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Multi-Institutional Clinical Outcomes of Biopsy Gleason Grade Group 5 Prostate Cancers Treated With Contemporary High-Dose Radiation and Long-Term Androgen Deprivation Therapy
Abstract
Aims:
This multicentric retrospective study reports long-term clinical outcomes of non-metastatic grade group 5 prostate cancers treated with external beam radiotherapy (EBRT) alone with long-term androgen deprivation therapy (ADT).
Materials and methods:
Patients treated across 19 institutions were studied. The key endpoints that were evaluated were 5-year biochemical recurrence-free survival (bRFS), metastases-free survival (MFS), overall survival, together with EBRT-related acute and late toxicities. The impact of various prognostic factors on the studied endpoints was analysed using univariate and multivariate analyses.
Results:
Among the 462 patients, 88% (405) had Gleason 9 disease and 31% (142) had primary Gleason pattern 5. A prostate-specific membrane antigen positron emission tomography-computed tomography scan was used for staging in 33% (153), 80% (371) were staged as T3/T4 and 30% (142) with pelvic nodal disease. The median ADT duration was 24 months; 66% received hypofractionated EBRT and 71.4% (330) received pelvic nodal irradiation. With a median follow-up of 56 months, the 5-year bRFS, MFS and overall survival were 73.1%, 77.4% and 90.5%, respectively. Primary Gleason pattern 5 was associated with worse bRFS, MFS and overall survival with hazard ratios of 0.51 (95% confidence interval 0.35 to 0.73, P < 0.001), 0.64 (95% confidence interval 0.43 to 0.96, P = 0.031) and 0.52 (95% confidence interval 0.28 to 0.97, P = 0.040), respectively, whereas pelvic nodal disease was associated with worse bRFS (hazard ratio 0.67, 95% confidence interval 0.46 to 0.98, P = 0.039) and MFS (hazard ratio 0.56, 95% confidence interval 0.37 to 0.85, P = 0.006). The acute and late radiation-related toxicities were low overall and pelvic nodal irradiation was associated with higher toxicities.
Conclusion:
Contemporary EBRT and long-term ADT led to excellent 5-year clinical outcomes and low rates of toxicity in this cohort of non-metastatic grade group 5 prostate cancers. Primary Gleason pattern 5 and pelvic node disease portends inferior clinical outcomes.
... Understanding the severity of prostate cancer (PCa) is crucial for treatment decisions, Gleason score (ranging from 6 to 10), and grade groups (Roman numerals I to V). Gleason patterns 3+4 (low GP4) and 4+3 (high GP4) correspond to grade groups 2 and 3, respectively, in prognosis, quality of life, and research direction [83][84][85][86]. The 2018 updates from AJCC and UICC refined the TNM method for PCa staging, considering anatomical (tumor, lymph node, metastasis) and non-anatomical factors like PSA levels and grade groups, indicating advanced PCa with high Gleason grades [85][86][87][88][89]. ...
Androgen (AR) signaling is the main signaling for the development of the prostate and its normal functioning. AR is highly specific for testosterone and dihydrotestosterone, significantly contributing to prostate development, physiology, and cancer. All these receptors have emerged as crucial therapeutic targets for PCa. In the year 1966, the Noble prize was awarded to Huggins and Hodge for their groundbreaking discovery of AR. As it is a pioneer transcription factor, it belongs to the steroid hormone receptor family and consists of domains, including DNA binding domain (DBD), hormone response elements (HRE), C-terminal ligand binding domain (LBD), and N-terminal regulatory domains. Structural variations in AR, such as AR gene amplification, LBD mutations, alternative splicing of exons, hypermethylation of AR, and co- regulators, are major contributors to PCa. It's signaling is crucial for the development and functioning of the prostate gland, with the AR being the key player. The specificity of AR for testosterone and dihydrotestosterone is important in prostate physiology. However, when it is dysregulated, AR contributes significantly to PCa. However, the structural variations in AR, such as gene amplification, mutations, alternative splicing, and epigenetic modifications, drive the PCa progression. Therefore, understanding AR function and dysregulation is essential for developing effective therapeutic strategies. Thus, the aim of this review was to examine how AR was initially pivotal for prostate development and how it turned out to show both positive and detrimental implications for the prostate.
Background
Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.
Methods
These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8–10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0–2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544.
Findings
Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63–73) and median PSA 34 ng/ml (14·7–47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60–84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]–NE) than in the control groups (not reached, 97–NE; hazard ratio [HR] 0·53, 95% CI 0·44–0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70–1·50, p=0·91) and no evidence of between-trial heterogeneity (I² p=0·90). Overall survival (median not reached [IQR NE–NE] in the combination-therapy groups vs not reached [103–NE] in the control groups; HR 0·60, 95% CI 0·48–0·73, p<0·0001), prostate cancer-specific survival (not reached [NE–NE] vs not reached [NE–NE]; 0·49, 0·37–0·65, p<0·0001), biochemical failure-free-survival (not reached [NE–NE] vs 86 months [83–NE]; 0·39, 0·33–0·47, p<0·0001), and progression-free-survival (not reached [NE–NE] vs not reached [103–NE]; 0·44, 0·36–0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death).
Interpretation
Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population.
Funding
Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
Importance:
The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown.
Objective:
To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment.
Design, setting, and participants:
This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020.
Exposures:
Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT).
Main outcomes and measures:
The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models.
Results:
A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001).
Conclusions and relevance:
These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.
Purpose
To validate the clinical outcomes and prognostic factors in prostate cancer (PCa) patients with Gleason score (GS) 8–10 disease treated with external beam radiotherapy (EBRT) + androgen deprivation therapy (ADT) in the modern era.
