Long-term Renal Function Outcomes After Stereotactic Ablative Body Radiotherapy for Primary Renal Cell Carcinoma Including Patients with a Solitary Kidney: A Report from the International Radiosurgery Oncology Consortium of the Kidney.

BACKGROUND AND OBJECTIVE: Renal function preservation is particularly important following nonoperative treatment of localized renal cell carcinoma (RCC) since patients are often older with medical comorbidities. Our objective was to report long-term renal function outcomes after stereotactic ablative radiotherapy (SABR) including patients with a solitary kidney. METHODS: Patients with primary RCC treated with SABR with ≥2 yr of follow-up at 12 International Radiosurgery Consortium for Kidney institutions were included. Renal function was measured by estimated glomerular filtration rate (eGFR). KEY FINDINGS AND LIMITATIONS: In total, 190 patients (56 with a solitary kidney) underwent SABR and were followed for a median of 5.0 yr (interquartile range [IQR]: 3.4-6.8). In patients with a solitary kidney versus bilateral kidneys, pre-SABR eGFR (mean [standard deviation]) was 61.1 (23.2) versus 58.0 (22.3) ml/min (p = 0.32) and the median tumor size was 3.65 cm (IQR: 2.59-4.50 cm) versus 4.00 cm (IQR: 3.00-5.00 cm; p = 0.026). At 5 yr after SABR, eGFR decreased by -14.5 (7.6) and -13.3 (15.9) ml/min (p = 0.67), respectively, and there were similar rates of post-SABR dialysis (3.6% [n = 2/56] vs 3.7% [n = 5/134]). A multivariable analysis demonstrated that increasing tumor size (odds ratio [OR] per 1 cm: 1.57; 95% confidence interval [CI]: 1.14-2.16, p = 0.0055) and baseline eGFR (OR per 10 ml/min: 1.30; 95% CI: 1.02-1.66, p = 0.034) were associated with an eGFR decline of ≥15 ml/min at 1 yr. CONCLUSIONS AND CLINICAL IMPLICATIONS: With long-term follow-up after SABR, kidney function decline remains moderate, with no observed difference between patients with a solitary kidney and bilateral kidneys. Tumor size and baseline eGFR are dominant factors predictive of long-term renal function decline. PATIENT SUMMARY: With long-term follow-up, stereotactic ablative radiotherapy (SABR) yields moderate long-term renal function decline and low dialysis rates even in patients with a solitary kidney. SABR thus represents a promising noninvasive, nephron-sparing option for patients with localized renal cell carcinoma.

Adjuvant and salvage radiotherapy after neoadjuvant therapy and radical prostatectomy for high-risk localized prostate cancer.

BACKGROUND: We sought to describe patterns of delivery of adjuvant (aRT) and salvage RT (sRT) in patients who underwent RP after receiving neoadjuvant androgen receptor pathway inhibitor (ARPI) before radical prostatectomy (RP) for high-risk localized prostate cancer (HRLPC). METHODS: Two hundred eighteen patients treated on phase 2 neoadjuvant trials between 2006 and 2018 at two academic centers were evaluated. aRT and sRT were defined as receipt of RT with a PSA of ≤0.1 or >0.1 ng/mL, respectively. Primary outcomes were biochemical recurrence (BCR), defined as time from aRT/sRT to a PSA rising to >0.1 ng/mL, and metastasis-free survival (MFS) after RT. RESULTS: Twenty-three (11%) and 55 (25%) patients received aRT and sRT respectively. Median PSA at start of aRT and sRT was 0.01 and 0.16 ng/mL, and median duration from RP to RT was 5 and 14 months, respectively. All aRT patients had NCCN high-risk disease, 30% were pN1 and 43% had positive surgical margins; 52% had prostate bed RT. Fifty-one percent of sRT patients had biopsy Gleason 9-10, 29% were pT2 and 9% had positive surgical margins; 63% had RT to the prostate bed/pelvis. At a median follow-up of 5.3 and 3.0 years after aRT and sRT, 3-year freedom from BCR was 55% and 47%, and 3-year MFS was 56% and 53%, respectively. CONCLUSIONS: aRT was infrequently used in patients who received neoadjuvant ARPI before RP for HRLPC. Outcomes of aRT and sRT were similar but generally poor. Studies evaluating intensified systemic therapy approaches with postoperative RT in this high-risk population are needed.

A pancreatic cancer risk prediction model (Prism) developed and validated on large-scale US clinical data.

