Focal Therapy in Prostate Cancer: International Multidisciplinary Consensus on Trial Design

Background

Focal therapy has been introduced for the treatment of localised prostate cancer (PCa). To provide the necessary data for consistent assessment, all focal therapy trials should be performed according to uniform, systematic pre- and post-treatment evaluation with well-defined end points and strict inclusion and exclusion criteria.

Objective

To obtain consensus on trial design for focal therapy in PCa.

Design, setting, and participants

A four-staged consensus project based on a modified Delphi process was conducted in which 48 experts in focal therapy of PCa participated. According to this formal consensus-building method, participants were asked to fill out an iterative sequence of questionnaires to collect data on trial design. Subsequently, a consensus meeting was held in which 13 panellists discussed acquired data, clarified the results, and defined the conclusions.

Outcome measurements and statistical analysis

A multidisciplinary board from oncologic centres worldwide reached consensus on patient selection, pretreatment assessment, evaluation of outcome, and follow-up.

Results and limitations

Inclusion criteria for candidates in focal therapy trials are patients with prostate-specific antigen <15 ng/ml, clinical stage T1c–T2a, Gleason score 3 + 3 or 3 + 4, life expectancy of >10 yr, and any prostate volume. The optimal biopsy strategy includes transrectal ultrasound-guided biopsies to be taken between 6 mo and 12 mo after treatment. The primary objective should be focal ablation of clinically significant disease with negative biopsies at 12 mo after treatment as the primary end point.

Conclusions

This consensus report provides a standard for designing a feasible focal therapy trial.

Patient summary

A variety of ablative technologies have been introduced and applied in a focal manner for the treatment of prostate cancer (PCa). In this consensus report, an international panel of experts in the field of PCa determined pre- and post-treatment work-up for focal therapy research.     

The Role of Focal Therapy in the Management of Localised Prostate Cancer: A Systematic Review

Context

The incidence of localised prostate cancer is increasing worldwide. In light of recent evidence, current, radical, whole-gland treatments for organ-confined disease have being questioned with respect to their side effects, cancer control, and cost. Focal therapy may be an effective alternative strategy.

Objective

To systematically review the existing literature on baseline characteristics of the target population; preoperative evaluation to localise disease; and perioperative, functional, and disease control outcomes following focal therapy.

Evidence acquisition

Medline (through PubMed), Embase, Web of Science, and Cochrane Review databases were searched from inception to 31 October 2012. In addition, registered but not yet published trials were retrieved. Studies evaluating tissue-preserving therapies in men with biopsy-proven prostate cancer in the primary or salvage setting were included.

Evidence synthesis

A total of 2350 cases were treated to date across 30 studies. Most studies were retrospective with variable standards of reporting, although there was an increasing number of prospective registered trials. Focal therapy was mainly delivered to men with low and intermediate disease, although some high-risk cases were treated that had known, unilateral, significant cancer. In most of the cases, biopsy findings were correlated to specific preoperative imaging, such as multiparametric magnetic resonance imaging or Doppler ultrasound to determine eligibility. Follow-up varied between 0 and 11.1 yr. In treatment-naïve prostates, pad-free continence ranged from 95% to 100%, erectile function ranged from 54% to 100%, and absence of clinically significant cancer ranged from 83% to 100%. In focal salvage cases for radiotherapy failure, the same outcomes were achieved in 87.2–100%, 29–40%, and 92% of cases, respectively. Biochemical disease-free survival was reported using a number of definitions that were not validated in the focal-therapy setting.

Conclusions

Our systematic review highlights that, when focal therapy is delivered with intention to treat, the perioperative, functional, and disease control outcomes are encouraging within a short- to medium-term follow-up. Focal therapy is a strategy by which the overtreatment burden of the current prostate cancer pathway could be reduced, but robust comparative effectiveness studies are now required.     

Prostate Cancer Tumour Features on Template Prostate-mapping Biopsies: Implications for Focal Therapy

Background

Focal therapy is being offered as a viable alternative for men with localised prostate cancer (PCa), but it is unclear which men may be suitable.

