A multi-institutional prediction model to estimate the risk of recurrence and mortality after mastectomy for T1-2N1 breast cancer.

BACKGROUND: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial. METHODS: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM). RESULTS: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more adverse risk factors than those patients not receiving PMRT: younger age, larger tumors, more positive lymph nodes, lymphovascular invasion, extracapsular extension, and positive margins (p < .05 for all). On competing risk regression analysis, receipt of PMRT was significantly associated with a decreased risk of LRR (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.14-0.31; p < .001) and OR (HR, 0.76; 95% CI, 0.62-0.94; p = .011). Model performance metrics for each end point showed good discrimination and calibration. An online prediction model to estimate predicted risks for each outcome based on individual patient and tumor characteristics was created from the model. CONCLUSIONS: In a large multi-institutional cohort of patients, PMRT for T1-2N1 breast cancer was associated with a significant reduction in locoregional and overall recurrence after accounting for known prognostic factors. An online calculator was developed to aid in personalized decision-making regarding PMRT in this population.

Cost effectiveness of treatment strategies for high risk prostate cancer.

BACKGROUND: Patients with high-risk prostate cancer (HRPC) have multiple accepted treatment options. Because there is no overall survival benefit of one option over another, appropriate treatment must consider patient life expectancy, quality of life, and cost. METHODS: The authors compared quality-adjusted life years (QALYs) and cost effectiveness among treatment options for HRPC using a Markov model with three treatment arms: (1) external-beam radiotherapy (EBRT) delivered with 20 fractions, (2) EBRT with 23 fractions followed by low-dose-rate (LDR) brachytherapy boost, or (3) radical prostatectomy alone. An exploratory analysis considered a simultaneous integrated boost according to the FLAME trial (ClinicalTrials.gov identifier NCT01168479). RESULTS: Treatment strategies were compared using the incremental cost-effectiveness ratio (ICER). EBRT with LDR brachytherapy boost was a cost-effective strategy (ICER, $20,929 per QALY gained). These results were most sensitive to variations in the biochemical failure rate. However, the results still demonstrated cost effectiveness for the brachytherapy boost paradigm, regardless of any tested parameter ranges. Probabilistic sensitivity analysis demonstrated that EBRT with LDR brachytherapy was favored in 52% of 100,000 Monte Carlo iterations. In an exploratory analysis, EBRT with a simultaneous integrated boost was also a cost-effective strategy, resulting in an ICER of $62,607 per QALY gained; however, it was not cost effective compared with EBRT plus LDR brachytherapy boost. CONCLUSIONS: EBRT with LDR brachytherapy boost may be a cost-effective treatment strategy compared with EBRT alone and radical prostatectomy for HRPC, demonstrating high-value care. The current analysis suggests that a reduction in biochemical failure alone can result in cost-effective care, despite no change in overall survival.

Outcomes with Partial Breast Irradiation vs. Whole Breast Irradiation: a Meta-Analysis.

BACKGROUND: Several randomized trials have been performed comparing partial breast irradiation (PBI) and whole breast irradiation (WBI) though controversy remains, including regarding differences by PBI technique. We performed a meta-analysis to compare results between WBI versus PBI and between PBI techniques. METHODS: A systematic review was performed to identify modern randomized studies listed in MEDLINE from 2005 to 2020. PBI trials were divided into external beam radiation and brachytherapy techniques, with intraoperative radiation excluded. A Bayesian logistic regression model evaluated the risk of ipsilateral breast tumor recurrence (IBTR) and acute and chronic toxicities. The primary outcome was IBTR at 5 years with WBI compared with PBI. RESULTS: A total of 9758 patients from 7 studies were included (4840-WBI, 4918-PBI). At 5 years, no statistically significant difference in the rate of IBTR was noted between PBI (1.8%, 95% HPD 0.68-3.2%) and WBI (1.7%, 95% HPD 0.92-2.4%). By PBI technique, the 5-year rate of IBTR rate for external beam was 1.7% and 2.2% for brachytherapy. Rates of grade 2 + acute toxicity were 7.1% with PBI versus 47.5% with WBI. For late toxicities, grade 2/3 rates were 0%/0% with PBI compared with 1.0%/0% with WBI. CONCLUSIONS: IBTR rates were similar between PBI and WBI with no significant differences noted by PBI technique; PBI had reduced acute toxicities compared to WBI. Because studies did not provide toxicity data in a consistent fashion, definitive conclusions cannot be made with additional data from randomized trials needed to compare toxicity profiles between PBI techniques.

