Archive for year: 2015

Article of the Week: Complications following artificial urinary sphincter placement after RP and EBRT

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.

Complications following artificial urinary sphincter placement after radical prostatectomy and radiotherapy: A meta-analysis

Anthony S. Bates, Richard M. Martin* and Tim R. Terry

Department of Urology, Leicester General Hospital, University Hospitals of Leicester NHS Trust, Leicester, and *School of Social and Community Medicine, University of Bristol, Bristol, UK

OBJECTIVE

To conduct a systematic review and meta-analysis of artificial urinary sphincter (AUS) placement after radical prostatectomy (RP) and external beam radiotherapy (EBRT).

PATIENTS AND METHODS

There were 1 886 patients available for analysis of surgical revision outcomes and 949 for persistent urinary incontinence (UI) outcomes from 15 and 11 studies, respectively. The mean age (sd) was 66.9 (1.4) years and the number of patients per study was 126.6 (41.7). The mean (sd, range) follow-up was 36.7 (3.9, 18–68) months. A systematic database search was conducted using keywords, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Published series of AUS implantations were retrieved, according to the inclusion criteria. The Newcastle–Ottawa Score was used to ascertain the quality of evidence for each study. Surgical results from each case series were extracted. Data were analysed using CMA® statistical software.

RESULTS

AUS revision was higher in RP + EBRT vs RP alone, with a random effects risk ratio of 1.56 (95% confidence interval [CI] 1.02–2.72; P <0.050; I2 = 82.0%) and a risk difference of 16.0% (95% CI 2.05–36.01; P < 0.080). Infection/erosion contributed to the majority of surgical revision risk compared with urethral atrophy (P = 0.020). Persistent UI after implantation was greater in patients treated with EBRT (P <0.001).

CONCLUSIONS

Men receiving RP + EBRT appear at increased risk of infection/erosion and urethral atrophy, resulting in a greater risk of surgical revision compared with RP alone. Persistent UI is more common with RP + EBRT

 

Editorial: Post-prostatectomy incontinence in the irradiated patient: more than just a drop in the ocean

Improved early detection of prostate cancer has led to an increased incidence of this disease, and an increase in the number of patients undergoing radical prostatectomy (RP). The rate of post-prostatectomy incontinence (PPI) is difficult to determine because of the varying definitions of incontinence, but approximately one in five men require the use of pads in the long term after RP. Incontinence has a significant negative impact on quality of life, and remains many men’s greatest fear, especially for the one in four who present at the age of <65 years. While significant advancements have been made in prostate cancer treatment, strong evidence for the optimum management of PPI remains lacking. Most guidelines are based on grade B or C recommendation and many questions about its surgical management remain unanswered.

The artificial urinary sphincter (AUS) has stood the test of time and has long been considered the ‘gold standard’ treatment for PPI, especially for those with moderate to severe incontinence. The quoted success rates achieved with this device vary from study to study based on the varying definition of ‘dry’. The use of radiotherapy (RT) after prostatectomy is generally considered to have a negative impact on its efficacy and revision rate, although some data have been conflicting. In this month’s BJUI, Bates et al. [1] present a timely and well-structured systematic review and meta-analysis of AUS placement after RP and RT. By analysing pooled results, the authors set out to clarify the effect of RT on AUS efficacy and outcomes. In total, 1886 patients from 15 studies published between 1989 and 2014 were included in the meta-analysis, including 14 studies assessing surgical revision and 11 looking at persistent urinary incontinence. No randomized controlled trials were available for analysis. Retrospective reporting and a lack of standardized postoperative validated assessments were a weakness of individual studies, and efforts to limit the effects of study heterogeneity and risk of bias were made using statistical models. The revision rate after a mean follow-up of 38.4 months was significantly higher in irradiated vs. non-irradiated men (mean 37.3 vs 19.8%; P < 0.007); the risk ratio was 1.56 and number needed to harm was 4 (i.e. one surgical revision for every four AUS devices implanted in irradiated men). Infection/erosion and urethral atrophy accounted for approximately half and one-third of all revisions respectively. Persistent urinary incontinence was also more than twice as likely in irradiated vs non-irradiated men (29.5 vs 12.1%; P = 0.003; risk ratio 2.08, number needed to harm 9).

