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Editorial: What is behind the flare phenomenon?

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In the present issue of BJUI, Shiota et al. [1] propose a potential explanation for the PSA ‘flare’ observed in many patients as they initiate docetaxel chemotherapy. The PSA flare or ‘surge’ phenomenon has been noted for years, and may affect up to one-fifth of patients treated with docetaxel. Multiple reviews have concluded that the development of flare does not influence disease-specific outcomes [2, 3], which is further supported by the present paper [1]. However, there are no pragmatic analyses of how this flare is interpreted in real-world practice. As treatment of prostate cancer becomes more complex, and definitions of progression on treatment continue to evolve, practitioners must be aware of this laboratory pattern to avoid unnecessary discontinuation of therapy based on early PSA change alone.

The cause of such flare has only been postulated. Many suggest that it could be caused by PSA release from lysed cells or by aberrant androgen receptor (AR) activation, but other theories are also proposed. The present paper supports the hypothesis that transactivation of the AR by corticosteroids contributes to the flare. Further translational work may provide additional insight into this mechanism, but we have long discussed the influence of steroid administration on the AR. Similar flare phenomena have been observed with cabazitaxel [4] and abiraterone acetate, two regimens that are reliant on concomitant steroid use. Interestingly, patients in the present cohort treated with steroids before treatment initiation had less flare. This is a unique observation in that steroid activation may occur, but at an earlier time point, mitigating the coincidental rise when starting chemotherapy. Just as one must be aware of the existence of flare to avoid premature abandonment of a regimen, perhaps we now must take into account previous steroid use and interpret a PSA rise slightly differently. The present work is certainly hypothesis-generating and larger series may offer additional insight.

Recent data have shown significant survival gains using docetaxel in the hormone-sensitive metastatic setting, in which patients received chemotherapy without daily prednisone use [5]. Practitioners may find themselves managing patients on docetaxel chemotherapy who may or may not be taking corticosteroids. These recent data will probably also contribute to a ‘resurgence’ of sorts in the use of chemotherapy, and remembrance of the flare is important. We may find ourselves interpreting PSA flare in multiple steps: we will assess the agent (i.e. a taxane) and the use of prednisone (i.e. present prior to treatment or initiated at the start) and then interpret the results accordingly. The work of Shiota et al. in this observational study continues to highlight the flare phenomenon and the fact that the use of steroids before, or during, chemotherapy may further complicate our approach to the care of patients on chemotherapy. The field is moving forward and, as we work to understand the intricacies of PSA response, we also create more and more reliance on providers to really marry the art and science of medicine.

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Elizabeth R. Kessler

 

Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

 

References

 

1 Shiota M, Yokomizo A, Takeuchi A et al. Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare. BJU Int 2016; 118: 880–4

 

2 Sella A, Sternberg CN, Skoneczna I, Kovel S. Prostate-specific antigen flare phenomenon with docetaxel-based chemotherapy in patients with androgen-independent prostate cancer. BJU Int 2008; 102: 1607–9

 

3 Nelius T, Klatte T, de Riese W, Filleur S. Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy. Int Urol Nephrol 2008; 40: 97–104

 

4 Angelergues A, Maillet D, Flechon A et al. Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer. Eur J Cancer 2014; 50: 1602–9

 

5 Sweeney CJ, Chen YH, Carducci M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737–46

 

Editorial: ‘Killing Two Birds With One Stone’ – PROMS from the ProtecT Trial

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Very few areas of medicine generate more controversy than the management of clinically localised prostate cancer. This is in large part due to the somewhat conflicting nature of the scant level I evidence that exists on the subject. Whereas the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) demonstrated a clinically meaningful and durable survival advantage for surgery when compared to watchful waiting in a predominantly White Scandinavian population of patients with clinically palpable yet localised prostate cancer [1], the Radical Prostatectomy Versus Observation for Localized Prostate Cancer (PIVOT) trial reported a mostly null effect of surgery in a predominantly older, less healthy population of American patients with clinically indolent disease [2]. Neither trial addresses the effect of radiotherapy on prostate cancer survival and both may lack relevance in contemporary prostate cancer practice.

For these reasons and a myriad of others, the medical community eagerly awaits the results of the Prostate Testing for Cancer and Treatment (ProtecT) trial [3]. With a fastidiously designed protocol that involves 337 primary care centres across nine cities in the UK, the use of dedicated study nurses, the successful enrolment of pre-specified sample size targets, and the inclusion of patient-reported quality-of-life measures, the ProtecT trial is poised to make enormous inroads for men with prostate cancer and the providers who care for them.