Methods
Institutional databases of biopsy proven 641 patients with GS 8–10 PCa treated between 2000 and 2015 were collected from 11 institutions. In this multi-institutional Turkish Radiation Oncology Group study, a standard database sheet was sent to each institution for patient enrollment. The inclusion criteria were, T1–T3N0M0 disease according to AJCC (American Joint Committee on Cancer) 2010 Staging System, no prior diagnosis of malignancy, at least 70 Gy total irradiation dose to prostate ± seminal vesicles delivered with either three-dimensional conformal RT or intensity-modulated RT and patients receiving ADT.
Results
The median follow-up time was 5.9 years (range 0.4–18.2 years); 5‑year overall survival (OS), biochemical relapse-free survival (BRFS) and distant metastases-free survival (DMFS) rates were 88%, 78%, and 79%, respectively. Higher RT doses (≥78 Gy) and longer ADT duration (≥2 years) were significant predictors for improved DMFS, whereas advanced stage was a negative prognosticator for DMFS in patients with GS 9–10.
Conclusions
Our results validated the fact that oncologic outcomes after radical EBRT significantly differ in men with GS 8 versus those with GS 9–10 prostate cancer. We found that EBRT dose was important predictive factor regardless of ADT period. Patients receiving ‘non-optimal treatment’ (RT doses <78 Gy and ADT period <2 years) had the worst treatment outcomes.
Purpose
To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers.
Methods and Materials
In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity.
Results
One hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group.
Conclusions
PIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established.
Purpose:
Up to 30% of patients who undergo radiation for intermediate- or high-risk localized prostate cancer relapse biochemically within 5 years. We assessed if biochemical disease-free survival (DFS) is improved by adding 6 months of androgen suppression (AS; two injections of every-3-months depot of luteinizing hormone-releasing hormone agonist) to primary radiotherapy (RT) for intermediate- or high-risk localized prostate cancer.
Patients and methods:
A total of 819 patients staged: (1) cT1b-c, with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≥ 7, or (2) cT2a (International Union Against Cancer TNM 1997), with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread, with PSA ≤ 50 ng/mL, were centrally randomized 1:1 to either RT or RT plus AS started on day 1 of RT. Centers opted for one dose (70, 74, or 78 Gy). Biochemical DFS, the primary end point, was defined from entry until PSA relapse (Phoenix criteria) and clinical relapse by imaging or death of any cause. The trial had 80% power to detect hazard ratio (HR), 0.714 by intent-to-treat analysis stratified by dose of RT at the two-sided α = 5%.
Results:
The median patient age was 70 years. Among patients, 74.8% were intermediate risk and 24.8% were high risk. In the RT arm, 407 of 409 patients received RT; in the RT plus AS arm, 403 patients received RT plus AS and three patients received RT only. At 7.2 years median follow-up, RT plus AS significantly improved biochemical DFS (HR, 0.52; 95% CI, 0.41 to 0.66; P < .001, with 319 events), as well as clinical progression-free survival (205 events, HR, 0.63; 95% CI, 0.48 to 0.84; P = .001). In exploratory analysis, no statistically significant interaction between treatment effect and dose of RT could be evidenced (heterogeneity P = .79 and P = .66, for biochemical DFS and progression-free survival, respectively). Overall survival data are not mature yet.
Conclusion:
Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk cT1b-c to cT2a (with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread) prostatic carcinoma, treated by radiation.
In November, 2014, 65 prostate cancer pathology experts, along with 17 clinicians including urologists, radiation oncologists, and medical oncologists from 19 different countries gathered in a consensus conference to update the grading of prostate cancer, last revised in 2005. The major conclusions were: (1) Cribriform glands should be assigned a Gleason pattern 4, regardless of morphology; (2) Glomeruloid glands should be assigned a Gleason pattern 4, regardless of morphology; (3) Grading of mucinous carcinoma of the prostate should be based on its underlying growth pattern rather than grading them all as pattern 4; and (4) Intraductal carcinoma of the prostate without invasive carcinoma should not be assigned a Gleason grade and a comment as to its invariable association with aggressive prostate cancer should be made. Regarding morphologies of Gleason patterns, there was clear consensus on: (1) Gleason pattern 4 includes cribriform, fused, and poorly formed glands; (2) The term hypernephromatoid cancer should not be used; (3) For a diagnosis of Gleason pattern 4, it needs to be seen at 10x lens magnification; (4) Occasional/seemingly poorly formed or fused glands between well-formed glands is insufficient for a diagnosis of pattern 4; (5) In cases with borderline morphology between Gleason pattern 3 and pattern 4 and crush artifacts, the lower grade should be favored; (6) Branched glands are allowed in Gleason pattern 3; (7) Small solid cylinders represent Gleason pattern 5; (8) Solid medium to large nests with rosette-like spaces should be considered to represent Gleason pattern 5; and (9) Presence of unequivocal comedonecrosis, even if focal is indicative of Gleason pattern 5. It was recognized by both pathologists and clinicians that despite the above changes, there were deficiencies with the Gleason system. The Gleason grading system ranges from 2 to 10, yet 6 is the lowest score currently assigned. When patients are told that they have a Gleason score 6 out of 10, it implies that their prognosis is intermediate and contributes to their fear of having a more aggressive cancer. Also, in the literature and for therapeutic purposes, various scores have been incorrectly grouped together with the assumption that they have a similar prognosis. For example, many classification systems consider Gleason score 7 as a single score without distinguishing 3+4 versus 4+3, despite studies showing significantly worse prognosis for the latter. The basis for a new grading system was proposed in 2013 by one of the authors (J.I.E.) based on data from Johns Hopkins Hospital resulting in 5 prognostically distinct Grade Groups. This new system was validated in a multi-institutional study of over 20,000 radical prostatectomy specimens, over 16,000 needle biopsy specimens, and over 5,000 biopsies followed by radiation therapy. There was broad (90%) consensus for the adoption of this new prostate cancer Grading system in the 2014 consensus conference based on: (1) the new classification provided more accurate stratification of tumors than the current system; (2) the classification simplified the number of grading categories from Gleason scores 2 to 10, with even more permutations based on different pattern combinations, to Grade Groups 1 to 5; (3) the lowest grade is 1 not 6 as in Gleason, with the potential to reduce overtreatment of indolent cancer; and (4) the current modified Gleason grading, which forms the basis for the new grade groups, bears little resemblance to the original Gleason system. The new grades would, for the foreseeable future, be used in conjunction with the Gleason system [ie. Gleason score 3+3=6 (Grade Group 1)]. The new grading system and the terminology Grade Groups 1-5 have also been accepted by the World Health Organization for the 2016 edition of Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs.