TARGIT-R (Retrospective): 5-Year Follow-Up Evaluation of Intraoperative Radiation Therapy (IORT) for Breast Cancer Performed in North America.

BACKGROUND: Intraoperative radiation therapy (IORT) has been investigated for patients with low-risk, early-stage breast cancer. The The North American experience was evaluated by TARGIT-R (retrospective) to provide outcomes for patients treated in "real-world" clinical practice with breast IORT. This analysis presents a 5-year follow-up assessment. METHODS: TARGIT-R is a multi-institutional retrospective registry of patients who underwent lumpectomy and IORT between the years 2007 and 2013. The primary outcome of the evaluation was ipsilateral breast tumor recurrence (IBTR). RESULTS: The evaluation included 667 patients with a median follow-up period of 5.1 years. Primary IORT (IORT at the time of lumpectomy) was performed for 72%, delayed IORT (after lumpectomy) for 3%, intended boost for 8%, and unintended boost (primary IORT followed by whole-breast radiation) for 17% of the patients. At 5 years, IBTR was 6.6% for all the patients, with 8% for the primary IORT cohort and 1.7% for the unintended-boost cohort. No recurrences were identified in the delayed IORT or intended-boost cohorts. Noncompliance with endocrine therapy (ET) was associated with higher IBTR risk (hazard ratio [HR], 3.67). Patients treated with primary IORT who were complaint with ET had a 5-year IBTR rate of 3.9%. CONCLUSION: The local recurrence rates in this series differ slightly from recent results of randomized IORT trials and are notably higher than in previous published studies using whole-breast radiotherapy for similar patients with early-stage breast cancer. Understanding differences in this retrospective series and the prospective trials will be critical to optimizing patient selection and outcomes going forward.

Treatment Options in Oligometastatic Disease in Prostate Cancer: Thinking Outside the Box.

OPINION STATEMENT: Due to its relatively indolent disease course, the sensitivity of PSA testing, and the emergence of novel PET imaging, metastatic prostate cancer is particularly likely to present with a limited volume of disease. Patients with up to five metastatic lesions should be considered for an oligometastatic treatment approach. Systemic therapy remains the cornerstone of treatment for these patients. The optimal type and duration are unknown; however, the addition of a second agent to ADT appears to be beneficial. Multiple recent studies have found significant benefits to the integration of systemic therapy and local metastasis-directed therapies (MDT), including radiation and surgery, to the prostate and metastatic sites. MDT may also be used in select patients wishing to delay the initiation of systemic therapy. For patients with isolated regional nodal recurrences, whole pelvic radiotherapy or extensive lymphadenectomy is preferred, in combination with ADT.

Outcomes with intraoperative radiation therapy for early-stage breast cancer.

Adjuvant radiation therapy has been associated with improved local control following breast-conserving surgery. Traditionally, treatment has been delivered with whole breast irradiation over 3-6 weeks or partial breast irradiation over 1-3 weeks. However, intraoperative radiation therapy (IORT) has emerged as a technique that delivers a single dose of radiotherapy at the time of surgery for early-stage breast cancers. We report initial outcomes and acute toxicities with intraoperative radiation from a single institution. Patients with DCIS or Stage I-II breast cancer who underwent lumpectomy and sentinel lymph node biopsy (nodal sampling excluded in some cases) were included. All patients in this analysis were treated with IORT as at the time of surgery, 20 Gy in 1 fraction with 50 kV x-ray. Patients were treated at a single institution between 2011 and 2019. Follow-up was per standard institutional protocol. Two hundred and one patients were included in the analysis, with a median follow-up of 23 months (range: 0-73 months). Median age was 71 years old. Overall, 4 (2.0%) patients had DCIS, 186 (92.5%) patients had Stage 1 disease, and 11 patients had (5.5%) Stage 2 disease. All patients were estrogen receptor-positive, 175 (87.9%) progesterone receptor-positive, and 1 (0.5%) HER2 amplified. The crude rate of local recurrence was 2.0% (n = 4) and distant metastasis rate was 0.5% (n = 1). The rate of arm lymphedema was 0.5% (n = 1) and chronic telangiectasia rate was 1.1% (n = 2). Intraoperative radiation therapy, in a cohort of low-risk patients, demonstrated low rates of recurrence and reproducibility in a multi-disciplinary setting. Further follow-up, analysis of patient satisfaction and cosmesis, and comparison to whole breast irradiation and partial breast techniques is necessary in order to further validate these findings.

