Ann M. Henry

EAU–ESTRO–SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent

OBJECTIVEnTo present a summary of the 2016 version of the European Association of Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) - International Society of Geriatric Oncology (SIOG) Guidelines on screening, diagnosis, and local treatment with curative intent of clinically localised prostate cancer (PCa).nnnEVIDENCE ACQUISITIONnThe working panel performed a literature review of the new data (2013-2015). The guidelines were updated and the levels of evidence and/or grades of recommendation were added based on a systematic review of the evidence.nnnEVIDENCE SYNTHESISnBRCA2 mutations have been added as risk factors for early and aggressive disease. In addition to the Gleason score, the five-tier 2014 International Society of Urological Pathology grading system should now be provided. Systematic screening is still not recommended. Instead, an individual risk-adapted strategy following a detailed discussion and taking into account the patients wishes and life expectancy must be considered. An early prostate-specific antigen test, the use of a risk calculator, or one of the promising biomarker tools are being investigated and might be able to limit the overdetection of insignificant PCa. Breaking the link between diagnosis and treatment may lower the overtreatment risk. Multiparametric magnetic resonance imaging using standardised reporting cannot replace systematic biopsy, but robustly nested within the diagnostic work-up, it has a key role in local staging. Active surveillance always needs to be discussed with very low-risk patients. The place of surgery in high-risk disease and the role of lymph node dissection have been clarified, as well as the management of node-positive patients. Radiation therapy using dose-escalated intensity-modulated technology is a key treatment modality with recent improvement in the outcome based on increased doses as well as combination with hormonal treatment. Moderate hypofractionation is safe and effective, but longer-term data are still lacking. Brachytherapy represents an effective way to increase the delivered dose. Focal therapy remains experimental while cryosurgery and HIFU are still lacking long-term convincing results.nnnCONCLUSIONSnThe knowledge in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. The 2016 EAU-ESTRO-SIOG Guidelines on PCa summarise the most recent findings and advice for the use in clinical practice. These are the first PCa guidelines endorsed by the European Society for Radiotherapy and Oncology and the International Society of Geriatric Oncology and reflect the multidisciplinary nature of PCa management. A full version is available from the EAU office and online (http://uroweb.org/guideline/prostate-cancer/).nnnPATIENT SUMMARYnThe 2016 EAU-STRO-IOG Prostate Cancer (PCa) Guidelines present updated information on the diagnosis, and treatment of clinically localised prostate cancer. In Northern and Western Europe, the number of men diagnosed with PCa has been on the rise. This may be due to an increase in opportunistic screening, but other factors may also be involved (eg, diet, sexual behaviour, low exposure to ultraviolet radiation). We propose that men who are potential candidates for screening should be engaged in a discussion with their clinician (also involving their families and caregivers) so that an informed decision may be made as part of an individualised risk-adapted approach.

EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer

OBJECTIVEnTo present a summary of the 2016 version of the European Association of Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) - International Society of Geriatric Oncology (SIOG) Guidelines on the treatment of relapsing, metastatic, and castration-resistant prostate cancer (CRPC).nnnEVIDENCE ACQUISITIONnThe working panel performed a literature review of the new data (2013-2015). The guidelines were updated, and the levels of evidence and/or grades of recommendation were added based on a systematic review of the literature.nnnEVIDENCE SYNTHESISnRelapse after local therapy is defined by a rising prostate-specific antigen (PSA) level >0.2ng/ml following radical prostatectomy (RP) and >2ng/ml above the nadir after radiation therapy (RT). 11C-choline positron emission tomography/computed tomography is of limited importance if PSA is <1.0ng/ml; bone scans and computed tomography can be omitted unless PSA is >10ng/ml. Multiparametric magnetic resonance imaging and biopsy are important to assess biochemical failure following RT. Therapy for PSA relapse after RP includes salvage RT at PSA levels <0.5ng/ml and salvage RP, high-intensity focused ultrasound, cryosurgical ablation or salvage brachytherapy of the prostate in radiation failures. Androgen deprivation therapy (ADT) remains the basis for treatment of men with metastatic prostate cancer (PCa). However, docetaxel combined with ADT should be considered the standard of care for men with metastases at first presentation, provided they are fit enough to receive the drug. Follow-up of ADT should include analysis of PSA, testosterone levels, and screening for cardiovascular disease and metabolic syndrome. Level 1 evidence for the treatment of metastatic CRPC (mCRPC) includes, abiraterone acetate plus prednisone (AA/P), enzalutamide, radium 223 (Ra 223), docetaxel at 75xa0mg/m2 every 3 wk and sipuleucel-T. Cabazitaxel, AA/P, enzalutamide, and radium are approved for second-line treatment of CRPC following docetaxel. Zoledronic acid and denosumab can be used in men with mCRPC and osseous metastases to prevent skeletal-related complications.nnnCONCLUSIONSnThe knowledge in the field of advanced and metastatic PCa and CRPC is changing rapidly. The 2016 EAU-ESTRO-SIOG Guidelines on PCa summarise the most recent findings and advice for use in clinical practice. These PCa guidelines are the first endorsed by the European Society for Therapeutic Radiology and Oncology and the International Society of Geriatric Oncology and reflect the multidisciplinary nature of PCa management. A full version is available from the EAU office or online (http://uroweb.org/guideline/prostate-cancer/).nnnPATIENT SUMMARYnIn men with a rise in their PSA levels after prior local treatment for prostate cancer only, it is important to balance overtreatment against further progression of the disease since survival and quality of life may never be affected in many of these patients. For patients diagnosed with metastatic castrate-resistant prostate cancer, several new drugs have become available which may provide a clear survival benefit but the optimal choice will have to be made on an individual basis.

