Influence of Active Surveillance on Gleason Score Upgrade and Prognosis in Low- and Favorable Intermediate-Risk Prostate Cancer

Few studies have focused on the link between active surveillance (AS) and Gleason score upgrade (GSU) and its impact on the prognosis of patients with prostate cancer (PCa). This study aimed to analyze the effect of AS duration on GSU and prognostic value based on risk stratification. All eligible patients were risk-stratified according to AUA guidelines into low-risk (LR), favorable intermediate-risk (FIR), and unfavorable intermediate-risk (UIR) PCa. Within the Surveillance, Epidemiology, and End Results Program (SEER) database, 28,368 LR, 27,243 FIR, and 12,210 UIR PCa patients were included. The relationship between AS duration and GSU was identified with univariate and multivariate logistic regression. Discrimination according to risk stratification of AS duration and GSU was tested by Kaplan–Meier analysis and competing risk regression models. The proportion of patients who chose AS was the highest among LR PCa (3434, 12.1%), while the proportion in UIR PCa was the lowest (887, 7.3%). The AS duration was only associated with GSU in LR PCa, with a high Gleason score (GS) at diagnosis being a strong predictor of GSU for FIR and UIR PCa. Kaplan–Meier analysis indicated that long-term surveillance only made a significant difference in prognosis in UIR PCa. The competing risk analysis indicated that once GS was upgraded to 8 or above, the prognosis in each group was significantly worse. AS is recommended for LR and FIR PCa until GS is upgraded to 8, but AS may not be suitable for some UIR PCa patients.     

Pathologic Outcomes of Gleason 6 Favorable Intermediate-Risk Prostate Cancer Treated With Radical Prostatectomy: Implications for Active Surveillance

Background

The safety of active surveillance (AS) for Gleason 6 favorable intermediate-risk (FIR) prostate cancer is unknown. To provide guidance, we examined the incidence and predictors of upgrading or upstaging for Gleason 6 FIR patients treated with radical prostatectomy.

Four-year Prostate-specific Antigen Response Rate as a Predictive Measure in Intermediate-risk Prostate Cancer Treated With Ablative Therapies: The SPRAT Analysis

AimsThere is a lack of early predictive measures of outcome for patients with intermediate-risk prostate cancer (PCa) treated with stereotactic body radiotherapy (SBRT). The aim of the present study was to explore 4-year prostate-specific antigen response rate (4yPSARR) as an early predictive measure.Materials and methodsIndividual patient data from six institutions for patients with intermediate-risk PCa treated with SBRT between 2006 and 2016 with a 4-year (42–54 months) PSA available were analysed. Cumulative incidences of biochemical failure and metastasis were calculated using Nelson-Aalen estimates and overall survival was calculated using the Kaplan–Meier method. Biochemical failure-free survival was analysed according to 4yPSARR, with groups dichotomised based on PSA <0.4 ng/ml or ≥0.4 ng/ml and compared using the Log-rank test. A multivariable competing risk analysis was carried out to predict for biochemical failure and the development of metastases.ResultsSix hundred and thirty-seven patients were included, including 424 (67%) with favourable and 213 (33%) with unfavourable intermediate-risk disease. The median follow-up was 6.2 years (interquartile range 4.9–7.9). The cumulative incidence of biochemical failure and metastasis was 7 and 0.6%, respectively; overall survival at 6 years was 97%. The cumulative incidence of biochemical failure at 6 years if 4yPSARR <0.4 ng/ml was 1.7% compared with 27% if 4yPSARR ≥0.4 ng/ml (P < 0.0001). On multivariable competing risk analysis, 4yPSARR was a statistically significant predictor of biochemical failure-free survival (subdistribution hazard ratio 15.3, 95% confidence interval 7.5–31.3, P < 0.001) and metastasis-free survival (subdistribution hazard ratio 31.2, 95% confidence interval 3.1–311.6, P = 0.003).Conclusion4yPSARR is an encouraging early predictor of outcome in patients with intermediate-risk PCa treated with SBRT. Validation in prospective trials is warranted.     

