Evaluation of Treatment Outcomes of Prostate Cancer Patients With Lymph Node Metastasis Treated With Definitive Radiotherapy: Comparative Analysis of PSMA PET/CT and Conventional Imaging.

PURPOSE: We investigated the impact of prostate-specific membrane antigen (PSMA) PET/CT compared with conventional imaging on treatment outcomes for node-positive prostate cancer (PCa) patients who underwent androgen deprivation therapy (ADT) and external radiotherapy (RT). PATIENTS AND METHODS: A multicentric, retrospective study recruited patients with node-positive PCa patients who underwent conventional radiological evaluation or PSMA PET/CT and received ADT and RT at 3 hospitals from 2009 to 2021 were enrolled. Patients underwent prostate and pelvis RT, accompanied by a minimum of 6 months of ADT. The primary endpoints were progression-free survival (PFS) and PCa-specific survival (PCSS). Cox regression analyzed the association of survival with potential prognostic factors, whereas logistic regression identified the predictors of bone and lymph node metastasis. RESULTS: The median follow-up time was 64.0 months. The majority of patients (64.1%) underwent PSMA PET/CT for staging. The 5-year rates of PFS and PCSS were 63.7% and 83.7%, respectively. Disease progression was observed in 90 patients (36.3%). In multivariable analysis, ADT duration of less than 24 months and post-RT prostate-specific antigen (PSA) nadir were prognostic for PFS. Early clinical T stage and PSMA PET/CT predicted better PCSS. Patients staged with PSMA PET/CT had exhibited significantly higher 5-year PCSS rates than compared with those staged with conventional imaging (95.1% vs 76.9%; P = 0.01). Shorter ADT duration and higher PSA levels after RT independently predicted bone metastasis in multivariable logistic regression. Advanced T stage, shorter ADT duration, and higher PSA levels after neoadjuvant ADT predicted nonregional lymph node recurrence. CONCLUSIONS: ADT with pelvis RT is an effective treatment option for node-positive PCa patients. The PSMA PET/CT outperformed conventional imaging in PCSS, emphasizing the importance of precise clinical staging for patients undergoing definitive RT.

Genomic Determinants Associated with Modes of Progression and Patterns of Failure in Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND AND OBJECTIVE: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC. METHODS: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ2 tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure. KEY FINDINGS AND CLINICAL IMPLICATIONS: We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles. CONCLUSIONS AND CLINICAL IMPLICATIONS: Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism. PATIENT SUMMARY: We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients.

Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival After Stereotactic Ablative Radiation in Oligometastatic Prostate Cancer.

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUVmax) was measured for all lesions, and PSMA response was defined as the percent change in SUVmax of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUVmax), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months (P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population. Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

Multi-institutional Analysis of Metastasis-directed Therapy with or Without Androgen Deprivation Therapy in Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND: Metastasis-directed therapy (MDT) is increasingly being used in oligometastatic castration-sensitive prostate cancer (omCSPC). However, it is currently unclear how to optimally integrate MDT with the standard of care of systemic hormonal therapy. OBJECTIVE: To report long-term outcomes of MDT alone versus MDT and a defined course of androgen deprivation therapy (ADT) in omCSPC. DESIGN, SETTING, AND PARTICIPANTS: Here, a multicenter, international retrospective cohort of omCSPC as defined by conventional imaging was reported. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical progression-free survival (bPFS), distant progression-free survival (dPFS), and combined biochemical or distant progression-free survival (cPFS) were evaluated with Kaplan-Meier and multivariable Cox proportional hazard regression models. RESULTS AND LIMITATIONS: A total of 263 patients were included, 105 with MDT + ADT and 158 with MDT alone. The majority of patients had metachronous disease (90.5%). Five-year bPFS, dPFS, and cPFS were, respectively, 24%, 41%, and 19% in patients treated with MDT + ADT and 11% (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.36-0.64), 29% (HR 0.56, 95% CI 0.40-0.78), and 9% (HR 0.50, 95% CI 0.38-0.67) in patients treated with MDT alone. On a multivariable analysis adjusting for pretreatment variables, the use of ADT was associated with improved bPFS (HR 0.43, p < 0.001), dPFS (HR 0.45, p = 0.002), and cPFS (HR 0.44, p < 0.001). CONCLUSIONS: In this large multi-institutional report, the addition of concurrent ADT to MDT appears to improve time to prostate-specific antigen progression and distant recurrence, noting that about 10% patients had durable control with MDT alone. Ongoing phase 3 studies will help further define treatment options for omCSPC. PATIENT SUMMARY: Here, we report a large retrospective review evaluating the outcomes of metastasis-directed therapy with or without a limited course of androgen deprivation for patients with oligometastatic castration-sensitive prostate cancer. This international multi-institutional review demonstrates that the addition of androgen deprivation therapy to metastasis-directed therapy (MDT) improves progression-free survival. While a proportion of patients appear to have long-term disease control with MDT alone, further work in biomarker discovery is required to better identify which patients would be appropriate for de-escalated therapy.