Initial outcomes with image-guided partial breast irradiation delivered with intensity-modulated radiation therapy.

Patients were treated at a single institution to a dose of 30 Gy in five fractions delivered every other day using image-guided intensity modulated radiation therapy (IMRT) partial breast irradiation. A total of 34 patients were treated with a median follow-up of 4.6 months. The rate of acute Grade 1 dermatitis was 23.5% (n = 8), and Grade 1 fatigue was 17.6% (n = 6), with no Grade 2 or higher acute toxicities. The rate of chronic Grade 1 dermatitis was 25.0% (n = 6), Grade 1 fat necrosis 4.2% (n=1), with no patients demonstrating other chronic toxicities. Image-guided APBI delivered with IMRT is associated with low rates of acute and chronic toxicity though additional follow-up is warranted.

Impact of Cribriform Pattern and Intraductal Carcinoma on Gleason 7 Prostate Cancer Treated with External Beam Radiotherapy.

PURPOSE: We assessed the impact of cribriform pattern and/or intraductal carcinoma on Gleason 7 prostate cancer treated with external beam radiotherapy. METHODS: We evaluated men with Gleason 7 (Grade Groups 2 and 3) prostate cancer treated with dose escalated external beam radiotherapy with or without androgen deprivation. We reviewed biopsies for the presence of cribriform pattern and/or intraductal carcinoma. Study end points included biochemical recurrence-free, distant metastasis-free and disease specific survival. RESULTS: In the 237 patients median followup was 117 months (range 3 to 236). According to National Comprehensive Cancer Network® risk groups 24% of patients were at favorable intermediate risk, 53% were at unfavorable intermediate risk and 23% were at high risk. The rate of cribriform pattern without intraductal carcinoma, cribriform pattern with intraductal carcinoma, intraductal carcinoma without cribriform pattern and none of these morphologies was 36%, 13%, 0% and 51%, respectively. On multivariable analysis cribriform pattern with intraductal carcinoma (HR 4.22, 95% CI 2.08-8.53, p <0.0001), prostate specific antigen 10 to 20 ng/ml (HR 1.97, 95% CI 1.03-3.79, p=0.04) and prostate specific antigen greater than 20 ng/ml (HR 2.26, 95% CI 1.21-4.23, p=0.01) were associated with worse biochemical recurrence-free survival. On multivariable analysis only cribriform pattern with intraductal carcinoma was associated with inferior distant metastasis-free survival (HR 4.18, 95% CI 1.43-12.28, p=0.01) and disease specific survival (HR 14.26, 95% CI 2.75-74.04, p=0.0016). Factors associated with cribriform pattern with or without intraductal carcinoma included Grade Group 3, high risk group and 50% or more positive biopsy cores. When stratified by neither morphology present, cribriform pattern without intraductal carcinoma and cribriform pattern with intraductal carcinoma the differences in biochemical recurrence-free, distant metastasis-free and disease specific survival were statistically significant (p=0.00042, p=0.017 and p <0.0001, respectively). CONCLUSIONS: Cribriform pattern with intraductal carcinoma was associated with adverse outcomes in men with Gleason 7 prostate cancer treated with external beam radiotherapy while cribriform pattern without intraductal carcinoma was not so associated. Future studies may benefit from dichotomizing these 2 histological entities.

Long-term complications and reconstruction failures in previously radiated breast cancer patients receiving salvage mastectomy with autologous reconstruction or tissue expander/implant-based reconstruction.