BACKGROUND: Pancreatic Duct Adenocarcinoma (PDAC) screening can enable early-stage disease detection and long-term survival. Current guidelines use inherited predisposition, with about 10% of PDAC cases eligible for screening. Using Electronic Health Record (EHR) data from a multi-institutional federated network, we developed and validated a PDAC RISk Model (Prism) for the general US population to extend early PDAC detection. METHODS: Neural Network (PrismNN) and Logistic Regression (PrismLR) were developed using EHR data from 55 US Health Care Organisations (HCOs) to predict PDAC risk 6-18 months before diagnosis for patients 40 years or older. Model performance was assessed using Area Under the Curve (AUC) and calibration plots. Models were internal-externally validated by geographic location, race, and time. Simulated model deployment evaluated Standardised Incidence Ratio (SIR) and other metrics. FINDINGS: With 35,387 PDAC cases, 1,500,081 controls, and 87 features per patient, PrismNN obtained a test AUC of 0.826 (95% CI: 0.824-0.828) (PrismLR: 0.800 (95% CI: 0.798-0.802)). PrismNN's average internal-external validation AUCs were 0.740 for locations, 0.828 for races, and 0.789 (95% CI: 0.762-0.816) for time. At SIR = 5.10 (exceeding the current screening inclusion threshold) in simulated model deployment, PrismNN sensitivity was 35.9% (specificity 95.3%). INTERPRETATION: Prism models demonstrated good accuracy and generalizability across diverse populations. PrismNN could find 3.5 times more cases at comparable risk than current screening guidelines. The small number of features provided a basis for model interpretation. Integration with the federated network provided data from a large, heterogeneous patient population and a pathway to future clinical deployment. FUNDING: Prevent Cancer Foundation, TriNetX, Boeing, DARPA, NSF, and Aarno Labs.

Conditional survival following radical cystectomy for urothelial carcinoma of the bladder.

INTRODUCTION: Traditional surveillance protocols do not adequately account for the decreasing risk of mortality over time in aggressive malignancies, such as bladder cancer. Rather, the risk of death depends on both the baseline risk of mortality and the time survived since treatment. We therefore evaluated the conditional survival of patients diagnosed with urothelial carcinoma of the bladder (UCB) following radical cystectomy (RC). PATIENTS AND METHODS: We identified patients aged 18 to 75 with Charlson 0-1 and pTany pN0-3 cM0 UCB diagnosed from 2006 to 2015 in the National Cancer Database and treated with RC. The 2- and 5-year conditional overall survival (COS)-i.e., the probability of surviving an additional 2- or 5-years given a specified time survived since treatment-was estimated using the Kaplan-Meier method. Multivariable Cox regression models with landmark time analysis were used to evaluate the associations of baseline characteristics with OS over time. RESULTS: A total of 15,594 patients were included in the study. Median follow-up was 27.8 months. The 2- and 5-year COS for the overall cohort increased through 36 months follow-up and then plateaued. When stratified by pT and pN stage, the COS gain increased with higher pT and pN stage, demonstrating the greatest increase over time for patients with pTany N1-3 disease (5-year COS of 23% at baseline, 58% at 36-months, and 71% at 60-months). In multivariable Cox regression modeling, pT and pN stage were significantly associated with higher all-cause mortality at baseline (HR 3.27 for pT4, HR 2.57 for pT3 vs. ≤pT2; HR 2.26 for pN2-3, HR 1.77 for pN1 vs. pN0), but these associations were attenuated in magnitude with increasing landmark times of 36- and 60-months (HR 1.63 for pT4, HR 1.35 for pT3 vs. ≤pT2; HR 1.34 for pN2-3, HR 1.27 for pN1 vs. pN0). Our study is limited by the retrospective design and the lack of cancer-specific survival data. CONCLUSIONS: Risk of death after RC varies with time elapsed since treatment and disease stage. Accordingly, stage-specific COS may be used to improve prognostication and surveillance protocols.

Five-Year Patient-Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer.

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 week and a day [twice a week]) or 12 fractions (4.3Gy in 2.5 weeks [5 times a week]). Secondary objectives assessed patient-reported toxicity at 5 years using the EPIC. Chi-square tests were used to assess the proportion of patients with a deterioration from baseline of >5 points for bowel, >2 points for urinary, and >11 points for sexual score. RESULTS: The study enrolled 127 patients to 5 fractions (121 eligible) and 128 patients to 12 fractions (125 eligible). The median follow-up for all patients at the time of analysis was 5.38 years. The 5-year frequency for >5 point change in bowel score were 38.4% (P = .27) and 23.4% (P = 0.98) for 5 and 12 fractions, respectively. The 5-year frequencies for >2 point change in urinary score were 46.6% (P = .15) and 36.4% (P = .70) for 5 and 12 fractions, respectively. For 5 fractions, 49.3% (P = .007) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points; for 12 fractions, 54% (P < .001) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points. Disease-free survival at 5 years is 89.6% (95% CI: 84.0-95.2) in the 5-fraction arm and 92.3% (95% CI: 87.4-97.1) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. CONCLUSIONS: This study confirms that, based on long-term changes in bowel and urinary domains and toxicity, the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.