Prognostic Significance of Immune Cell Infiltration in Muscle-invasive Bladder Cancer Treated with Definitive Chemoradiation: A Secondary Analysis of RTOG 0524 and RTOG 0712.

Chemoradiation therapy (CRT) is a treatment for muscle-invasive bladder cancer (MIBC). Using a novel transcriptomic profiling panel, we validated prognostic immune biomarkers to CRT using 70 pretreatment tumor samples from prospective trials of MIBC (NRG/RTOG 0524 and 0712). Disease-free survival (DFS) and overall survival (OS) were estimated via the Kaplan-Meier method and stratified by genes correlated with immune cell activation. Cox proportional-hazards models were used to assess group differences. Clustering of gene expression profiles revealed that the cluster with high immune cell content was associated with longer DFS (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.26-1.10; p = 0.071) and OS (HR 0.48, 95% CI 0.24-0.97; p = 0.040) than the cluster with low immune cell content. Higher expression of T-cell infiltration genes (CD8A and ICOS) was associated with longer DFS (HR 0.40, 95% CI 0.21-0.75; p = 0.005) and OS (HR 0.49, 95% CI 0.25-0.94; p = 0.033). Higher IDO1 expression (IFNγ signature) was also associated with longer DFS (HR 0.44, 95% CI 0.24-0.88; p = 0.021) and OS (HR 0.49, 95% CI 0.24-0.99; p = 0.048). These findings should be validated in prospective CRT trials that include biomarkers, particularly for trials incorporating immunotherapy for MIBC. PATIENT SUMMARY: We analyzed patient samples from two clinical trials (NRG/RTOG 0524 and 0712) of chemoradiation for muscle-invasive bladder cancer using a novel method to assess immune cells in the tumor microenvironment. Higher expression of genes associated with immune activation and high overall immune-cell content were associated with better disease-free survival and overall survival for patients treated with chemoradiation.

Identification of a Predictive Genomic Biomarker for Prostate-directed Therapy in Synchronous Low-volume Metastatic Castration-sensitive Prostate Cancer.