A randomised phase-III trial compared external beam radiotherapy (EBRT) alone with EBRT combined with high-dose-rate brachytherapy boost (HDR-BTb) in localised prostate adenocarcinoma.
From December 1997 to August 2005, 218 patients were assigned to EBRT alone (n=108) or EBRT followed by a temporary high-dose-rate implant (n=110). Patients were stratified according to tumour stage, PSA, Gleason score and androgen deprivation therapy (ADT). Biochemical/clinical relapse-free survival (RFS) was the primary endpoint. Secondary endpoints were overall survival (OS), urinary and bowel toxicity.
RFS was significantly higher in patients treated with EBRT+HDR-BTb (log rank p=0.04). In multivariate analysis treatment arm, risk category and ADT were significant covariates for risk of relapse. Differences in OS were not significant. Incidence of severe late urinary and bowel morbidity was similar.
EBRT+HDR-BTb resulted in a significant improvement in RFS compared to EBRT alone with a 31% reduction in the risk of recurrence (p=0.01) and similar incidence of severe late urinary and rectal morbidity.
Aims:
There is a paucity of long-term data on outcomes of high-risk prostatic adenocarcinoma after moderately hypofractionated radiotherapy with elective nodal treatment and long-term androgen deprivation therapy (ADT). We report long-term control and toxicity outcomes and analyse the predictors of failure and toxicity.
Materials and methods:
The records of 120 consecutive high-risk prostate cancer patients treated in a single institution between February 2012 and December 2016 were retrospectively analysed. A moderately hypofractionted radiotherapy (HypoRT) regimen of 60 Gy in 20 fractions over 4 weeks with simultaneous elective pelvic irradiation to 44 Gy in 20 fractions with intensity-modulated radiotherapy was used, together with long-term ADT with either orchiectomy or medical castration for a total duration of 2-3 years. We analysed biochemical control, metastasis-free survival and late toxicities and their predictive factors using survival analysis.
Results:
Patients had locally advanced cancers (cT3 77.5%, median pretreatment prostate-specific antigen 30 ng/ml, Gleason score 8-10 in 45.8%). The median follow-up time was 70 months. The 3- and 5-year probability of freedom from biochemical progression was 93% and 80%, respectively. The 5-year probability of freedom from local relapse/intra-pelvic nodal relapse/distant metastases as the site of first failure was 96%/97%/86%, respectively. Gleason score 8-10 and medical ADT for 2-3 years (as opposed to orchidectomy) were independent risk factors for distant metastases. A total of 18 grade 2 and above late gastrointestinal toxicity events and a total of 23 grade 2 and above late genitourinary toxicity events were documented. Patients who underwent a transurethral resection of prostate prior to radiotherapy had worse urological toxicity.
Conclusions:
HypoRT with elective nodal treatment results in excellent pelvic control. Distant metastases are the primary mode of failure. Risk of metastases is associated with Gleason score and the duration of ADT. Late urinary toxicities are more common in those with prior transurethral resection of prostate.
Introduction
The addition of brachytherapy (BT) in high risk prostate cancer is supported by Level 1 evidence. Whether all high risk patients benefit from BT to the same extent is unknown. The National Cancer Database (NCDB) was used to investigate overall survival (OS) differences between GS 8 and 9-10 treated with external beam radiation (EBRT) only or BT +/- EBRT.
Materials and Methods
We included localized prostate adenocarcinoma definitively treated with radiation between 2004-2014. Patients were stratified into various radiation treatment groups: EBRT 7560 - 8640 cGy, EBRT 5940 - 7540 cGy, and BT +/- EBRT. All EBRT only and BT +/- EBRT patients received ADT. A multivariable Cox proportional hazard model was used to assess OS. Propensity score matching was used to account for differences between groups. Median survival was determined based on Kaplan-Meier survival curves.
Results
30,698 patients were included. On multivariable analysis among GS 8 patients, BT was associated with improved OS compared to 7560 - 8640 cGy (HR–0.80 (95% CI 0.70-0.92, P = 0.002). In Gleason 9-10 BT did not result in improved OS compared to 7560 – 8640 cGy (HR- 0.91 (95% CI 0.79 – 1.05, P = 0.212). Results remained significant with propensity score matching and removing patients with medical comorbidities.
Conclusion
BT was associated with improved OS when compared to 7560 – 8640 cGy in GS 8, but not in Gleason 9-10 disease. This hypothesis generating study suggests there may be variable benefit with BT in high risk prostate cancer patients on OS. Future prospective studies are needed to investigate whether the benefit of BT is similar across all high risk prostate cancer patients.
Objective
To test for baseline prostate cancer characteristics and survival differences after salvage radical prostatectomy (SRP) across 18 Surveillance, Epidemiology and End Results (SEER) registries from 2004 and 2016.
Material and Methods
We tabulated PSA, cT-stage, age and SRP rates across individual SEER registries. Kaplan-Meier and competing risks regression methodologies depicted cancer-specific mortality (CSM) and other cause mortality (OCM). Finally, overall mortality (OM) was compared to predicted life expectancy.
