Tag: #PCSM

Posts

Editorial: The Advanced Prostate Cancer Consensus on a regional level – what can we learn?

January 16, 2019/by Aurelius Omlin and Silke Gillessen

In this issue of BJUI Chiong et al [1] present the results of the Asia Pacific (APAC) Advanced Prostate Cancer Consensus Conference (APCCC) 2018, during which the implications of the APCCC 2017 findings were discussed in the context of the APAC region. For background, it is important to understand the concept of the original APCCC and why it was initiated [1,2,3].

The consensus conference aims to target areas of controversy in the clinical management of advanced prostate cancer where evidence is either limited or lacking or where interpretation of evidence is controversial. The expert consensus aims to complement existing clinical practice guidelines that are mostly based on high‐level evidence. The APCCC’s most prominent aim is knowledge translation, in the sense of improving care of men with advanced prostate cancer worldwide who are treated outside of centres of excellence. During the original APCCC in St Gallen, where 61 prostate cancer experts and scientists were assembled, the majority of the consensus questions were discussed; these had been prepared prior to the conference under the idealistic assumption that all diagnostic procedures and treatments (including expertise in their interpretation and application) mentioned were readily available. These assumptions have been specifically chosen, because availability of systemic treatment options for advanced prostate cancer, access to next‐generation imaging (whole‐body MRI and positron‐emission tomography [PET]) and expertise in molecular techniques and interpretation of results vary widely across the world. The original global APCCC did not generally address regional or country‐specific situations, but APCCC 2017 did have a special session and also voting questions for treatment options in countries with limited resources. Importantly, consensus recommendations may even inform and influence regulatory authorities, for example, if a specific treatment is considered to be the best option by the majority of experts and availability in a certain country is lacking.

The APAC APCCC 2018 consisted of 20 experts (mostly urologists) from 15 countries and discussed the findings and voting results of five of the 10 APCCC 2017 topics. Whether or not Turkey should be considered an APAC country is unclear. The most relevant observations were as set out below:

There is huge variation in access to drugs used for treatment of advanced prostate cancer in the APAC region. Australia and Hong Kong have access to almost all treatment options (notably cabazitaxel is not mentioned) compared with countries such as Vietnam or the Philippines, where there is limited availability of many compounds. Regarding imaging technologies (standard CT is not mentioned), there seems to be wide availability of next‐generation imaging such as whole‐body MRI and choline‐ or PSMA‐PET technologies; however, these imaging methods are often not reimbursed.
Pharmaco‐ethnic issues have so far not been considered by the original APCCC and the APAC report clearly highlights the need to address such issues. The higher toxicity of docetaxel in Asian men may influence treatment recommendations, especially in situations such as low‐volume metastatic castration‐naïve prostate cancer, where the role of early addition of docetaxel to androgen deprivation therapy is less clear.
The authors of the APAC meeting state that ketoconazole and bicalutamide are still widely used despite the proven superiority of enzalutamide vs bicalutamide. A possible reason for this is the lack of reimbursement in some APAC countries.
There is an obvious need for clinical trials in the APAC region because of variations in genetics, genomics, epidemiology and pharmaco‐ethnicity. Such trials may answer questions about toxicity/tolerability and also optimal use of resources in the context of economic limitations.

In summary, the APAC APCCC 2018 is an excellent example of how the global APCCC findings should be discussed and integrated on a regional or even country‐specific level. The authors are therefore to be congratulated for their efforts and for writing up the discussions. The next APCCC (2019; apccc.org) will take up a number of points raised by the APAC meeting, namely, more panel experts from APAC countries and pharmaco‐ethnic topics.

References

Edmund C, Declan GM, Hideyuki A et al. Management of patients with advanced prostate cancer in the Asia Pacific region: ‘real‐world’ consideration of results from the Advanced Prostate Cancer Consensus Conference (APCCC) 2017. BJU Int 2019; 123: 22–34
Gillessen S, Omlin A, Attard G et al. Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015. Ann Oncol 2015; 26: 1589–604
Gillessen S, Attard G, Beer TM et al. Management of patients with advanced prostate cancer: the report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol 2018; 73: 178–211

Editorial: Retzius‐sparing robot‐assisted radical prostatectomy

January 9, 2019/by Akshay Sood

In their commentary in the current issue of BJUI, Stonier et al. [1] examine the potential technical pitfalls and published results of the Retzius‐sparing technique of robotic radical prostatectomy. The authors reviewed three studies from three different groups [2,3], including a study by our group [4], and raised three specific concerns: the oncological efficacy of the procedure; the long learning curve; and the generalizability of the technique to challenging surgical scenarios. We offer a few clarifications and comments.