Salvage mastectomy (SM) is the standard of care for patients with local recurrence (LR) after breast conservation therapy (BCT), often with immediate reconstruction. Complications of reconstruction are a concern for these patients, and long-term data are limited. We sought to compare rates of complications requiring re-operation (CRR) and reconstruction failure (RF) between autologous reconstruction (AR) and tissue expander/implant reconstruction (TE/I). Patients with locally recurrent breast cancer after BCT, treated with SM and immediate AR or TE/I between 2000 and 2008, were identified. CRR was defined as unplanned return to operating room for wound infection, dehiscence, necrosis (including flap, skin, or fat), hematoma, or hernia (for AR) and extrusion, leak, or capsular contracture (for TE/I). RF was defined as conversion to another reconstruction technique or to flat chest wall. This study included 103 patients with 107 reconstructions. Median follow-up was 6.6 years. CRR and RF were significantly higher with TE/I (n = 34) compared to AR (n = 73) at 5 years (50.9% vs 25.5%; P = 0.02) and (42.1% vs 5.8%; P < 0.001). On univariate analysis (UVA), TE/I (HR = 2.14; P = 0.02) and diabetes (HR = 5.10; P = 0.007) were significant predictors for CRR. On UVA, TE/I (HR = 7.30; P < 0.001) and older age at reconstruction (HR = 1.03; P = 0.003) were significant predictors for RF. In this population of previously irradiated patients, TE/I was associated with significantly higher CRR and RF. Complications continue to occur up to 10 years after TE/I. AR should be considered in appropriately selected patients, though TE/I may remain a reasonable option in patients without high-risk factors for surgical complications.

Most patients are eligible for an alternative to conventional whole breast irradiation for early-stage breast cancer: A National Cancer Database Analysis.

We evaluated the proportion of patients eligible for alternatives to standard whole breast irradiation (WBI) following breast-conserving surgery using the National Cancer Database (NCDB). Using the 2016 dataset, Stage I-III patients were identified. Eligibility for hypofractionated WBI (HFRT), accelerated partial breast irradiation (APBI) and endocrine therapy (ET-alone) was defined using eligibility from large clinical trials as well as consensus guidelines. For patients with pN0 breast cancer, 20.6% and 37.0% were eligible for ET-alone based on the CALGB 9343/PRIME-II trials, respectively. In terms of HFRT, 72.5% and 50.4% were eligible based on IMPORT LOW/ASTRO HFRT guidelines, respectively. Based on IMPORT LOW/GEC-ESTRO trial/ASTRO guidelines/ABS guidelines/GEC-ESTRO guidelines, 72.5%, 86.1%, 39.0%, 72.5%, 45.7%, respectively, were eligible for APBI. Of those who qualify for HFRT per ASTRO guidelines, approximately 90% were eligible for APBI and 50% for ET-alone. This analysis shows that a large proportion of patients with node-negative breast cancer are eligible for HFRT, APBI and/or ET-alone after breast-conserving surgery.

Volumetric-based image guidance is superior to marker-based alignments for stereotactic body radiotherapy of prostate cancer.

PURPOSES: The aim of this study was to evaluate a dual marker-based and soft-tissue based image guidance for inter-fractional corrections in stereotactic body radiotherapy (SBRT) of prostate cancer. METHODS/MATERIALS: We reviewed 18 patients treated with SBRT for prostate cancer. An endorectal balloon was inserted at simulation and each treatment. Planning margins were 3 mm/0 mm posteriorly. Prior to each treatment, a dual image guidance protocol was applied to align three makers using stereoscopic x ray images and then to the soft tissue using kilo-voltage cone beam CT (kV-CBCT). After treatment, prostate (CTV), rectal wall, and bladder were delineated on each kV-CBCT, and delivered dose was recalculated. Dosimetric endpoints were analyzed, including V36.25 Gy for prostate, and D0.03 cc for bladder and rectal wall. RESULTS: Following initial marker alignment, additional translational shifts were applied to 22 of 84 fractions after kV-CBCT. Among the 22 fractions, ten fractions exceeded 3 mm shifts in any direction, including one in the left-right direction, four in the superior-inferior direction, and five in the anterior-posterior direction. With and without the additional kV-CBCT shifts, the average V36.25 Gy of the prostate for the 22 fractions was 97.6 ± 2.6% with the kV x ray image alone, and was 98.1 ± 2.4% after applying the additional kV-CBCT shifts. The improvement was borderline statistical significance using Wilcoxon signed-rank test (P = 0.007). D0.03 cc was 45.8 ± 6.3 Gy vs. 45.1 ± 4.9 Gy for the rectal wall; and 49.5 ± 8.6 Gy vs. 49.3 ± 7.9 Gy for the bladder before and after applying kV-CBCT shifts. CONCLUSIONS: Marker-based alignment alone is not sufficient. Additional adjustments are needed for some patients based kV-CBCT.