Results
Overall, 428 SRP patients (2004-2016) were identified in the SEER database. Median follow-up duration was 74 months (IQR 31-114). Their median age at diagnosis was 68 (IQR 61-73) with a median PSA at diagnosis of 8.8 ng/ml (IQR 5.4-18.6 ng/ml) and 10% cT3-4-stage (range 0-23.8%). Variability existed across individual SEER registries regarding age, PSA, cT-stage and annual number of SRPs (range: 0-17), as well as cumulative numbers of SRPs (range: 7-73) between 2004 and 2016. At ten years, CSM was 23.2% vs. OCM 19.3%. Finally, SRP patients exhibited higher ten-year OM (43.3%) than that predicted by life tables (31.8%).
Conclusion
SRP is rarely performed. In most SEER registries SRP use is very occasional: More than two average annual SRPs were reported in only five of all registries. Nonetheless, across all registries, SRP patients showed marginal to moderate differences in PSA, cT-stage and age at diagnosis. However, at ten years of follow-up, one out of five SRP patients died of other causes and observed OM was higher than expected (36%).
PURPOSE
We report the clinical outcomes of a randomized trial comparing prophylactic whole-pelvic nodal radiotherapy to prostate-only radiotherapy (PORT) in high-risk prostate cancer.
METHODS
This phase III, single center, randomized controlled trial enrolled eligible patients undergoing radical radiotherapy for node-negative prostate adenocarcinoma, with estimated nodal risk ≥ 20%. Randomization was 1:1 to PORT (68 Gy/25# to prostate) or whole-pelvic radiotherapy (WPRT, 68 Gy/25# to prostate, 50 Gy/25# to pelvic nodes, including common iliac) using computerized stratified block randomization, stratified by Gleason score, type of androgen deprivation, prostate-specific antigen at diagnosis, and prior transurethral resection of the prostate. All patients received image-guided, intensity-modulated radiotherapy and minimum 2 years of androgen deprivation therapy. The primary end point was 5-year biochemical failure-free survival (BFFS), and secondary end points were disease-free survival (DFS) and overall survival (OS).
RESULTS
From November 2011 to August 2017, a total of 224 patients were randomly assigned (PORT = 114, WPRT = 110). At a median follow-up of 68 months, 36 biochemical failures (PORT = 25, WPRT = 7) and 24 deaths (PORT = 13, WPRT = 11) were recorded. Five-year BFFS was 95.0% (95% CI, 88.4 to 97.9) with WPRT versus 81.2% (95% CI, 71.6 to 87.8) with PORT, with an unadjusted hazard ratio (HR) of 0.23 (95% CI, 0.10 to 0.52; P < .0001). WPRT also showed higher 5-year DFS (89.5% v 77.2%; HR, 0.40; 95% CI, 0.22 to 0.73; P = .002), but 5-year OS did not appear to differ (92.5% v 90.8%; HR, 0.92; 95% CI, 0.41 to 2.05; P = .83). Distant metastasis-free survival was also higher with WPRT (95.9% v 89.2%; HR, 0.35; 95% CI, 0.15 to 0.82; P = .01). Benefit in BFFS and DFS was maintained across prognostic subgroups.
CONCLUSION
Prophylactic pelvic irradiation for high-risk, locally advanced prostate cancer improved BFFS and DFS as compared with PORT, but OS did not appear to differ.
The five-tier grade group (GG) classification for prostate cancer (PCa) does not differentiate between primary (5+4) or secondary (4+5) histological Gleason 5 pattern in GG 5. We addressed the prognostic value of primary versus secondary biopsy Gleason 5 for GG 5 among 18 555 PCa patients treated with radical prostatectomy (RP) between 1992 and 2014. Of these, 922 patients had GG 5 PCa with primary (n=295) or secondary (n=627) Gleason 5 on biopsy. Prediction of biochemical recurrence (BCR), metastasis, and cancer-specific mortality (CSM) was assessed using Kaplan-Meier curves and univariable/multivariable Cox regression controlling for known prognosticators. Median follow-up was 74.8 mo (interquartile range [IQR] 49.2-120.2). BCR developed in 24.3% of patients (n=4508) at a median of 23.6 mo (IQR 7.1-48.6). Metastasis developed in 4.5% (n=827) and 2.0% (n=370) died of PCa. When stratifying GG 5 by primary versus secondary Gleason 5, the estimated 5-yr metastasis-free survival was 80.4% (95% confidence interval [CI] 76.1-85.0%) versus 86.9% (95% CI 84.2-89.7%; p= 0.002) and cancer-specific survival was 90.9% (95% CI 87.5-94.4%) versus 96.3% (95% CI 94.7-98.0%; p< 0.001). On multivariable analysis, the negative impact of primary biopsy Gleason 5 among GG 5 patients remained significant for metastasis (hazard ratio [HR] 1.58; p< 0.001) and CSM (HR 2.44; p< 0.001). Therefore, stratifying GG 5 into primary (5 + 4, 5 + 5) and secondary (4 + 5) Gleason 5 may be warranted. PATIENT SUMMARY: We recorded worse oncological outcomes for patients with a primary histological Gleason 5 pattern on prostate biopsy compared to patients with a secondary biopsy Gleason 5 pattern.
Aim: To report toxicity and quality of life (QOL) outcomes from a randomised trial of prostate only versus whole pelvic radiotherapy in high risk, node negative prostate cancer.
Materials/methods: Patients with localised prostate adenocarcinoma and nodal involvement risk > 20%, were randomised to prostate only (PORT, 68 Gy/25# to prostate) and whole pelvis (WPRT, 68 Gy/25# to prostate and 50 Gy/25# to pelvis) arms with stratification for TURP, Gleason score, baseline PSA, and type of androgen deprivation therapy (ADT). Image guided intensity modulated radiotherapy (IG-IMRT) and two years of ADT were mandatory. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were graded using RTOG grading. QOL was assessed using EORTC QLQ-C30 and PR-25 questionnaire pre-treatment and every 3-6 months post RT.
