Christopher J.D. Wallis

Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT To date, there is no Level 1 evidence comparing the efficacy of radical prostatectomy and radiotherapy for patients with clinically-localized prostate cancer. OBJECTIVE To conduct a meta-analysis assessing the overall and prostate cancer-specific mortality among patients treated with radical prostatectomy or radiotherapy for clinically-localized prostate cancer. EVIDENCE ACQUISITION We searched Medline, EMBASE, and the Cochrane Library through June 2015 without year or language restriction, supplemented with hand search, using Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis of Observational Studies in Epidemiology guidelines. We used multivariable adjusted hazard ratios (aHRs) to assess each endpoint. Risk of bias was assessed using the Newcastle-Ottawa scale. EVIDENCE SYNTHESIS Nineteen studies of low to moderate risk of bias were selected and up to 118 830 patients were pooled. Inclusion criteria and follow-up length varied between studies. Most studies assessed patients treated with external beam radiotherapy, although some included those treated with brachytherapy separately or with the external beam radiation therapy group. The risk of overall (10 studies, aHR 1.63, 95% confidence interval 1.54-1.73, p<0.00001; I(2)=0%) and prostate cancer-specific (15 studies, aHR 2.08, 95% confidence interval 1.76-2.47, p < 0.00001; I(2)=48%) mortality were higher for patients treated with radiotherapy compared with those treated with surgery. Subgroup analyses by risk group, radiation regimen, time period, and follow-up length did not alter the direction of results. CONCLUSIONS Radiotherapy for prostate cancer is associated with an increased risk of overall and prostate cancer-specific mortality compared with surgery based on observational data with low to moderate risk of bias. These data, combined with the forthcoming randomized data, may aid clinical decision making. PATIENT SUMMARY We reviewed available studies assessing mortality after prostate cancer treatment with surgery or radiotherapy. While the studies used have a potential for bias due to their observational design, we demonstrated consistently higher mortality for patients treated with radiotherapy rather than surgery.

Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis

Objective To determine the association between exposure to radiotherapy for the treatment of prostate cancer and subsequent second malignancies (second primary cancers). Design Systematic review and meta-analysis of observational studies. Data sources Medline and Embase up to 6 April 2015 with no restrictions on year or language. Study selection Comparative studies assessing the risk of second malignancies in patients exposed or unexposed to radiotherapy in the course of treatment for prostate cancer were selected by two reviewers independently with any disagreement resolved by consensus. Data extraction and synthesis Two reviewers independently extracted study characteristics and outcomes. Risk of bias was assessed with the Newcastle-Ottawa scale. Outcomes were synthesized with random effects models and Mantel-Haenszel weighting. Unadjusted odds ratios and multivariable adjusted hazard ratios, when available, were pooled. Main outcome measures Second cancers of the bladder, colorectal tract, rectum, lung, and hematologic system. Results Of 3056 references retrieved, 21 studies were selected for analysis. Most included studies were large multi-institutional reports but had moderate risk of bias. The most common type of radiotherapy was external beam; 13 studies used patients treated with surgery as controls and eight used patients who did not undergo radiotherapy as controls. The length of follow-up among studies varied. There was increased risk of cancers of the bladder (four studies; adjusted hazard ratio 1.67, 95% confidence interval 1.55 to 1.80), colorectum (three studies; 1.79, 1.34 to 2.38), and rectum (three studies; 1.79, 1.34 to 2.38), but not cancers of the hematologic system (one study; 1.64, 0.90 to 2.99) or lung (two studies; 1.45, 0.70 to 3.01), after radiotherapy compared with the risk in those unexposed to radiotherapy. The odds of a second cancer varied depending on type of radiotherapy: treatment with external beam radiotherapy was consistently associated with increased odds while brachytherapy was not. Among the patients who underwent radiotherapy, from individual studies, the highest absolute rates reported for bladder, colorectal, and rectal cancers were 3.8%, 4.2%, and 1.2%, respectively, while the lowest reported rates were 0.1%, 0.3%, and 0.3%. Conclusion Radiotherapy for prostate cancer was associated with higher risks of developing second malignancies of the bladder, colon, and rectum compared with patients unexposed to radiotherapy, but the reported absolute rates were low. Further studies with longer follow-up are required to confirm these findings.

The impact of a BRCA2 mutation on mortality from screen-detected prostate cancer

Background:Men with a BRCA2 mutation face an increased risk of prostate cancer. These cancers tend to have an aggressive nature and it has not yet been demonstrated that regular screening of BRCA2 carriers is associated with improved survival.Methods:We identified 4187 men who underwent a prostate cancer biopsy for an elevated PSA or an abnormal digital rectal examination between 1998 and 2010. We screened the BRCA2 gene in its entirety for mutations and we followed the men for death from prostate cancer until December 2012.Results:The 12-year prostate cancer-specific survival rate was 94.3% for men without a BRCA2 mutation and was 61.8% for men with a mutation (P<10−4; log-rank test).Conclusions:The survival of men with screen-detected prostate cancer and a BRCA2 mutation is much poorer than expected.