Objective

To determine the proportion of men with localised PCa who are potentially suitable for focal therapy.

Design, setting, and participants

Our institutional transperineal template prostate-mapping (TTPM) biopsy registry of 377 men from 2006 to 2010 identified 291 consecutive men with no prior treatment.

Intervention

TTPM biopsies using a 5-mm sampling frame.

Outcome measurements and statistical analysis

Suitability for focal therapy required the cancer to be (1) unifocal, (2) unilateral, (3) bilateral/bifocal with at least one neurovascular bundle avoided, or (4) bilateral/multifocal with one dominant index lesion and secondary lesions with Gleason ≤3 + 3 and cancer core involvement ≤3 mm. Binary logistic regression modelling was used to determine variables predictive for focal therapy suitability.

Results and limitations

The median age was 61 yr, and the median prostate-specific antigen was 6.8 ng/ml. The median total was 29 cores, with a median of 8 positive cores. Of 239 of 291 men with cancer, 29% (70 men), 60% (144 men), and 8% (20 men) had low-, intermediate-, and high-risk PCa, respectively. Ninety-two percent (220 men) were suitable for one form of focal therapy: hemiablation (22%, 53 men), unifocal ablation (31%, 73 men), bilateral/bifocal ablation (14%, 33 men), and index lesion ablation (26%, 61 men). Binary logistic regression modelling incorporating transrectal biopsy parameters showed no statistically significant predictive variable. When incorporating TTPM parameters, only T stage was a significant negative predictor for suitability (p = 0.001) (odds ratio: 0.001 [95% confidence interval, 0.000–0.048]). Limitations of the study include potential selection bias caused by tertiary referral practise and lack of long-term results on focal therapy efficacy.

Conclusions

Focal therapy requires an accurate tool to localise individual cancer lesions. When such a test, TTPM biopsy, was applied to men with low- and intermediate-risk PCa, most of the men were suitable for a tissue preservation strategy.     

Androgen-deprivation Therapy and Risk for Biliary Disease in Men with Prostate Cancer

Background

Androgen-deprivation therapy (ADT) by either a gonadotropin-releasing hormone (GnRH) agonist or bilateral orchiectomy improves disease-related outcomes of men with prostate cancer but has a variety of adverse metabolic effects including obesity, increased abdominal girth, increased triglycerides, and insulin resistance. Each is a risk factor for gallstone disease. Additionally, GnRH agonist treatment was recently shown in metabolomic analyses to increase plasma levels of some bile acids.

Objective

To assess the relationship between ADT and the incidence of biliary disease in men with prostate cancer.

Design, setting, and participants

We studied 183 842 men >65 yr of age living in Surveillance, Epidemiology, and End Results regions who were diagnosed with prostate cancer from 1992 to 2007 and followed through 2009.

Outcome measurements and statistical analysis

We calculated incidence rates for biliary disease during treatment with GnRH agonists, orchiectomy, or no therapy. We used Cox proportional hazard models to assess the association of ADT with biliary disease.

Results and limitations

Among 183 842 men with locoregional prostate cancer, 48.4% received GnRH agonist treatment and 2.2% underwent bilateral orchiectomy during follow-up. GnRH agonist treatment was associated with a significantly higher incidence of biliary disease compared with no treatment (15.7 vs 13.4 cases per 1000 person-years; p < 0.001). In adjusted analyses, GnRH agonist use was associated with the risk of biliary disease (adjusted hazard ratio: 1.10; 95% confidence interval, 1.05–1.15; p < 0.001). Orchiectomy was not significantly associated with biliary disease.

Conclusions

GnRH agonist treatment may be associated with a greater risk of incident biliary disease.     

Systematic Review of the Efficacy and Safety of High-Intensity Focussed Ultrasound for the Primary and Salvage Treatment of Prostate Cancer

Context

High-intensity focussed ultrasound (HIFU) is an emerging minimally invasive treatment option for prostate cancer.

Objective

Our aim was to assess the efficacy and safety of HIFU in both primary treatment of men with localised and locally advanced prostate cancer as well as salvage treatment of men with recurrent prostate cancer following treatment failure of radical prostatectomy or external-beam radiation therapy.

