Salvage Prostate Stereotactic Body Radiation Therapy After Definitive Cryoablation
Purpose: Whole gland cryoablation is a guideline-approved definitive treatment for localized prostate cancer, and is being explored for partial gland ablation. However, there is limited data regarding management of cryoablation failures. Stereotactic body radiation therapy (SBRT) is a well-established method of primary treatment for prostate cancer. Here we review salvage SBRT after cryoablation failures. Methods and Materials: A large database of patients treated with definitive SBRT was interrogated to identify those who underwent primary cryoablation. All patients were determined to have progressive disease based on a rising prostate specific antigen and/or postcryoablation biopsy. All patients were treated with SBRT over 5 treatment fractions using a robotic radiosurgical platform. Baseline cryoablation characteristics and pre- and posttreatment Expanded Prostate Cancer Index Composite questionnaires were analyzed. Acute and late toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Cancer outcomes after salvage SBRT were stratified by disease and treatment characteristics. Results: A total of 51 patients were identified who underwent cryoablation followed by salvage SBRT. The majority (47%) were found to have intermediate-risk disease at the time of SBRT salvage and most commonly were treated with 3500 cGy in 5 fractions to the prostate and seminal vesicles. Only 1 grade 3+ toxicity was identified. Patient-reported quality of life metrics after SBRT salvage followed prior patterns observed in the de novo SBRT setting. With a median follow-up of 40 months, 76% of the cohort demonstrated disease control. Median time to prostate cancer recurrence was 57.5 months, and recurrence was predominantly seen in patients with underlying high-risk disease. Conclusions: This is the largest cohort of patients treated with any radiation therapy salvage after cryoablation and the first institution to report SBRT as a modality of salvage. Salvage SBRT after cryoablation results in low rates of high-grade toxicity, acceptable changes in patient-reported quality of life, and durable rates of long-term oncologic control.
PKM2 is essential for bladder cancer growth and maintenance
Pyruvate kinase M2 (PKM2) has been shown to promote tumorigenesis by facilitating the Warburg effect and enhancing the activities of oncoproteins. However, this paradigm has recently been challenged by studies in which the absence of PKM2 failed to inhibit and instead accelerated tumorigenesis in mouse models. These results seem inconsistent with the fact that most human tumors overexpress PKM2. To further elucidate the role of PKM2 in tumorigenesis, we investigated the effect of PKM2 knockout in oncogenic HRAS-driven urothelial carcinoma. While PKM2 ablation in mouse urothelial cells did not affect tumor initiation, it impaired the growth and maintenance of HRAS-driven tumors. Chemical inhibition of PKM2 recapitulated these effects. Both conditions substantially reduced complex formation of PKM2 with STAT3, their nuclear translocation, and HIF1Î±- and VEGF-related angiogenesis. The reduction in nuclear STAT3 in the absence of PKM2 also correlated with decreased autophagy and increased apoptosis. Time-controlled, inducible PKM2 overexpression in simple urothelial hyperplasia did not trigger tumorigenesis, while overexpression of PKM2, but not PKM1, in nodular urothelial hyperplasia with angiogenesis strongly accelerated tumorigenesis. Finally, in human patients, PKM2 was overexpressed in low-grade non-muscle invasive and high-grade muscle-invasive bladder cancer. Based on these data, PKM2 is not required for tumor initiation but is essential for tumor growth and maintenance by enhancing angiogenesis and metabolic addiction. The PKM2-STAT3-HIF1Î±/VEGF signaling axis may play a critical role in bladder cancer and may serve as an actionable therapeutic target.