MiR-182 Is Associated with Growth, Migration and Invasion in Prostate Cancer via Suppression of FOXO1

Background: MicroRNA (miRNA) have been shown to regulate gene expression in many cancers. MiR-182 has recently been found to be prognostic for patients treated with radical prostatectomy for prostate cancer. We sought to assess miR-182 as a prognostic marker and understand its role in prostate cancer progression and metastasis. Methods: We analysed miR-182 expression among 147 men treated for prostate cancer using biochemical recurrence and metastasis as the endpoints. We examined miR-182 expression in prostate cancer cells and created cell lines that overexpressed miR-182 for functional assays. Finally, we examined pathways through which miR-182 may function using prediction algorithms and confirmed by Western blotting and knock-down assays. Results: We found that miR-182 was not associated with biochemical recurrence (p=0.1111) or metastasis (p=0.9268) following radical prostatectomy. However, in mechanistic assays, we found that miR-182 expression was higher among aggressive prostate cancer cells and that ectopic miR-182 expression resulted in increased proliferation, migration and invasion in vitro. We identified FOXO1 as regulated by miR-182 in prostate cancer cells, confirmed that ectopic miR-182 expression resulted in diminished FOXO1 levels, and showed that miR-182 inhibition results in increased FOXO1 levels. Expression of FOXO1 (p=0.0014) in tumors from patients who developed biochemical recurrence compared to tumors from patients who were recurrence-free five years after their radical prostatectomy. Conclusions: Our findings suggest that miR-182 may act to increase prostate cancer proliferation, migration and invasion through suppression of FOXO1. This may be valuable in the development of further therapeutic interventions.

MiR‐301a regulates E‐cadherin expression and is predictive of prostate cancer recurrence

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression post‐transcriptionally. Dysregulation of miRNA has been implicated in the development and progression of prostate cancer. Through next generation miRNA sequencing, we recently identified a panel of five miRNAs associated with prostate cancer recurrence and metastasis. Of the five miRNAs, miR‐301a had the strongest association with prostate cancer recurrence. Overexpression of miR‐301a in prostate cancer cells, PC3, and LNCaP resulted in increased growth both in vitro and in xenografted tumors. We therefore sought to examine its role in prostate carcinogenesis in greater detail.

Comparison of postoperative outcomes among patients treated by male and female surgeons: a population based matched cohort study

Objective To examine the effect of surgeon sex on postoperative outcomes of patients undergoing common surgical procedures. Design Population based, retrospective, matched cohort study from 2007 to 2015. Setting Population based cohort of all patients treated in Ontario, Canada. Participants Patients undergoing one of 25 surgical procedures performed by a female surgeon were matched by patient age, patient sex, comorbidity, surgeon volume, surgeon age, and hospital to patients undergoing the same operation by a male surgeon. Interventions Sex of treating surgeon. Main outcome measure The primary outcome was a composite of death, readmission, and complications. We compared outcomes between groups using generalised estimating equations. Results 104 630 patients were treated by 3314 surgeons, 774 female and 2540 male. Before matching, patients treated by female doctors were more likely to be female and younger but had similar comorbidity, income, rurality, and year of surgery. After matching, the groups were comparable. Fewer patients treated by female surgeons died, were readmitted to hospital, or had complications within 30 days (5810 of 52 315, 11.1%, 95% confidence interval 10.9% to 11.4%) than those treated by male surgeons (6046 of 52 315, 11.6%, 11.3% to 11.8%; adjusted odds ratio 0.96, 0.92 to 0.99, P=0.02). Patients treated by female surgeons were less likely to die within 30 days (adjusted odds ratio 0.88; 0.79 to 0.99, P=0.04), but there was no significant difference in readmissions or complications. Stratified analyses by patient, physician, and hospital characteristics did not significant modify the effect of surgeon sex on outcome. A retrospective analysis showed no difference in outcomes by surgeon sex in patients who had emergency surgery, where patients do not usually choose their surgeon. Conclusions After accounting for patient, surgeon, and hospital characteristics, patients treated by female surgeons had a small but statistically significant decrease in 30 day mortality and similar surgical outcomes (length of stay, complications, and readmission), compared with those treated by male surgeons. These findings support the need for further examination of the surgical outcomes and mechanisms related to physicians and the underlying processes and patterns of care to improve mortality, complications, and readmissions for all patients.

Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer

Background:Men undergoing treatment of clinically localised prostate cancer may experience a number of treatment-related complications, which affect their quality of life.Methods:On the basis of population-based retrospective cohort of men undergoing surgery, with or without subsequent radiotherapy, or radiotherapy alone for prostate cancer in Ontario, Canada, we measured the incidence of treatment-related complications using administrative and billing data.Results:Of 36 984 patients, 15 870 (42.9%) underwent surgery alone, 4519 (12.2%) underwent surgery followed by radiotherapy, and 16 595 (44.9%) underwent radiotherapy alone. For all end points except urologic procedures, the 5-year cumulative incidence rates were lowest in the surgery only group and highest in the radiotherapy only group. Intermediary rates were seen in the surgery followed by radiotherapy group, except for urologic procedures where rates were the highest in this group. Although age and comorbidity were important predictors, radiotherapy as the primary treatment modality was associated with higher rates for all complications (adjusted hazard ratios 1.6–4.7, P=0.002 to <0.0001).Conclusions:In patients treated for prostate cancer, radiation after surgery increases the rate of complications compared with surgery alone, though these rates remain lower than patients treated with radiation alone. This information may inform patient and physician decision making in the treatment of prostate cancer.

Complications after radical prostatectomy or radiotherapy for prostate cancer: results of a population-based, propensity score-matched analysis.

OBJECTIVE To assess rates of treatment-related complications after radical prostatectomy or radiotherapy monotherapy, using propensity score matching to account for baseline differences between these patient populations. METHODS On the basis of a population-based study of men undergoing surgery or radiotherapy for prostate cancer in Ontario between 2002 and 2009, we undertook a propensity score-matched analysis including age, comorbidity, and year of treatment to assess treatment-related complication end points. These included hospital admission; urologic, rectal, or anal procedures; open surgeries; and secondary malignancies. RESULTS From the original cohort of 32,465 patients, 15,870 (48.9%) had surgery and 16,595 (51.1%) had radiation. Propensity score matching produced 8797 pairs (17,594 patients). Among these, when compared with patients treated with surgery, those treated with radiation experienced fewer admissions to hospital (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.78-0.92) and urologic procedures (HR, 0.50; 95% CI, 0.46-0.53) at year 1 but higher rates at year 3 (HR, 5.65; 95% CI, 4.61-6.91 and HR, 1.86; 95% CI, 1.62-2.13, respectively) and year 5. Although there was no significant difference in open surgeries at year 1, patients undergoing radiotherapy were at higher risk by year 3 (HR, 2.06; 95% CI, 1.23-3.47) and this rose by year 5. Over the study period, patients undergoing radiotherapy experienced more rectal-anal procedures (HR, 2.64; 95% CI, 2.37-2.95) and were diagnosed with more secondary malignancies (HR, 2.44; 95% CI, 1.16-5.14). Direct matching produced similar results. CONCLUSION From a propensity score-matched analysis, we found that patients undergoing radiation therapy for prostate cancer had higher rates of long-term complications in all 5 categories studied than patients undergoing surgery.

The role of resection of pulmonary metastases from prostate cancer: a case report and literature review.

We report a case of a 53-year-old man who presented with two nodules in the lower lobe and one nodule in the upper lobe of the right lung almost 7 years after radical prostatectomy for pT3aN0M0, Gleason 4+5 disease, without evidence of osseous or lymphatic spread. Surgical resection of the lower lung nodules confirmed metastases, but prostate-specific antigen did not drop to undetectable levels. Isolated pulmonary metastases from prostate cancer are rare with only 33 previously described cases in the English-language literature, 18 of which were solitary metastases. We review the principles of management, including metastasectomy and long-term prognosis.

A Pilot Study to Evaluate the Role of Magnetic Resonance Imaging for Prostate Cancer Screening in the General Population.

PURPOSE To our knowledge the role of magnetic resonance imaging as a first line screening test for prostate cancer is unknown. We performed a pilot study to evaluate the feasibility of prostate magnetic resonance imaging as the primary screening test for prostate cancer. MATERIALS AND METHODS We recruited unselected men from the general population. Prostate multiparametric magnetic resonance imaging and random or targeted biopsies were performed in all patients, in addition to prostate specific antigen testing. We compared the performance of prostate magnetic resonance imaging and prostate specific antigen test results to predict prostate cancer. RESULTS Of the 47 recruited patients 18 (38.3%) had cancer while 29 (61.7%) had no evidence of cancer. The adjusted OR of prostate cancer was significantly higher for magnetic resonance imaging score than for prostate specific antigen level (2.7, 95% CI 1.4-5.4, p = 0.004 vs 1.1, 95% CI 0.9-1.4, p = 0.21). Among the 30 patients with a normal prostate specific antigen (less than 4.0 ng/ml) the positive predictive value in those with a magnetic resonance imaging score of 4 or more was 66.7% (6 of 9) and the negative predictive value in those with a magnetic resonance imaging score of 3 or less was 85.7% (18 of 21, p = 0.004). CONCLUSIONS In this pilot study we determined the feasibility of using multiparametric prostate magnetic resonance imaging as the primary screening test for prostate cancer. Initial results showed that prostate magnetic resonance imaging was better to predict prostate cancer than prostate specific antigen in an unselected sample of the general population.