Urothelial carcinoma of the bladder with isolated lymph node metastasis: Natural history and outcomes following surgical resection.

INTRODUCTION: Although pathologic lymph node involvement carries a poor prognosis in patients with urothelial carcinoma of the bladder (UCB), a subset of patients may demonstrate durable survival following surgical resection. To this end, there are limited contemporary data describing the natural history of UCB in patients with isolated lymph node involvement (cN0pN+) following radical cystectomy (RC) with pelvic lymph node dissection (PLND). We therefore utilized a large, nationwide oncology dataset to examine the natural history and outcomes of cN0 pN+ UCB after surgical resection. MATERIALS AND METHODS: We identified patients in the National Cancer Database (NCDB) with cN0 pN+ cM0 UCB from 2006 to 2015 treated with RC and PLND. The associations of baseline characteristics with all-cause mortality (ACM) were evaluated using Cox regression. RESULTS: A total of 2,884 patients formed the study cohort, including 42% with pN1 and 58% with pN2-3 disease. Of these, 606 (21%) received multiagent neoadjuvant chemotherapy, while 1,172 (41%) received postoperative adjuvant chemotherapy. A median of 15 (IQR 9-23) LNs were removed during PLND. The 5- and 7-year OS for the entire cohort were 20% and 17%, respectively. Compared to the overall cohort, patients surviving ≤5 years had lower pN stage (59% vs. 42% pN1) and lower pT stage (41% vs. 22% ≤pT2). On multivariable analysis, higher pT stage (HR 2.85, 95% CI 1.52-5.36 for pT3, HR 3.27, 95% CI 1.73-6.18 for pT4 vs. pT0), higher pN stage (HR 1.17, 95% CI 1.05-1.31 for pN2-3 vs. pN1), and increasing LN density (HR 2.37, 95% CI 1.88-2.99) were most strongly associated with increased ACM, while receipt of adjuvant chemotherapy (HR 0.61, 95% CI 0.55-0.68) was associated with reduced ACM. CONCLUSIONS: Although OS for patients with cN0 pN+ M0 UCB is poor, a subset of patients demonstrates durable long-term survival with 5- and 7-year OS of 20% and 17%, respectively. pT and pN stage represent important prognostic characteristics, while administration of adjuvant chemotherapy represents a potential therapeutic intervention associated with improved ACM.

Immediate radiotherapy versus observation in patients with node-positive prostate cancer after radical prostatectomy.

BACKGROUND: The optimal management of node-positive (pN1) prostate cancer following radical prostatectomy (RP) remains uncertain. Despite randomized evidence, utilization of immediate, life-long androgen deprivation therapy (ADT) remains poor, and recent trials of early salvage radiotherapy included only a minority of pN1 patients. We therefore emulated a hypothetical pragmatic trial of adjuvant radiotherapy versus observation in men with pN1 prostate cancer. METHODS: Using the RADICALS-RT trial to inform the design of a hypothetical trial, we identified men aged 50-69 years with pT2-3 Rany pN1 M0, pre-treatment PSA < 50 ng/mL prostate cancer in the NCDB from 2006 to 2015 treated with 60-72 Gy of adjuvant RT (aRT) ± ADT within 26 weeks of RP or observation. After estimating a propensity score for receipt of aRT, we estimated absolute and relative treatment effects using stabilized inverse probability of treatment (sIPW) re-weighting. RESULTS: In total, 3510 patients were included in the study, of whom 587 (17%) received aRT (73% with concurrent ADT). Median follow-up was 40.0 -months, during which 333 deaths occurred. After sIPW re-weighting, baseline characteristics were well-balanced. Adjusted overall survival (OS) was 93% versus 89% at 5-years and 82% versus 79% at 7-years for aRT versus observation (p = 0.11). In IPW-reweighted Cox regression, aRT was associated with a lower risk of all-cause mortality (ACM) than observation, but this did not reach statistical significance (HR 0.70 p = 0.06). In analyses examining heterogeneity of treatment effects, aRT was associated with improved ACM only for men with Gleason 8-10 disease (HR 0.59, p = 0.01), ≥2 positive LNs (HR 0.49, p = 0.04 for 2 positive LNs; HR 0.42, p = 0.01 for ≥3 positive LNs), or negative surgical margins (HR 0.50, p = 0.02). CONCLUSIONS: In observational analyses designed to emulate a hypothetical target trial of aRT versus observation in pN1 prostate cancer, aRT was associated with improved OS only for men with Gleason 8-10 disease, ≥2 positive LNs, or negative surgical margins.

5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney).