In this issue of the BJUI, the investigators from the ProtecT trial publish baseline patient-reported outcome measures (PROMs) from the ProtecT trial [4]. While others have previously reported baseline PROMs in large comparative effectiveness studies [5], the findings from this study are notable for several reasons. First, this is the first randomised trial comparing the effect of surgery, radiation, and active monitoring on PROMs. While several high-quality prospective observational cohort studies have reported long-term quality-of-life outcomes after prostate cancer treatment [6, 7], ProtecT will offer randomised comparisons that minimise confounding and selection bias from the outset. Second, the ProtecT trial will not only measure disease-specific health-related quality of life through the use of psychometrically validated survey instruments, such as the Expanded Prostate Index Composite, but also general health-related quality of life through the use of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C-30 (as well as depression and anxiety through the use of the Hospital Anxiety and Depression Scale). Finally, and perhaps most importantly, the investigators collected baseline PROMs at the time of the first biopsy before cancer diagnosis, which will offer distinct advantages when modelling patient-reported function over time, as well as avoiding recall bias associated with retrospective collection of baseline patient-reported outcomes.

In the absence of the long-term survival data from randomised trials comparing surgery and radiation, previous studies have rightly focused on understanding how the effect of prostate cancer treatments differ with respect to PROMs. With the ProtecT trial, we will not only start to have answers to longstanding questions about how surgery, radiation and active surveillance compare with respect to clinical outcomes, such as survival and cancer control, but also with respect to PROMs. By addressing both of these domains, the ProtecT investigators are in position to ‘kill two birds with one stone’ and in so doing will undoubtedly make large strides in facilitating data-driven decision-making for patients with prostate cancer worldwide.

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Mark D. Tyson* and David F. Penson*,†,‡

 

Departments of *Urologic Surgery and †Health Policy, Vanderbilt University Medical Center, and‡ Geriatric, Research, and Educational Center, Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA

 

References

 

1 Bill-Axelson A, Holmberg L, Garmo H et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014; 370: 932–42

 

2 Wilt TJ, Brawer MK, Jones KM et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203–13

 

3 Lane JA, Donovan JL, Davis M et al. Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol 2014; 15: 1109–18

 

4 Lane A, Metcalfe C, Young GJ et al. Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life. BJU Int 2016; 118: 869–79

 

5 Resnick MJ, Barocas DA, Morgans AK et al. Contemporary prevalence of pretreatment urinary, sexual, hormonal, and bowel dysfunction: defining the population at risk for harms of prostate cancer treatment. Cancer 2014; 120: 1263–71

 

6 Sanda MG, Dunn RL, Michalski J et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008; 358: 1250–61

 

7 Resnick MJ, Koyama T, Fan KH et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 2013; 368: 436–45

 

Editorial: PCA3 assay in the MRI/US fusion TBx era: a future to believe in

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Men with persistently elevated serum PSA levels after a negative first TRUS-guided systematic prostate biopsy (SBx) represent a great diagnostic challenge. To meet this challenge, urologists need new imaging methods and biomarkers for use in daily clinical practice. The study by De Luca et al. [1] in the present issue of BJUI contributes further data to a growing body of literature addressing the role of prostate cancer gene 3 (PCA3) score and MRI/ultrasonography fusion-targeted prostate biopsy (TBx) in the detection of prostate cancer (PCa) in men who had undergone a previous negative SBx.

De Luca et al. retrospectively analysed data from 282 men undergoing a TBx after a previous negative SBx and PCA3 urine assay for an ongoing suspicion of PCa. They found that the PCA3 score was significantly higher in patients with a positive TBx as compared to those with a negative TBx (121 vs 56; P < 0.001). Futhermore, PCA3 was significantly associated with Prostate Imaging Reporting and Data System (PI-RADS) group (The median PCA3 scores for PI-RADS groups 3, 4 and 5 were 58, 104 and 146, respectively; P = 0.006). Similarly, an increasing PCA3 score was associated with a worse Gleason score (GS) after TBx. These findings are not necessarily novel, but rather are consistent with some of the previous literature [2, 3]. Conversely, Kaufmann et al. [4] did not find any association between PCA3 score and either PI-RADS group or GS. Importantly from a clinical perspective, the authors of the present study observed a statistically significant association between PCA3 score and the ‘indeterminate’ PI-RADS grade III subgroup, thus allowing for the possibility that the combined use of these two diagnostic tools could prevent unnecessary biopsies.