Evidence acquisition

We conducted a systematic literature search for studies conducted on humans and published in either English or German in several databases from 2000 to 2010. In addition, we screened several Web sites for assessments on HIFU in prostate cancer and contacted the manufacturers of the two currently available HIFU devices for supplemental information on HIFU. We included all prospective studies with >50 study participants and assessed their quality using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Evidence synthesis

We identified 20 uncontrolled prospective case series, each of which treated between 58 and 517 patients. These studies were all conducted within the past decade. In total, 3018 patients were treated with HIFU, 93% for primary therapy and 7% for salvage HIFU. For all HIFU procedures, the biochemical disease-free survival rate at 1, 5, and 7 yr, respectively, was 78–84%, 45–84%, and 69%. The negative biopsy rate was 86% at 3 mo and 80% at 15 mo. Overall survival rates and prostate cancer–specific survival rates were 90% and 100% at 5 yr and 83% and 98% at 8 yr, respectively. Adverse events concerned the urinary tract (1–58%), potency (1–77%), the rectum (0–15%), and pain (1–6%). Quality-of-life assessment yielded controversial results.

Conclusions

Applying the GRADE approach, the available evidence on efficacy and safety of HIFU in prostate cancer is of very low quality, mainly due to study designs that lack control groups. More research is needed to explore the use of HIFU in prostate cancer.     

Cost-effectiveness of Magnetic Resonance (MR) Imaging and MR-guided Targeted Biopsy Versus Systematic Transrectal Ultrasound–Guided Biopsy in Diagnosing Prostate Cancer: A Modelling Study from a Health Care Perspective

Background

The current diagnostic strategy using transrectal ultrasound–guided biopsy (TRUSGB) raises concerns regarding overdiagnosis and overtreatment of prostate cancer (PCa). Interest in integrating multiparametric magnetic resonance imaging (MRI) and magnetic resonance–guided biopsy (MRGB) into the diagnostic pathway to reduce overdiagnosis and improve grading is gaining ground, but it remains uncertain whether this image-based strategy is cost-effective.

Objective

To determine the cost-effectiveness of multiparametric MRI and MRGB compared with TRUSGB.

Design, setting, and participants

A combined decision tree and Markov model for men with elevated prostate-specific antigen (>4 ng/ml) was developed. Input data were derived from systematic literature searches, meta-analyses, and expert opinion.

Outcome measurements and statistical analysis

Quality-adjusted life years (QALYs) and health care costs of both strategies were modelled over 10 yr after initial suspicion of PCa. Probabilistic and threshold analyses were performed to assess uncertainty.

Results and limitations

Despite uncertainty around the presented cost-effectiveness estimates, our results suggest that the MRI strategy is cost-effective compared with the standard of care. Expected costs per patient were €2423 for the MRI strategy and €2392 for the TRUSGB strategy. Corresponding QALYs were higher for the MRI strategy (7.00 versus 6.90), resulting in an incremental cost-effectiveness ratio of €323 per QALY. Threshold analysis revealed that MRI is cost-effective when sensitivity of MRGB is ≥20%. The probability that the MRI strategy is cost-effective is around 80% at willingness to pay thresholds higher than €2000 per QALY.

Conclusions

Total costs of the MRI strategy are almost equal with the standard of care, while reduction of overdiagnosis and overtreatment with the MRI strategy leads to an improvement in quality of life.

Patient summary

We compared costs and quality of life (QoL) of the standard “blind” diagnostic technique with an image-based technique for men with suspicion of prostate cancer. Our results suggest that costs were comparable, with higher QoL for the image-based technique.     

Combination of Diffusion-weighted Magnetic Resonance Imaging and Extended Prostate Biopsy Predicts Lobes Without Significant Cancer: Application in Patient Selection for Hemiablative Focal Therapy

Background

Significant cancer in contralateral sides of the prostate that was missed on prostate biopsy (PBx) is a concern in hemiablative focal therapy (FT) of prostate cancer (PCa). However, extended PBx, a common diagnostic procedure, has a limited predictive ability for lobes without significant cancer.