BACKGROUND: Standard of care management for synchronous metastatic castration-sensitive prostate cancer (mCSPC) includes androgen deprivation therapy with a second-generation antiandrogen therapy and/or docetaxel. Recently, randomized data have demonstrated that prostate-directed therapy (PDT) is associated with an improvement in overall survival (OS) among patients with low-volume metastatic disease. Tumor genomics represents an additional dimension to define the clinical trajectory of patients with mCSPC. OBJECTIVE: To evaluate a high-risk (HiRi) genomic signature to predict the benefit from PDT. DESIGN, SETTING, AND PARTICIPANTS: We performed a single-institution retrospective review of men with synchronous low-volume mCSPC who underwent DNA panel sequencing of their tumor. Patients were classified according to the presence of HiRi mutation including pathogenic mutations in TP53, ATM, BRCA1, BRCA2, or Rb1. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was to determine the effect of PDT on OS in patients with and without a HiRi mutation. A survival analysis was performed with the Kaplan-Meier method compared with log-rank test and multivariable Cox regression. The interaction between HiRi mutation and PDT was evaluated. RESULTS AND LIMITATIONS: A total of 101 patients with synchronous low-volume CSPC were included with a median follow-up of 44 mo. Approximately half of patients were found to have a HiRi pathogenic mutation (49%). Patients with HiRi mutations demonstrated median OS of 73 versus 66.8 mo (p = 0.3) for no PDT versus PDT. Conversely, patients without a HiRi mutation demonstrated a significant improvement in OS of 60 versus 105.3 mo (p < 0.001) for no PDT versus PDT. The p value for interaction for OS between PDT and HiRi mutation was statistically significant (p < 0.001). Limitations include the retrospective nature of the study. CONCLUSIONS: Here, we have identified a HiRi genomic biomarker that appears predictive for the lack of benefit from PDT in men with synchronous low-volume mCSPC. Further work validating these results is warranted. PATIENT SUMMARY: In this report, we evaluated a high-risk genomic biomarker to predict the benefit from prostate-directed therapy for men with synchronous low-volume metastatic castration-sensitive prostate cancer. We found that men without a high-risk mutation appear to experience a greater clinical benefit from prostate-directed therapy than those with a high-risk mutation.

TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment.

PURPOSE: Despite well-informed work in several malignancies, the phenotypic effects of TP53 mutations in metastatic castration-sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure-function and clinical impact of TP53 mutations in mCSPC. PATIENTS AND METHODS: We performed an international retrospective review of men with mCSPC who underwent next-generation sequencing and were stratified according to TP53 mutational status and metastatic burden. Clinical outcomes included radiographic progression-free survival (rPFS) and overall survival (OS) evaluated with Kaplan-Meier and multivariable Cox regression. We also utilized isogenic cancer cell lines to assess the effect of TP53 mutations and APR-246 treatment on migration, invasion, colony formation in vitro, and tumor growth in vivo. Preclinical experimental observations were compared using t-tests and ANOVA. RESULTS: Dominant-negative (DN) TP53 mutations were enriched in patients with synchronous (vs. metachronous) (20.7% vs. 6.3%, p < 0.01) and polymetastatic (vs. oligometastatic) (14.4% vs. 7.9%, p < 0.01) disease. On multivariable analysis, DN mutations were associated with worse rPFS (hazards ratio [HR] = 1.97, 95% confidence interval [CI]: 1.31-2.98) and overall survival [OS] (HR = 2.05, 95% CI: 1.14-3.68) compared to TP53 wild type (WT). In vitro, 22Rv1 TP53 R175H cells possessed stronger migration, invasion, colony formation ability, and cellular movement pathway enrichment in RNA sequencing analysis compared to 22Rv1 TP53 WT cells. Treatment with APR-246 reversed the effects of TP53 mutations in vitro and inhibited 22Rv1 TP53 R175H tumor growth in vivo in a dosage-dependent manner. CONCLUSIONS: DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.

Histology Specific Molecular Biomarkers: Ushering in a New Era of Precision Radiation Oncology.

Histopathology and clinical staging have historically formed the backbone for allocation of treatment decisions in oncology. Although this has provided an extremely practical and fruitful approach for decades, it has long been evident that these data alone do not adequately capture the heterogeneity and breadth of disease trajectories experienced by patients. As efficient and affordable DNA and RNA sequencing have become available, the ability to provide precision therapy has become within grasp. This has been realized with systemic oncologic therapy, as targeted therapies have demonstrated immense promise for subsets of patients with oncogene-driver mutations. Further, several studies have evaluated predictive biomarkers for response to systemic therapy within a variety of malignancies. Within radiation oncology, the use of genomics/transcriptomics to guide the use, dose, and fractionation of radiation therapy is rapidly evolving but still in its infancy. The genomic adjusted radiation dose/radiation sensitivity index is one such early and exciting effort to provide genomically guided radiation dosing with a pan-cancer approach. In addition to this broad method, a histology specific approach to precision radiation therapy is also underway. Herein we review select literature surrounding the use of histology specific, molecular biomarkers to allow for precision radiotherapy with the greatest emphasis on commercially available and prospectively validated biomarkers.