Prostate biopsies are associated with discomfort, anxiety and severe complications. Repeated SBx also results in a greater economic cost and has been associated with overall low PCa detection rates (being negative in almost 80% of examined men). The recent literature has therefore focused on additional tests with the goal of preventing unnecessary biopsies and increasing the probability of detecting PCa during a repeat biopsy. Since its introduction in clinical practice, the urinary PCA3 assay has shown promising results for PCa detection, staging and prognosis; however, recent studies have shown high variability in PCA3 sensitivity and specificity, which can be explained by the low diagnostic performance of SBx in detecting PCa. MRI-guided TBx has shown higher detection rates than SBx and thus could be of clinical utility in improving PCA3 prognostic accuracy in detecting PCa in men with previous negative SBx. De Luca et al. [1], using a univariate logistic regression model to estimate the effect of PCA3 score on TBx results, found that a 1-unit increase in PCA3 score was associated with a 2.4% increase in the odds of having a positive TBx result (odds ratio [OR] 1.024; P < 0.001). The accuracy of this model was 76.2%, with a sensitivity of 82.3% and specificity of 68.5%. A multivariate logistic regression model showed that PI-RADS group ≥4 (OR 10.85) and a PCA3 score >80 (OR 7.17) were independent risk factors for a positive TBx (all P < 0.001). The authors concluded that TBx improved the diagnostic and prognostic performance of the PCA3 score for PCa. Importantly, considering only the ‘indeterminate’ PI-RADS grade III subgroup, a 1-unit increase in PCA3 score was associated with a 2.2% increase in the odds of having a positive TBx (OR 1.022; P < 0.001). These findings are consistent with recent literature showing that the use of multiparametric (mp)MRI to direct biopsies can significantly improve PCA3 score sensitivity [5]. Similarly, Busetto et al. [2] estimated the sensitivity and specificity for PCA3 test and mpMRI to be 68 and 49%, and 74 and 90%, respectively, for cancer detection after an initial negative biopsy, and concluded that mpMRI increased PCA3 score test accuracy.

Repeated prostate biopsy strategies for the suspicion of PCa remain one of the most controversial dilemmas in urology. The results of the present trial help strengthen the evidence in favour of the diagnostic role of the PCA3 score, which could aid the selection of patients for mpMRI. Large prospective trials are needed to confirm the association between PCA3, PI-RADS group and GS in men with PCa. Interestingly, De Luca et al. believe that PCA3 score could be part of a ‘fusion-biopsy era’ in the not-so-distant future. Should the positive correlation between PCA3 and GS be confirmed, PCA3 could have a role in the selection of candidates for active surveillance, and in predicting disease progression during active surveillance follow-up.

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Bernardo Rocco*† and Luca Boeri*

 

*Department of Urology, University of Milan Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Milan, Italy and †Urology, Global Robotics Institute, Florida Hospital Celebration Health, Celebration, FL, USA

 

References

 

1 De Luca S, Passera R, Cattaneo G et al. High prostate cancer gene 3 (PCA3) scores are associated with elevated Prostate Imaging Reporting and Data System (PI-RADS) grade and biopsy Gleason Score, at magnetic resonance imaging/ultrasonography fusion software-based targeted prostate biopsy after a previous negative standard biopsy. BJU Int 2016; 118: 723–30

 

2 Busetto GM, De Berardinis E, Sciarra A et al. Prostate cancer gene 3 and multiparametric magnetic resonance can reduce unnecessary biopsies: decision curve analysis to evaluate predictive models. Urology 2013; 82: 1355–60

 

3 De Luca S, Passera R, Bollito E et al. Biopsy and radical prostatectomy pathological patterns influence Prostate cancer gene 3 (PCA3) score. Anticancer Res 2013; 33: 4657–62

 

4 Kaufmann S, Bedke J, Gatidis S et al. Prostate cancer gene 3 (PCA3) is of additional predictive value in patients with PI-RADS grade III (intermediate) lesions in the MR-guided re-biopsy setting for prostate cancer. World J Urol 2016; 34: 509–15

 

5 Sciarra A, Panebianco V, Cattarino S et al. Multiparametric magnetic resonance imaging of the prostate can improve the predictive value of the urinary prostate cancer antigen 3 test in patients with elevated prostate- specific antigen levels and a previous negative biopsy. BJU Int 2012; 110: 1661–5

 

Editorial: RC & VTE – Are We Doing Enough?

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Using a large comprehensive population-based cohort from Canada, Doiron et al. [1] present an in-depth analysis of risk factors and timing of venous thromboembolism (VTE) after radical cystectomy (RC) for bladder cancer. This report reiterates what is already known, which is that VTE after RC occurs at a non-negligible rate (5.4%) and most VTEs occur after hospital discharge (55%). VTE is an established complication in patients undergoing major oncological surgery, with some guidelines recommending 4 weeks of VTE prophylaxis after major pelvic surgery. This significant incidence of VTE after discharge highlights the potential impact of extended VTE prophylaxis for up to 28 days. Level I evidence for such practice was published more than a decade ago [2]. Yet, the uptake of these data remains low, at least in urological oncology. A recent survey-based study of pelvic cancer centres from the UK showed that only two-thirds of centres use post-discharge prophylaxis [3]. Using highly granular data, Doiron et al. [1] provide a detailed timeline of VTE occurrence after RC. They found that among patients who were diagnosed with VTE after discharge, >60% of these events occurred at ≤4 weeks of discharge. Unfortunately, there were no data on whether VTE prophylaxis was used in the study population.