The first study on Retzius‐sparing robot‐assisted radical prostatectomy came from the Bocciardi group [2]. This was a prospective, single‐arm study of 200 patients. The authors reported a 14‐day continence rate of 90–92%, a 1‐year potency rate of 71–81% (in preoperatively potent patients undergoing bilateral intrafascial nerve‐sparing) and a positive surgical margin rate of 25.5%. The positive surgical margin rate improved in patients with pT2 disease, from 22% to 9% (P = 0.04) over the course of the study (initial 100 vs subsequent 100 patients), while in patients with pT3 disease, it remained stable at ~45%. Lim et al. [3] also noted an improvement in their overall positive surgical margin rate from 20% to 8% when comparing the initial 25 patients with the subsequent 25 patients. In that study, a standard robot‐assisted radical prostatectomy comparator arm was included and there were no differences in overall positive surgical margin rates (14% in both arms), while continence was better with the Retzius‐sparing approach.

Recognizing the potentially technically challenging nature of the Bocciardi approach, we performed a randomized controlled trial to objectively evaluate the technique. Randomized controlled trials are typically designed to answer a single question. Our trial was designed to determine whether there were differences in the rate of return of urinary continence, the primary benefit that previous non‐controlled studies had reported. This our study clearly showed [4].

Once the trial was completed, post hoc analysis of secondary outcomes was performed [5]. One of these outcomes was the positive surgical margin rate. In our trial, we noted an overall positive surgical margin rate of 25% in the Retzius‐sparing arm vs 13% in the control arm, a difference that did not achieve statistical significance (P = 0.11). Stonier et al. [1] suggested that if the sample size of our trial were doubled, then the positive surgical margin rate in each group would be doubled as well, leading to significance. This conclusion is problematic. The likelihood that doubling the sample size would result in the exact doubling of numbers in all four cells of a 2 × 2 contingency table is estimated at <5% using Fisher’s exact test (this calculation is different from the P value). Furthermore, the surgical margins depend as much on the pathological stage as on surgical approach. In our trial, patients were matched preoperatively for risk in the best manner possible for a pragmatic randomized trial. However, it is impossible to predict and control for the final pathological characteristics. Pathological analysis showed that patients undergoing Retzius‐sparing surgery did have significantly more aggressive disease: ≥pT3 disease in 45% vs 23.3% of patients (P = 0.04) [4, 5]. This, by itself, could account for a substantial difference in surgical margin rates.

In writing our paper, we made no judgements as to whether the Bocciardi or posterior technique is fundamentally superior to an anterior or Menon approach, whether it is easier to perform, how generalizable it is [6], or what the learning curve may be. That is best left to the individual surgeon’s training and judgement. We do suggest, however, that surgical margins be interpreted as a function of pathological variables, and not in isolation, and that it is simplistic to assume that identical results will be obtained by doubling sample size. We suggest that such conclusions are hypothesis‐generating, and should best be explored through a separate, purpose‐designed randomized trial.