Predictive factors on outcomes in metaplastic breast cancer.

PURPOSE: Metaplastic breast cancer (MBC) is a rare, aggressive variant of breast cancer, with limited data available regarding treatment and outcomes. This study aims to review patients with MBC treated at our tertiary care institution with an emphasis on the role of treatment modality and histologic classification. METHODS: With IRB-approval, we queried our pathology database for patients with MBC diagnosis. All cases were re-evaluated by dedicated breast pathologists and confirmed as MBC breast cancer. Patient demographics, clinical/pathologic histology, and treatment were analyzed with respect to outcomes including local-regional recurrence (LRR), distant metastasis (DM), and overall survival (OS). Univariate and multivariate Cox proportional hazards models were performed to evaluate the impact on outcomes. Kaplan-Meier methods estimated survival. RESULTS: We evaluated 113 patients with MBC diagnosed between 2002 and 2013. Median age was 61 years and median pathologic tumor size 2.5 cm; 76 (67%) were ER/PR/Her2 negative, 83 (74%) grade 3. Median follow-up was 38 months. 47 (42%) underwent breast conservation therapy (BCT), 66 (58%) had mastectomy, 61 (54%) underwent adjuvant radiation (RT), and 85 (75%) had chemotherapy. At 2 and 5 years, the LRR/DM/OS rates were 12%/15%/90% and 21%/35%/69%, respectively. On Cox regression analysis, only adjuvant RT correlated with reduced LRR [RR 3.1 (1.13-9.88), p = 0.027], while chemotherapy, type of surgery, and T-N stage did not. Only T-stage (p = 0.008) correlated with DM, however chemotherapy, RT, surgery type, and N-stage were not. Univariate analysis demonstrated histologic subtype did not significantly correlate with local (p = 0.54) or distant (p = 0.83) disease control. CONCLUSIONS: This study represents among the largest institutional experiences in the outcomes of MBC. At this time, there does not appear to be a clear histologic subset of MBC which has significantly different clinical outcomes from the other subtypes. Although limited in its sample size, this study shows RT remains important in local-regional control.

Determinants of short and long term outcomes in patients undergoing immediate breast reconstruction following neoadjuvant chemotherapy.

BACKGROUND: We evaluated oncologic outcomes and complications of skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM) with immediate reconstruction (IR) after neoadjuvant chemotherapy (NAC) in patients with early-stage and locally advanced breast cancer (BC). METHODS: BC patients from 2000 to 2014 treated with NAC followed by SSM/NSM and IR were reviewed. Patient demographics, tumor characteristics, NAC response, complications, and recurrence were analyzed. RESULTS: Two hundred sixty-nine patients with 280 BCs were treated with NAC followed by SSM (94%) or NSM (6%) with IR. Median age was 47 (26-72) years with a median follow-up of 45 months. Pathologic complete response (pCR) was noted in 49 (17.5%) cases. Overall 30-day complication rate was 13.2%. Variables associated with complications included BMI (P < 0.0001), tobacco use (P = 0.015), and adjuvant radiation (P = 0.025). Local-regional recurrence was 3.2% and metastatic recurrence was 13.2%. Variables predicting recurrence risk were pre-NAC tumor size (P < 0.001), residual tumor size (P = 0.002), Grade III (P = 0.002), HER-2 negative (P = 0.025), pre-NAC nodal disease (P = 0.05), and lack of pCR (P = 0.045). CONCLUSION: Following NAC, risk factors for complications in patients undergoing SSM/NSM with IR are high BMI, smoking, and adjuvant XRT. SSM/NSM following NAC is associated with excellent local control. These data support expanding the indications for NSM/SSM to include patients receiving NAC.

TARGIT-R (Retrospective): North American Experience with Intraoperative Radiation Using Low-Kilovoltage X-Rays for Breast Cancer.