The authors identified greater surgeon volume and increased length of hospital stay as risk factors for postoperative VTE, while accounting for important disease-related covariates. As mentioned by the authors, surgeon volume is most likely a surrogate for another unmeasured confounder. Higher volume surgeons, who often practice in large/academic institutions, may have increased case complexity with patients at higher risk for VTE. Additionally, such institutions may be more prone to perform diagnostic testing in high-risk patients and identify VTEs that would have otherwise gone unnoticed. A report from France found that the rate of VTE after RC was 24% in a cohort of patients who all underwent complete lower limb ultrasound, yet the vast majority (92%) were asymptomatic [4]. In other words, if you are looking for a VTE, you are more likely to find one. However, the clinical relevance of these VTEs remains unclear.

As shown from prior studies, length of stay was also found to be a risk factor for VTEs. Why does an increase in length of stay lead to a higher rate of VTE? One explanation is that patients who stay in the hospital longer are more likely to be immobilised for longer. This may explain why patients undergoing RC have higher rates of VTE than those undergoing other urological oncology procedures. However, immobilisation is a difficult variable to define or to measure. If longer immobilisation leads to increased VTE incidence, recently implemented enhanced recovery after surgery (ERAS) protocols that lead to earlier mobilisation would be expected to be associated with fewer VTEs. It is important to mention that other previously associated factors with VTE, including operative time and body mass index, which may be related to immobilisation time are not recorded in this study.

The use of neoadjuvant chemotherapy (NACT) for muscle-invasive bladder cancer has been shown to improve overall survival and is being increasingly used in RC patients. This study examined NACT as a risk factor but did not find an association. Notably, they were limited by the few patients who had received NACT. The use of chemotherapy in patients with cancer is a well-recognised risk factor for VTE [5]. It will be important in the future to continue to examine the incidence of VTE in NACT patients as this population grows.

Taken together, patients undergoing major cancer surgery have a significant risk of postoperative VTE, with evidence showing that rates of VTE are increasing over time [6]. Although guidelines for VTE prophylaxis are not uniform, this study’s findings [1] that most VTEs occur after discharge is a reason for urological surgeons to strongly consider extended VTE prophylaxis in this high-risk population.

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Nawar Hanna and Jacqueline M. Speed

 

Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

 

References

 

1 Doiron RC, Booth CM, Wei X, Siemens DR. Risk factors and timing of venous thromboembolism after radical cystectomy in routine clinical practice: a population-based study. BJU Int 2016; 118: 714–22

 

2 Bergqvist D, Agnelli G, Cohen AT et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002; 346: 975–80

 

3 Pridgeon S, Allchorne P, Turner B, Peters J, Green J. Venous thromboembolism (VTE) prophylaxis and urological pelvic cancer surgery: a UK national audit. BJU Int 2015; 115: 223–9

 

4 Clement C, Rossi P, Aissi K et al. Incidence, risk profile and morphological pattern of lower extremity venous thromboembolism after urological cancer surgery. J Urol 2011; 186: 2293–7

 

5 Blom JW, Vanderschoot JPM, Oostindier MJ, Osanto S, van der Meer FJM, Rosendaal FR. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb Haemost 2006; 4: 529–35

 

6 Trinh VQ, Karakiewicz PI, Sammon J et al. Venous thromboembolism after major cancer surgery: temporal trends and patterns of care. JAMA Surg 2014; 149: 43–9

 

Editorial: Prostate cancer risk calculators – still much work ahead

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Several risk calculators (RCs) have been developed to predict prostate cancer (PCa) diagnosis at prostate biopsy. These multivariable tools have constantly been shown to be superior to risk prediction using PSA testing alone. Their use in personalized clinical decision-making is thus increasingly recommended to reduce overdiagnosis and overtreatment of PCa [1]. Foley et al. [2] conducted a multi-institutional external validation of the most recent versions of the European Randomised Study of Screening for Prostate Cancer Risk Calculator (ERSPC-RC) and the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) in a large cohort of patients from six different Irish tertiary referral centres. The study showed that the two RCs performed moderately well. Both RCs performed less optimistic compared with their original reports. The ERSPC-RC showed superior discrimination (area under the curve of 0.74 vs 0.69 for high grade PCa) and a greater net benefit in decision-curve analysis (DCA) than the PCPT-RC; however, although the ERSPC-RC was superior to the PCPT-RC in this well-conducted study, neither RC can be recommended for PCa risk prediction in this specific Irish cohort.

The authors chose to perform DCAs, which are of great value for further assessing the utility of a risk prediction model using visualization of the clinical net benefit and net harm. The benefit threshold of >30%, as shown in the DCA of the ERSPC-RC for high grade PCa, is too high for a clinically meaningful prediction tool. Below this threshold the RC did not provide further benefit compared with a strategy of performing a biopsy on everybody. It is questionable whether clinicians or patients would opt to use an RC which only provides a benefit if a risk of 30% as the lowest acceptable threshold for high grade disease is accepted.