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a non-invasive treatment option for primary renal cell carcinoma, for which long-term data are awaited. The primary aim of this study was to report on long-term efficacy and safety of SABR for localised renal cell carcinoma. METHODS: This study was an individual patient data meta-analysis, for which patients undergoing SABR for primary renal cell carcinoma across 12 institutions in five countries (Australia, Canada, Germany, Japan, and the USA) were eligible. Eligible patients had at least 2 years of follow-up, were aged 18 years or older, had any performance status, and had no previous local therapy. Patients with metastatic renal cell carcinoma or upper-tract urothelial carcinoma were excluded. SABR was delivered as a single or multiple fractions of greater than 5 Gy. The primary endpoint was investigator-assessed local failure per the Response Evaluation Criteria in Solid Tumours version 1.1, and was evaluated using cumulative incidence functions. FINDINGS: 190 patients received SABR between March 23, 2007, and Sept 20, 2018. Single-fraction SABR was delivered in 81 (43%) patients and multifraction SABR was delivered in 109 (57%) patients. Median follow-up was 5·0 years (IQR 3·4-6·8). 139 (73%) patients were men, and 51 (27%) were women. Median age was 73·6 years (IQR 66·2-82·0). Median tumour diameter was 4·0 cm (IQR 2·8-4·9). 96 (75%) of 128 patients with available operability details were deemed inoperable by the referring urologist. 56 (29%) of 190 patients had a solitary kidney. Median baseline estimated glomerular filtration rate (eGFR) was 60·0 mL/min per 1·73 m2 (IQR 42·0-76·0) and decreased by 14·2 mL/min per 1·73 m2 (IQR 5·4-22·5) by 5 years post-SABR. Seven (4%) patients required dialysis post-SABR. The cumulative incidence of local failure at 5 years was 5·5% (95% CI 2·8-9·5) overall, with single-fraction SABR yielding fewer local failures than multifraction (Gray's p=0·020). There were no grade 3 toxic effects or treatment-related deaths. One (1%) patient developed an acute grade 4 duodenal ulcer and late grade 4 gastritis. INTERPRETATION: SABR is effective and safe in the long term for patients with primary renal cell carcinoma. Single-fraction SABR might yield less local failure than multifraction, but further evidence from randomised trials is needed to elucidate optimal treatment schedules. These mature data lend further support for renal SABR as a treatment option for patients unwilling or unfit to undergo surgery. FUNDING: None.

Adjuvant chemotherapy versus observation following radical cystectomy for locally advanced urothelial carcinoma of the bladder.

BACKGROUND: The role of adjuvant chemotherapy (AC) in patients with locally advanced bladder cancer following radical cystectomy (RC) remains uncertain, with contemporary clinical trials underpowered and closed early due to low accrual. OBJECTIVE: To conduct observational analyses designed to emulate a completed randomized trial of AC in patients with locally advanced bladder cancer. DESIGN, SETTINGS, AND PARTICIPANTS: Based on EORTC 30994 eligibility criteria, we identified adult patients aged 35 to 75 with pT3/pT4 Nany M0 or Tany pN1-3 M0, R0 urothelial carcinoma of the bladder treated with RC and lymphadenectomy from 2006 to 2015 in the National Cancer Database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A propensity score for receipt of AC within 3 months of RC was estimated, and the associations of AC with overall survival were evaluated after reweighting by stabilized inverse probability of treatment weights. RESULTS: Of the 2,416 patients who met inclusion criteria, 945 (39%) received AC after RC. After propensity score adjustment, baseline characteristics were well-balanced. Median follow-up was 26.0 months. After IPW-reweighting, overall survival was 43% vs. 36% at 5-years and 34% vs. 24% at 10-years, among those who did and did not receive AC, respectively (P < 0.01). In IPW-adjusted Cox regression models, AC was associated with improved all-cause mortality (HR 0.71; 95% CI 0.63-0.81; P < 0.01). Estimates were overall consistent in analyses that examined heterogeneity of treatment effects. Limitations include unmeasured confounding, selection bias, and lack of baseline renal function data. CONCLUSION: In observational analyses designed to emulate EORTC 30994, AC was associated with improved overall survival compared to observation after RC. Results were consistent across baseline patient and tumor characteristics.

Adjuvant Chemotherapy Plus Radiotherapy versus Chemotherapy Alone for Locally Advanced Bladder Cancer after Radical Cystectomy.