Cost–Utility Analysis of Radiation Treatment Modalities for Intermediate-Risk Prostate Cancer

Introduction: Variable costs of different radiation treatment modalities have played an important factor in selecting the most appropriate treatment for patients with intermediate-risk prostate cancer. Methods: Analysis using a Markov model was conducted to simulate 20-year disease trajectory, quality-adjusted life years (QALYs) and health system costs of a cohort of intermediate-risk prostate cancer patients with mean age of 60 years. Clinical outcomes on toxicity and disease recurrence were measured and a probabilistic sensitivity analysis was performed, varying input parameters simultaneously according to their distributions. Results: Among the six radiation treatment modalities, including conventionally fractionated intensity-modulated radiation therapy (IMRT), hypofractionated IMRT, IMRT combined with high-dose-rate (HDR) brachytherapy, HDR brachytherapy monotherapy, low-dose-rate brachytherapy monotherapy, and stereotactic body radiotherapy (SBRT), SBRT was found to be more cost-effective when compared with LDR-b and other treatment modalities, resulting in an incremental cost–utility ratio of $2985 per QALY. Conclusions: Stereotactic body radiotherapy is the most cost-effective radiation treatment modality in treatment of intermediate-risk prostate cancer, while treatment toxicity and cost data are the key drivers of the cost–utility. Further work is required with long-term follow-up for SBRT.     

Lenalidomide in Treating Patients with Castration-Resistant Prostate Cancer

Background: This analysis was conducted to evaluate the efficacy and safety of lenalidomide based regimen intreating patients with castration-resistant prostate cancer. Materials and Methods: Clinical studies evaluating theefficacy and safety of lenalidomide based regimens on response and safety for patients with castration-resistantprostate cancer were identified using a predefined search strategy. A pooled response rate (rate of PSA leveldecline of ≥50%) to treatment was calculated. Results: In lenalidomide based regimen, 3 clinical studies whichincluding 98 patients with castration-resistant prostate cancer were considered eligible for inclusion. Theselenalidomide based regimens included cisplatin, doxorubicin, or GM-CSF. Pooled analysis suggested that, inall patients, the pooled PSA level decline of ≥50% was 13.3% (13/98) in lenalidomide based regimens. Fatigue,nausea and vomitting were the main side effects. No grade III or IV renal or liver toxicity were observed. Notreatment related death occurred in patients with lenalidomide based regimens. Conclusions: This evidencebased analysis suggests that lenalidomide based regimens are associated with mild response rate and acceptabletoxicities for treating patients with castration-resistant prostate cancer.     

Androgens and Overall Survival in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Docetaxel

BackgroundPre-treatment androgen levels are associated with overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) treated with androgen synthesis inhibitors. The current study sought to determine whether pre-treatment serum androgens predict clinical outcome among patients with metastatic CRPC treated with docetaxel chemotherapy.Materials and MethodsData were obtained from 1050 men who were chemotherapy-naive prior to treatment with docetaxel, prednisone, and either bevacizumab or placebo (CALGB 90401). Pretreatment serum assays for testosterone, androstenedione, and dehydroepiandrosterone (DHEA) were performed with tandem liquid chromatography-mass spectrometry.ResultsMedian values for testosterone, androstenedione, and DHEA were 1.00, 13.50, and 8.12 ng/dL, respectively. The median was used to define the midpoint between low and high values. In univariate analysis, median OS for low versus high levels was 21.4 and 24.2 months for testosterone, 23.8 and 21.9 months for androstenedione, and 20.2 and 25.2 months for DHEA (P = NS). In multivariable analysis of all androgens, baseline DHEA was prognostic of ≥ 50% PSA decline from baseline (P = .008). In multivariable analysis adjusting for 10 known prognostic values and prior ketoconazole use for metastatic CRPC, a 10-unit increase in baseline testosterone increased risk of death (hazard ratio, 1.11; 95% confidence interval, 1.01-1.23; P = .039), whereas a 10-unit increase in androstenedione lowered risk of death (hazard ratio, 0.92; 95% confidence interval, 0.88-0.97; P = .001).ConclusionConsistent with prior studies, higher androstenedione levels in patients with metastatic CRPC treated with docetaxel are associated with improved survival. However pretreatment levels of other androgen levels are associated with varied effects on clinical outcome in chemotherapy-treated patients.     