This study highlights the significant negative impact of RT after RP on functional outcomes and its treatment. This is particularly important considering that approximately one-third of patients will require adjuvant or salvage radiotherapy at some stage after RP. The development of incontinence after RT is primarily attributable to the negative effect of radiation on bladder and urethral tissue. Unlike outcomes with regard to erectile function, the type of primary surgery performed (open vs robotic) does not appear to have any significant impact on PPI [2]. Timing of RT also does not seem to affect function, with similar rates of incontinence reported for early (<6 months after RP) vs late (>6 months after RP) irradiation reported 3 years after RT (24.5 vs 23.3%, respectively; P = 0.79) [3].

New devices, such as the male sling, have increased the options for PPI treatment. Male slings have achieved popularity because of their safety, relative ease of insertion and patients’ strong desire to void naturally without fiddling with pumps. Kumar et al. [4] reported that one in four men who were recommended an AUS as the best option by their surgeon chose a sling; 92% who were offered either also opted against the gold standard AUS. Slings, however, have not fared well in patients with severe incontinence or those who have undergone RT. Pooled analysis of the AdVance® sling reported ‘success’ rates of 56 and 54%, respectively, in these scenarios, compared with a mean overall ‘success’ rate of 75% [5]. Reported success, however, does not equate to being ‘dry’, as reported in many AUS studies, and this lack of uniformity in describing outcomes prevents adequate clarity when comparing different devices. Despite the lower success rate after RT, slings, unlike the AUS, do not appear to have any additional complications in this setting [1, 6], and sling failure does not appear to prejudice subsequent AUS placement [7].

To date, no randomized controlled trial has directly compared efficacy of the newer slings with the AUS. Well-designed trials, with standardized protocols and uniform long-term assessments of outcome, including complications and quality of life, are required to clarify their place in managing PPI. Current randomized controlled trials are evaluating these devices prospectively, and will provide much needed level 1 evidence in this field. The most interesting of these is the MASTER trial (Male synthetic sling vs Artificial urinary Sphincter Trial). This multicentre UK randomized controlled trial is for men with incontinence after prostate surgery for cancer or benign disease [8]. Patients of any age, with any level of incontinence are eligible, and previous RT is not an exclusion criterion. The trial aims to randomize 360 men and will also follow up 360 non-randomized men, and runs until 2019. This trial will help clarify the relative benefits of the devices by incontinence severity. It will also provide some prospective data on the effect of RT on outcomes, although the 2-year follow-up will be too short to evaluate this fully.

The question remains regarding which strategy is the best for post-prostatectomy irradiated patients. Until the results of good quality trials are available, the jury is out. The AUS remains the gold standard in this setting, for now. For patients with mild to moderate incontinence, the sling is an option, and offers some advantages, but offers a lower overall chance of becoming pad free. Patients must be carefully counselled about the risk/benefit of this approach compared with an AUS. Results of the MASTER trial will help better define management of this subgroup. For moderate to severe incontinence, the AUS is the gold standard, albeit with an increased risk of failure and revision. The present meta-analysis arms the clinician with much needed data to quantify the relative risk of complications and adverse outcomes in this setting, and will allow better counselling and management of patient’s expectations.

Majid Shabbir

Department of Urology, Guy’s Hospital, London, UK

References

1 Bates A, Martin R, Terry T. Complications following artificial urinary sphincter placement after radical prostatectomy and radiotherapy: a metaanalysis. BJU Int 2015; 116: 623–33

2 Haglind E, Carlsson S, Stranne J et al. Urinary incontinence and erectile dysfunction after robotic versus open radical prostatectomy: a prospective, controlled, nonrandomised trial. Eur Urol 2015. doi: 10.1016/j.eururo. 2015.02.029. [Epub ahead of print]

3 Sowerby RJ, Gani J, Yim H. Long-term complications in men who have early or late radiotherapy after radical prostatectomy. Can Urol Assoc J 2014; 8: 253–8.