Authors: Akshay Sood, Firas Abdollah and Mani Menon

References

Stonier T, Simson N, Davis J, Challacombe B. Retzius‐sparing robot‐assisted radical prostatectomy (RS‐RARP) vs standard RARP: it’s time for critical appraisal. BJU Int 2019; 123: 5–10
Galfano A, Di Trapani D, Sozzi F et al. Beyond the learning curve of the Retzius‐sparing approach for robot‐assisted laparoscopic radical prostatectomy: oncologic and functional results of the first 200 patients with >/= 1 year of follow‐up. Eur Urol 2013; 64: 974–80
Lim SK, Kim KH, Shin TY et al. Retzius‐sparing robot‐assisted laparoscopic radical prostatectomy: combining the best of retropubic and perineal approaches. BJU Int 2014; 114: 236–44
Dalela D, Jeong W, Prasad MA et al. A pragmatic randomized controlled trial examining the impact of the Retzius‐sparing approach on early urinary continence recovery after robot‐assisted radical prostatectomy. Eur Urol 2017; 72: 677–85
Menon M, Dalela D, Jamil M et al. Functional recovery, oncologic outcomes and postoperative complications after robot‐assisted radical prostatectomy: an evidence‐based analysis comparing the Retzius sparing and standard approaches. J Urol 2018; 199: 1210–7
Galfano A, Secco S, Bocciardi AM. Will Retzius‐sparing prostatectomy be the future of prostate cancer surgery? Eur Urol 2017; 72: 686–8

Article of the Month: Use of machine learning to predict early biochemical recurrence after robot‐assisted prostatectomy

January 2, 2019/by Admin

Every month, the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Use of machine learning to predict early biochemical recurrence after robot‐assisted prostatectomy

Nathan C. Wong , Cameron Lam, Lisa Patterson and Bobby Shayegan
Division of Urology, Department of Surgery, McMaster University, Hamilton, ON, Canada

Read the full article

Visual abstract created Rebecca Fisher @beckybeckyfish

Abstract

Objectives

To train and compare machine‐learning algorithms with traditional regression analysis for the prediction of early biochemical recurrence after robot‐assisted prostatectomy.

Patients and Methods

A prospectively collected dataset of 338 patients who underwent robot‐assisted prostatectomy for localized prostate cancer was examined. We used three supervised machine‐learning algorithms and 19 different training variables (demographic, clinical, imaging and operative data) in a hypothesis‐free manner to build models that could predict patients with biochemical recurrence at 1 year. We also performed traditional Cox regression analysis for comparison.

= 0.686) and with a univariate regression model (AUC = 0.865).

Results

K‐nearest neighbour, logistic regression and random forest classifier were used as machine‐learning models. Classic Cox regression analysis had an area under the curve (AUC) of 0.865 for the prediction of biochemical recurrence. All three of our machine‐learning models (K‐nearest neighbour (AUC 0.903), random forest tree (AUC 0.924) and logistic regression (AUC 0.940) outperformed the conventional statistical regression model. Accuracy prediction scores for K‐nearest neighbour, random forest tree and logistic regression were 0.976, 0.953 and 0.976, respectively.

Conclusions

Machine‐learning techniques can produce accurate disease predictability better that traditional statistical regression. These tools may prove clinically useful for the automated prediction of patients who develop early biochemical recurrence after robot‐assisted prostatectomy. For these patients, appropriate individualized treatment options can improve outcomes and quality of life.

Video: Development and internal validation of a side‐specific, mpMRI‐based nomogram for the prediction of extracapsular extension of PCa

December 5, 2018/by Admin

Development and internal validation of a side‐specific, multiparametric magnetic resonance imaging‐based nomogram for the prediction of extracapsular extension of prostate cancer

Read the full article

Abstract

Objectives

To develop a nomogram for predicting side‐specific extracapsular extension (ECE) for planning nerve‐sparing radical prostatectomy.

Materials and Methods

We retrospectively analysed data from 561 patients who underwent robot‐assisted radical prostatectomy between February 2014 and October 2015. To develop a side‐specific predictive model, we considered the prostatic lobes separately. Four variables were included: prostate‐specific antigen; highest ipsilateral biopsy Gleason grade; highest ipsilateral percentage core involvement; and ECE on multiparametric magnetic resonance imaging (mpMRI). A multivariable logistic regression analysis was fitted to predict side‐specific ECE. A nomogram was built based on the coefficients of the logit function. Internal validation was performed using ‘leave‐one‐out’ cross‐validation. Calibration was graphically investigated. The decision curve analysis was used to evaluate the net clinical benefit.