Outcomes Following Iodine-125 Monotherapy for Localized Prostate Cancer: The Results of Leeds 10-Year Single-Center Brachytherapy Experience

PURPOSEnThis study reports the 10-year experience of permanent brachytherapy monotherapy at a single UK center.nnnMETHODS AND MATERIALSnBetween March 1995 and September 2004, 1,298 patients underwent trans-rectal ultrasound (TRUS) planned transperineal brachytherapy delivering 145 Gy using I-125. No patient received supplemental external beam; 44.2% received neoadjuvant hormones. In 688, CT postimplant dosimetry was available. Outcome data were analyzed in terms of overall survival (OS), disease specific survival (DSS), and PSA relapse-free survival (PSA-RFS).nnnRESULTSnThe mean age was 62.9 (range, 34-83) years. Median follow-up was 4.9 years (range, 2.03-11.7 years). OS and DSS were 85% and 95%, respectively, at 10 years. Twenty-one patients died from prostate cancer (1.6%) and 34 (2.5%) from unrelated causes. Seventy-four (5.7%) developed evidence of clinical failure. Overall PSA-RFS was 79.9% and 72.1% at 10 years (American Society for Therapeutic Radiology and Oncology [ASTRO] and Nadir+2 definitions, respectively). Higher presenting PSA or Gleason score and use of neoadjuvant hormones were associated with an increased risk of biochemical failure (p <0.01). Biochemical control was achieved in 86.4%, 76.7%, and 60.6% (ASTRO) and 72.3%, 73.5%, and 57.6% (Nadir+2) of patients in low-, intermediate-, and high-risk groups, respectively. Biochemical control was achieved in 88% of patients with D(90) > or =140 Gy and in 78% of patients with D(90) <140 Gy (p <0.01).nnnCONCLUSIONSnI-125 brachytherapy alone achieved excellent rates of medium-term biochemical control in both low- and selected intermediate-risk localized prostate cancer patients. Postimplant dosimetry improved with experience and longer follow-up, confirming the relationship of D(90) with biochemical control.

What Is the Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in Excluding Prostate Cancer at Biopsy? A Systematic Review and Meta-analysis from the European Association of Urology Prostate Cancer Guidelines Panel