4 Kumar A, Litt ER, Ballert KN, Nitti VW. Artificial urinary sphincter versus male sling for post-prostatectomy incontinence-what do patients choose? J Urol 2009; 181: 1231–5.

5 Van Bruwaene S, Van der Aa F, De Ridder D. Review: the use of sling versus sphincter in post-prostatectomy urinary incontinence. BJU Int 2015; 116: 330–42

6 Zuckerman JM, Tisdale B, McCammon K. AdVance male sling in irradiated patients with stress urinary incontinence. Can J Urol 2011; 18: 6013–7.

7 Lentz AC, Peterson AC, Webster GD. Outcomes following artificial sphincter implantation after prior unsuccessful male sling. J Urol 2012; 187: 2149–53.

8 Abrams P. Male synthetic sling versus Artificial urinary Sphincter Trial for men with urodynamic stress incontinence after prostate surgery: Evaluation by Randomised controlled trial (MASTER), 2014. Available at: www.controlled-trials.com/ISRCTN49212975/MASTER. Accessed May 2015

 

Video: Complications following AUS placement after RP and radiotherapy

Complications following artificial urinary sphincter placement after radical prostatectomy and radiotherapy: a meta-analysis

Anthony S. Bates1,*, Richard M. Martin2 and Tim R. Terry1

1Department of Urology, Leicester General Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK 2School of Social and Community Medicine, University of Bristol, Bristol, UK

Read the full article
Objective

To conduct a systematic review and meta-analysis of artificial urinary sphincter (AUS) placement after radical prostatectomy (RP) and external beam radiotherapy (EBRT).

Patients and Methods

There were 1 886 patients available for analysis of surgical revision outcomes and 949 for persistent urinary incontinence (UI) outcomes from 15 and 11 studies, respectively. The mean age (sd) was 66.9 (1.4) years and the number of patients per study was 126.6 (41.7). The mean (sd, range) follow-up was 36.7 (3.9, 18–68) months. A systematic database search was conducted using keywords, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Published series of AUS implantations were retrieved, according to the inclusion criteria. The Newcastle–Ottawa Score was used to ascertain the quality of evidence for each study. Surgical results from each case series were extracted. Data were analysed using CMA® statistical software.

Results

AUS revision was higher in RP + EBRT vs RP alone, with a random effects risk ratio of 1.56 (95% confidence interval [CI] 1.02–2.72; P < 0.050; I2 = 82.0%) and a risk difference of 16.0% (95% CI 2.05–36.01; P < 0.080). Infection/erosion contributed to the majority of surgical revision risk compared with urethral atrophy (P = 0.020). Persistent UI after implantation was greater in patients treated with EBRT (P < 0.001).

Conclusions

Men receiving RP + EBRT appear at increased risk of infection/erosion and urethral atrophy, resulting in a greater risk of surgical revision compared with RP alone. Persistent UI is more common with RP + EBRT.

 

Abandoning PSA screening: What is an acceptable price to pay?

MoonThe PSA screening debate continues to rage with conflicting advice from various bodies as to appropriate guidelines for men considering prostate cancer screening. In Australia the Urological Society of Australia and New Zealand (USANZ) has supported offering screening to men aged 55-69 [Urological Society of Australia and New Zealand Position Statement on PSA testing 2009], as has the Royal Australasian College of Pathologists [Royal College of Pathologists Australia Position Statement on PSA testing 2014], however the guidelines for General Practitioners is yet to endorse this approach.   A consensus group gathered by the Cancer Council of Australia, including Urologists, Oncologists, Epidemiologists and consumer advocates have recently put together proposals being considered by the NHMRC that recommend screening in men of an appropriate age with >7 year life expectancy, as long as active surveillance is offered to those diagnosed with low risk disease [Cancer Council Australia: Draft Clinical Practice Guideline PSA Testing and Early Management of Test-Detected Prostate Cancer]. The US Preventative Service Task Force Grade D recommendation against screening has been well documented, yet widely criticized for failing to include Urologists in its deliberations – the very specialists tasked with evaluating and treating localized prostate cancer.