BACKGROUND: Survival with locally advanced bladder cancer (LABC) following radical cystectomy (RC) remains poor. Although adjuvant chemotherapy (AC) is standard of care, one small, randomized trial has suggested a potential survival benefit when combined with post-operative radiotherapy (PORT). OBJECTIVE: We examined the association of AC + PORT with overall survival (OS) in patients with LABC after RC. METHODS: Using a prior phase 2 trial to inform design, we conducted observational analyses to emulate a hypothetical target trial of patients aged 18-79 years with pT3-4 Nany M0 or pTany N1-3 M0 urothelial bladder carcinoma following RC who were treated with AC (multiagent chemotherapy within 3 months of RC) with or without PORT (≥45 Gy to the pelvis) from 2006-2015 in the NCDB. Patients who received preoperative chemotherapy or radiotherapy were excluded. The associations of treatment with OS were evaluated using multivariable Cox regression. RESULTS: 1,684 patients were included, with 66 receiving AC + PORT and 1,618 AC alone. Compared to patients treated with AC alone, those treated with AC + PORT were more likely to have pT4 disease (52% vs 26%; p < 0.01), positive surgical margins (44% vs 17%; p < 0.01), and be treated at a non-academic facility (75% vs 53%; p < 0.01). Crude 5-year OS was 19% for AC + PORT versus 36% for AC alone (p = 0.01). Adjusted 5-year OS was 33% for AC + PORT versus 36% for AC alone (p = 0.49). After adjusting for baseline characteristics including pathologic features, AC + PORT was not associated with improved OS compared to AC alone (HR 1.11; 95% CI 0.82-1.51). CONCLUSIONS: Although infrequently utilized, the addition of radiotherapy to AC is not associated with improved OS in LABC. These results highlight the need for prospective trials to better define the potential benefits from PORT with regard to symptomatic progression and oncologic outcomes.

Toxicity After Stereotactic Body Radiation Therapy for Prostate Cancer in Patients With Inflammatory Bowel Disease: A Multi-institutional Matched Case-Control Series.

PURPOSE: To evaluate the safety of stereotactic body radiation therapy (SBRT) for prostate cancer in men with inflammatory bowel disease (IBD). METHODS AND MATERIALS: We queried a consortium database for patients with IBD receiving SBRT for prostate cancer between 2006 and 2012. Identified patients were matched with patients without a history of IBD in a 3:1 fashion based on dose, fractionation, use of androgen deprivation therapy, and age distribution. Logistic regression was used to evaluate the association between having IBD and experiencing acute and late gastrointestinal (GI) and genitourinary (GU) toxicities as scored on the Common Terminology Criteria for Adverse Events scale. Time to late toxicity was evaluated using proportional hazard Cox models. Our study was limited by absence of data on prostate size, baseline International Prostate Symptom Score, and rectal dose-volume histogram parameters. RESULTS: Thirty-nine patients with flare-free IBD at time of treatment (median follow-up 83.9 months) and 117 matched controls (median follow-up 88.7 months) were identified. A diagnosis of IBD was associated with increased odds of developing any late grade GI toxicity (odds ratio [OR] 6.11, P <.001) and GU toxicity (odds ratio 6.14, P < .001), but not odds of developing late grade ≥2 GI (P = .08) or GU toxicity (P = .069). Acute GI and GU toxicity, both overall and for grade ≥2 toxicities, were more frequent in men with IBD (P < .05). Time to late GI and GU toxicity of any grade was significantly shorter in patients with IBD (P < .001). Time to late grade ≥2 GU, but not grade ≥2 GI toxicity, was also shorter in patients with IBD (P = .044 for GU and P = .144 for GI). CONCLUSIONS: Patients with IBD who received SBRT for PCa had a higher likelihood of developing acute GI and GU toxicity, in addition to experiencing lower grade late toxicities that occurred earlier. However, patients with IBD did not have a higher likelihood for late grade ≥2 GI or GU toxicity after SBRT compared with the control cohort. Interpretation of this data are limited by the small sample size. Thus, men with IBD in remission should be properly counseled about these risks when considering SBRT.

Preloaded 22-gauge fine-needle system facilitates placement of a higher number of fiducials for image-guided radiation therapy compared with traditional backloaded 19-gauge approach.

BACKGROUND AND AIMS: Image-guided radiation therapy (IGRT) often relies on EUS-guided fiducial markers. Previously used manually backloaded fiducial needles have multiple potential limitations including safety and efficiency concerns. Our aim was to evaluate the efficacy, feasibility, and safety of EUS-guided placement of gold fiducials using a novel preloaded 22-gauge needle compared with a traditional, backloaded 19-gauge needle. METHODS: This was a single-center comparative cohort study. Patients with pancreatic and hepatobiliary malignancy who underwent EUS-guided fiducial placement (EUS-FP) between October 2014 and February 2018 were included. The main outcome was the technical success of fiducial placement. Secondary outcomes were mean procedure time, fiducial visibility during IGRT, technical success of IGRT delivery, and adverse events. RESULTS: One hundred fourteen patients underwent EUS-FP during the study period. Of these, 111 patients had successful placement of a minimum of 2 fiducials. Fifty-six patients underwent placement using a backloaded 19-gauge needle and 58 patients underwent placement using a 22-gauge preloaded needle. The mean number of fiducials placed successfully at the target site was significantly higher in the 22-gauge group compared with the 19-gauge group (3.53 ± .96 vs 3.11 ± .61, respectively; P = .006). In the 22-gauge group, the clinical goal of placing 4 fiducials was achieved in 78%, compared with 23% in the 19-gauge group (P < .001). In univariate analyses, gender, age, procedure time, tumor size, and location did not influence the number of successfully placed fiducials. Technical success of IGRT with fiducial tracking was high in both the 19-gauge (51/56, 91%) and the 22-gauge group (47/58, 81%; P = .12). CONCLUSIONS: EUS-FP using a preloaded 22-gauge needle is feasible, effective, and safe and allows for a higher number of fiducials placed when compared with the traditional backloaded 19-gauge needle.