Results

The study population consisted of 829 side‐specific cases, after excluding negative biopsy observations (n = 293). ECE was reported on mpMRI and final pathology in 115 (14%) and 142 (17.1%) cases, respectively. Among these, mpMRI was able to predict ECE correctly in 57 (40.1%) cases. All variables in the model except highest percentage core involvement were predictors of ECE (all P ≤ 0.006). All variables were considered for inclusion in the nomogram. After internal validation, the area under the curve was 82.11%. The model demonstrated excellent calibration and improved clinical risk prediction, especially when compared with relying on mpMRI prediction of ECE alone. When retrospectively applying the nomogram‐derived probability, using a 20% threshold for performing nerve‐sparing, nine out of 14 positive surgical margins (PSMs) at the site of ECE resulted above the threshold.

Conclusion

We developed an easy‐to‐use model for the prediction of side‐specific ECE, and hope it serves as a tool for planning nerve‐sparing radical prostatectomy and in the reduction of PSM in future series.

View more videos

Article of the week: External validation of the prostascore model in metastatic hormone‐sensitive PCa patients recruited to the CHAARTED study

September 19, 2018/by Admin

Every Week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

If you only have time to read one article this week, it should be this one.

External validation of the prostascore model in patients with metastatic hormone‐sensitive prostate cancer recruited to the CHAARTED study

Omar Abdel‐Rahman* and Winson Y. Cheung†

*Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; †Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada

Read the full article

Abstract

Objective

To externally validate ‘prostascore’ in patients with metastatic hormone‐sensitive prostate cancer recruited to the phase III CHAARTED study.

Methods

We conducted a retrospective analysis of the prospectively collected data from patients with metastatic hormone‐sensitive prostate cancer in the CHAARTED study, a phase III multicentre study conducted between 2006 and 2014. The main outcome of the present analysis was overall survival, assessed using Kaplan–Meier analysis or log‐rank testing, in the whole cohort according to different prostascores. In addition, patients with different scores were compared according to treatment arm.

Fig 1. Kaplan-Meier curves for (A) overall survival according to Prostascore.

Results

A total of 702 cases had complete baseline data, allowing calculation of prostascores and inclusion in the present analysis. Overall survival was assessed according to prostascores in the entire cohort and the P value for overall survival trend was significant (P < 0.001). Likewise, progression‐free survival was assessed according to prostascores in the entire cohort and the P value for progression‐free survival trend was also significant (P < 0.001). Overall survival comparisons according to treatment arm were evaluated among different prostascores. Notably, the P value for overall survival difference was not significant for a prostascore = 2 (P = 0.702), but was significant for scores of 3, 4 and 5 (P < 0.05). The cause‐specific hazard ratio for cancer‐specific survival (adjusted for treatment arm used) was also evaluated. The P value for pairwise comparisons between different scores was significant (P < 0.01) except for the comparison between scores 4 and 5.

Conclusion

The present study further confirms the role of prostascore in predicting the outcomes of patients with metastatic hormone‐sensitive prostate cancer and also highlights its potential role in therapeutic decision‐making.

Editorial: Prognostic and predictive models in hormone-sensitive PCa

September 19, 2018/by Nicholas James

The article by Abdel‐Rahmen and Cheung [1] in the current issue of BJUI takes the Prostascore model [2] developed from epidemiological Surveillance, Epidemiology and End Results (SEER) data and applies it to the prospective randomised trial data from the ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) [3]. This sort of modelling is invaluable, given the inevitable limitations of epidemiological data (retrospective, no data cleaning, key items such as performance status missing, etc.). For models to be useful, they need to be able to discern prognostic categories reliably and with sufficient difference in outcome that they can usefully contribute to clinical decision‐making. They also need to perform better than existing oncological models, such as TNM stage, as outcome predictors. To be truly useful, they also need to identify subgroups of patients who may differentially benefit from different treatments (e.g. human epidermal growth factor receptor 2 [HER2] status in breast cancer therapy with trastuzumab). It is thus important to differentiate prognostic models (which predict outcome but do not help select treatment) from predictive models (which predict outcome and also help select who may benefit from treatment). A common mistake in this setting is to assume that patients with worse outcomes may benefit from more aggressive treatment, whilst those with better outcomes may require less treatment. This is a frequent confounding bias in retrospective data such as SEER. The key test is to look at good‐ and poor‐prognosis patients and examine whether the benefit from (say) chemotherapy is proportionately the same or different in both groups. If the proportional benefit is the same, the model is purely prognostic, if the proportional benefit is different (e.g., a bigger benefit in worse patients), the model is, in addition, predictive. A randomised trial such as CHAARTED is thus ideal for separating these two factors. It is also worth noting that just because a model predicts a relatively better outcome in one subgroup vs another, it does not mean that all patients do not benefit. For example, programmed death 1 (PD‐1) pathway molecule staining is generally prognostic in advanced bladder cancer and partly predictive of better response to PD‐1 pathway drugs such as atezolizumab [4] and pembrolizumab [5], but all patients derive benefit and hence PD‐1 pathway staining is not useful in selecting for treatment.

