prostatic position with image guidance. Prostate motion can occur during the delivery of each radiation treatment between the time of localization imaging and completion of treatment. The objective of this work is to review the literature on intrafraction motion (IFM) of the prostate during radiation therapy and offer clinical recommendations on management. METHODS AND MATERIALS: A comprehensive literature review was conducted on prostate motion during prostate cancer radiation therapy. Information was organized around 3 key clinical questions, followed by an evidence-based recommendation. RESULTS: IFM of the prostate during radiation therapy is typically ≤3 mm and is unlikely to compromise prostate dosimetry to a clinically meaningful degree for men treated in a relatively short treatment duration with planning target volume (PTV) margins of ≥3 to 5 mm. IFM of 5 mm or more has been observed in up to ∼10% of treatment fractions, with limited dosimetric effect related to the infrequency of occurrence and longer fractionation of therapy. IFM can be monitored in continuous or discontinuous fashion with a variety of imaging platforms. Correction of IFM may have the greatest value when tighter PTV margins are desired (such as with stereotactic body radiation therapy or intraprostatic nodule boosting), ultrahypofractionated courses, or when treatment time exceeds several minutes. CONCLUSIONS: This focused review summarizes literature and provides practical recommendations regarding IFM in the treatment of prostate cancer with external beam radiation therapy.

Bladder-Preserving Trimodality Therapy With Capecitabine.

INTRODUCTION: Many patients with muscle-invasive bladder cancer are poor candidates for radical cystectomy or trimodality therapy with maximal transurethral resection of bladder tumor (TURBT) and chemoradiotherapy with cisplatin or mitomycin C. Given the benefit of chemotherapy in bladder-preserving therapy, less-intense concurrent chemotherapy regimens are needed. This study reports on efficacy and toxicity for patients treated with trimodality therapy using single-agent concurrent capecitabine. MATERIALS AND METHODS: Patients deemed ineligible for radical cystectomy or standard chemoradiotherapy by a multidisciplinary tumor board and patients who refused cystectomy were included. Following TURBT, patients received twice-daily capecitabine (goal dose 825 mg/m2) concurrent with radiotherapy to the bladder +/- pelvis depending on nodal staging and patient risk factors. Toxicity was evaluated prospectively in weekly on-treatment visits and follow-up visits by the treating physicians. Descriptive statistics are provided. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival were estimated using the Kaplan-Meier method. RESULTS: Twenty-seven consecutive patients met criteria for inclusion from 2013 to 2023. The median age was 79 with 9 patients staged cT3-4a and 7 staged cN1-3. The rate of complete response in the bladder and pelvis was 93%. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival at 2 years were estimated as 81%, 65%, 91%, 75%, and 92%, respectively. There were 2 bladder recurrences, both noninvasive. There were 7 grade 3 acute hematologic or metabolic events but no other grade 3+ toxicities. CONCLUSION: Maximal TURBT followed by radiotherapy with concurrent capecitabine offers a high rate of bladder control and low rates of acute and late toxicity.

Tobacco use and external beam radiation therapy for prostate cancer: Influence on biochemical control and late toxicity.

BACKGROUND: The objective of this study was to examine the effect of tobacco use on disease control and late gastrointestinal and genitourinary toxicity in men undergoing external beam radiotherapy (EBRT) for prostate cancer. METHODS: In total, 633 men with known tobacco history at consultation underwent definitive EBRT between 1988 and 2008. Tobacco use was defined as positive (current or prior) or negative (never). The median EBRT dose was 74 gray (Gy). In univariate analysis, tobacco use and other prognostic factors were compared with disease control and toxicity. Multivariable analysis included tobacco use and the covariates that were associated with outcome on univariate analysis (P < .1). RESULTS: The rate of 5-year freedom from biochemical failure (FFBF) was 76% for current smokers, 81% for prior smokers, and 87% for never smokers (P < .02). Risk group, the percentage of involved cores, and EBRT dose ≥74 Gy were associated with FFBF (all P < .01). On multivariable analysis, smoking was not associated with FFBF (P = .19). Factors that were associated with late grade ≥2 genitourinary toxicity on univariate analysis included positive tobacco history, intensity-modulated radiotherapy, and EBRT dose ≥74 Gy (all P < .05). Prior transurethral resection of the prostate (P < .01) and current smoking status (P = .06) were associated with grade ≥3 toxicity. On multivariable analysis, a positive tobacco history was associated with grade ≥2 toxicity (hazard ratio, 1.45; P < .02), and current smoking status was associated with grade ≥3 toxicity (hazard ratio, 3.02; P < .05). Tobacco use was not associated with late gastrointestinal toxicity. CONCLUSIONS: In men who are receiving EBRT for prostate cancer, tobacco use may be associated with higher rates of late grade ≥2 toxicity, and current smokers may have higher rates of late grade ≥3 genitourinary toxicity.

A Contemporary Report of Low-Dose-Rate Brachytherapy for Prostate Cancer Using MRI for Risk Stratification: Disease Outcomes and Patient-Reported Quality of Life.