What are the reasons for the suboptimum performance of the RCs in the Irish cohort? It is well known that RC performance is often less optimistic in external validations [3]. Differences in cohort characteristics, biopsy strategies and screening recommendations between RC development cohorts and the tested cohorts, but also changes in clinical practice over time, are potential reasons. Although the RCs have constantly been modified to establish their role as a general one-size-fits-all risk prediction model, their performance varied significantly in different cohorts. We recently evaluated the same RCs in a large Swiss single-centre cohort and found similar discrimination but better calibration, a greater net benefit and a lower and thus clinically useful benefit threshold in DCAs compared with the present Irish study [4]. The cohort in the present study was unique because it consisted of a highly preselected group of patients. This is attributable to the specific referral practice for prostate biopsies in Ireland and is reflected in the high number of patients with a positive DRE (47% in the group diagnosed with PCa) or a positive family history (11%). Accordingly, the overall PCa detection rate (58%) and the detection rate of high grade disease (35%) were higher than usually expected. From a scientific point of view, the Irish cohort is not the optimum cohort to validate these RCs. Far more importantly, however, from a clinical point of view, the evaluation showed that these RCs are not really useful in the specific Irish health system.

What can be done to improve the performance RCs in the future? It is obvious that specific characteristics of the tested cohorts will affect RC performance. These local or regional characteristics usually cannot be changed. Thus modifications of available RCs according to local patient practice might be necessary. This concept has recently been examined by Strobl et al. [5]. They were able to show that recalibration of the static PCPT-RC according to local cohort and practice characteristics can improve its accuracy. Additionally, RCs developed from contemporary clinical cohorts that were, for example, diagnosed using current state-of-the-art biopsy strategies (i.e. 12-core biopsies) instead of historical cohorts from, for example, randomized clinical trials might also result in better RC performance in clinical practice. Furthermore, the inclusion of novel variables in the RC might be useful. Results from imaging studies, such as multiparametric prostate MRI, or promising new biomarkers might increase the overall performance of PCa RCs. The study by Foley et al. shows that the inclusion of novel markers can be of benefit. The ERSPC-PHI RC, which includes the Prostate Health Index (PHI) as an additional variable, was investigated in a subset of patients in their study and was superior to the conventional ERSPC-RC; however, when novel variables are integrated, their potential clinical harm (e.g. unpleasant or costly investigations) has to be balanced against their potential benefit.

The work of Foley et al. nicely illustrates the limitations of current PCa RCs. Locally tailored static RCs, RCs based on contemporary clinical cohorts, or RCs including novel variables need to be developed to assess whether overall RC performance can be improved in the future. There is still much work to do!

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Cedric Poyet and Thom as Hermanns 

 

Department of Urology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

 

References

 

1 Heidenreich A, Abrahamsson PA, Artibani W et al. Early detection of prostate cancer: European association of urology recommendation. Eur Urol 2013; 64: 347–54

 

2 Foley RW, Maweni RM, Gorma n L e t al . European Randomised Study of S creening for Prostate Cancer (ERSPC) risk calculators significantly outperform the Prostate Cancer Prevention Trial (PCPT) 2.0 in the predict ion of prostate cancer: a multi-institutional study. BJU Int 2016; 118: 706– 13

 

3 Ankerst DP, Boeck A, Freedland SJ et al. Evaluating the PCPT risk calculator in ten international biopsy cohorts: results from the Prostate Biopsy Collaborative Group. World J Urol 2012; 30: 181–7

 

4 Poyet C, Nieboer D, Bhindi B et al. Prostate cancer risk prediction using the novel versions of the ERSPC and PCPT risk calculators: independent validation and comparison in a contemporary European cohort. BJU Int 2015; 117: 401–8

 

5 Strobl AN, Vickers AJ, Van Calster B et al. Improving patient prostate cancer risk assessment: moving from static, globally-applied to dynamic, practice-specific risk calculators. J Biomed Inform 2015; 56: 87–93

 

Editorial: Semen Proteome Alterations in the Smoking Male

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Infertility affects 15% of couples, with male factor infertility influencing half of such couples [1]. Multiple environmental risk factors for male infertility have been identified, including: diet, exposure to pollution, and multiple substance abuses, e.g. alcohol, tobacco, marijuana, opiates [2].

In this issue of BJUI, the study of Antoniassi et al. [3] makes an important contribution to the literature regarding the impact of a particular environmental factor, smoking, on male factor infertility. Standard semen analysis does not have strong sensitivity or specificity for male factor infertility given that it only examines sperm. Guzick et al. [4] demonstrated this in a study that showed extensive overlap in the sperm motility, concentration, and morphology in the male partners of fertile and infertile couples. Given this, multiple aspects of functional sperm testing have been added to standard semen analysis. Proteins added to the semen by the male accessory sex organs play a vital role in male reproductive capacity, providing nourishment and protection to spermatozoa. Batruch et al. [5] identified >2300 proteins in the semen of both fertile and infertile men using mass spectrometry. The physiological role of most of these proteins is unknown. Proteomics identifies the protein complement present in the semen using mass spectrometry. Sharma et al. [6] reported that the proteome of men with reactive oxygen species present is altered and that the absence of certain proteins may impair the neutralization of oxidative stress in semen. Prior studies have shown that the protein complement of the semen is different in men with clinical varicocoeles [7].