How does the Prostascore model fare against these various tests? As a prognostic model it clearly separates patients into groups with plausible differences in outcome. However, there exist many systems already that do this and in the clinic, these are probably not useful – it is well understood that men with extensive disease and visceral metastases will do worse than those with less disease – treatment for all will include androgen‐deprivation therapy (ADT). More recently, trial data have emerged showing survival benefit from the first‐line addition of either docetaxel [3, 6] or abiraterone [7, 8] to ADT. There is controversy about whether this benefit is confined to men with high‐volume disease as claimed by some [9], or applies more generally, as per Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) [6] and the Systemic Treatment Options for Cancer of the Prostate (STOpCaP) meta‐analysis [10]. Can Prostascore help to resolve this problem? Sadly the answer is no. The analysis presented here [1] does not offer convincing evidence of a useful predictive value with respect to selection for first‐line docetaxel. Firstly, the sample size is small (702 men), with only 118 in the lowest risk category (who of course also have the lowest event rate, hence proportionately even less power). In the higher‐risk categories, there seems to be clear evidence of benefit from docetaxel (larger numbers of men and higher event rates). No pooled analysis is presented, but it seems likely that this would show a benefit from docetaxel in the whole sample set, exactly as reported in CHAARTED [3]. Data from underpowered, post hoc, subgroup analysis should not be over‐interpreted [11].

How should we move forward from here? The STAMPEDE group will be presenting data from both the docetaxel and abiraterone parts of the study, classified both by the high‐/low‐volume split in CHAARTED [3] and the high‐/low‐risk split in the LATITUDE trial (multinational, randomised placebo‐controlled phase III clinical trial of men with newly diagnosed, high‐risk metastatic prostate cancer who had not previously received ADT. All patients had at least two of three risk factors: Gleason score of ≥8, ≥3 bone metastases, or ≥3 visceral metastases) [7]. If evidence of a differential response to these agents by these prognostic tools exists, it may be worth applying the Prostascore tool to the STAMPEDE dataset. If there is no evidence of these existing prognostic classifiers also being predictive of best therapy choice, there is probably only a limited role for Prostascore as a prognostic tool in an already crowded space. risk factors and risk of developing cancer.

Nicholas D. James

Institute of Cancer and Genomic Sciences, University of Birmingham,
Queen Elizabeth Hospital, Birmingham, UK

References

Abdel‐Rahman O, Cheung WY. External validation of the prostascore model in patients with metastatic hormone‐sensitive prostate cancer recruited to the CHAARTED study. BJU Int 2018; 122: 394–400
Abdel‐Rahman O. Prostascore: a simplified tool for predicting outcomes among patients with treatment‐naive advanced prostate cancer. Clin Oncol (R Coll Radiol) 2017; 29: 732–8
Sweeney CJ, Chen YH, Carducci M et al. Chemohormonal therapy in metastatic hormone‐sensitive prostate cancer. N Engl J Med 2015; 373: 737–46
Balar AV, Galsky MD, Rosenberg JE et al. Atezolizumab as first‐line treatment in cisplatin‐ineligible patients with locally advanced and metastatic urothelial carcinoma: a single‐arm, multicentre, phase 2 trial. Lancet 2017; 389: 67–76
Bellmunt J, de Wit R, Vaughn DJ et al. Pembrolizumab as second‐line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376: 1015–26
James ND, Sydes MR, Clarke NW et al. Addition of docetaxel, zoledronic acid, or both to first‐line long‐term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387: 1163–77
Fizazi K, Tran N, Fein L et al. Abiraterone plus prednisone in metastatic, castration‐sensitive prostate cancer. N Engl J Med 2017; 377: 352–60
James ND, de Bono JS, Spears MR et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017; 377: 338–51
Gravis G, Boher JM, Chen YH et al. Burden of metastatic castrate naive prostate cancer patients, to identify men more likely to benefit from early docetaxel: further analyses of CHAARTED and GETUG‐AFU15 Studies. Eur Urol 2018; 73: 847–55
10 Vale CL, Burdett S, Rydzewska LH et al. Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone‐sensitive prostate cancer: a systematic review and meta‐analyses of aggregate data. Lancet Oncol 2016; 17: 243–56
Spears MR, James ND, Sydes MR. ‘Thursday’s child has far to go’ – interpreting subgroups and the STAMPEDE trial. Ann Oncol 2017; 28: 2327–30