Screening trials have reported conflicting results [Schroder et al, Pinsky et al], however with longer follow-up it becomes easier to demonstrate a survival advantage in men who are screened, and this does not even directly take into account the reduction in morbidity from advanced disease in populations as a result of early detection.

The issue at hand seems inherently very simple – that mass PSA screening will inevitably lead to overdiagnosis and, if a conservative approach is not adopted in low-risk disease or men with significant co-morbidities, overtreatment. Since PSA testing was introduced, the natural history of prostate cancer has become better understood [Albertsen], along with the understanding that many men with prostate cancer harbor “clinically insignificant” disease. Urologists have recognized this internationally and developed active surveillance protocols in response [Kates et al, Klotz]. Here in Australia the Victorian prostate cancer registry now confirms a significant number of men with low-risk disease being managed conservatively [Evans].

In the meantime, however, the pendulum is swinging the other way, and on the back of the USPSTF recommendations we are now seeing evidence of a drop in PSA screening.   Confusing the debate is the extrapolation of negative studies to men of an entirely different population (e.g. using the Prostate Cancer Intervention vs Observation Trial [PIVOT], which comprised an average age of 67 to conclude that men in their 50s will not benefit from screening), poor design of the reported screening trials (e.g. the PLCO trial, which formed the backbone of USPSTF recommendations but due to compliance/contamination compared a population of 52% screened vs 85% screened), and the accusations of vested interests, particularly when Urologists take a pro-screening position (just read comment section on BJUI 2013 report of “Melbourne consensus statement on prostate cancer testing”)

What is the end result at a population level? In Victoria, Cancer Council data confirm a drop in prostate cancer screening and diagnosis [FIGURE]. There is no reason to believe that true prostate cancer incidence has suddenly declined, and we can conclude therefore that the negative publicity surrounding PSA screening is having an impact and less men are undertaking screening and diagnosis; a reversal of the jump in incidence that occurred when PSA testing was first introduced.   Is this a bad thing though? Could this just be that we are finally reducing the diagnosis of clinically irrelevant cancers that are the bane of a PSA screening programme?

 

MoonFig1
Trends in prostate cancer incidence and PSA testing rates, 2001-2014

Source: Cancer in Victoria: Statistics and Trends 2014. Cancer Council Victoria

 

My disclosure is that as a Urologist with a subspecialty practice in prostate cancer management, I deal at a personal level with patients, rather than population statistics, and in the last few months alone, multiple patients have highlighted for me the sacrifice we must admit to making if we are to abandon or even discourage PSA testing. A few specific cases are worth sharing as scenarios that GPs could consider including in the risk/benefit discussion required before ordering a PSA test.

Case 1:
64-year-old, well man with no relevant past/family history was referred with a rising PSA from 3.9μg/L in 2010 to 6.6μg/L in 2011. No abnormality was found on rectal examination and a biopsy was advised but refused given contemporary publicity in the lay press outlining the risk of biopsy and harms of overdiagnosis/overtreatment. Over the next 5 years the patient undertook various natural remedies and in 2014 when the PSA was 13.3μg/L, an MRI was performed that demonstrated a PIRADS 4 lesion. It was only until 2015 when the PSA had reached 21.9μg/L that a biopsy demonstrated a significant volume of Gleason 9 adenocarcinoma, with pelvic lymphadenopathy on staging.