While the concern about the impact of smoking on male reproductive health is well documented, the effect that it has on the semen proteome is unknown. Antoniassi et al. [3] compared the semen proteome in both non-smoking and smoking men who presented to their laboratory for semen analysis. Given that patients rather than volunteers were used in this study, one cannot easily generalize the study findings to the general male population. After testing the samples for mitochondrial activity, acrosome function, and DNA integrity, the samples underwent liquid chromatography/mass spectroscopy to analyze the proteome. Sperm from smokers showed lesser sperm integrity, higher DNA fragmentation rates, and a lower percentage of intact mitochondria. The investigators demonstrated that smoking causes changes in the semen proteome. In smoking men one protein was absent, 27 proteins were under-represented, and six were over-represented. This study [3] provides some insight into how certain proteins may impact fertility. The protein S100A9 is overexpressed in smoking men and is associated with chronic inflammation, which corresponds with the fact that smokers frequently exhibit leukocytospermia. Mammoglobin B, the protein absent in men who smoke, is involved in the binding of steroid hormones; therefore, it is conceivable that its absence inhibits the ability of sperm to respond to sex hormones. you can find more info on Theihcc.com around these and other steroids.

This study [3] establishes that, among men who present for fertility evaluation, smokers have an altered proteome compared to non-smokers. This highlights the need for a greater understanding of how the semen proteome interacts with cellular elements. Further studies that examine the proteome of smokers and non-smokers with no history of infertility are warranted.

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Kenneth J. DeLay and Wayne J.G. Hellstrom

 

Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA

 

References

 

1 Sabanegh E Jr, Agarwal A. Male infertility. In Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA eds, Campbell-Walsh Urology, 10th edn, Philadelphia, PA: Elsevier Saunders: 2011

 

2 Barazani Y, Katz BF, Nagler HM, Stember DS. Lifestyle, environment, and male reproductive health. Urol Clin North Am 2014; 41: 55–66

 

3 AntoniassiMP, Intasqui P, Camargo M et al.Analysisofthefunctional aspects and seminal plasma proteomic profileofspermfromsmokers. BJU Int 2016; 118: 814–22

 

4 GuzickDS, Overstreet JW, Factor-Litvak P et al.Spermmorphology, motility, and concentration in fertile and infertile men. NEnglJMed2001; 345: 1388–93

 

5 Batruch I, Lecker I, Kagedan D et al. Proteomic analysis of seminal plasma from normal volunteers and post-vasectomy patients identifies over 2000 proteins and candidate biomarkers of the urogenital system. J Proteome Res 2011; 10: 941–53

 

6 Sharma R, Agarwal A, Mohanty G et al. Proteomic analysis of seminal fluid from men exhibiting oxidative stress. Reprod Biol Endocrinol 2013; 11: 85.

 

7 Zylbersztejn DS, Andreoni C, Del Giudice PT et al. Proteomic analysis of seminal plasma in adolescents with and without varicocele. Fertil Steril 2013; 99: 92–8

 

Editorial: Cutaneous Ureterostomy: ‘Back to the Future’

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An increasingly ageing and frail population undergoing cystectomy and urinary diversion has rekindled interest in urinary diversions with a lower risk of peri-operative complications, such as cutaneous ureterostomy (CU).

The study in this issue of BJUI by Longo et al. [1] compares complications and quality of life in elderly patients with high comorbidities (American Society of Anesthesiologists [ASA] physical status score 3–4 and Charlson Comorbidity Index [CCI] ~5) receiving either an ileal conduit (IC) or a CU with a single stoma. Although the IC group had longer surgery, greater intra-operative blood loss, a higher number of patients needing intensive care monitoring, a longer time to drain removal and a longer hospital stay, as well as a higher number of intra- and early postoperative complications, the intensive care unit length of stay and quality of life did not differ.

Complication rates are high for cystectomy and urinary diversion, especially in the frail elderly population with comorbidities [2]. Most studies are retrospective and the reported complication rates differ largely. Few centres have compared IC with CU and, probably as a result of selection biases, the results vary [3, 4]. Obvious advantages of CU are the reduced length of surgery and the lack of a bowel anastomosis, and peritoneal lesions can be minimized or omitted, thus reducing the risk of postoperative ileus (POI), a common complication after urinary diversion. These advantages were confirmed in the present study, with prolonged POI observed in 25.7% in the IC group vs 5.7% in the CU group and the duration of surgery being 226 min in the IC group vs 150 min in the CU group. Interestingly, there was no difference in major complications classified as Clavien–Dindo grades III–IV, with the exception of urinary leakage from the uretero-ileal anastomosis (14.2%).