Results:Total 224 patients were randomised (PORT 114, WPRT 110) from November 2011 to August2017. Median follow up was 44.5 months. No RTOG grade IV toxicity was observed. Acute GI and GU toxicities were similar between both the arms. Cumulative�grade II late GI toxicity was similar for WPRTand PORT (6.5% vs. 3.8%,p= 0.39) but GU toxicity was higher (17.7% vs. 7.5%,p= 0.03). Dosimetric analysis showed higher bladder volume receiving 30–40 Gy in the WPRT arm (V30, 60% vs. 36%,p< 0.001;V40, 41% vs. 25%,p< 0.001). There was no difference in QOL scores of any domain between both arms.
Conclusion:Pelvic irradiation using hypofractionated IG-IMRT resulted in increased grade II or higher late genitourinary toxicity as compared to prostate only RT, but the difference was not reflected in patient reported QOL.
Clinicaltrials.gov NCT02302105:Prostate Only or Whole Pelvic Radiation Therapy in High Risk Prostate Cancer (POP-RT).
Purpose:
Gleason Score (GS) 9-10 prostate cancer is associated with particularly adverse oncological outcomes and the optimal treatment is unknown. Therefore, cancer-specific mortality (CSM) rates after radical prostatectomy (RP) ± adjuvant radiation therapy (aRT) vs. external beam radiation therapy (EBRT) were tested.
Methods:
Within the Surveillance, Epidemiology, and End Results database (2004-2015), 17,897 clinically localized prostate cancer patients with biopsy GS 9-10 were identified who either received RP ± aRT or EBRT. Temporal trends, cumulative incidence plots and multivariable competing-risks regression analyses were used after propensity score matching. Sensitivity analyses were performed according to primary treatment type (RP only vs. EBRT).
Results:
Of all, 8,890 (49.7%) underwent EBRT vs. 9,007 (50.3%) underwent RP. Of those, 2,584 (28.7%) received aRT. No significant change in treatment assignment was recorded over time. In cumulative incidence smoothed plots, 10 year CSM rates were 19.9% vs. 19.6% (P = 0.3) and 10 year other-cause mortalityrates were 11.5% vs. 31.2%, respectively, in RP vs. EBRT patients (P < 0.001). In multivariable competing-risks regression analyses, RP did not reach independent predictor status of lower CSM (hazard ratio (HR): 0.93, P = 0.2). In sensitivity analyses within RP only vs. EBRT patients, RP represented an independent predictor of lower CSM (HR: 0.76, P < 0.001).
Conclusions:
In biopsy GS 9-10 patients, no CSM differences were observed after RP ± aRT vs. EBRT. However, in patients in whom RP did not have to be combined with aRT, RP seems to be associated with a minor improvement in cancer-specific survival compared to EBRT. This applied to the majority of GS 9-10 RP patients.
Background/purpose:
Stratification of Gleason score (GS) into three categories (2-6, 7, and 8-10) may not fully utilize its prognostic discrimination, with Gleason pattern 5 (GP5) previously identified as an independent adverse factor.
Materials/methods:
Patients treated on RTOG 9202 (n = 1292) or RTOG 9902 (n = 378) were pooled and assessed for association of GS and GP5 on biochemical failure (BF), local failure (LF), distant metastasis (DM), and overall survival (OS). Fine and Gray's regression and cumulative incidence methods were used for univariate and multivariate analyses.
Results:
With median follow-up of 9.4 years, patients with GS 8-10 with GP5 had worse outcome than GS 4 + 4 for DM on both RTOG9202 (p = 0.038) and RTOG9902 (p < 0.001) with a trend toward worse OS (p = 0.059 and p = 0.089, respectively), but without differences in BF or LF. At 10-years DM was higher by 11% (RTOG 9202) and 18% (RTOG 9902) with GP5 compared to GS 4 + 4. On multivariate analysis restricted to long-term androgen deprivation therapy the presence of GP5 substantially increased distant metastasis (HR = 0.43, 95%CI: 0.24-0.76, p = 0.0039) with a trend toward worse OS (HR:0.74, 95% CI:0.54-1.0, p = 0.052) without association with LF (HR:0.55, 95%CI:0.28-1.09, p = 0.085) or BF (HR:1.15, 95%CI:0.84-1.59, p = 0.39). We did not observed substantial differences between Gleason 3 + 5, 5 + 3, or Gleason 9-10.
Conclusions:
These results validate GP5 as an independent prognostic factor which is strongest for DM. As a result GP5 should be considered when stratifying patients with GS 8 and may be a patient population in which to evaluate newly approved systemic therapies or additional local treatments.
Importance
It is unknown how treatment with radical prostatectomy (RP) and adjuvant external beam radiotherapy (EBRT), androgen deprivation therapy (ADT), or both (termed MaxRP) compares with treatment with EBRT, brachytherapy, and ADT (termed MaxRT).
Objective
To investigate whether treatment of Gleason score 9-10 prostate cancer with MaxRP vs MaxRT was associated with prostate cancer–specific mortality (PCSM) and all-cause mortality (ACM) risk.
Design, Setting, and Participants
The study cohort comprised 639 men with clinical T1-4,N0M0 biopsy Gleason score 9-10 prostate cancer. Between February 6, 1992, and April 26, 2013, a total of 80 men were consecutively treated with MaxRT at the Chicago Prostate Cancer Center, and 559 men were consecutively treated with RP and pelvic lymph node dissection at the Martini-Klinik Prostate Cancer Center. Follow-up started on the day of prostate EBRT or RP and concluded on October 27, 2017.
Exposures
Of the 559 men managed with RP and pelvic lymph node dissection, 88 (15.7%) received adjuvant EBRT, 49 (8.8%) received ADT, and 50 (8.9%) received both.
Main Outcomes and Measures
Treatment propensity score–adjusted risk of PCSM and ACM and the likelihood of equivalence of these risks between treatments using a plausibility index.