PURPOSE: We examined a prospective consecutive cohort of low dose rate (LDR) brachytherapy for prostate cancer to evaluate the efficacy of monotherapy for unfavorable-intermediate risk (UIR) disease, and explore factors associated with toxicity and quality of life (QOL). METHODS: 149 men with prostate cancer, including 114 staged with MRI, received Iodine-125 brachytherapy alone (144-145 Gy) or following external beam radiation therapy (110 Gy; EBRT). Patient-reported QOL was assessed by the Expanded Prostate Index Composite (EPIC) survey, and genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively recorded (CTC v4.0). Global QOL scores were assessed for decline greater than the minimum clinically important difference (MCID). Univariate analysis (UVA) was performed, with 30-day post-implant dosimetry covariates stratified into quartiles. Median follow-up was 63 mo. RESULTS: Men with NCCN low (n = 42) or favorable-intermediate risk (n = 37) disease were treated with brachytherapy alone, while most with high-risk disease had combined EBRT (n = 17 of 18). Men with UIR disease (n = 52) were selected for monotherapy (n = 42) based on clinical factors and MRI findings. Freedom from biochemical failure-7 yr was 98%. Of 37 men with MRI treated with monotherapy for UIR disease, all 36 men without extraprostatic extension were controlled. Late Grade 2+/3+ toxicity occurred in 55/3% for GU and 8/2% for GI, respectively. Fifty men were sexually active at baseline and had 2 yr sexual data; 37 (74%) remained active at 2 yr. Global scores for urinary incontinence (UC), urinary irritation/obstruction (UIO), bowel function, and sexual function (SF) showed decreases greater than the MCID (p < 0.05) in UC at 2 mo, UIO at 2 and 6 mo, and SF at 2-24 mo, and >5 yr. Analysis did not reveal any significant associations with any examined rectal or urethral dosimetry for late toxicity or QOL. CONCLUSION: Disease outcomes and patient-reported QOL support LDR brachytherapy, including monotherapy for UIR disease.

Multidisciplinary Management and Radiotherapy Recommendations for Clinically and Pathologically Node-positive Bladder Cancer.

There are limited data regarding the optimal management of patients with pelvic node-positive, but non-metastatic, bladder cancer. Increasing data demonstrate that this is a distinct clinical entity with outcomes bridging between bladder-confined muscle-invasive bladder cancer and metastatic advanced bladder cancer. Guidelines and staging systems have formalized the need to incorporate the unique considerations of management of pelvic node-positive bladder cancer. However, there remains an absence of a definite standard of care. Treatment options include systemic therapy alone, neoadjuvant chemotherapy followed by radical cystectomy, or bladder-preserving trimodality therapy. Furthermore, ongoing studies aim to determine the benefit of incorporating immunotherapy into these treatment paradigms. In this review article, we will discuss the key considerations for management of patients with pelvic node-positive bladder cancer.

Phase 1 Randomized Trial of Stereotactic Body Radiation Therapy Followed by Nivolumab plus Ipilimumab or Nivolumab Alone in Advanced/Unresectable Hepatocellular Carcinoma.

PURPOSE: Immunotherapy has emerged as a promising therapeutic option for advanced or unresectable hepatocellular carcinoma (HCC). However, survival remains poor with only a subset of patients deriving benefit. This trial investigated the safety and efficacy of stereotactic body radiation therapy (SBRT) with immunotherapy in HCC. METHODS AND MATERIALS: In this multicenter phase 1 randomized trial, patients with advanced or unresectable HCC received liver SBRT (40 Gy in 5 fractions) followed by either nivolumab alone or nivolumab plus ipilimumab. The primary endpoint was dose-limiting toxicity occurring within 6 months of SBRT. Secondary endpoints included overall response rate, progression-free survival, overall survival (OS), distant disease control, and local control of the irradiated tumor. Disease status and response endpoints were assessed radiographically every 8 weeks until progression or initiation of nonprotocol therapy. Response was determined using both RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 and iRECIST. RESULTS: Fourteen patients were enrolled across 3 centers. Thirteen patients were evaluated for study endpoints. The study was closed early because of slow accrual. The median follow-up time was 42.7 months. Dose-limiting toxicities within 6 months occurred in 2 (15.4%) of 13 patients: 1 of 6 patients in the nivolumab arm (16.7%; 90% confidence interval [CI], 0.9%-58.2%) and 1 of 7 patients in the nivolumab plus ipilimumab arm (14.3%; 90% CI, 0.7%-52.1%). Grade 3 adverse events occurred in 8 (61.6%), 5 (71.4%), and 3 (50.0%) patients in the overall nivolumab plus ipilimumab and nivolumab cohorts. Grade 3 hepatotoxicity occurred in 4 (30.8%), 3 (42.9%), and 1 (16.7%) patients in the respective cohorts. Clinical outcomes favored the nivolumab plus ipilimumab arm compared with nivolumab alone, including an overall response rate of 57% (4 of 7 patients; 90% CI, 23%-87%) versus 0% (0 of 6 patients; 90% CI, 0%-39%), median progression-free survival of 11.6 months (90% CI, 4.5 months to not reached) versus 2.7 months (90% CI, 1.3-4.7 months), and median OS of 41.6 months (90% CI, 4.5 months to not reached) versus 4.7 months (90% CI, 2.0-16.2 months) (all P < .05). With combination immunotherapy, 3-year OS was 57% (90% CI, 23%-81%), with 2 patients alive after 42.7 months without progression and negative PET. CONCLUSIONS: In this first prospective trial investigating the combination of SBRT and immunotherapy for HCC, multimodal therapy demonstrated acceptable safety. SBRT with nivolumab plus ipilimumab compared favorably to outcomes of immunotherapy alone and warrants further investigation.