Article of the Week: Analysis of hydrogel spacer for PCa RT

September 5, 2018/by admin Z.9

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video discussing the paper.

If you only have time to read one article this week, it should be this one.

Prospective analysis of hydrogel spacer for patients with prostate cancer undergoing radiotherapy

Michael Chao*†, Huong Ho† , Yee Chan*‡, Alwin Tan§, Trung Pham¶, Damien Bolton*‡, Andrew Troy*, Catherine Temelcos**, Shomik Sengupta*†† , Kevin McMillan‡, Chee Wee Cham§, Madalena Liu‡, Wei Ding†, Brindha Subramanian†, Jason Wasiak*‡‡, Daryl Lim Joon*†, Sandra Spencer† and Nathan Lawrentschuk*

*The Austin Hospital, Heidelberg, Vic., Australia, †Genesis Cancer Care Victoria, Ringwood East, Vic., Australia, ‡Ringwood Private Hospital, Ringwood East, Vic., Australia, §The Bays Hospital, Mornington, Vic., Australia, ¶ The Valley Private Hospital, Mulgrave, Vic., Australia, **St Vincent’s Hospital, Fitzroy, Vic., Australia, ††Melbourne University; Eastern Health Clinical School, Monash University, Clayton, Vic., Australia, and ‡‡University of Melbourne, Melbourne, Vic., Australia

Read the full article

Abstract

Objective

To report on the dosimetric benefits and late toxicity outcomes after injection of hydrogel spacer (HS) between the prostate and rectum for patients treated with prostate radiotherapy (RT).

Patients and Methods

In all, 76 patients with a clinical stage of T1–T3a prostate cancer underwent general anaesthesia for fiducial marker insertion plus injection of the HS into the perirectal space before intensity‐modulated RT (IMRT) or volumetric‐modulated arc RT (VMAT). HS safety, dosimetric benefits, and the immediate‐ to long‐term effects of gastrointestinal (GI) toxicity were assessed.

Results

There were no postoperative complications reported. The mean (range) prostate size was 66.0 (25.0–187.0) mm. Rectal dose volume parameters were observed and the volume of rectum receiving 70 Gy (rV₇₀), 75 Gy (rV₇₅) and 78 Gy (rV₇₈) was 7.8%, 3.6% and 0.4%, respectively. In all, 21% of patients (16/76) developed acute Grade 1 GI toxicities, but all were resolved completely by 3 months after treatment; whilst, 3% of patients (2/76) developed late Grade 1 GI toxicities. No patients had acute or late Grade ≥2 GI toxicities.

Conclusion

Injection of HS resulted in a reduction of irradiated rectal dose volumes along with minimal GI toxicities, irrespective of prostate size.