CONTEXTnIt remains unclear whether patients with a suspicion of prostate cancer (PCa) and negative multiparametric magnetic resonance imaging (mpMRI) can safely obviate prostate biopsy.nnnOBJECTIVEnTo systematically review the literature assessing the negative predictive value (NPV) of mpMRI in patients with a suspicion of PCa.nnnEVIDENCE ACQUISITIONnThe Embase, Medline, and Cochrane databases were searched up to February 2016. Studies reporting prebiopsy mpMRI results using transrectal or transperineal biopsy as a reference standard were included. We further selected for meta-analysis studies with at least 10-core biopsies as the reference standard, mpMRI comprising at least T2-weighted and diffusion-weighted imaging, positive mpMRI defined as a Prostate Imaging Reporting Data System/Likert score of ≥3/5 or ≥4/5, and results reported at patient level for the detection of overall PCa or clinically significant PCa (csPCa) defined as Gleason ≥7 cancer.nnnEVIDENCE SYNTHESISnA total of 48 studies (9613 patients) were eligible for inclusion. At patient level, the median prevalence was 50.4% (interquartile range [IQR], 36.4-57.7%) for overall cancer and 32.9% (IQR, 28.1-37.2%) for csPCa. The median mpMRI NPV was 82.4% (IQR, 69.0-92.4%) for overall cancer and 88.1% (IQR, 85.7-92.3) for csPCa. NPV significantly decreased when cancer prevalence increased, for overall cancer (r=-0.64, p<0.0001) and csPCa (r=-0.75, p=0.032). Eight studies fulfilled the inclusion criteria for meta-analysis. Seven reported results for overall PCa. When the overall PCa prevalence increased from 30% to 60%, the combined NPV estimates decreased from 88% (95% confidence interval [95% CI], 77-99%) to 67% (95% CI, 56-79%) for a cut-off score of 3/5. Only one study selected for meta-analysis reported results for Gleason ≥7 cancers, with a positive biopsy rate of 29.3%. The corresponding NPV for a cut-off score of ≥3/5 was 87.9%.nnnCONCLUSIONSnThe NPV of mpMRI varied greatly depending on study design, cancer prevalence, and definitions of positive mpMRI and csPCa. As cancer prevalence was highly variable among series, risk stratification of patients should be the initial step before considering prebiopsy mpMRI and defining those in whom biopsy may be omitted when the mpMRI is negative.nnnPATIENT SUMMARYnThis systematic review examined if multiparametric magnetic resonance imaging (MRI) scan can be used to reliably predict the absence of prostate cancer in patients suspected of having prostate cancer, thereby avoiding a prostate biopsy. The results suggest that whilst it is a promising tool, it is not accurate enough to replace prostate biopsy in such patients, mainly because its accuracy is variable and influenced by the prostate cancer risk. However, its performance can be enhanced if there were more accurate ways of determining the risk of having prostate cancer. When such tools are available, it should be possible to use an MRI scan to avoid biopsy in patients at a low risk of prostate cancer.

The benefits and harms of different extents of lymph node dissection during radical prostatectomy for prostate cancer : a systematic review

CONTEXTnThere is controversy regarding the therapeutic role of pelvic lymph node dissection (PLND) in patients undergoing radical prostatectomy for prostate cancer (PCa).nnnOBJECTIVEnTo systematically review the relevant literature assessing the relative benefits and harms of PLND for oncological and non-oncological outcomes in patients undergoing radical prostatectomy for PCa.nnnEVIDENCE ACQUISITIONnMEDLINE, MEDLINE In-Process, Embase, and the Cochrane Central Register of Controlled Trials were searched up to December 2015. Comparative studies evaluating no PLND, limited, standard, and (super)-extended PLND that reported oncological and non-oncological outcomes were included. Risk-of-bias and confounding assessments were performed. A narrative synthesis was undertaken.nnnEVIDENCE SYNTHESISnOverall, 66 studies recruiting a total of 275,269 patients were included (44 full-text articles and 22 conference abstracts). Oncological outcomes were addressed by 29 studies, one of which was a randomized clinical trial (RCT). Non-oncological outcomes were addressed by 43 studies, three of which were RCTs. There were high risks of bias and confounding in most studies. Conflicting results emerged when comparing biochemical and clinical recurrence, while no significant differences were observed among groups for survival. Conversely, the majority of studies showed that the more extensive the PLND, the greater the adverse outcomes in terms of operating time, blood loss, length of stay, and postoperative complications. No significant differences were observed in terms of urinary continence and erectile function recovery.nnnCONCLUSIONSnAlthough representing the most accurate staging procedure, PLND and its extension are associated with worse intraoperative and perioperative outcomes, whereas a direct therapeutic effect is still not evident from the current literature. The current poor quality of evidence indicates the need for robust and adequately powered clinical trials.nnnPATIENT SUMMARYnBased on a comprehensive review of the literature, this article summarizes the benefits and harms of removing lymph nodes during surgery to remove the prostate because of PCa. Although the quality of the data from the studies was poor, the review suggests that lymph node removal may not have any direct benefit on cancer outcomes and may instead result in more complications. Nevertheless, the procedure remains justified because it enables accurate assessment of cancer spread.