Chemotherapy-Induced Neutropenia and Outcome in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With First-Line Docetaxel

Background

Neutropenia is a common side effect associated with docetaxel use. We retrospectively investigated the association between chemotherapy-induced neutropenia and survival in metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line docetaxel.

Risk Stratification of Patients With Early Breast Cancer

BackgroundSentinel lymph node biopsy (SLNB) is the standard procedure performed to stage the axillae, and axillary node clearance (ANC) or radiotherapy is the treatment for nodal involvement. The aims of this study were to assess (1) the role of preoperative axillary ultrasonography (US), (2) the number of positive lymph nodes on ANC after either positive SLNB results or preoperative ultrasonographically guided nodal biopsy, and (3) the role of ANC in patients with node-positive breast cancer.Patients and MethodsAll patients with invasive breast cancer and axillary node involvement (but clinically negative nodes on presentation) who underwent ANC between January 2008 and December 2009 were identified, and information regarding clinicopathologic parameters and the nodal yield was collected. ANC was performed for 3 groups: patients with micrometastasis seen in SLNB specimens, macrometastasis seen in SLNB specimens, and positive axillary nodes detected on US biopsy.ResultsANC was performed 141 times over the 2-year period. Forty-two percent of axillary node involvement was diagnosed by biopsy or preoperative US, and 40% of these patients received neoadjuvant chemotherapy. The remainder of cases were diagnosed by SLNB: 30% had micrometastases and 70% had macrometastases. Fifty percent of cancers with an ultrasonographic diagnosis of lymph node involvement were high grade and 56% had 4 or more positive nodes on ANC; this was significantly higher than in patients with positive SLNB results (P = .0001). Only 20% of patients with macrometastases on SLNB had 4 or more positive nodes in comparison with 56% with positive axillary lymph nodes by US (P < .0001).ConclusionThe routine use of preoperative axillary US and biopsy of abnormal nodes helps in identifying high-risk patients and thus aids in planning treatment.     

Clinical Outcomes from Dose-Reduced Radiotherapy to the Prostate in Elderly Patients with Localized Prostate Cancer

Radical treatment of localized prostate cancer in elderly patients may lead to unacceptable treatment-associated toxicities that adversely impact quality of life without improving survival outcomes. This study reports on a cohort of 54 elderly (>70 years) patients that received 4000–5000 cGy of palliative external beam radiotherapy (EBRT) as an alternative to androgen deprivation therapy (ADT). The primary outcome of interest was the period of ADT-free survival, and secondary outcomes included overall survival (OS) and metastases-free survival (MFS). Kaplan–Meier regression was used to estimate survival outcomes. Thirty-six (67%) patients achieved a break in ADT post-radiotherapy, with a median time to ADT reinitiation of 20 months. Common Terminology Criteria for Adverse Events (CTCAE) were limited to low-grade gastrointestinal (GI) or genitourinary (GU) toxicities, with no skin toxicities observed. Grade 1 GI toxicity was observed in 9 (17%) patients, and grades 1 and 2 GU toxicities were observed in 13 (24%) and 3 (6%) patients, respectively, with no higher-grade toxicities reported. Five-year MFS and OS were 56% and 78%, respectively. In summary, the treatment regimen was well-tolerated and achieved durable ADT-free survival in most patients. Dose-reduced EBRT appears to be a viable alternative to ADT in elderly patients with localized prostate cancer.     

Intermediate-risk grouping of cervical cancer patients treated with radical hysterectomy: a Korean Gynecologic Oncology Group study

Background:

In this study, we sought to identify a criterion for the intermediate-risk grouping of patients with cervical cancer who exhibit any intermediate-risk factor after radical hysterectomy.

Methods:

In total, 2158 patients with pathologically proven stage IB–IIA cervical cancer with any intermediate-risk factor after radical hysterectomy were randomly assigned to two groups, a development group and a validation group, at a ratio of 3 : 1 (1620 patients:538 patients). To predict recurrence, multivariate models were developed using the development group. The ability of the models to discriminate between groups was validated using the log-rank test and receiver operating characteristic (ROC) analysis.