Objective

To identify prostate lobes without significant cancer using extended PBx combined with diffusion-weighted imaging (DWI), which has the potential to provide pathophysiologic information on pretreatment assessment.

Design, setting, and participants

We conducted a prebiopsy DWI study between 2007 and 2012 that included 270 prostate lobes in 135 patients who underwent radical prostatectomy (RP) for clinically localized PCa.

Intervention

Participants underwent DWI and 14-core PBx; those with PBx-proven PCa and who were treated with RP were analyzed.

Outcome measurements and statistical analysis

Imaging and pathology were assessed in each side. Based on RP pathology, lobes were classified into lobes with no cancer (LNC), lobes with indolent cancer (LIC), and lobes with significant cancer (LSC). Predictive performance of DWI, PBx, and their combination in identifying lobes without significant cancer was examined.

Results and limitations

LNC, LIC, and LSC were identified in 23 (8.5%), 64 (23.7%), and 183 sides (67.8%), respectively. The negative predictive values (NPV) of DWI, PBx, and their combination were 22.1%, 27.8%, and 43.5%, respectively, for lobes with any cancer (ie, either LIC or LSC), and 68.4%, 72.2%, and 95.7%, respectively, for LSC. The NPV of PBx for LSC was improved by the addition of DWI findings (p = 0.001), with no adverse influence on the positive predictive value. Limitations included a possible selection bias under which the decision to perform PBx might be affected by DWI findings.

Conclusions

The combination of DWI and extended PBx efficiently predicts lobes without significant cancer. This procedure is applicable to patient selection for hemiablative FT.     

The Role of Primary Androgen Deprivation Therapy in Localized Prostate Cancer

Background

Primary androgen deprivation therapy (PADT) is frequently used as a sole modality of treatment in men with localized prostate cancer, despite a lack of clinical trial data supporting its use.

Objective

To measure the impact of treatment with PADT compared to observation on overall survival in men with organ-confined prostate cancer.

Design, setting, and participants

The design was for an observational cohort from Surveillance, Epidemiology, and End Results (SEER) Medicare data. The cohort consisted of 16 535 men aged 65–80 yr at diagnosis with organ-confined well-differentiated or moderately differentiated prostate cancer who survived >1 yr past diagnosis and did not undergo treatment with prostatectomy or radiation therapy within 6 mo of diagnosis. They were diagnosed between 1991 and 1999 and followed until death or until the end of the study period (December 31, 2002).

Intervention

Study subjects were selected to receive PADT alone if they received luteinizing hormone-releasing hormone agonists or bilateral orchiectomy in the first 6 mo after diagnosis, and they were selected to be observed if they did not have claims for PADT during the same interval.

Measurements

Overall survival.

Results and limitations

After adjusting for potential confounders (ie, tumor characteristics, comorbidities, and demographics), patients who received ADT had a worse overall survival rate than patients who were observed (hazard ratio: 1.20; 95% confidence interval: 1.13–1.27).In observational studies there may be unmeasured differences between the treated and untreated groups. The SEER database does not provide information on prostate-specific antigen levels.

Conclusions

This large, population-based study suggests that PADT did not improve survival in men with localized prostate cancer, but it suggests that PADT may instead result in worse outcomes compared with observation. Patients and physicians should be cognizant of the potential long-term side effects of ADT in a patient population for which expectant observation is an acceptable treatment strategy.     

An Updated Critical Analysis of the Treatment Strategy for Newly Diagnosed High-grade T1 (Previously T1G3) Bladder Cancer

Context

High-grade T1 (formerly T1G3) bladder cancer (BCa) has a high propensity to recur and progress. As a result, decisions pertaining to its treatment are difficult. Treatment with bacillus Calmette-Guérin (BCG) risks progression and metastases but may preserve the bladder. Cystectomy may offer the best opportunity for cure but is associated with morbidity and a risk of mortality, and it may constitute potential overtreatment for many cases of T1G3 tumours. For purposes of this review, we continue to refer to high-grade T1 lesions as “T1G3.”