Editorial: 2018 – A Spacer Odyssey

September 5, 2018/by Simon Hughes

The optimisation of radical external-beam radiotherapy treatment is ultimately a compromise. The aim is to deliver a clinically effective radiation dose to the tumour target, whilst limiting the irradiation of surrounding normal tissue to minimise acute and late side effects. Modern image-guided intensity-modulated radiotherapy (IG-IMRT) allows very accurate treatment delivery, which improves this therapeutic ratio. However, there are limitations in its ability to reduce toxicity, due to the constraints of regional anatomy and the physical properties of photon beams. A variety of additional organ-specific techniques exist to further minimise the impact of radiotherapy on adjacent healthy tissue. These range in complexity from ovarian auto-transplantation in selected patients awaiting pelvic radiotherapy for gynaecological malignancies, to delivering radiotherapy for left-sided breast cancers at inspiratory breath-hold to maximise the distance of the chest wall from the left anterior descending coronary artery.

For prostate cancer radiotherapy, the normal structures that determine the optimal safely deliverable dose include the rectum (anterior rectal wall), bladder, femoral heads and penile bulb. IG-IMRT has facilitated dose-escalation, and the treatment of patients previously considered to be ineligible for a radical treatment; both with acceptable toxicity. Higher doses result in improved prostate-cancer biochemical (PSA) control rates, and metastasisfree survival, but as yet no overall survival benefit has been demonstrated in individual trials, despite 10-year follow-up [1]. This may due to the long natural history of localised prostate cancer, the impact of competing comorbidities [2], and the ever-increasing efficacy of treatments for metastatic disease on relapse.

Rectal spacers are a further refinement to the delivery of radical IG-IMRT to the prostate gland. By inserting a biodegradable substance / inflatable biodegradable balloon into the anterior perirectal space, the distance between the prostate and the anterior rectal wall can be increased by approximately 1cm. This reduces the volume of rectum lying within the high-dose radiation field, thereby reducing late bowel toxicity. A recently reported randomised Phase III trial found a reduction the 3-year incidence of ≥ Grade 1 and ≥ Grade 2 rectal toxicity (9.2% v 2.0%; p=0.28; and 5.7% v 0%; p=0.12 respectively) with the addition of a rectal spacer [3]. This was in a very select group of patients: PSA ≤20, cT1-2, International Society of Urological Pathology (ISUP) Prostate Cancer Grade 1-3 (<50% of cores involved), prostate volume <80cc, no use of androgen deprivation therapy, and the use of MRI-CT fusion to aid prostate delineation during the planning process.

In this issue of the BJUI, Chao et al. [4] report their prospective single-centre experience of using a rectal spacer device. This is not a randomised study, and no control arm exists to assist in quantifying the clinical impact of inserting a spacer. However, the patient population studied closely reflects that undergoing radical radiotherapy in most oncology departments world-wide. There were no limitations placed on prostate size (45% were 50- 100cc; 17% >100cc; maximum 187cc), PSA (10% had a PSA >20; maximum 117), or ISUP histological grade (27% were Grade 4 and 5); and 27% of patients were cT3a on imaging. They demonstrated that spacer insertion was safe across a diverse population of men with localised prostate cancer. Further, acceptable prostate-rectal wall separation and rectal dosimetry could be achieved irrespective of prostate size – which was reflected by the low rates of cumulative late rectal toxicity when assessed at a median follow-up of 14 months.

As with any new technique, additional clarification is required to determine exactly where rectal spacers fit into the radiotherapy armoury. In the study by Chao et. al. the Radiation Oncologists did not have access to CT-MRI fusion at the planning stage. As the electron densities for the prostate, rectal-spacer and rectal wall are similar, it can be challenging to determine the anatomical boundaries on CT alone. However, if growing clinical experience now permits accurate delineation by merely adjusting the window levels on the Planning CT, this could facilitate more widespread introduction of the technique, outside the specialist centres with MR-fusion capabilities.

Patient selection is also key to the introduction of this technique. Patient series have reported the safety of the spacer insertion technique across a range of prostate sizes, and prostate cancer risk groups. However, prospective randomised data is lacking on whether treatment efficacy is affected by using a spacer in high-risk / locally advanced disease – the population most likely to benefit from dose-escalated radical radiotherapy [5]. Further, in the only randomised study to date, >90% of patients in the control arm experienced no late rectal toxicity, and >94% experienced no ≥Grade 2 rectal toxicity. Based on long-term follow-up data from the RT01 study, this was an appropriate time-point at which to assess late bowel toxicity, which peaks at 12-36 months before declining [6]. Therefore, the majority of patients do not experience clinically significant late toxicity even without a spacer.