Phase II Randomized Study of Salvage Radiation Therapy Plus Enzalutamide or Placebo for High-Risk Prostate-Specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy: The SALV-ENZA Trial.

PURPOSE: We sought to investigate whether enzalutamide (ENZA), without concurrent androgen deprivation therapy, increases freedom from prostate-specific antigen (PSA) progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP). PATIENTS AND METHODS: Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double-blind, phase II, placebo-controlled, multicenter study of SRT plus ENZA or placebo (ClinicalTrials.gov identifier: NCT02203695). Random assignment (1:1) was stratified by center, surgical margin status (R0 v R1), PSA before salvage treatment (PSA ≥ 0.5 v < 0.5 ng/mL), and pathologic Gleason sum (7 v 8-10). Patients were assigned to receive either ENZA 160 mg once daily or matching placebo for 6 months. After 2 months of study drug therapy, external-beam radiation (66.6-70.2 Gy) was administered to the prostate bed (no pelvic nodes). The primary end point was FFPP in the intention-to-treat population. Secondary end points were time to local recurrence within the radiation field, metastasis-free survival, and safety as determined by frequency and severity of adverse events. RESULTS: Eighty-six (86) patients were randomly assigned, with a median follow-up of 34 (range, 0-52) months. Trial arms were well balanced. The median pre-SRT PSA was 0.3 (range, 0.06-4.6) ng/mL, 56 of 86 patients (65%) had extraprostatic disease (pT3), 39 of 86 (45%) had a Gleason sum of 8-10, and 43 of 86 (50%) had positive surgical margins (R1). FFPP was significantly improved with ENZA versus placebo (hazard ratio [HR], 0.42; 95% CI, 0.19 to 0.92; P = .031), and 2-year FFPP was 84% versus 66%, respectively. Subgroup analyses demonstrated differential benefit of ENZA in men with pT3 (HR, 0.22; 95% CI, 0.07 to 0.69) versus pT2 disease (HR, 1.54; 95% CI, 0.43 to 5.47; Pinteraction = .019) and R1 (HR, 0.14; 95% CI, 0.03 to 0.64) versus R0 disease (HR, 1.00; 95% CI, 0.36 to 2.76; Pinteraction = .023). There were insufficient secondary end point events for analysis. The most common adverse events were grade 1-2 fatigue (65% ENZA v 53% placebo) and urinary frequency (40% ENZA v 49% placebo). CONCLUSION: SRT plus ENZA monotherapy for 6 months in men with PSA-recurrent high-risk prostate cancer after RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time.

Combined modality therapy for rectal cancer: the relative value of posttreatment versus pretreatment CEA as a prognostic marker for disease recurrence.

PURPOSE: To evaluate the prognostic significance of the first postsurgery carcinoembryonic antigen (CEA) level in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation (nCRT) and total mesorectal excision. METHODS: A total of 100 patients underwent nCRT and had baseline and posttreatment CEA levels recorded within 6 months of surgery. The median radiotherapy dose was 50.4 Gy. Eighty-six patients received adjuvant 5-fluorouracil-based chemotherapy. Prognostic factors were analyzed for possible associations with freedom from failure (FFF) by univariate and multivariate analyses. Median follow-up was 30 months. RESULTS: The median CEA (ng/ml) levels at baseline before nCRT, after nCRT, and after total mesorectal excision were 3.6, 1.7, and 1.3, respectively. Pathologic complete response was observed in 22%. FFF at 36 months was 78%. Local failure and distant failure occurred in 4 and 20% of the patients, respectively. On univariate analysis, pathologic complete response, margin status, and both pretreatment and postsurgery CEA levels were associated with recurrence (all P < 0.05). On multivariate analysis, pathologic complete response (P < 0.007), margin status (P < 0.001), and postsurgery CEA level (P = 0.003), but not baseline CEA level (P = 0.2), were found to be associated with recurrence. CONCLUSIONS: After nCRT for rectal cancer, postsurgery CEA level may have more prognostic value than pretreatment level. Patients with a postsurgery CEA level of >2.5 ng/ml have higher rates of recurrence and may warrant closer surveillance.