Objective

To review the current literature on the management of T1G3 BCa and to provide recommendations for its treatment.

Evidence acquisition

A National Center for Biotechnology Information (NCBI) PubMed search for relevant articles published between 1996 and 9 January 2009 was performed using the Medical Subject Headings “T1G3” or “T1” and “Bladder cancer.” Articles relevant to the treatment of T1G3 BCa were retained.

Evidence synthesis

The diagnosis of T1G3 disease is difficult because pathologic staging is often unreliable and because of the risk of significant understaging at initial transurethral resection (TUR) of bladder tumour. A secondary restaging TUR is recommended for all cases of T1G3. A single dose of immediate post-TUR chemotherapy is recommended. For a bladder-sparing approach, intravesical BCG should be given as induction with maintenance dosing. Immediate or early radical cystectomy (RC) should be offered to all patients with recurrent or multifocal T1G3 disease, those who are at high risk of progression, and those failing BCG treatment.

Conclusions

Both bladder preservation and RC are appropriate options for T1G3 BCa. Risk stratification of patients based on pathologic features at initial TUR or at recurrence can select those most appropriate for bladder preservation compared to those for whom cystectomy should be strongly considered.     

Association of catechol-O-methyltransferase genetic variants with outcome in patients undergoing surgical treatment for lumbar degenerative disc disease

Background context

Surgical treatment for lumbar degenerative disc disease (DDD) has been associated with highly variable results in terms of postoperative pain relief and functional improvement. Many experts believe that DDD should be considered a chronic pain disorder as opposed to a degenerative disease. Genetic variation of the catechol-O-methyltransferase (COMT) gene has been associated with variation in human pain sensitivity and response to analgesics in previous studies.

Purpose

To determine whether genetic variation of COMT is associated with clinical outcome after surgical treatment for DDD.

Study design

Prospective genetic association study.

Patient sample

Sixty-nine patients undergoing surgical treatment for lumbar DDD. Diagnosis was based on documentation of chronic disabling low back pain (LBP) present for a minimum of 6 months and unresponsive to supervised nonoperative treatment, including activity modification, medication, physical therapy, and/or injection therapy. Plain radiographs and magnetic resonance imaging revealed intervertebral disc desiccation, tears, and/or collapse without focal herniation, nerve root compression, stenosis, spondylolisthesis, spondylolysis, or alternative diagnoses.

Outcome measures

Oswestry Disability Index (ODI) and visual analog score (VAS) for LBP.

Methods

Surgical treatment included 65 instrumented fusions and four disc arthroplasty procedures. All patients completed preoperative and 1-year postoperative ODI questionnaires. DNA was extracted from a sample of venous blood, and genotype analysis was performed for five common COMT single nucleotide polymorphisms (SNPs). Potential genetic association between these COMT SNPs and the primary outcome variable, 1-year change in ODI, was investigated using both single-marker and haplotype association analyses. Association with VAS scores for LBP was analyzed as a secondary outcome variable.

Results

Single-marker analysis revealed that the COMT SNP rs4633 was significantly associated with greater improvement in ODI score 1 year after surgery (p=.03), with individuals homozygous for the less common “T” allele demonstrating the largest improvement in ODI. Haplotype analysis of four COMT SNPs, rs6269, rs4633, rs4818, and rs4680, also identified a common haplotype “ATCA” (haplotype frequency of 39.3% in the study population) associated with greater improvement in ODI (p=.046). The greatest mean improvement in ODI was observed in patients homozygous for the “ATCA” COMT haplotype. A nonsignificant trend was observed between SNP rs4633 and greater improvement in VAS score for LBP.

Conclusions

This is the first study to report an association between surgical treatment success in DDD patients and genetic variation in the putative pain sensitivity gene COMT. These findings require replication in other DDD populations but suggest that genetic testing for pain-relevant genetic markers such as COMT may provide useful clinical information in terms of predicting outcome after surgery for patients diagnosed with DDD.     