Radical prostatectomy versus external beam radiation therapy for high-grade, clinically localized prostate cancer: Emulation of a target clinical trial.

PURPOSE: The comparative effectiveness of surgery and radiation therapy for high-grade, clinically localized prostate cancer remains a seminal, open question in urologic oncology, with no randomized controlled trials to inform management. We therefore emulated a hypothetical target clinical trial of radical prostatectomy (RP) versus external beam radiotherapy (EBRT) for high-grade, clinically localized prostate cancer. MATERIALS AND METHODS: We conducted observational analyses using the National Cancer Database from 2006-2015 to emulate a target clinical trial in men 55-69 years with cT1-3cN0cM0, PSA<20 ng/mL, Gleason 8 to 10 prostate adenocarcinoma treated with RP or 75 to 81 Gy EBRT with androgen deprivation therapy (EBRT+ADT). The associations of treatment type with overall survival (OS) were estimated using Cox regression with stabilized inverse probability weights (IPW). RESULTS: A total of 26,806 men formed the study cohort (RP: 23,990; EBRT+ADT: 2,816). Baseline characteristics were well-balanced after IPW-adjustment. Median follow-up was 48.4 (IQR 25.5-76.2) months. After IPW-reweighting, RP was associated with improved OS compared to EBRT+ADT (HR 0.54;95% CI 0.48-0.62; P<0.001), with 5- and 10-year OS of 93% vs 87%, and 76% vs 60%, respectively. RP was associated with improved OS across all categories of Gleason score, PSA, cT stage, age, and Charlson comorbidity index examined. In sensitivity analyses adjusting for biopsy tumor volume and a biopsy-specific Gleason score, RP remained associated with improved OS compared to EBRT+ADT (HR 0.62;95% CI 0.49-0.78; P<0.001). CONCLUSIONS: In observational analyses designed to emulate a target clinical trial of men with high-grade, clinically localized prostate cancer, RP was associated with improved OS compared with EBRT+ADT.

The impact of pretreatment PSA on risk stratification in men with Gleason 6 prostate cancer: Implications for active surveillance.

BACKGROUND: There are limited data to support the safety of active surveillance in men with favorable-intermediate risk prostate cancer due only to a prostate specific antigen (PSA) above 10 ng/ml. We therefore evaluated the impact of pretreatment PSA on risk-stratification in men with Gleason 6 prostate cancer. METHODS: We identified men aged 18 to 75 with cT1-2cN0cM0, pre-treatment PSA < 20 ng/ml, Gleason 6 prostate cancer diagnosed from 2010 to 2016 in the National Cancer Database who underwent radical prostatectomy. The associations of patient and disease features with Gleason score upgrading or adverse pathologic features at prostatectomy were evaluated using logistic regression. To evaluate for non linear relationships between PSA and each outcome, we examined predicted marginal event rates standardized for baseline characteristics with PSA modeled using restricted cubic splines RESULTS: A total of 75,566 patients were included in the cohort. In unadjusted analyses, patients with pretreatment PSA ≥ 10 ng/ml had higher rates of Gleason core upgrading (58.8% vs. 47.9%; P< 0.001) and adverse pathologic features (19.7% vs. 10.0%; P< 0.001) compared to patients with PSA < 10 ng/ml. In multivariable analyses, PSA ≥ 10 ng/ml was associated with statistically significantly increased risks of Gleason score upgrading (OR 1.47;95%CI 1.39 - 1.55) and adverse pathologic features (OR 2.15;95%CI 2.01 - 2.30). When modeled as a non linear continuous covariate, PSA was associated with increased adjusted rates of Gleason score upgrading and adverse pathologic features without a clear dichotomization at a threshold of 10 ng/ml. CONCLUSION: Higher pretreatment PSA was independently associated with increased risks of Gleason score upgrading and adverse pathologic features at prostatectomy. Flexible modeling of the relationship between PSA and each outcome did not support dichotomization at a threshold of 10 ng/ml. These results can be used to improve patient risk-stratification for active surveillance.