Somewhat surprisingly, 42.8% of patients with IC required a blood transfusion compared with 17.1% with UC. The main blood loss usually takes place during cystectomy, whereas blood loss during urinary diversion is minimal [5]. The authors explain this through bleeding from the mesenteric vessels associated with isolating a bowel segment for IC, an occurrence not commonly observed in our experience or in other published reports. Overall the transfusion rate seems high, but this is highly dependent on the preoperative haemoglobin level/anaemia and the haemoglobin level set for transfusion, which differs between centres.

One of the main problems with CU is ureteric obstruction, especially of the left ureter. The rationale behind this is the more extensive mobilization of the left ureter to enable its transfer to the right side, which can result in ischaemic lesions of the distal ureter. Stenosis and kinking of the ureters when passing through the abdominal wall can also lead to obstruction. For these reasons, many patients have long-term ureteric stents. In the present study, the ureteric stents were changed every month. Foreign bodies in the urinary tract can cause problems such as upper urinary tract infections, stent encrustation and nephrolithiasis [3]. To reduce these problems, meticulous care of the CU and frequent changes of the silicone JJ stent with antibiotic prophylaxis are generally recommended. A cost assessment would be of interest to determine the long-term cost of regular stent changes compared with the management of a higher rate of peri-operative complications in patients receiving an IC. Tubeless approaches have been described, and one study reported less ureteric obstruction with deferred stent removal after surgery [6].

The Bladder Cancer Index score as a measure of quality of life did not differ between groups. Quality of life questionnaires assessing urinary diversion have inherent problems. When comparing leakage (frequency of leakage) and control (amount of leakage) in a patient with an IC or a CU, it is not surprising that there is no difference. However, the need for regular hospital visits to change the stents, which can be bothersome for patients, especially the frail and dependent elderly or those with problems travelling, because of the need to transport the necessary aides (stoma bags, pads, catheters), are rarely addressed in questionnaires.

Cutaneous ureterostomy, which is being rediscovered, belongs in the armamentarium of every surgeon performing cystectomy. However, each type of urinary diversion has its pros and cons, and careful selection is necessary to balance benefits against risks in an effort to offer the best individual option to the older and frail patient.

Read the full article

 

Fiona C. Burkhard* and Patrick Y. Wuethrich†

 

*Department of Urology, University Hospital Bern, Inselspital Anna Seiler-Haus, Bern, Switzerland and †Department of Anaesthesiology and Pain Medicine, University Hospital Bern, Bern, Switzerland

 

References

 

1 Longo N, Imbimbo C, Fusco F et al. Complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy. BJU Int 2016; 118: 521–6

 

2 Izquierdo L, Peri L, Leon P et al. The role of cystectomy in elderly patients – a multicentre analysis. BJU Int 2015; 116(Suppl 3): 73–9

 

3 Deliveliotis C, Papatsoris A, Chrisofos M et al. Urinary diversion in high-risk elderly patients: modified cutaneous ureterostomy or ileal conduit? Urology 2005; 66: 299–304

 

4 Kilciler M, Bedir S, Erdemir F et al. Comparison of ileal conduit and transureteroureterostomy with ureterocutaneostomy urinary diversion. Urol Int 2006; 77: 245–50

 

5 Wuethrich PY, Studer UE, Thalmann GN et al. Intraoperative continuous norepinephrine infusion combined with restrictive deferred hydration significantly reduces the need for blood transfusion in patients undergoing open radical cystectomy: results of a prospective randomised trial. Eur Urol 2014; 66: 352–60

 

6 Rodriguez AR, Lockhart A, King J et al. Cutaneous ureterostomy technique for adults and effects of ureteral stenting: an alternative to the ileal conduit. J Urol 2011; 186: 1939–43

 

Editorial: Managing expectations after radical prostatectomy; time to change

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There have been numerous advances in the management of prostate cancer. Developments in imaging, surgical and radiotherapy technology, and pathological grading, have led to improvements in the diagnosis and management of this common malignancy. Such progress has translated to earlier diagnosis and improved disease-specific outcomes.

With improved outcomes comes increased attention on life after treatment. Survivorship in cancer has been an area of increasing focus. The aim; to live as healthy and as good a quality of life for as long as possible after diagnosis, by managing the consequences of the cancer and its treatment. In prostate cancer, the functional impact of surgery on quality of life can be considerable, especially given the falling age at first presentation. The consequences of treatment are often the reason patients’ select one form of therapy over another.