Case 2:
A 57-year-old man requested PSA screening in 2013; however, he was advised by his local doctor that this was unnecessary based on current guidelines. In 2015 the patient’s brother was diagnosed elsewhere with prostate cancer and underwent radical prostatectomy. The patient then demanded a PSA, which was performed and found to be 40μg/L. Rectal examination revealed a firm, clinical stage T3 malignancy and biopsy demonstrated extensive Gleason 4+4 prostate cancer.

Case 3:
A 51-year-old man was found in 2010 to have a mildly elevated screening PSA of 4.5μg/L. Despite repeated recalls from the GP to have this repeated and further investigated the patient refused until in 2015 he presented with obstructive voiding symptoms and was found on examination to have a diffusely firm, clinical stage T3 malignant prostate. Repeat PSA was 39μg/L and subsequent investigation confirmed extensive Gleason 9 prostate cancer with positive pelvic lymph nodes.

For these men curative treatment is probably no longer an option. Whilst a small anecdotal group, these are real men seen at a community level who demonstrate the power of PSA screening to identify aggressive, clinically significant disease, at an early, curable stage. This is the coalface that General Practitioners and Urologists work at. When the USPSTF ratifies the Grade D recommendations on the basis of flawed and often misinterpreted trials in the absence of specialists who treat such patients, when Epidemiologists and well-meaning Oncologists who never see or evaluate localized prostate cancer lobby against the harms of overdiagnosis and overtreatment, they are condemning these men, and many others, to suffer and die from a preventable disease.

This risk of increased advanced cancer in a non-screened population has already been foreseen and reported [Scosyrev]. How many such men is it acceptable to sacrifice in the name of preventing overdiagnosis and overtreatment?

Rather than the knee-jerk response to abandon PSA testing, the answer, which is increasingly accepted by Urologists, is clearly to unlink prostate cancer diagnosis from treatment. It is to improve diagnostics as we are seeing with development of multiparametric MRI and molecular/genetic markers to make screening and treatment selection smarter. I fear that if this is not more widely accepted and the current situation continues, it is helpful that so much research is being conducted in the management of men with high-risk, oligometastatic and advanced disease, because it will be more and more of these cancers that we will be treating.

 

Dr Daniel Moon is Director of Robotic Surgery at the Epworth Healthcare, and a Urologist at the Peter MacCallum Cancer Institute, Melbourne
@drdanielmoon

 

 

 

What’s the Diagnosis?

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This gentleman presented with symptoms of bladder outflow obstruction.

Test yourself against our experts with our weekly quiz. You can type your answers here if you want to compare with our answers.

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Article of the Week: A phase I study of TRC105 anti-CD105 (endoglin) antibody in mCRPC

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.

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 from Dr. Jon Rees discussing his paper. 

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

A phase I study of TRC105 anti-CD105 (endoglin) antibody in metastatic castration-resistant prostate cancer

Fatima H. Karzai, Andrea B. Apolo, Liang Cao, Ravi A. Madan, David E. AdelbergHoward Parnes, David G. McLeod, Nancy Harold, Cody Peer, Yunkai Yu, Yusuke Tomita,,Min-Jung Lee, Sunmin Lee, Jane B. Trepel, James L. Gulley, William D. Figg and William L. Dahut

 

Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA

 

Read the full article
OBJECTIVE

TRC105 is a chimeric immunoglobulin G1 monoclonal antibody that binds endoglin (CD105). This phase I open-label study evaluated the safety, pharmacokinetics and pharmacodynamics of TRC105 in patients with metastatic castration-resistant prostate cancer (mCRPC).

PATIENTS AND METHODS

Patients with mCRPC received escalating doses of i.v. TRC105 until unacceptable toxicity or disease progression, up to a predetermined dose level, using a standard 3 + 3 phase I design.

RESULTS

A total of 20 patients were treated. The top dose level studied, 20 mg/kg every 2 weeks, was the maximum tolerated dose. Common adverse effects included infusion-related reaction (90%), low grade headache (67%), anaemia (48%), epistaxis (43%) and fever (43%). Ten patients had stable disease on study and eight patients had declines in prostate specific antigen (PSA). Significant plasma CD105 reduction was observed at the higher dose levels. In an exploratory analysis, vascular endothelial growth factor (VEGF) was increased after treatment with TRC105 and VEGF levels were associated with CD105 reduction.