Results
The cohort included 639 men, with a mean (SD) age of 65.83 (6.52) years. After median follow-ups of 5.51 years (interquartile range, 2.19-6.95 years) among 80 men treated with MaxRT and 4.78 years (interquartile range, 4.01-6.05 years) among 559 men treated with RP-containing treatments, 161 men had died, 106 (65.8%) from prostate cancer. There was no significant difference in the risk of PCSM (adjusted hazard ratio, 1.33; 95% CI, 0.49-3.64; P = .58) and ACM (adjusted hazard ratio, 0.80; 95% CI, 0.36-1.81; P = .60) when comparing men who underwent MaxRP vs MaxRT, with plausibility indexes for equivalence of 76.75% for the end point of the risk of PCSM and 77.97% for the end point of the risk of ACM. Plausibility indexes for all other treatment comparisons were less than 63%.
Conclusions and Relevance
Results of this study suggest that it is plausible that treatment with MaxRP or MaxRT for men with biopsy Gleason score 9-10 prostate cancer can lead to equivalent risk of PCSM and ACM.
Importance:
Androgen deprivation therapy (ADT) improves survival outcomes in patients with high-risk prostate cancer (PCa) treated with radiotherapy (RT). Whether this benefit differs between patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease remains unknown.
Objective:
To determine whether the effectiveness of ADT duration varies between patients with GG 4 vs GG 5 PCa.
Design, setting, and participants:
Traditional and network individual patient data meta-analyses of 992 patients (593 GG 4 and 399 GG 5) who were enrolled in 6 randomized clinical trials were carried out.
Main outcomes and measures:
Multivariable Cox proportional hazard models were used to obtain hazard ratio (HR) estimates of ADT duration effects on overall survival (OS) and distant metastasis-free survival (DMFS). Cause-specific competing risk models were used to estimate HRs for cancer-specific survival (CSS). The interaction of ADT with GS was incorporated into the multivariable models. Traditional and network meta-analysis frameworks were used to compare outcomes of patients treated with RT alone, short-term ADT (STADT), long-term ADT (LTADT), and lifelong ADT.
Results:
Five hundred ninety-three male patients (mean age, 70 years; range, 43-88 years) with GG 4 and 399 with GG 5 were identified. Median follow-up was 6.4 years. Among GG 4 patients, LTADT and STADT improved OS over RT alone (HR, 0.43; 95% CI, 0.26-0.70 and HR, 0.59; 95% CI, 0.38-0.93, respectively; P = .03 for both), whereas lifelong ADT did not (HR, 0.84; 95% CI, 0.54-1.30; P = .44). Among GG 5 patients, lifelong ADT improved OS (HR, 0.48; 95% CI, 0.31-0.76; P = .04), whereas neither LTADT nor STADT did (HR, 0.80; 95% CI, 0.45-1.44 and HR, 1.13; 95% CI, 0.69-1.87; P = .45 and P = .64, respectively). Among all patients, and among those receiving STADT, GG 5 patients had inferior OS compared with GG 4 patients (HR, 1.25; 95% CI, 1.07-1.47 and HR, 1.40; 95% CI, 1.05-1.88, respectively; P = .02). There was no significant OS difference between GG 5 and GG 4 patients receiving LTADT or lifelong ADT (HR, 1.21; 95% CI, 0.89-1.65 and HR, 0.85; 95% CI, 0.53-1.37; P = .23 and P = .52, respectively).
Conclusions and relevance:
These data suggest that prolonged durations of ADT improve survival outcomes in both GG 4 disease and GG 5 disease, albeit with different optimal durations. Strategies to maintain the efficacy of ADT while minimizing its duration (potentially with enhanced potency agents) should be investigated.
Importance
The optimal treatment for Gleason score 9-10 prostate cancer is unknown.
Objective
To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment.
Design, Setting, and Participants
Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013.
Exposures
Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy.
Main Outcomes and Measures
The primary outcome was prostate cancer–specific mortality; distant metastasis-free survival and overall survival were secondary outcomes.
Results
Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer–specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer–specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer–specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]).
Conclusions and Relevance
Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer–specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.
Purpose
To determine the impact on long-term survival from the addition of brachytherapy to external beam radiation therapy (EBRT) in patients with prostate cancer.
Materials and Methods
Between 1992 and 1997, 104 men with cT2-3, surgically staged node-negative prostate cancer were randomized to receive either EBRT (40Gy/20 fractions) with iridium implant (35Gy/48 h) or EBRT alone (66Gy/33 fractions) to the prostate. Based on T- stage, Gleason score and PSA (Prostate-Specific Antigen), 60% of patients had high-risk disease. Substantial improvements in biochemical control at 8 years have previously been reported. Additional follow up was collected on deaths and metastases.
Results
Median follow-up was 14 years. Five patients were lost to follow up. All other patients have been followed a minimum of 13 years. There have been 75 deaths, including 21 from prostate cancer and 25 from second cancers. No patients developing a second cancer have died from prostate cancer. There was no difference in overall survival between the two treatment groups, 34 (67%) deaths in the Implant arm and 41 (77%) in the EBRT arm, hazard ratio (HR) = 1.00, 95% confidence interval (CI) = (0.63, 1.59). Similarly, there was no difference in prostate cancer-specific deaths, 9 (18%) patients in the Implant arm compared to 12 (23%) in the EBRT arm, HR= 0.79, 95% CI = (0.34, 1.87). There was no statistically significant difference in the number of patients developing metastatic disease, 10 (20%) in the Implant arm to 15 (28%) in the EBRT arm, HR= 0.70, 95% CI = (0.32, 1.57). Improvements in biochemical control were maintained, HR = 0.53, 95% CI = (0.31, 0.88).
Conclusions
Despite a dramatic reduction of biochemical recurrence rates, the addition of iridium implant to EBRT did not translate into improved overall survival or prostate cancer-specific survival.