BACKGROUND: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America. METHODS: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed. RESULTS: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated. CONCLUSIONS: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

In Search of Joy and Meaning in Modern Medicine.

Inspired by Simone's maxims, a physician shares their search for restoring joy and meaning in modern medicine.

Intratumoral androgen biosynthesis associated with 3ß-hydroxysteroid dehydrogenase 1 promotes resistance to radiotherapy in prostate cancer.

Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3ß-hydroxysteroid dehydrogenase 1 (3ßHSD1) and promotes intracellular androgen biosynthesis. Germline inheritance of the adrenally permissive allele confers worse outcomes in men with advanced PCa. We investigated whether HSD3B1 (1245C) drives resistance to combined androgen deprivation and radiotherapy. Adrenally permissive 3ßHSD1 enhanced resistance to radiotherapy in PCa cell lines and xenograft models engineered to mimic the human adrenal/gonadal axis during androgen deprivation. The allele-specific effects on radiosensitivity were dependent on availability of DHEA, the substrate for 3ßHSD1. In lines expressing the HSD3B1 (1245C) allele, enhanced expression of DNA damage response (DDR) genes and more rapid DNA double-strand break (DSB) resolution were observed. A correlation between androgen receptor (AR) expression and increased DDR gene expression was confirmed in 680 radical prostatectomy specimens. Treatment with the nonsteroidal antiandrogen enzalutamide reversed the resistant phenotype of HSD3B1 (1245C) PCa in vitro and in vivo. In conclusion, 3ßHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele.

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis.

PURPOSE: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. METHODS AND MATERIALS: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. RESULTS: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38). CONCLUSIONS: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Integrating Prostate-specific Antigen Kinetics into Contemporary Predictive Nomograms of Salvage Radiotherapy After Radical Prostatectomy.

BACKGROUND: Salvage radiotherapy (SRT) is an established treatment for men with biochemical recurrence following radical prostatectomy (RP). There are several risk factors associated with adverse outcomes; however, the value of postoperative prostate-specific antigen (PSA) kinetics is less clear in the ultrasensitive PSA era. OBJECTIVE: To characterize the impact of PSA kinetics on outcomes following SRT and generate nomograms to aid in identifying patients with an increased risk of adverse clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional analysis was conducted of 1005 patients with prostate cancer treated with SRT after RP, with a median follow-up of 5 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variables examined include immediate postoperative PSA, postoperative PSA doubling time (DT), and pre-SRT PSA, in addition to previously identified predictive factors. Multivariable survival analyses were completed using Fine-Gray competing risk regression. Rates of biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM) were estimated by the cumulative incidence method. Nomograms were generated from multivariable competing risk regression with bootstrap cross-validation. RESULTS AND LIMITATIONS: Factors associated with BF after SRT include PSA DT <6 mo, initial postoperative PSA ≥0.2 ng/ml, higher pre-SRT PSA, lack of androgen deprivation therapy, a higher Gleason score (GS), negative margins, seminal vesicle invasion, lack of pelvic nodal radiation, radiation total dose <66 Gy, a longer RP to SRT interval, and older age (p < 0.05 for each). Factors associated with DM include PSA DT <6 mo, pre-SRT PSA, a higher GS, and negative margins. Factors associated with PCSM include PSA DT not calculable or <6 mo and a higher GS. Nomograms were generated to estimate the risks of BF (concordance index [CI] 0.74), DM (CI 0.77), and PCSM (CI 0.77). Limitations include retrospective nature, broad treatment eras, institutional variations, and multiple methods available for the estimation of PSA DT. CONCLUSIONS: Postoperative PSA kinetics, particularly pre-SRT PSA and PSA DT, are strongly associated with adverse oncologic outcomes following SRT and should be considered in management decisions. PATIENT SUMMARY: In this report of men with prostate cancer who developed a prostate-specific antigen (PSA) recurrence after prostatectomy, we found that PSA levels after surgery and how quickly a PSA level doubles significantly impact the chance of prostate cancer recurrence after salvage radiation therapy. Based on this information, we created a tool to calculate a man's chance of cancer recurrence after salvage radiation therapy, and these estimations can be used to discuss whether additional treatment with radiation should be considered.