The role of TAp63Î³ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells
It has long been recognized that non-muscle-invasive bladder cancer (NMIBC) has a low propensity (20%) of becoming muscle-invasive (MIBC), and that MIBC carry many more p53 point mutations (p53m) than NMIBC (50% vs 10%). MIBC also has a higher mutation burden than NMIBC. These results suggest that DNA repair capacities, mutational susceptibility and p53m are crucial for MIBC development. We found MIBC cells are hypermutable, deficient in DNA repair and have markedly downregulated DNA repair genes, XPC, hOGG1/2 and Ref1, and the tumor suppressor, TAp63Î³. In contrast, NMIBC cells are hyperactive in DNA repair and exhibit upregulated DNA repair genes and TAp63Î³. A parallel exists in human tumors, as MIBC tissues have markedly lower DNA repair activity, and lower expression of DNA repair genes and TAp63Î³ compared to NMIBC tissues. Forced TAp63Î³ expression in MIBC significantly mitigates DNA repair deficiencies and reduces mutational susceptibility. Knockdown of TAp63Î³ in NMIBC greatly reduces DNA repair capacity and enhances mutational susceptibility. Manipulated TAp63Î³ expression or knockdown of p53m reduce the invasion of MIBC by 40-60%. However, the combination of p53m knockdown with forced TAp63Î³ expression reduce the invasion ability to nil suggesting that p53m contributes to invasion phenotype independent from TAp63Î³. These results indicate that in BC, TAp63Î³ regulates DNA repair capacities, mutational susceptibility and invasion, and that p53m contribute to the invasion phenotype. We conclude that concurrent TAp63Î³ suppression and acquisition of p53m are a major cause for MIBC development.
Interaction between race and prostate cancer treatment benefit in the Veterans Health Administration
BACKGROUND:Studies have demonstrated that Black men may undergo definitive prostate cancer (CaP) treatment less often than men of other races, but it is unclear whether they are avoiding overtreatment of low-risk disease or experiencing a reduction in appropriate care. The authors' aim was to assess the role of race as it relates to treatment benefit in access to CaP treatment in a single-payer population. METHODS:The authors used the Veterans Health Administration (VHA) Corporate Data Warehouse to perform a retrospective cohort study of veterans diagnosed with low- or intermediate-risk CaP between 2011 and 2017. RESULTS:The authors identified 35,427 men with incident low- or intermediate-risk CaP. When they controlled for covariates, Black men had 1.05 times the odds of receiving treatment in comparison with non-Black men (P < .001), and high-treatment-benefit men had 1.4 times the odds of receiving treatment in comparison with those in the low-treatment-benefit group (P < .001). The interaction of race and treatment benefit was significant, with Black men in the high-treatment-benefit category less likely to receive treatment than non-Black men in the same treatment category (odds ratio, 0.89; P < .001). CONCLUSIONS:Although race does appear to influence the receipt of definitive treatment in the VHA, this relationship varies in the context of the patient's treatment benefit, with Black men receiving less definitive treatment in high-benefit situations. The influence of patient race at high treatment benefit levels invites further investigation into the driving forces behind this persistent disparity in this consequential group.
Stereotactic Body Radiation Therapy for Ultra-Large (> 100 cc) Prostate Glands: Oncologic, Toxicity and Patient-Reported Outcomes
PURPOSE/OBJECTIVE(S): Historically, caution has been warranted when irradiating large target volumes particularly those in close proximity to organs at risk. Prior literature has demonstrated an increased incidence of GI and GU toxicity when men with large prostates were treated with conventionally fractionated radiation therapy. However, there is very limited data regarding the clinical outcomes when SBRT is used as a definitive treatment modality. We explore the long term oncologic, toxicity, and patient reported outcomes of men treated with definitive SBRT with ultra-large prostate glands (>= 100 cc.) MATERIALS/METHODS: From 2006 to 2020, a total of 3,393 patients with low and intermediate risk prostate cancer were treated with definitive robotic-SBRT. We performed a retrospective review to identify all patients in this cohort with pre-treatment prostate volumes >= 100 cc. Prostate volume was measured at the time of treatment regardless of ADT incorporation. All patients were treated to a total dose of 35-36.25 Gy in 5 fractions. All patients had a minimum of 2 years follow-up and were given pre- and post-treatment EPIC questionnaires at defined intervals. Biochemical control was assessed using the Phoenix definition. Late toxicity was defined using CTCAE version 5.0 and was characterized as occurring >= 6 months post treatment.