CONCLUSION

TRC105 was tolerated at 20 mg/kg every other week with a safety profile distinct from that of VEGF inhibitors. A significant induction of plasma VEGF was associated with CD105 reduction, suggesting anti-angiogenic activity of TRC105. An exploratory analysis showed a tentative correlation between the reduction of CD105 and a decrease in PSA velocity, suggestive of potential activity of TRC105 in the patients with mCRPC. The data from this exploratory analysis suggest that rising VEGF level is a possible compensatory mechanism for TRC105-induced anti-angiogenic activity.

Editorial: Is angiogenesis still an attractive target in metastatic castration-resistant prostate cancer?

In this issue of BJU International, Karzai et al. [1] report the results of a phase I study of the anti-endoglin antibody TRC105 in patients with metastatic castration-resistant prostate cancer (mCRPC). This is a new anti-angiogenic compound with a unique mechanism of action.

Since the introduction of the concept of angiogenesis as a requirement for tumour growth and survival of solid cancers, a substantial body of research has emerged, establishing inhibition of angiogenic pathways as an important part of the armamentarium in several tumour types [2]. The idea of dynamic tumour angiogenic factors that are able to mediate neovascularisation has also been associated with tumour growth, progression and metastases in prostate cancer [1].

Some studies have revealed that microvessel density, a histological measurement of tumour angiogenesis assessed by immunohistochemical CD105 (endoglin), correlates with higher Gleason score and may predict disease progression, as well as poorer survival outcomes in patients with mCRPC. Accordingly, angiogenesis is considered an attractive target for therapeutic intervention in this disease and anti-angiogenic strategies have been studied in several clinical settings. Unfortunately, well established anti-angiogenic therapies have failed to improve survival outcomes in advanced prostate cancer. Bevacizumab or afilbercept, both combined with docetaxel, were evaluated in phase III clinical trials and no survival benefit was observed over docetaxel alone. Similarly, sunitinib was no better than placebo after chemotherapy treatment. Moreover, the recent COMET-1 trial failed to show survival benefit with cabozantinib, a dual vascular endothelial growth factor (VEGF) and MET inhibitor, in patients with mCRPC and, as a consequence, enrolment in other studies evaluating this agent has been discontinued. Strikingly, although no survival benefit has been reported, progression-free survival benefit has been observed in all of these trials.

Other anti-angionenic therapies have been investigated in patients with mCRPC. A phase II study combining thalidomide and bevacizumab with docetaxel plus prednisone showed that this is an active combination in this subset of patients. Unfortunately, the combination resulted in significant neurotoxicity and myelotoxicity, limiting its clinical use [3]. Lenalidomide was developed to have a more favourable toxicity profile compared with thalidomide and has shown activity as a single agent in patients with non-metastatic, biochemically-relapsed prostate cancer. Again, the large randomised phase III trial comparing docetaxel plus lenalidomide vs docetaxel plus placebo failed to show improvement in overall survival with the addition of this agent [4]. Finally, tasquinimod, another compound targeting angiogenesis, is under evaluation and the final results have not yet been reported. A phase III placebo-controlled study (NCT01234311), designed based on promising phase II data, is ongoing in men with mCRPC with bone metastases and is powered to detect an improvement in overall survival.

Overall, limited activity have been reported with the available agents and, until the results of the tasquinimod trial become available, additional investigations with better-targeted therapies and tools for patient selection are needed to define how this class of agents can improve survival outcome in mCRPC. In this setting, CD105 (endoglin), a homodimeric cell membrane glycoprotein that was initially identified as a human leukaemia-associated antigen, and later also found on endothelial cells, might serve as a reasonable reference point to continue research in this direction. CD105 is a TGFβ co-receptor that is essential for angiogenesis and is selectively expressed on proliferating endothelial cells of tumour vessels. All these properties make CD105 an attractive target for drug development, as targeting the vasculature of the tumour may be more effective than conventional anti-angiogenic therapy, such as anti-VEGF therapy [5].