Outcomes from Gleason 7, intermediate risk, localized prostate cancer treated with Iodine-125 monotherapy over 10 years

BACKGROUND AND PURPOSEnThe effect of predominating Gleason grade (3+4 versus 4+3) in Gleason sum score (GS) 7 prostate cancer (PCa) on brachytherapy outcomes is unclear. The 10 year experience of permanent brachytherapy monotherapy at a single UK centre for GS 7, intermediate risk (Memorial Sloan-Kettering model), PSA < or = 10 ng/ml, localised PCa is reported.nnnMATERIALS AND METHODSnBetween 1995 and 2004, the outcomes of 187 patients with GS 7 PCa (PSA < or = 10 ng/ml) were analysed from a cohort of 1298 men treated with permanent Iodine-125 prostate brachytherapy, including PSA relapse-free survival (PSA-RFS).nnnRESULTSnMedian follow-up was 5.0 years (range 2.0-10.1 years). One patient has died of PCa. At 10 years, PSA-RFS was 82.4%/78% (ASTRO consensus and nadir +2 definitions). For GS 3+4, 5 year PSA-RFS was 86.7%/87.9% and for GS 4+3: 85.2%/96.6% respectively, with no significant difference between groups. Five year PSA-RFS (ASTRO) of 92.6% was seen for D(90) > or = 140 Gy (50% total), compared with 77.0% below 140 Gy (p=0.08).nnnCONCLUSIONSnIodine-125 brachytherapy monotherapy achieved good rates of medium term biochemical control in GS 7, intermediate risk localised PCa patients. There was a trend to improved outcomes in men with a D90 in excess of 140 Gy.

Dosimetry Modeling for Focal Low-Dose-Rate Prostate Brachytherapy

PURPOSEnFocal brachytherapy targeted to an individual lesion(s) within the prostate may reduce side effects experienced with whole-gland brachytherapy. The outcomes of a consensus meeting on focal prostate brachytherapy were used to investigate optimal dosimetry of focal low-dose-rate (LDR) prostate brachytherapy targeted using multiparametric magnetic resonance imaging (mp-MRI) and transperineal template prostate mapping (TPM) biopsy, including the effects of random and systematic seed displacements and interseed attenuation (ISA).nnnMETHODS AND MATERIALSnNine patients were selected according to clinical characteristics and concordance of TPM and mp-MRI. Retrospectively, 3 treatment plans were analyzed for each case: whole-gland (WG), hemi-gland (hemi), and ultra-focal (UF) plans, with 145-Gy prescription dose and identical dose constraints for each plan. Plan robustness to seed displacement and ISA were assessed using Monte Carlo simulations.nnnRESULTSnWG plans used a mean 28 needles and 81 seeds, hemi plans used 17 needles and 56 seeds, and UF plans used 12 needles and 25 seeds. Mean D90 (minimum dose received by 90% of the target) and V100 (percentage of the target that receives 100% dose) values were 181.3 Gy and 99.8% for the prostate in WG plans, 195.7 Gy and 97.8% for the hemi-prostate in hemi plans, and 218.3 Gy and 99.8% for the focal target in UF plans. Mean urethra D10 was 205.9 Gy, 191.4 Gy, and 92.4 Gy in WG, hemi, and UF plans, respectively. Mean rectum D2 cm(3) was 107.5 Gy, 77.0 Gy, and 42.7 Gy in WG, hemi, and UF plans, respectively. Focal plans were more sensitive to seed displacement errors: random shifts with a standard deviation of 4 mm reduced mean target D90 by 14.0%, 20.5%, and 32.0% for WG, hemi, and UF plans, respectively. ISA has a similar impact on dose-volume histogram parameters for all plan types.nnnCONCLUSIONSnTreatment planning for focal LDR brachytherapy is feasible. Dose constraints are easily met with a notable reduction to organs at risk. Treating smaller targets makes seed positioning more critical.

Multi-parametric MRI-guided focal tumor boost using HDR prostate brachytherapy: A feasibility study

PURPOSEnThis study investigates the feasibility of delivering focal boost dose to tumor regions, identified with multi-parametric MRI, in high-dose-rate prostate brachytherapy.nnnMETHODS AND MATERIALSnT2-weighted, diffusion-weighted, and dynamic-contrast-enhanced MRI were acquired the day before treatment and analyzed retrospectively for 15 patients. Twelve patients had hormone therapy before the MRI scan. The tumor was delineated on MRI by a radiologist and registered to treatment planning transrectal ultrasound images. A margin based on analysis of delineation and registration uncertainties was applied to create a focal boost planning target volume (F-PTV). Delivered treatment plans were compared with focal boost plans optimized to increase F-PTV dose as much as allowed by urethral and rectal dose constraints.nnnRESULTSnTumors were delineated in all patients with volumes 0.4-23.0cc. The margin for tumor delineation and image registration uncertainties was estimated to be 4.5xa0mm. For F-PTV, the focal boost treatment plans increased median D90 from 17.6 to 20.9xa0Gy and median V150 from 27.3% to 75.9%.nnnCONCLUSIONSnMRI-guided high-dose-rate prostate brachytherapy focal tumor boost is feasible-tumor regions can be identified even after hormone therapy, and focal boost dose can be delivered without violating urethral and rectal dose constraints.