Enzalutamide With Radiation Therapy for Intermediate-Risk Prostate Cancer: A Phase 2 Study.

PURPOSE: Androgen deprivation therapy (ADT) is often used as adjuvant treatment with radiation therapy (RT) for intermediate-risk prostate cancer. ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, antiandrogen monotherapy has been generally better tolerated. This study aimed to assess the effectiveness of enzalutamide (an antiandrogen) monotherapy with RT for the treatment of intermediate-risk prostate cancer. METHODS AND MATERIALS: This trial was an open-label, phase 2 study of 6 months of enzalutamide monotherapy with external beam RT for intermediate-risk prostate cancer. Enzalutamide was initiated 2 months before external beam RT. The primary endpoint was prostate-specific antigen (PSA) response measured at the end of enzalutamide administration at the 6-month timepoint. Secondary endpoints included assessment of toxicity and changes in anthropomorphic body measurement, sexual function, and metabolism. The sample size was 64 patients. The hypothesis was that if ≥60% of the patients did not achieve a PSA nadir of ≤0.2 ng/mL, the study results would be deemed negative. RESULTS: The results met the prespecified endpoint for efficacy in that PSA values ≤0.2 ng/mL were observed in 49 of 64 patients (77%), and 60 of 64 patients (94%) had PSA values ≤0.5ng/mL. The most frequent adverse events were hypertension and gynecomastia. There were no changes in anthropomorphic body measurements and only modest erectile dysfunction. CONCLUSIONS: Using PSA response as an endpoint, enzalutamide monotherapy may be as effective as ADT in combination with external beam RT for patients with intermediate-risk prostate cancer, and it is associated with fewer side effects. Randomized trials comparing enzalutamide with ADT are justified.

Development and validation of a pancreatic cancer risk model for the general population using electronic health records: An observational study.

AIM: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at a late, incurable stage. We sought to determine whether individuals at high risk of developing PDAC could be identified early using routinely collected data. METHODS: Electronic health record (EHR) databases from two independent hospitals in Boston, Massachusetts, providing inpatient, outpatient, and emergency care, from 1979 through 2017, were used with case-control matching. PDAC cases were selected using International Classification of Diseases 9/10 codes and validated with tumour registries. A data-driven feature selection approach was used to develop neural networks and L2-regularised logistic regression (LR) models on training data (594 cases, 100,787 controls) and compared with a published model based on hand-selected diagnoses ('baseline'). Model performance was validated on an external database (408 cases, 160,185 controls). Three prediction lead times (180, 270 and 365 days) were considered. RESULTS: The LR model had the best performance, with an area under the curve (AUC) of 0.71 (confidence interval [CI]: 0.67-0.76) for the training set, and AUC 0.68 (CI: 0.65-0.71) for the validation set, 365 days before diagnosis. Data-driven feature selection improved results over 'baseline' (AUC = 0.55; CI: 0.52-0.58). The LR model flags 2692 (CI 2592-2791) of 156,485 as high risk, 365 days in advance, identifying 25 (CI: 16-36) cancer patients. Risk stratification showed that the high-risk group presented a cancer rate 3 to 5 times the prevalence in our data set. CONCLUSION: A simple EHR model, based on diagnoses, can identify high-risk individuals for PDAC up to one year in advance. This inexpensive, systematic approach may serve as the first sieve for selection of individuals for PDAC screening programs.

Survivorship Care Plans: Reaching a Benchmark and Striving to Achieve Intent.

PURPOSE: Survivorship care plans (SCPs) have been endorsed by major oncologic organizations despite challenges in implementation and unclear patient-specific benefits. In January 2020, the Commission on Cancer removed a 2018 provision that required accredited programs to deliver SCPs to eligible patients. Programs must determine whether to continue SCP use or begin de-implementation. We detail a framework to increase SCP delivery for programs continuing to provide SCPs as a component of survivorship care and suggest a patient-centered approach to evaluate continued utility amidst updated national standards. METHODS: We surveyed medical, surgical, and radiation oncologists at our academic and community sites to identify barriers to SCP use and performed a Pareto analysis to highlight the most notable barriers. We then designed an intervention that used SCP templates within the medical record, disease-specific recommendations, delegation to nonphysician staff, and provider education. We monitored our intervention via a statistical process control analysis and assessed patient perceptions of SCP usefulness via a questionnaire. RESULTS: Before implementing our process improvements, our SCP completion rate during a 10-month period was 45%. During the 6-month period after our intervention, the SCP completion rate increased to 89%. Greater than 80% of patients who had recently received an SCP found the information helpful and were satisfied with the amount of information received. More than 40% did not remember receiving their original SCP. CONCLUSION: We demonstrated a feasible method for increasing SCP delivery for all cancers across a cancer network and used a patient-specific questionnaire to assess continued value amidst changing national standards.