TRC105, an antibody to CD105, caused a overall reduction in angiogenic biomarkers and reduced tumour burden in a phase I study of advanced solid tumours at doses that were well tolerated. Karzai et al. [1] report the results of a phase I study of TRC105 in patients with mCRPC. This study was designed to define the maximum tolerated dose and to access the safety and tumour activity of TRC105 in a small cohort of patients with mCRPC. Of note, given that TRC105 has a unique mechanism of action, the toxicity profile was not similar with those commonly associated with VEGF inhibition and, at 20 mg/kg, the drug was well tolerated. Although evaluating a small number of patients, the tumour activity of this agent seems to be similar to that of the other anti-angiogenic therapies, and the potential benefit will most likely be seen when combined with other therapies. In addition, exploratory analyses have identified changes in plasma VEGF and CD105 staining on endothelial cells of tumour vessels after treatment with TRC105. These findings suggest that higher levels of VEGF are a possible compensatory mechanism for TRC105-induced anti-angiogenic activity, providing a rationale for TRC105 combination with other anti-VEGF therapies.

It has been hypothesised that endoglin-expressing vessels resist treatment, with antibody targeting the VEGF receptor by allowing continued growth of human tumour xenografts. Therefore, combining anti-angiogenic strategies with agents having different mechanisms of action may be an option to overcome resistance and produce anti-tumour responses [6]. Results from the combination of TRC105 with axitinib in patients with metastatic RCC may support this concept and are now under evaluation (NCT01806064).

Over the last 5 years, treatment of mCRPC has evolved rapidly. Immunotherapy agents (sipuleucel-T), androgen inhibitors (abiraterone acetate and enzalutamide), radioisotope (Radium-223) and cytotoxic chemotherapy (cabazitaxel) have been shown to improve overall survival in randomised phase III clinical trials. However, despite these recent advances, disease progression remains a major cause of morbidity and mortality and new therapies or combinations are required to improve patient care offering them a higher chance of achieving long-term survival.

Anti-angiogenic agents are active in certain settings of prostate cancer and some significant responses have been reported. However, a deeper understanding of the biology of mCRPC is required to characterise the complex angiogenic pathways and to elucidate mechanisms of resistance to this class of agents. This, together with the development of biomarkers to predict responses to anti-angiogenic therapies, might assist in guiding novel treatment combinations and optimising clinical benefit based on patient selection.

Read the full article

 

Andre P. Fay*† and Joaquim Bellmunt*

 

*DanaFarber Cancer Institute, Harvard Medical SchoolBoston, MA, USA, Faculdade de Medicina, Pontifıcia Universidade Catolica do Rio Grande do Sul, Porto AlegreBrazil and University Hospital del Mar, IMIM, Barcelona, Spain

 

References

 

 

Video: A phase I study of TRC105 anti-CD105 (endoglin) antibody in mCRPC

A phase I study of TRC105 anti-CD105 (endoglin) antibody in metastatic castration-resistant prostate cancer

Fatima H. Karzai, Andrea B. Apolo, Liang Cao, Ravi A. Madan, David E. AdelbergHoward Parnes, David G. McLeod, Nancy Harold, Cody Peer, Yunkai Yu, Yusuke Tomita,,Min-Jung Lee, Sunmin Lee, Jane B. Trepel, James L. Gulley, William D. Figg and William L. Dahut

 

Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA

 

Read the full article
OBJECTIVE

TRC105 is a chimeric immunoglobulin G1 monoclonal antibody that binds endoglin (CD105). This phase I open-label study evaluated the safety, pharmacokinetics and pharmacodynamics of TRC105 in patients with metastatic castration-resistant prostate cancer (mCRPC).