Purpose
Patients with prostate cancer (PCa) containing Gleason pattern (GP) 5 disease have a higher and earlier incidence of prostate cancer-specific mortality (PCSM) than general PCa patients. This affords the statistical power to compare PCSM outcomes between different treatment modalities even when restricting analysis only to patients treated in the modern era. The purpose of this work was to compare survival outcomes among patients with GP 5 PCa on needle core biopsy or transurethral resection of prostate (TURP) treated with extremely dose-escalated radiotherapy (exemplified by external beam radiotherapy with a brachytherapy boost [EBRT+BT]) versus radical prostatectomy (RP) in the modern era.
Materials/Methods
7,669 men diagnosed with GP 5 PCa from 2004-2013 who received EBRT+BT or RP were identified using the Surveillance, Epidemiology, and End Results (SEER) database. After propensity score matching to balance patient characteristic variables, PCSM was compared between modalities using a multivariate Fine and Gray competing risk model that accounted for other-cause mortality (OCM), with adjustment for age, race, GP, and clinical T-stage.
Results
Patients treated with RP were younger, had lower burden of GP 5, lower T-stage, and lower OCM than patients treated with EBRT+BT. After propensity score matching, there was no difference in PCSM between patients treated with RP and EBRT+BT (adjusted hazard ratio [AHR] 1.018, p=0.910). The cumulative 5-year PCSM incidence rates were 5.6% and 6.1% for patients treated with RP and EBRT+BT, respectively. Patients with primary GP 5 had significantly higher PCSM than those with secondary GP 5, regardless of treatment modality.
Conclusions
For patients with GP 5 PCa based on needle core biopsy or TURP, RP and EBRT+BT offer equivalent PCSM in a competing risk model after propensity score matching to balance differences in patient characteristics.
Purpose:
To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer.
Methods and materials:
ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398 trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years.
Results:
In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62).
Conclusions:
Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.
Background
The newly proposed five-tiered prostate cancer grading system (PCGS) divides Gleason score (GS) 8–10 disease into GS 8 and GS 9–10 on the basis of biochemical recurrence (BCR) following radical prostatectomy (RP) as an outcome. However, BCR does not necessarily portend worse survival outcomes.
Objective
To assess the significance of distinguishing GS 8 versus 9–10 disease in terms of long-term survival outcomes for both the preoperative setting using biopsy (Bx) GS and the postoperative setting with RP GS.
Design, setting, and participants
Of 23 918 men who underwent RP between 1984 and 2014, there were 721 men with biopsy GS 8–10, and 1047 men with RP GS 8–10.
Outcome measures and statistical analysis
Clinicopathologic characteristics were compared between men with GS 8 and those with GS 9–10. We compared all-cause mortality (ACM) and prostate cancer–specific mortality (PCSM) risk between the groups using Cox regression and competing-risks analyses, adjusting for other perioperative variables and death from other causes as the competing event.
Results and limitations
Compared to men with GS 8, men with GS 9–10 had later RP year and higher pathologic stage. Among men with Bx GS 8–10, 115 died (82 due to PC) with median follow-up of 3 yr (interquartile range [IQR] 1–7) for both overall and cancer-specific survival. Of men with RP GS 8–10, 221 died (151 due to PC) with median follow-up of 4 yr (IQR 2–8) and 4 yr (IQR 2–9) for overall and cancer-specific survival, respectively. PC-specific survival rates were significantly lower for men with GS 9–10 compared to men with GS 8 for both Bx (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.37–3.30; p < 0.01) and RP GS (HR 2.38, 95% CI 1.74–3.28; p < 0.01). This association persisted in multivariable models after adjusting for perioperative variables.
Conclusions
Men with GS 9–10 had higher ACM and PCSM rates compared to those with GS 8. GS 8 and GS 9–10 PC should be considered separately in both the preoperative and postoperative setting as suggested by the new PCGS.
Patient summary
The prostate cancer grading system can predict mortality risk after radical prostatectomy (RP) for men with Gleason score 8–10 disease based on both biopsy and RP Gleason scores. There are significant differences in all-cause mortality and prostate cancer–specific mortality following surgery between men with Gleason score 8 and those with Gleason score 9–10 disease.
Background:
The long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy [ADT] and radiotherapy dose-escalation]. Gleason score (GS) 9-10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful comparisons.
Objective:
To compare outcomes of patients with GS 9-10 CaP following EBRT, extremely-dose escalated radiotherapy (as exemplified by EBRT+brachytherapy [EBRT+BT]), and RP.
Design, setting, participants:
Retrospective analysis of 487 patients with biopsy GS 9-10 CaP treated between 2000 and 2013 (230 with EBRT, 87 with EBRT+BT, and 170 with RP). Most radiotherapy patients received ADT and dose-escalated radiotherapy.
Outcome measurements and statistical analysis:
Kaplan-Meier analysis and multivariate Cox regression estimated and compared 5-yr and 10-yr rates of distant metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS).
Results and limitations:
The median follow-up was 4.6 yr. Local salvage and systemic salvage were performed more frequently in RP patients (49.0% and 30.1%) when compared with either EBRT patients (0.9% and 19.7%) or EBRT+BT patients (1.2% and 16.1%, p<0.0001). Five-yr and 10-yr distant metastasis-free survival rates were significantly higher with EBRT+BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%, p=0.0005) or RP (79.1% and 61.5%, p<0.0001). The 5-yr and 10-yr CSS and OS rates were similar across all three cohorts.
Conclusions:
Radiotherapy and RP provide equivalent CSS and OS. Extremely dose-escalated radiotherapy with ADT in particular offers improved systemic control when compared with either EBRT or RP. These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9-10 CaP.
Patient summary:
While some prostate cancers are slow-growing requiring many years, sometimes decades, of follow-up in order to compare between radiation and surgery, high-risk and very aggressive cancers follow a much shorter time course allowing such comparisons to be made and updated as treatments, especially radiation, rapidly evolve. We showed that radiation-based treatments and surgery, with contemporary standards, offer equivalent survival for patients with very aggressive cancers (defined as Gleason score 9-10). Extremely-dose escalated radiotherapy with short-course androgen deprivation therapy offered the least risk of developing metastases, and equivalent long term survival.