Results:

Four factors (histology, tumour size, deep stromal invasion (DSI), and lymphovascular space involvement (LVSI)) were significantly associated with disease recurrence and included in the models. Among the nine possible combinations of the four variables, models consisting of any two of the four intermediate-risk factors (tumour size ⩾3 cm, DSI of the outer third of the cervix, LVSI, and adenocarcinoma or adenosquamous carcinoma histology) demonstrated the best performance for predicting recurrence.

Conclusion:

This study identified a ‘four-factor model'' in which the presence of any two factors may be useful for predicting recurrence in patients with cervical cancer treated with radical hysterectomy.     

Pattern of Recurrence After Stereotactic Radiotherapy in Prostate Cancer Patients With Nodal Pelvic Relapse. A Multi-Institutional Retrospective Analysis

AimsCurrently, when nodal pelvic oligorecurrent disease is detected, no standard treatment option is recommended. One possible salvage option is nodal stereotactic body radiotherapy (SBRT). Here we analysed recurrence patterns after nodal SBRT in patients affected by pelvic oligometastatic relapse after radical prostatectomy, and androgen deprivation therapy (ADT)-free survival in this population.Materials and methodsData on 93 patients consecutively treated in five different institutions for pelvic oligorecurrent disease were reviewed. Inclusion criteria were biochemical recurrence after radical prostatectomy and imaging showing three or fewer metachronous lymphoadenopathies under aortic bifurcation. Patients underwent SBRT on all sites of disease. Concomitant ADT was allowed.ResultsAfter a median follow-up of 20 months (interquartile range 11–41), 57 patients had post-SBRT radiological evidence of relapse, for a median disease-free survival (DFS) of 15 months (95% confidence interval 9–24). Concomitant ADT was administered in 20 patients (21.5%). Overall, eight (8.6%), 21 (22.6%) and 28 (30.1%) patients had prostate bed only, pelvic nodal or distant relapse, respectively. The median ADT-free survival was not reached. Concomitant ADT, International Society for Urologic Pathology pattern at diagnosis < or ≥3, time to relapse ≤ or >12 months, prostate-specific antigen at recurrence < or ≥1.10 ng/ml and prostate-specific membrane antigen staging were not significantly associated with DFS. After relapse, 42 patients (45.2%) received a second SBRT course.ConclusionNodal SBRT yielded encouraging DFS and ADT-free survival in this population. Only a minority of patients developed prostate bed recurrence, suggesting that local treatment may be safely avoided. A consistent percentage of patients could be managed with a second SBRT course.     

Long-Term Biochemical Control of a Prospective Cohort of Prostate Cancer Patients Treated With Interstitial Brachytherapy Versus Radical Prostatectomy

AimsTo report long-term oncological outcomes of men treated prospectively as part of the American College of Surgeons Oncology Group phase III Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT) at our institution.Materials and methodsIn 2003–2004, patients eligible for SPRIT attended a multidisciplinary educational session, following which they could choose radical prostatectomy, low dose rate brachytherapy (LDR-BT) or randomisation to SPIRIT. Biochemical failure was determined by the accepted definitions of a prostate-specific antigen (PSA) level ≥0.2 ng/ml after radical prostatectomy and the Phoenix definition of PSA ≥2 ng/ml above the nadir after LDR-BT. A sensitivity analysis, using a PSA >0.5 ng/ml to define biochemical failure after LDR-BT and a threshold PSA ≥0.2 ng/ml, was carried out to test the robustness of the results. To account for the competing risk of death, Gray's test was used to test the equality of the cumulative incidence function of biochemical failure between treatment groups. The Kaplan–Meier method was used to estimate overall survival and prostate cancer-specific survival. A P-value ≤0.05 was considered statistically significant.ResultsOf 156 patients, 100 received LDR-BT (15 after randomisation) and 56 underwent radical prostatectomy (15 after randomisation). The median follow-up was 12.6 and 14.7 years for LDR-BT and radical prostatectomy, respectively. The median age was 60 years; the median pre-treatment PSA was 5.5 (interquartile range 4.3–7.1). No significant differences in patient characteristics were found between groups. Two patients received adjuvant radiotherapy after radical prostatectomy. The cumulative incidence function of biochemical failure was 0%, 1.1% and 2.4% at 5, 10 and 15 years, respectively, in the LDR-BT arm versus 8.5%, 15.8% and 15.8% in the radical prostatectomy arm (P < 0.001). These results were consistent when varying the definition of biochemical failure defined as PSA ≥0.5 ng/ml (P = 0.01). At 15 years, overall survival was higher in patients treated with radical prostatectomy compared with those treated with LDR-BT; however, no statistical difference was found in prostate cancer-specific survival.ConclusionIn low-risk prostate cancer patients, LDR-BT offers excellent long-term oncological outcomes comparable with radical prostatectomy, in addition to the previously reported advantage for LDR-BT in urinary and sexual quality of life domains and patient satisfaction.     