Radiation-induced second primary cancer risks from modern external beam radiotherapy for early prostate cancer: impact of stereotactic ablative radiotherapy (SABR), volumetric modulated arc therapy (VMAT) and flattening filter free (FFF) radiotherapy

Risks of radiation-induced second primary cancer following prostate radiotherapy using 3D-conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), flattening filter free (FFF) and stereotactic ablative radiotherapy (SABR) were evaluated. Prostate plans were created using 10u2009MV 3D-CRT (78u2009Gy in 39 fractions) and 6u2009MV 5-field IMRT (78u2009Gy in 39 fractions), VMAT (78u2009Gy in 39 fractions, with standard flattened and energy-matched FFF beams) and SABR (42.7u2009Gy in 7 fractions with standard flattened and energy-matched FFF beams). Dose-volume histograms from pelvic planning CT scans of three prostate patients, each planned using all 6 techniques, were used to calculate organ equivalent doses (OED) and excess absolute risks (EAR) of second rectal and bladder cancers, and pelvic bone and soft tissue sarcomas, using mechanistic, bell-shaped and plateau models. For organs distant to the treatment field, chamber measurements recorded in an anthropomorphic phantom were used to calculate OEDs and EARs using a linear model. Ratios of OED give relative radiation-induced second cancer risks. SABR resulted in lower second cancer risks at all sites relative to 3D-CRT. FFF resulted in lower second cancer risks in out-of-field tissues relative to equivalent flattened techniques, with increasing impact in organs at greater distances from the field. For example, FFF reduced second cancer risk by up to 20% in the stomach and up to 56% in the brain, relative to the equivalent flattened technique. Relative to 10u2009MV 3D-CRT, 6u2009MV IMRT or VMAT with flattening filter increased second cancer risks in several out-of-field organs, by up to 26% and 55%, respectively. For all techniques, EARs were consistently low. The observed large relative differences between techniques, in absolute terms, were very low, highlighting the importance of considering absolute risks alongside the corresponding relative risks, since when absolute risks are very low, large relative risks become less meaningful. A calculated relative radiation-induced second cancer risk benefit from SABR and FFF techniques was theoretically predicted, although absolute radiation-induced second cancer risks were low for all techniques, and absolute differences between techniques were small.

A systematic review of randomised controlled trials of radiotherapy for localised prostate cancer

BACKGROUNDnProstate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males. A systematic review of randomised controlled trials (RCTs) of radiotherapy and other non-pharmacological management options for localised prostate cancer was undertaken.nnnMETHODSnA search of thirteen databases was carried out until March 2014. RCTs comparing radiotherapy (brachytherapy (BT) or external beam radiotherapy (EBRT)) to other management options i.e. radical prostatectomy (RP), active surveillance, watchful waiting, high intensity focused ultrasound (HIFU), or cryotherapy; each alone or in combination, e.g. with adjuvant hormone therapy (HT), were included. Methods followed guidance by the Centre for Reviews and Dissemination and the Cochrane Collaboration. Indirect comparisons were calculated using the Bucher method.nnnRESULTSnThirty-six randomised controlled trials (RCTs, 134 references) were included. EBRT, BT and RP were found to be effective in the management of localised prostate cancer. While higher doses of EBRT seem to be related to favourable survival-related outcomes they might, depending on technique, involve more adverse events, e.g. gastrointestinal and genitourinary toxicity. Combining EBRT with hormone therapy shows a statistically significant advantage regarding overall survival when compared to EBRT alone (Relative risk 1.21, 95% confidence interval 1.12-1.30). Aside from mixed findings regarding urinary function, BT and radical prostatectomy were comparable in terms of quality of life and biochemical progression-free survival while favouring BT regarding patient satisfaction and sexual function. There might be advantages of EBRT (with/without HT) compared to cryoablation (with/without HT). No studies on HIFU were identified.nnnCONCLUSIONSnBased on this systematic review, there is no strong evidence to support one therapy over another as EBRT, BT and RP can all be considered as effective monotherapies for localised disease with EBRT also effective for post-operative management. All treatments have unique adverse events profiles. Further large, robust RCTs which report treatment-specific and treatment combination-specific outcomes in defined prostate cancer risk groups following established reporting standards are needed. These will strengthen the evidence base for newer technologies, help reinforce current consensus guidelines and establish greater standardisation across practices.