Long-term androgen deprivation therapy (ADT) was proven in randomized trials to be superior to short-term ADT for radiation-managed patients who have clinical T3 (cT3) disease, but it is unknown whether patients with T3 disease seen only on magnetic resonance imaging require similarly aggressive treatment. We attempted to study this issue by analogy by comparing the long-term post-prostatectomy survival of patients with cT3 disease versus cT1/T2 disease upstaged to pathologic T3 disease.
The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 60,165 men diagnosed with prostate adenocarcinoma between 1995 and 2002 who underwent prostatectomy. Prostate cancer-specific mortality (PCSM) was evaluated by stage after adjusting for grade, marital status, race, sex, year of diagnosis, and age.
The median follow-up was 10.5 years. Patients with cT1/T2 but pathologic T3a disease had significantly better 10-year PCSM than men with cT3 disease had (3.0% vs. 9.9%, adjusted hazard ratio [AHR] = 0.420, P<0.001), but they had worse PCSM than men with pathologic T2 disease had (3.0% vs. 0.91%, AHR = 2.53, P<0.001). Of patients with occult T3a disease, those with low-grade/intermediate-grade disease (Gleason score 7 or less) had a slightly higher 10-year PCSM when compared with those with pathologic T2 disease (1.34% vs. 0.91%, AHR = 1.69, P<0.001). Patients with cT1/T2 and pathologic T3b disease had similar PCSM as men presenting with cT3 disease (11.0% vs. 9.86%, AHR = 1.14 [0.862, 1.52], P = 0.353).
Patients with occult T3a disease had less than half the risk of PCSM as those with cT3 disease, and a subset of those men had similar risk as patients with pathologic T2 disease. Therefore, it is possible that radiation-managed patients with low-grade/intermediate-grade T3a disease by magnetic resonance imaging only might not require long-term ADT. However, patients with occult T3b or high-grade occult T3a disease have similar PCSM as that of those presenting with cT3 disease, so they should be treated as aggressively, including long-course ADT when managed by radiation.
Copyright © 2015 Elsevier Inc. All rights reserved.
Purpose:
There is a paucity of data on the prognosis after radical prostatectomy for Gleason score 9-10 disease on needle biopsy. To our knowledge we report the largest study to date to specifically analyze the correlation of Gleason score 9-10 on needle core biopsy with radical prostatectomy outcomes.
Materials and methods:
We identified 259 men with Gleason score 9-10 on biopsy who underwent radical prostatectomy from 1987 to 2012 at our institution. Preoperative variables analyzed were age, race, preoperative prostate specific antigen, adenocarcinoma site, perineural invasion, number of total biopsy cores, number of total positive cores, number of positive cores with Gleason score 9-10, maximum percent of core length with Gleason score 9-10 and maximum percent of adenocarcinoma overall. We determined pathological outcomes on univariate and multivariate analysis, including organ confinement, seminal vesicle invasion, margin status, lymph node metastasis, and biochemical-free and cancer specific survival.
Results:
Statistically significant predictors of radical prostatectomy outcome were organ confinement (total cores with Gleason score 9-10, maximum percent overall and perineural invasion), margin status (preoperative prostate specific antigen and clinical stage), seminal vesicle invasion (maximum percent overall, perineural invasion and clinical stage), lymph node metastasis (total number of cores with Gleason score 9-10 and clinical stage) and biochemical-free survival (maximum percent of Gleason score 9-10, maximum percent overall and clinical stage) (each p<0.05).
Conclusions:
In the highly select subset of patients who are good surgical candidates and have the appropriate combination of preoperative variables postoperative findings are sufficiently favorable to justify radical prostatectomy.
Research electronic data capture (REDCap) is a novel workflow methodology and software solution designed for rapid development and deployment of electronic data capture tools to support clinical and translational research. We present: (1) a brief description of the REDCap metadata-driven software toolset; (2) detail concerning the capture and use of study-related metadata from scientific research teams; (3) measures of impact for REDCap; (4) details concerning a consortium network of domestic and international institutions collaborating on the project; and (5) strengths and limitations of the REDCap system. REDCap is currently supporting 286 translational research projects in a growing collaborative network including 27 active partner institutions.
We conducted a randomized, prospective trial comparing external irradiation with external irradiation plus goserelin (an agonist analogue of gonadotropin-releasing hormone that reduces testosterone secretion) in patients with locally advanced prostate cancer.
From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. The patients had a median age of 71 years (range, 51 to 80). Patients in both groups received 50 Gy of radiation to the pelvis over a period of five weeks and an additional 20 Gy over an additional two weeks as a prostatic boost. Patients in the combined-treatment group received 3.6 mg of goserelin (Zoladex) subcutaneously every four weeks starting on the first day of irradiation and continuing for three years; those patients also received cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone associated with the administration of goserelin.
Data were available for analysis on 401 patients. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at five years were 79 percent (95 percent confidence interval, 72 to 86 percent) in the combined-treatment group and 62 percent (95 percent confidence interval, 52 to 72 percent) in the radiotherapy group (P=0.001). The proportion of surviving patients who were free of disease at five years was 85 percent (95 percent confidence interval, 78 to 92 percent) in the combined-treatment group and 48 percent (95 percent confidence interval, 38 to 58 percent) in the radiotherapy group (P<0.001).
Adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer.
EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer
- Bolla
Prostatic Carcinoma: definition of grading patterns and proposal for a new grading system
- J I Epstein
- L Egevad
- M B Amin
- B Delahunt
- J R Srigley
- P A Humphrey
- Grading Committee
Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR,
Humphrey PA, Grading Committee. The 2014 International
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