Less Satisfaction With Information in Patients With Prostate Cancer Treated With Surgery and Salvage Radiotherapy Compared With Patients Treated With Curative Radiotherapy Alone,Despite Similar Health-Related Quality of Life

BackgroundThis study examined patient perception of information received, satisfaction with that information, and its relation to health-related quality of life (HRQoL) and clinical and demographic variables before, during, and after radiotherapy (RT) for localized prostate cancer.Patients and MethodsIn 2010, 2 questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30] and EORTC QLQ information module [QLQ-INFO25]) were sent to 660 consecutive patients with prostate cancer who had undergone or were to undergo RT with curative intent between December 2006 and March 2010.ResultsThe response rate was 92%. Although most patients (69%) were satisfied with the information they received, statistically significant differences were found for all but 2 EORTC QLQ-INFO25 variables, favoring those who were treated with RT alone compared with those treated with both prostatectomy and salvage RT. Statistically significant associations between all HRQoL variables and satisfaction with information were found; higher levels of satisfaction were associated with better functioning and lower levels of symptoms and problems.ConclusionSatisfaction with the information received was studied in patients with prostate cancer with localized disease. Despite the fact that the majority of patients reported being satisfied with the information received, there is room for improvement, especially regarding “the disease,” “other services,” “different places of care,” and “things you can do to help yourself.” Patients treated with both prostatectomy and salvage RT reported significantly lower levels of satisfaction with information received and of having received significantly less information than did patients treated with RT alone.     

Open Label Phase II Study of Enzalutamide With Concurrent Administration of Radium 223 Dichloride in Patients With Castration-Resistant Prostate Cancer

BackgroundNumerous globally approved castration-resistant prostate cancer (CRPC) therapies are available. Enzalutamide and radium 223 (Ra 223) are approved for survival prolongation and ability to delay radiographic progression. Both have markedly different mechanisms of action as well as safety and tolerability profiles. We prospectively investigated their combined safety and tolerability.Patients and MethodsEnzaRadiCate, a phase II investigator-initiated trial, enrolled subjects with metastatic CRPC from 4 United States uro-oncology research sites. Safety assessment included physical examination, Eastern Cooperative Oncology Group status, electrocardiogram results, laboratory values, opioid use, radiographic responses, and adverse events (AEs). Quality of life and pain were assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and the Brief Pain Inventory Short Form (BPI-SF) questionnaires.ResultsThirty-nine subjects completed at least 2 cycles of Ra 223, and 34 (87%) completed all 6 cycles through and the EOT visit. Sixty-one treatment-related AEs were reported by 53.8% of subjects. The most frequent AEs were fatigue (25.6%), nausea (17.9%), and anemia (12.8%). Three subjects experienced non–treatment-related serious AEs. One subject was hospitalized for sepsis, and 2 deaths were attributed to disease progression. Fifteen (38.5%) subjects demonstrated radiographic progression, and 24 (61.5%) subjects had no radiographic progression.ConclusionsSafety and tolerability of combinatorial use of enzalutamide and Ra 223 were demonstrated. Subjects experienced improvements in quality of life and pain, without unexpected toxicities nor increases in falls, fractures, or deaths. Phase III combination trials of Ra 223 with novel oral hormonal agents are ongoing to further evaluate radiographic progression and overall survival benefit.