Comparative Effectiveness of External-Beam Radiation Approaches for Prostate Cancer

Background

Intensity-modulated radiotherapy (IMRT) is increasingly used to treat localized prostate cancer. Although allowing for the delivery of higher doses of radiation to the prostate, its effectiveness compared with the prior standard three-dimensional conformal therapy (3D-CRT) is uncertain.

Objective

To examine the comparative effectiveness of IMRT relative to 3D-CRT.

Design, setting, and participants

We performed a population-based cohort study using Surveillance, Epidemiology, and End Results-Medicare data to identify men diagnosed with prostate cancer between 2001 and 2007 who underwent either 3D-CRT (n = 6976) or IMRT (n = 11 039).

Outcome measurements and statistical analysis

We assessed our main outcomes (ie, the adjusted use of salvage therapy with androgen-deprivation therapy [ADT] and risk of a complication requiring an intervention) using Cox proportional hazards models.

Results and limitations

The percentage of men receiving IMRT increased from 9% in 2001 to 93% in 2007. Compared with those treated with 3D-CRT, low-risk patients treated with IMRT had similar likelihoods of using salvage therapy with ADT and similar risks of having a complication requiring an intervention (all p > 0.05). Conversely, a subset of higher risk patients treated with IMRT who did not receive concurrent ADT were less likely to use salvage therapy (p = 0.02) while maintaining similar complication rates. Because our cohort includes Medicare beneficiaries, our findings may not be generalizable to younger patients.

Conclusions

For a subset of higher risk patients, IMRT appears to show a benefit in terms of reduced salvage therapy without an increase in complications. For other patients, the risks of salvage therapy and complications are comparable between the two modalities.     

A Randomized Phase 1 Study of Testosterone Replacement for Patients with Low-Risk Castration-Resistant Prostate Cancer

Background

Even in castration-resistant prostate cancer (CRPC), the androgen pathway remains biologically relevant. In preclinical models, androgen therapy for CRPC leads to growth arrest, apoptosis, and tumor shrinkage.

Objective

This study sought to determine the toxicity and feasibility of a testosterone therapy in early CRPC.

Design, setting, and participants

Prostate cancer patients with progressive disease following androgen ablation, antiandrogen therapy, and withdrawal and no to minimal metastatic disease who were followed at the University of Chicago were randomized to treatment with three doses of transdermal testosterone.

Intervention

Patients were treated with transdermal testosterone at 2.5, 5.0, or 7.5 mg/day.

Measurements

Toxicity, prostate-specific antigen (PSA), imaging, quality of life (QoL), and strength were monitored. Treatment was discontinued for significant toxicity, clinical progression, or a 3-fold increase in PSA.

Results and limitations

Fifteen men with a median age of 73 yr (range: 62–92) and a median PSA of 11.1 ng/ml (range: 5.2–63.6) were treated. Testosterone increased from castrate to median concentrations of 305 ng/dl, 308 ng/dl, and 297 ng/dl for dosages of 2.5 mg/day (n = 4), 5.0 mg/day (n = 5), and 7.5 mg/day (n = 5), respectively. One patient was taken off of the study at 53 wk due to grade 4 cardiac toxicity. There were no other grade 3 or 4 toxicities related to the study medication, and the grade 2 toxicities were minimal. Only one patient experienced symptomatic progression, and three (20%) patients demonstrated a decrease in PSA (largest was 43%). Median time to progression was 9 wk (range: 2–96), with no detectable difference in the three dose cohorts. There was no significant improvement in QoL, and there was a borderline statistically significant improvement in hand-grip strength with treatment. The study was limited by sample size, single arm, and variability of baseline patient characteristics.

Conclusions

Testosterone is a feasible and reasonably well-tolerated therapy for men with early CRPC. A larger, randomized trial is under way to further characterize efficacy and impact on QoL measures.     

Insignificant Prostate Cancer and Active Surveillance: From Definition to Clinical Implications

Context

Due to early detection strategies, prostate cancer is diagnosed early in its natural history. It remains unclear whether all patients diagnosed with prostate cancer warrant radical treatment or may benefit from delayed intervention following active surveillance.

Objective

A systematic review of active surveillance protocols to investigate the inclusion criteria for active surveillance and the outcome of treatment.