Rectal spacers have the potential to make a valuable contribution to radical IG-IMRT treatment for localised prostate cancer. However, predictive factors are required to identify which patients are likely to benefit from the technique. For many patients, with access to the latest radiotherapy planning and delivery systems, spacers may represent an additional costly procedure with limited benefit.

S.R.Hughes
Oncology Department, Guy’s & St. Thomas’ NHS Trust, London, UK

Read the full article

References

1. Dearnaley DP, Jovic G, Syndikus I, et. al. The Lancet Oncol. 2014; 15(4): 464-473

2. Lu-Yao GL, Albertsen PC, Moore DF, Lin Y, DiPaola RS, Yao SL. Fifteen-year outcomes following conservative management among men aged 65 years or older with localised prostate cancer. Eur Urol. 2015; 68(5): 805-11

3. Hamstra DA, Mariados N, Sylvester J et. al. Continued Benefit to Rectal Separation for Prostate Radiation Therapy: Final Results of a Phase III Trial. Int J Radiat Oncol Biol Phys 2017; 97(5): 976-985

4. Chao M, Ho H, Chan Y et. al. Prospective Analysis of Hydrogel Spacer for Prostate Cancer Patients Undergoing Radiotherapy. BJUI 2018

5. Kalbasi A, Li J, Berman AT. Dose-Escalated Irradiation and Overall Survival in Men with Non-metastatic Prostate Cancer. JAMA Oncol. 2015; 1(7): 897-906

6. Syndikus I, Morgan RC, Sydes MR, Graham JD, Dearnaley DP. Late Gastrointestinal Toxicity After Dose-Escalated Conformal Radiotherapy For Early Prostate Cancer:

Video: Hydrogel spacer for PCa RT

September 5, 2018/by admin Z.9

Prospective analysis of hydrogel spacer for patients with prostate cancer undergoing radiotherapy

Read the full article

Abstract

Objective

To report on the dosimetric benefits and late toxicity outcomes after injection of hydrogel spacer (HS) between the prostate and rectum for patients treated with prostate radiotherapy (RT).

Patients and Methods

Results

Conclusion

Injection of HS resulted in a reduction of irradiated rectal dose volumes along with minimal GI toxicities, irrespective of prostate size.

View more videos

Article of the Week: Performance comparison of two AR-V7 detection methods

August 8, 2018/by admin Z.9

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Performance comparison of two androgen receptor splice variant 7 (AR‐V7) detection methods

Christof Bernemann* , Julie Steinestel*, Verena Humberg*, Martin Bogemann*, € Andres Jan Schrader* and Jochen K. Lennerz†

*Urology, University of Muenster Medical Center, Muenster, Germany, and † Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

Read the full article

Abstract

Objectives

To compare the performance of two established androgen receptor splice variant 7 (AR‐V7) mRNA detection systems, as paradoxical responses to next‐generation androgen‐deprivation therapy in AR‐V7 mRNA‐positive circulating tumour cells (CTC) of patients with castration‐resistant prostate cancer (CRPC) could be related to false‐positive classification using detection systems with different sensitivities.

Materials and Methods

We compared the performance of two established mRNA‐based AR‐V7 detection technologies using either SYBR Green or TaqMan chemistries. We assessed in vitro performance using eight genitourinary cancer cell lines and serial dilutions in three AR‐V7‐positive prostate cancer cell lines using even 2D barcoded tubes as well as in 32 blood samples from patients with CRPC.

Results

Both assays performed identically in the cell lines and serial dilutions showed identical diagnostic thresholds. Performance comparison in 32 clinical patient samples showed perfect concordance between the assays. In particular, both assays determined AR‐V7 mRNA‐positive CTCs in three patients with unexpected responses to next‐generation anti‐androgen therapy. Thus, technical differences between the assays can be excluded as the underlying reason for the unexpected responses to next‐generation anti‐androgen therapy in a subset of AR‐V7 patients.

Conclusions

Irrespective of the method used, patients with AR‐V7 mRNA‐positive CRPC should not be systematically precluded from an otherwise safe treatment option.