Clinical and Genomic Differences Between Advanced Molecular Imaging-detected and Conventional Imaging-detected Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel therapy, metastasis-directed therapy, and radiation to the prostate. Although there are multiple definitions of disease volume, they have commonly been studied in the context of metastases detected via conventional imaging (CIM). One such numeric definition of disease volume, termed oligometastasis, is heavily dependent on the sensitivity of the imaging modality. We performed an international multi-institutional retrospective review of men with metachronous oligometastatic CSPC (omCSPC), detected via either advanced molecular imaging alone (AMIM) or CIM. Patients were compared with respect to clinical and genomic features using the Mann-Whitney U test, Pearson's χ2 test, and Kaplan-Meier overall survival (OS) analyses with a log-rank test. A total of 295 patients were included for analysis. Patients with CIM-omCSPC had significantly higher Gleason grade group (p = 0.032), higher prostate-specific antigen at omCSPC diagnosis (8.0 vs 1.7 ng/ml; p < 0.001), more frequent pathogenic TP53 mutations (28% vs 17%; p = 0.030), and worse 10-yr OS (85% vs 100%; p < 0.001). This is the first report of clinical and biological differences between AMIM-detected and CIM-detected omCSPC. Our findings are particularly important for ongoing and planned clinical trials in omCSPC. PATIENT SUMMARY: Metastatic prostate cancer with just a few metastases only detected via newer scanning methods (called molecular imaging) is associated with fewer high-risk DNA mutations and better survival in comparison to metastatic cancer detected via conventional scan methods.

WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer.

PURPOSE: WNT signaling is a cellular pathway that has been implicated in the development and progression of prostate cancer. Oligometastatic castration-sensitive prostate cancer (omCSPC) represents a unique state of disease in which metastasis-directed therapy (MDT) has demonstrated improvement in progression-free survival. Herein, we investigate the clinical implications of genomic alterations in the WNT signaling cascade in men with omCSPC. METHODS AND MATERIALS: We performed an international multi-institutional retrospective study of 277 men with metachronous omCSPC who underwent targeted DNA sequencing of their primary/metastatic tumor. Patients were classified by presence or absence of pathogenic WNT pathway mutations (in the genes APC, RNF43, and CTNNB1). Pearson χ2 and Mann-Whitney U tests were used to determine differences in clinical factors between genomic strata. Kaplan-Meier survival curves were generated for radiographic progression-free survival and overall survival, stratified according to WNT pathway mutation status. RESULTS: A pathogenic WNT pathway mutation was detected in 11.2% of patients. Patients with WNT pathway mutations were more likely to have visceral metastases (22.6% vs 2.8%; P < .01) and less likely to have regional lymph node metastases (29.0% vs 50.4%; P = .02). At time of oligometastasis, these patients were treated with MDT alone (33.9%), MDT + limited course of systemic therapy (20.6%), systemic therapy alone (22.4%), or observation (defined as no treatment for ≥6 months after metastatic diagnosis). Multivariable cox regression demonstrated WNT pathway mutations associated with significantly worse overall survival (hazard ratio, 3.87; 95% confidence interval, 1.25-12.00). CONCLUSIONS: Somatic WNT pathway alterations are present in approximately 11% of patients with omCSPC and are associated with an increased likelihood of visceral metastases. Although these patients have a worse natural history, they may benefit from MDT.

Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

Genomic biomarkers to guide precision radiotherapy in prostate cancer.

Our ability to prognosticate the clinical course of patients with cancer has historically been limited to clinical, histopathological, and radiographic features. It has long been clear however, that these data alone do not adequately capture the heterogeneity and breadth of disease trajectories experienced by patients. The advent of efficient genomic sequencing has led to a revolution in cancer care as we try to understand and personalize treatment specific to patient clinico-genomic phenotypes. Within prostate cancer, emerging evidence suggests that tumor genomics (e.g., DNA, RNA, and epigenetics) can be utilized to inform clinical decision making. In addition to providing discriminatory information about prognosis, it is likely tumor genomics also hold a key in predicting response to oncologic therapies which could be used to further tailor treatment recommendations. Herein we review select literature surrounding the use of tumor genomics within the management of prostate cancer, specifically leaning toward analytically validated and clinically tested genomic biomarkers utilized in radiotherapy and/or adjunctive therapies given with radiotherapy.

Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics.

BACKGROUND: Several definitions have attempted to stratify metastatic castrate-sensitive prostate cancer (mCSPC) into low and high-volume states. However, at this time, comparison of these definitions is limited. Here we aim to compare definitions of metastatic volume in mCSPC with respect to clinical outcomes and mutational profiles. METHODS: We performed a retrospective review of patients with biochemically recurrent or mCSPC whose tumors underwent somatic targeted sequencing. 294 patients were included with median follow-up of 58.3 months. Patients were classified into low and high-volume disease per CHAARTED, STAMPEDE, and two numeric (≤3 and ≤5) definitions. Endpoints including radiographic progression-free survival (rPFS), time to development of castration resistance (tdCRPC), and overall survival (OS) were evaluated with Kaplan-Meier survival curves and log-rank test. The incidence of driver mutations between definitions were compared. RESULTS: Median OS and tdCRPC were shorter for high-volume than low-volume disease for all four definitions. In the majority of patients (84.7%) metastatic volume classification did not change across all four definitions. High volume disease was significantly associated with worse OS for all four definitions (CHAARTED: HR 2.89; p < 0.01, STAMPEDE: HR 3.82; p < 0.01, numeric ≤3: HR 4.67; p < 0.01, numeric ≤5: HR 3.76; p < 0.01) however, were similar for high (p = 0.95) and low volume (p = 0.79) disease across all four definitions. Those with discordant classification tended to have more aggressive clinical behavior and mutational profiles. Patients with low-volume disease and TP53 mutation experienced a more aggressive course with rPFS more closely mirroring high-volume disease. CONCLUSIONS: The spectrum of mCSPC was confirmed across four different metastatic definitions for clinical endpoints and genetics. All definitions were generally similar in classification of patients, outcomes, and genetic makeup. Given these findings, the simplicity of numerical definitions might be preferred, especially when integrating metastasis directed therapy. Incorporation of tumor genetics may allow further refinement of current metastatic definitions.

Post-Operative Morbidity and Mortality Following Total Neoadjuvant Therapy Versus Conventional Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

BACKGROUND: Standard of care for locally advanced rectal cancer (LARC) (stage II/III) includes preoperative chemoradiation (CRT) followed by resection and adjuvant chemotherapy. Total neoadjuvant therapy (TNT) is a new treatment paradigm that delivers systemic therapy prior to CRT aimed at improving outcomes for high-risk patients. Here we analyzed the national cancer database (NCDB) comparing short-term post-operative outcomes between patients receiving TNT and CRT. METHODS: The NCDB was queried to identify patients with LARC between the 2004 and 2014 treated with TNT or CRT. Primary outcomes included post-operative 30-day mortality and readmissions between TNT and CRT which were analyzed via logistic regression. Secondary outcomes included post-operative length of stay (LOS) and OS which were compared with two-tailed t-test and Kaplan-Meier with log rank testing, respectively. RESULTS: A total of 9066 patients met inclusion criteria with a median age at diagnosis that was 57 years (IQR, 19-65); 62.3% were male and 87.8% white. Neoadjuvant therapy consisted of either standard CRT (97.2%) or TNT (2.8%). Patients treated at academic programs and those with N1 [p < 0.001, OR 2.34, 95%CI 1.71-3.19] or N2 [p < 0.001, OR 3.29, 95%CI 2.19-4.94] disease were associated with increased utilization of TNT. TNT was not significantly associated with either 30-day mortality (p = 1.0) or readmissions (p = 0.82). Further, there was no significant difference identified between CRT and TNT for hospital LOS or OS (p = 0.18). CONCLUSION: This large-scale analysis of patients with LARC demonstrates increased utilization of TNT in patients harboring node-positive disease. Further, TNT does not appear to increase 30-day post-operative mortality, readmissions, or hospital LOS.