Evidence acquisition

Medline was searched using the following terms: prostate cancer, active surveillance and expectant management for dates up to October 2008. Further studies were chosen on the basis of manual searches of reference lists and review papers.

Evidence synthesis

Numerous studies on active surveillance were identified. The recent inclusion criteria of the studies are rather similar. Keeping the short follow-up of all studies in mind, the majority of men stay on active surveillance, and the percentage of patients receiving active treatment is as high as 35% of all patients. Once a patients requires active treatment, most patients still present with curable prostate cancer. Furthermore, only few deaths due to prostate cancer have occurred.

Conclusions

Active surveillance is an alternative option to immediate treatment of men with presumed insignificant prostate cancer. It seems that criteria used to identify men with low-risk prostate cancer are rather similar, and immediate treatment of men meeting these criteria may result in an unnecessary number of treatments in these highly selected patients. Data from randomised trials comparing active surveillance and active treatment will provide additional insight into outcome and follow-up strategies.     

Timing of Curative Treatment for Prostate Cancer: A Systematic Review

Context

Delaying definitive therapy unfavourably affects outcomes in many malignancies. Diagnostic, psychological, and logistical reasons but also active surveillance (AS) strategies can lead to treatment delay, an increase in the interval between the diagnosis and treatment of prostate cancer (PCa).

Objective

To review and summarise the current literature on the impact of treatment delay on PCa oncologic outcomes.

Evidence acquisition

A comprehensive search of PubMed and Embase databases until 30 September 2012 was performed. Studies comparing pathologic, biochemical recurrence (BCR), and mortality outcomes between patients receiving direct and delayed curative treatment were included. Studies presenting single-arm results following AS were excluded.

Evidence synthesis

Seventeen studies were included: 13 on radical prostatectomy, 3 on radiation therapy, and 1 combined both. A total of 34 517 PCa patients receiving radical local therapy between 1981 and 2009 were described. Some studies included low-risk PCa only; others included a wider spectrum of disease. Four studies found a significant effect of treatment delay on outcomes in multivariate analysis. Two included low-risk patients only, but it was unknown whether AS was applied or repeat biopsy triggered active therapy during AS. The two other studies found a negative effect on BCR rates of 2.5–9 mo delay in higher risk patients (respectively defined as any with T ≥2b, prostate-specific antigen >10, Gleason score >6, >34–50% positive cores; or D’Amico intermediate risk-group). All studies were retrospective and nonrandomised. Reasons for delay were not always clear, and time-to-event analyses may be subject to bias.

Conclusions

Treatment delay of several months or even years does not appear to affect outcomes of men with low-risk PCa. Limited data suggest treatment delay may have an impact on men with non–low-risk PCa. Most AS protocols suggest a confirmatory biopsy to avoid delaying treatment in those who harbour higher risk disease that was initially misclassified.     

Might Men Diagnosed with Metastatic Prostate Cancer Benefit from Definitive Treatment of the Primary Tumor? A SEER-Based Study

Background

Few data exist regarding the impact on survival of definitive treatment of the prostate in men diagnosed with metastatic prostate cancer (mPCa).

Objective

To evaluate the survival of men diagnosed with mPCa based on definitive treatment of the prostate.

Design, setting, and participants

Men with documented stage IV (M1a–c) PCa at diagnosis identified using Surveillance Epidemiology and End Results (SEER) (2004–2010) and divided based on definitive treatment of the prostate (radical prostatectomy [RP] or brachytherapy [BT]) or no surgery or radiation therapy (NSR).

Outcome measurements and statistical analysis

Kaplan-Meier methods were used to calculate overall survival (OS). Multivariable competing risks regression analysis was used to calculate disease-specific survival (DSS) probability and identify factors associated with cause-specific mortality (CSM).