PATIENTS AND METHODS

Patients with mCRPC received escalating doses of i.v. TRC105 until unacceptable toxicity or disease progression, up to a predetermined dose level, using a standard 3 + 3 phase I design.

RESULTS

A total of 20 patients were treated. The top dose level studied, 20 mg/kg every 2 weeks, was the maximum tolerated dose. Common adverse effects included infusion-related reaction (90%), low grade headache (67%), anaemia (48%), epistaxis (43%) and fever (43%). Ten patients had stable disease on study and eight patients had declines in prostate specific antigen (PSA). Significant plasma CD105 reduction was observed at the higher dose levels. In an exploratory analysis, vascular endothelial growth factor (VEGF) was increased after treatment with TRC105 and VEGF levels were associated with CD105 reduction.

CONCLUSION

TRC105 was tolerated at 20 mg/kg every other week with a safety profile distinct from that of VEGF inhibitors. A significant induction of plasma VEGF was associated with CD105 reduction, suggesting anti-angiogenic activity of TRC105. An exploratory analysis showed a tentative correlation between the reduction of CD105 and a decrease in PSA velocity, suggestive of potential activity of TRC105 in the patients with mCRPC. The data from this exploratory analysis suggest that rising VEGF level is a possible compensatory mechanism for TRC105-induced anti-angiogenic activity.

Guideline of guidelines: urinary incontinence

Urinary Incontinence Guideliens

 

Abstract

The objective of the article is to review key guidelines on the management of urinary incontinence (UI) to guide clinical management in a practical way. Guidelines produced by the European Association of Urology (updated in 2014), the Canadian Urological Association (updated in 2012), the International Consultation on Incontinence (updated in 2012), and the National Collaborating Centre for Women’s and Children’s Health (updated in 2013) were examined and their recommendations compared. In addition, specialised guidelines produced by the collaboration between the American Urological Association and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction on overactive bladder and the use of urodynamics were reviewed. The Appraisal of Guidelines for Research and Evaluation II (AGREE) instrument was used to evaluate the quality of these guidelines. There is general agreement between the groups on the recommended initial evaluation and the use of conservative therapies for first-line treatment, with a limited role for imaging or invasive testing in the uncomplicated patient. These groups have greater variability in their recommendations for invasive procedures; however, generally the mid-urethral sling is recommended for uncomplicated stress UI, with different recommendations on the approach, as well as the comparability to other treatments, such as the autologous fascial sling. This ‘Guideline of Guidelines’ provides a summary of the salient similarities and differences between prominent groups on the management of UI.

Urinary Incontinence key points

Access the full article

Guideline of Guidelines: Imaging of Localized Prostate Cancer

Guidelines Localised Prostate Cacner

 

Introduction

In the era before the widespread adoption of PSA screening for prostate cancer, most incident cases were already advanced stage. Because treatment options, such as surgery or radiation, are thought mainly to benefit patients with localised disease, prostate cancer imaging was necessary before treatment of almost all patients. However, in the PSA era >90% of incident cases are localised, making the need for routine imaging with CT, MRI, or bone scan obsolete [1]. Numerous studies show a relatively low rate of positive staging imaging in low- and intermediate-risk patients. Recognising these trends, several professional societies issued prostate cancer imaging guidelines in the mid-1990s in an effort to curb the overuse of imaging. However, despite these longstanding guidelines, a great number of patients undergo improper imaging [2]. Given how stubborn this problem has been to eradicate, there has been a renewed interest in finding ways to decrease unnecessary imaging, including a Physician Quality Reporting System (PQRS) quality measure and a highlighting of the problem in the ‘Choosing Wisely’ campaign [3-5]. In addition to the guidelines regarding the staging of incident prostate cancer, some groups have also presented guidelines on the use of imaging to follow men with advanced disease [6]. The purpose of the present article is to summarise the main points from multiple professional society guidelines on imaging in prostate cancer to help clarify when patients with prostate cancer should be imaged and with which modalities.

Prostate Cancer Key Points

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