RESULT(S): A total of 67 patients were identified with >= 100 cc prostate glands. Of these, 18 patients received ADT prior to treatment. Overall, the median prostate volume was 139.37 cc (range 100.1 - 227 cc). The D'Amico risk classification was low (n=19) and intermediate (n=48). The median age was 70 years (range 54 - 87 years) and the median pretreatment PSA was 8.7 ng/ml. The mean pre-treatment EPIC bowel and urinary scores were 87.8 and 79.7, respectively. One-month following SBRT, mean EPIC bowel and urinary scores worsened to 83.6 and 76.5, respectively. Three months following SBRT, mean epic bowel and urinary scores continued to decline to 83.2 and 77.1, respectively. However, bowel and bladder symptomatology improved by 1 year to 86.16 and 77.19, and by 2 years improved above baseline to 90.00 and 85.78, respectively. There were no high grade (3+) GI toxicities observed, though one grade 3 urinary retention was identified. Excellent oncologic outcomes were observed with a 5-year median PSA nadir of 0.6 ng/mL and a biochemical relapse free survival (bRFS) of 100% at 5 years.
CONCLUSION(S): SBRT has been demonstrated to be oncologically effective with minimal toxicity, and has become a more ubiquitous radiation option in men with localized prostate cancer. Although there is a historical reticence for treatment of men with large glands, we report excellent clinical outcomes. Five-year bRFS was 100% and grade 3+ urinary toxicity was 2%. Although EPIC scores transiently dropped at 1 and 3 months following SBRT, resolution was seen by 1 year following treatment. The use of SBRT for the treatment of localized prostate cancer in men with ultra-large prostate gland is feasible with minimal toxicity.
MRI predicts prostatic urethral involvement in men undergoing radical prostatectomy: implications for cryo-ablation of localized prostate cancer
PURPOSE/OBJECTIVE:To determine whether multi-parametric magnetic resonance imaging (mpMRI) can reliably predict proximity of prostate cancer to the prostatic urethra in a contemporary series of men undergoing radical prostatectomy (RP) at two academic centers. METHODS:Clinical characteristics of consecutive men undergoing pre-operative mpMRI prior to RP and whole-mount axial serial step-sectioned pathology examination at two academic centers between Jun 2016 and Oct 2018 were analyzed retrospectively. Every tumor was characterized by its pathologic minimum distance to the prostatic urethral lumen (pMDUL). Only the cancer closest to the urethra represented the prostatic urethral index lesion. The radiologic minimum distance of the index lesion to the prostatic urethral lumen was measured and noted asâ€‰â‰¤â€‰5Â mm versus â€‰>â€‰5Â mm. The sensitivity, specificity, positive and negative predicting values (PPV and NPV) and area under the receivers operating characteristics curve (AUC) were calculated for performance of mpMRI for predicting pMDULâ€‰â‰¤â€‰5Â mm. RESULTS:Of the 163 surgical specimens examined, 112 (69%) exhibited a pMDULâ€‰â‰¤â€‰5Â mm. These men had significantly higher grade group (GG) and advanced pathological and clinical stage. The rates of high PI-RADS score and presence of gross extracapsular extension were also significantly greater for the group with pMDULâ€‰â‰¤â€‰5Â mm. The AUC, sensitivity, specificity, PPV, and NPV were 0.641, 51.8, 76.5, 82.9, and 42.4%, respectively, for mpMRI to predict pMDULâ€‰<â€‰5Â mm. CONCLUSIONS:Nearly 70% of men undergoing RP present with tumor within 5Â mm of the prostatic urethra. These tumors present higher risk characteristics, and mpMRI exhibited moderate performance and high PPV in their pre-operative detection. Physicians performing partial gland ablation should take these results into consideration during treatment selection and planning.