Stereotactic Ablative Radiotherapy for ≥T1b Primary Renal Cell Carcinoma: A Report From the International Radiosurgery Oncology Consortium for Kidney (IROCK).

PURPOSE: Patients with larger (T1b, >4 cm) renal cell carcinoma (RCC) not suitable for surgery have few treatment options because thermal ablation is less effective in this setting. We hypothesize that SABR represents an effective, safe, and nephron-sparing alternative for large RCC. METHODS AND MATERIALS: Individual patient data from 9 institutions in Germany, Australia, USA, Canada, and Japan were pooled. Patients with T1a tumors, M1 disease, and/or upper tract urothelial carcinoma were excluded. Demographics, treatment, oncologic, and renal function outcomes were assessed using descriptive statistics. Kaplan-Meier estimates and univariable and multivariable Cox proportional hazards regression were generated for oncologic outcomes. RESULTS: Ninety-five patients were included. Median follow-up was 2.7 years. Median age was 76 years, median tumor diameter was 4.9 cm, and 81.1% had Eastern Cooperative Oncology Group performance status of 0 to 1 (or Karnofsky performance status ≥70%). In patients for whom operability details were reported, 77.6% were defined as inoperable as determined by the referring urologist. Mean baseline estimated glomerular filtration rate (eGFR) was 57.2 mL/min (mild-to-moderate dysfunction), with 30% of the cohort having moderate-to-severe dysfunction (eGFR <45mL/min). After SABR, eGFR decreased by 7.9 mL/min. Three patients (3.2%) required dialysis. Thirty-eight patients (40%) had a grade 1 to 2 toxicity. No grade 3 to 5 toxicities were reported. Cancer-specific survival, overall survival, and progression-free survival were 96.1%, 83.7%, and 81.0% at 2 years and 91.4%, 69.2%, 64.9% at 4 years, respectively. Local, distant, and any failure at 4 years were 2.9%, 11.1%, and 12.1% (cumulative incidence function with death as competing event). On multivariable analysis, increasing tumor size was associated with inferior cancer-specific survival (hazard ratio per 1 cm increase: 1.30; P < .001). CONCLUSIONS: SABR for larger RCC in this older, largely medically inoperable cohort, demonstrated efficacy and tolerability and had modest impact on renal function. SABR appears to be a viable treatment option in this patient population.

The Emerging Role of Stereotactic Ablative Radiotherapy for Primary Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.

CONTEXT: Stereotactic ablative radiotherapy (SABR) is an emerging treatment option for primary renal cell carcinoma (RCC). OBJECTIVE: To systematically review the literature on SABR for primary RCC and perform a meta-analysis evaluating local control (LC), toxicity, and renal function. EVIDENCE ACQUISITION: A PROSPERO-registered (#115573), Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA)-based systematic review of the literature was conducted (1995-2019). Studies of SABR targeting primary RCC tumors were included, while those targeting only metastases were excluded. The primary outcome was LC defined as tumor size reduction and/or absence of local progression. Secondary outcomes included toxicity (Common Terminology Criteria for Adverse Events) and renal function (change in estimated glomerular filtration rate [eGFR]). Weighted random-effect meta-analyses using the DerSimonian and Laird method were conducted for primary and secondary outcomes. The I2 statistic and Cochran's Q test were used to assess heterogeneity. EVIDENCE SYNTHESIS: From 2386 PubMed entries and 924 meeting abstracts, 26 studies were identified (11 prospective trials), including 383 tumors in 372 patients, most of whom were deemed inoperable. Weighted averages (ranges) of median follow-up, median age, and mean tumor size were 28.0 (5.8-79.2)mo, 70.4 (62-83)yr, and 4.6 (2.3-9.5)cm, respectively. RCC histology was confirmed in 78.9% of patients who underwent pretreatment biopsy. Dose fractionation varied, but 26Gy in one fraction and 40Gy in five fractions were most common. The random-effect estimates for LC, grade 3-4 toxicity, and post-SABR eGFR change were 97.2% (95% confidence interval [CI]: 93.9-99.5%, I2=20%), 1.5% (95% CI: 0-4.3%, I2=0%), and -7.7ml/min (95% CI: -12.5 to -2.8, I2=2%), respectively, and heterogeneity was minimal. Six patients with pre-existing renal dysfunction (2.9%) required dialysis. CONCLUSIONS: Renal SABR is locally effective and associated with low toxicity rates for primary RCC, despite treatment of larger tumors in older, mostly medically inoperable patients. PATIENT SUMMARY: Stereotactic ablative radiotherapy is a high-precision, noninvasive radiation treatment requiring few outpatient visits, and represents a safe and effective management option for primary renal cell carcinoma.