Early Exploratory Analysis for Patient-reported Quality of Life and Dosimetric Correlates in Hypofractionated Stereotactic Body Radiation Therapy (SBRT) for Low-risk and Intermediate-risk Prostate Cancer: Interim Results from a Prospective Phase II Clinical Trial.

OBJECTIVES: Given the relative novelty of stereotactic body radiation therapy as a treatment modality low-risk and intermediate-risk prostate cancer, little data exist evaluating dosimetry and its impact on patient-reported quality of life (PR-QOL) metrics. Herein, we present an interim analysis of a phase II clinical trial of PR-QOL and dosimetric correlates. METHODS: Patients with biopsy-proven low-risk or intermediate-risk prostate cancer, prostate volume ≤100 cm, and life expectancy ≥10 years were enrolled. Expanded Prostate Cancer Index Composite (EPIC) scores were tabulated by domain and evaluated in relation to dosimetry. Paired t test was performed to compare differences in scores from baseline. Minimally important differences were established using the anchor-based approach and correlations made using the χ test. RESULTS: A total of 95 patients were analyzed with a median follow-up of 18.1 months (range, 3.0 to 76.9 mo). There were no cases of acute or late grade 3+ GI or GU toxicities. Expanded Prostate Cancer Index Composite scores in urinary obstructive/irritative domain at 1 month (-4.8, P=0.03) and bowel domain at 1, 6, and 12 months (-10.8, -6.1, and -5.2) were significantly different from pretreatment, with both returning to nonsignificant differences around 24 months. Higher bladder V37Gy (≥3.35%) was associated with both late urinary incontinence and obstructive/irritative declines. Both higher rectal D5% and rectal V36Gy >0.6 cm were correlated with an enhanced proportion of patients with late minimally important difference declines. CONCLUSIONS: Higher dose volumes for the bladder and rectum predicted for poorer PR-QOL. In contrast to prostate brachytherapy data, neither prostate volume nor urethral dosimetry at this dose schedule correlated with urinary symptoms.

Initial Results of a Prospective Study of Adjuvant Pancreatic Stereotactic Body Radiation Therapy for Close or Positive Margins.

PURPOSE: Patients with close or positive margins after surgery for pancreatic carcinoma are at a high risk for recurrence. Stereotactic body radiation therapy (SBRT) allows for safe dose escalation with great conformity and short duration of treatment. Herein, we report the initial results of a prospective observational study that evaluated the efficacy and safety of this treatment option. METHODS AND MATERIALS: Patients eligible for the study had pathologically proven T1-4N0-1M0 pancreatic adenocarcinoma with a positive margin (≤1 mm) or a close margin defined as <2.5 mm. Patients were treated with either neoadjuvant or adjuvant chemotherapy, if eligible for systemic therapy. All patients received 36 Gy in 3 fractions to the close or positive margin site. RESULTS: From February 2013 to January 2018, 50 patients were enrolled with 49 patients treated on protocol and included in the analysis. The median age was 71 years. The median clinical target volume was 11.3 cc and median planning target volume 22.0 cc. The median overall survival was 23.7 months (95% confidence interval, 13.6-33.8). Local progression-free survival at 1 and 2 years was 85% and 77%, respectively. Regional progression-free survival at 1 and 2 years was 73% and 73%, respectively. Distant metastases-free survival was 57% and 49% at 1 and 2 years, respectively. Grade 3+ radiation toxicity was only 4.1% and occurred in 2 patients. CONCLUSIONS: Adjuvant pancreatic SBRT was shown to be a safe and feasible treatment option for patients with high-risk pancreatic adenocarcinoma and close or positive margins. This is the first prospective study of SBRT in high-risk postoperative pancreatic cancer. Our results yielded significant local and regional control with low rates of acute toxicity. This technique does not interrupt the administration of systemically dosed multiagent chemotherapy and can be safely interdigitated between cycles because SBRT is only 1 week of treatment.