5-Year Outcomes Following Focal Laser Ablation of Prostate Cancer
OBJECTIVE:To characterize the oncologic outcomes five years following focal laser ablation (FLA) of localized prostate cancer. METHODS:36 men underwent in-bore FLA of prostate cancer at our institution between 2013 and 2015. Follow up included digital rectal examination and PSA testing, multiparametric MRI, and MR-guided biopsies. The primary outcome of interest was failure-free survival (FFS), defined as avoidance of salvage whole gland treatment, systemic therapy, metastasis, or death from prostate cancer. RESULTS:Of the 36 men enrolled, six were ultimately lost to follow-up. Of the remaining 30, 25 (83%) have remained free from failure over a median follow-up of 71 months. Among these patients, 10 (40%) developed in-field recurrence, with nine undergoing salvage PGA with FLA, cryotherapy, or HIFU. Five patients underwent salvage whole gland or systemic treatment and were thus considered to have failed treatment. Two patients developed metastatic disease, and after receiving radiation and ADT, both currently have undetectable PSA levels. No patients in the cohort died from prostate cancer. Limitations include a small study cohort and lack of standardized surveillance protocols two years after treatment. CONCLUSIONS:FLA for select cases of prostate cancer provides high rates of FFS, defined as freedom from whole gland or systemic treatment, metastasis, or death from prostate cancer. However, in- or out-of-field recurrence is common and often necessitates salvage ablation.
The Association of Veterans' PSA Screening Rates with Changes in USPSTF Recommendations
BACKGROUND:In 2012, the United States Preventative Services Task Force (USPSTF) formally recommended against all Prostate Specific Antigen (PSA) screening for prostate cancer. Our goal was to characterize PSA screening trends in the Veterans Health Administration (VA) before and after the USPSTF recommendation, and to determine if PSA screening was more likely to be ordered based on a Veteran's race or age. METHODS:Using the VA Corporate Data Warehouse, we created 10 annual groups of PSA-eligible men covering 2009-2018. We identified all PSA tests performed in the VA to determine yearly rates of PSA screening. All statistical tests were two-sided. RESULTS:The overall rate of PSA testing in the VA decreased from 63.3% in 2009 to 51.2% in 2018 (p<.001). PSA screening rates varied markedly by age group during our study period, with men aged 70-80 having the highest initial rate and greatest decline (70.6% in 2009 to 48.4% in 2018, p<.001). Men aged 55-69 saw a smaller decline (65.2% in 2009 to 58.9% in 2018, p<.001) while the youngest men, aged 40-54, had an increase in PSA screening (26.2% in 2009 to 37.8 in 2018, p<.001). CONCLUSIONS:In this analysis of PSA screening rates among veterans before and after the 2012 USPSTF recommendation against screening, we found that overall PSA screening decreased only modestly, continuing for more than half of the men in our study. Veterans of different races had similar screening rates, suggesting that VA care may minimize racial disparities. Veterans of varying age experienced significantly different trends in PSA screening.
Early oncological control following partial gland cryo-ablation: a prospective experience specifying reflex MRI guided biopsy of the ablation zone
BACKGROUND:Several consensus statements recommend serial serum prostate-specific antigen (PSA), multi parametric magnetic resonance imaging (mpMRI), and prostate biopsy following partial gland ablation. We determined the rate of persistent in-field disease following primary partial gland cryo-ablation and whether PSA or mpMRI are reliable predictors of in-field disease persistence. METHODS:Between March 2017 and July 2019, subjects meeting eligibility criteria for partial gland cryoablation were enrolled into an IRB approved outcomes registry. PSA, mpMRI, and prostate biopsy (four cores targeting the ablation zoneâ€‰+â€‰six ipsilateral systematic cores) were performed per protocol 6 months following intervention. Binary logistic regression was employed to calculate odds ratio (OR) of PSA decrease, and suspicious mpMRI effect on cancer persistence. The performance of mpMRI for predicting in-field persistence of PCa was evaluated by area under the receiver operation characteristics curve (AUC). RESULTS:Of the 83 eligible men undergoing partial gland cryoablation, 70 (84.3%) underwent 6-month protocol prostate biopsy. Five (7.1%) biopsies exhibited any in-field disease persistence. Only one (1.4%) of these cancers was Gleason gradeâ€‰>â€‰1. Neither PSA decrease or suspicious mpMRI reliably predicted cancer persistence, with OR of 1.6 (0.25-8.6) and 1.5 (0.02-1.3), respectively. AUC of mpMRI for predicting in-field disease persistence was 0.554. CONCLUSIONS:In this cohort of patients undergoing partial gland cryo-ablation, the incidence of persistent disease was low. PSA and mpMRI were not reliable predictors of in-field disease persistence. Based on these data, consideration may be given to deferring early follow-up biopsy in appropriate patients.