Results and limitations

A total of 8185 patients were identified: NSR (n = 7811), RP (n = 245), and BT (n = 129). The 5-yr OS and predicted DSS were each significantly higher in patients undergoing RP (67.4% and 75.8%, respectively) or BT (52.6 and 61.3%, respectively) compared with NSR patients (22.5% and 48.7%, respectively) (p < 0.001). Undergoing RP or BT was each independently associated with decreased CSM (p < 0.01). Similar results were noted regardless of the American Joint Committee on Cancer (AJCC) M stage. Factors associated with increased CSM in patients undergoing local therapy included AJCC T4 stage, high-grade disease, prostate-specific antigen ≥20 ng/ml, age ≥70 yr, and pelvic lymphadenopathy (p < 0.05). The major limitation of this study was the lack of variables from SEER known to influence survival of patients with mPCa, including treatment with systemic therapy.

Conclusions

Definitive treatment of the prostate in men diagnosed with mPCa suggests a survival benefit in this large population-based study. These results should serve as a foundation for future prospective trials.

Patient summary

We used a large population-based cancer database to examine survival in men diagnosed with metastatic prostate cancer (mPCa) undergoing definitive therapy for the prostate. Local therapy (LT) appeared to confer a survival benefit. Therefore, we conclude that prospective trials are needed to further evaluate the role of LT in mPCa.     

Mortality After Prostate Cancer Treatment with Radical Prostatectomy,External-Beam Radiation Therapy,or Brachytherapy in Men Without Comorbidity

Background

Medical comorbidity is a confounding factor in prostate cancer (PCa) treatment selection and mortality. Large-scale comparative evaluation of PCa mortality (PCM) and overall mortality (OM) restricted to men without comorbidity at the time of treatment has not been performed.

Objective

To evaluate PCM and OM in men with no recorded comorbidity treated with radical prostatectomy (RP), external-beam radiation therapy (EBRT), or brachytherapy (BT).

Design, setting, and participants

Data from 10 361 men with localized PCa treated from 1995 to 2007 at two academic centers in the United States were prospectively obtained at diagnosis and retrospectively reviewed. We identified 6692 men with no recorded comorbidity on a validated comorbidity index. Median follow-up after treatment was 7.2 yr.

Intervention

Treatment with RP in 4459 men, EBRT in 1261 men, or BT in 972 men.

Outcome measurements and statistical analysis

Univariate and multivariate Cox proportional hazards regression analysis, including propensity score adjustment, compared PCM and OM for EBRT and BT relative to RP as reference treatment category. PCM was also evaluated by competing risks analysis.

Results and limitations

Using Cox analysis, EBRT was associated with an increase in PCM compared with RP (hazard ratio [HR]: 1.66; 95% confidence interval [CI], 1.05–2.63), while there was no statistically significant increase with BT (HR: 1.83; 95% CI, 0.88–3.82). Using competing risks analysis, the benefit of RP remained but was no longer statistically significant for EBRT (HR: 1.55; 95% CI, 0.92–2.60) or BT (HR: 1.66; 95% CI, 0.79–3.46). In comparison with RP, both EBRT (HR: 1.71; 95% CI, 1.40–2.08) and BT (HR: 1.78; 95% CI, 1.37–2.31) were associated with increased OM.

Conclusions

In a large multicenter series of men without recorded comorbidity, both forms of radiation therapy were associated with an increase in OM compared with surgery, but there were no differences in PCM when evaluated by competing risks analysis. These findings may result from an imbalance of confounders or differences in mortality related to primary or salvage therapy.     

Intérêts des manœuvres de réanimation à thorax ouvert en France ?

Objective

To expose and clarify indications, techniques, results, complications and cost for open chest cardiopulmonary resuscitation manoeuvres (OCCRM) in traumatic or nontraumatic cardiac arrest.

Data sources

References were obtained from Pubmed data bank using the following keywords: “emergency thoracotomy”, “resuscitative thoracotomy”.

Study selection

We focused on publications in English language, from 2000 to 2007.

Data synthesis

OCCRM are useful especially in case of traumatic cardiac arrest, penetrating trauma, but also in blunt trauma. Time between cardiac arrest and realisation of the thoracotomy seems to be the most important factor for the prognosis.

Conclusion

According to the French “physician in ambulance” prehospital system, OCCRM might be promising in France, because this system favours the fastness of care and therefore would minimize the time factor.