Both sexual function and urinary continence can be significantly affected after radical prostatectomy (RP). Despite numerous consequences of surgery on sexual function, the greatest focus in publications is erectile dysfunction (ED). The quoted incidence in published studies can vary from 20% to 90%, depending on whether the return of ‘normal’ erectile function is classed as the return of spontaneous erections, a ‘return to baseline function’, or functional recovery only with pharmacological assistance. This lack of agreed definition of ED after RP hampers progress by underestimating the impact of surgery and making an uneven playing field when comparing studies.

The tendency for surgeons and studies to focus solely on erectile function, when there are so many changes in sexual function after RP, does not give patients a realistic expectation of the impact of surgery on their life after treatment. Patients should be made aware 100% will experience some change in their sexual function after surgery. Patients should be aware of all the possible risks, including;

  1. ED: All will develop a degree of ED after any RP and should be aware that their risk is dependent on their baseline function, comorbidity, and nerve-spare status. They should be made aware of the protracted time course for recovery, even when the nerves are spared, the need for possible injection therapy, and the possible future dependence on some form of therapy to achieve functional erections in the long-term.
  2. Changes in ejaculation: All patients should be made aware of the loss of ejaculation as a permanent feature, and the impact this will have on their natural fertility. They should also be aware that some develop climacturia, and the possible risk of ejaculatory pain.
  3. Changes to penile size/shape: Patients should be aware of the possible reduction in penile length after RP, and the increased risk of developing Peyronie’s disease after RP, which can further impact their sexual function.

With high profile advances such as the rise of robot-assisted RP (RARP), much has been made of the improved view of local anatomy, and ability to manoeuvre within the confined space. The expectation that this translates to improved functional outcome existed way before any studies had been conducted to show any benefit. It is of no surprise, therefore, that patients’ expectations of outcomes after RP have been unrealistically raised by such technologies.

In this month’s BJUI, Deveci et al. [1] present their survey looking at patient expectations of sexual function after RP. In this study, patients who had undergone RP (open or robot-assisted) in the last 3 months were asked to recall the counselling they had received about possible changes in sexual function preoperatively. The comprehensive approach of this study examined patients’ expectations in all the different facets of sexual function, including erectile function, expected time to full recovery of erections, the possible need for intracavernosal injections (ICI), changes in ejaculation including intensity, pain, and climacturia, and awareness of penile length changes and risk of postoperative Peyronie’s disease.

Compared with those undergoing open RP, patient’s expectations after RARP were greater, with more expecting a shorter recovery time (6 vs 12 months, P = 0.02), a higher expectation of a recovery back to baseline erectile function (75% vs 50%, P = 0.01), and lower expected need for ICI (4% vs 20%, P = 0.01) [1]. This greater expectation of newer technology leads to greater regret, and a greater need to manage expectations preoperatively [1, 2].

In addition to the misconceptions on erectile function, ~50% were unaware of the risk of anejaculation, <10% were aware of changes to penile length, and none were aware of risks of developing Peyronie’s disease after RP.

While the Deveci et al. [1] study does have flaws, primarily the lack of ability to differentiate between what patients were exactly told before RP by the nine different operating surgeons, and what could be recalled after RP, it does highlight an important point. No matter what patients were told before surgery, within 3 months of surgery their recollection and understanding of its possible impact on sexual function was poor. Previous studies have highlighted this disparity between clinician’s recall of discussions on the consequences of surgery and patient recall. In one study, while 100% of clinicians felt they had adequately addressed patients concerns on ED, <30% of patients felt the issues had been adequately addressed [3].

Effective management of patients’ expectations of the possible consequences of RP preoperatively allows for better informed consent, a realistic expectation of outcome and time course for recovery, better compliance with postoperative treatments for ED, and less regret of the initial surgical approach.

Given the limited time in consultations, there is not enough time to address all the possible consequences of surgery in detail. When being diagnosed with cancer, often the last thing on the patients mind is sexual function a year down the line. The more important issue at first is coming to terms with the cancer diagnosis, and just making it through the surgery. In addition, one has to wonder if it is fitting for the oncological surgeon to discuss the functional consequences, possible outcomes and their management when other specialists will manage this in the future. A discussion of sexual consequences of surgery is very different coming from the robotic surgeon, rather than the andrologist who would see them after.

The most ideal approach would be for all patients to see an andrologist and continence specialist before RP or be seen in preoperative ‘survivorship’ seminars, based on discussing possible consequences and optimising functional recovery after treatment. Such seminars should be run by the teams involved in managing sexual function and continence postoperatively. Patients should be given a simple, one page sheet outlining the possible consequences of their intended treatment, be that radiotherapy or surgery, on sexual function and continence. In the same way that patients are given a key contact for their cancer care, they should have access to a key contact for their functional recovery. In addition to follow-up visits with the operating surgeon, focusing on the oncological outcome, a separate follow-up based on functional outcome with an andrologist and continence specialist would focus on functional recovery.

There has been a drive to develop high-volume cancer centres of excellence, with pooled resources to allow excellence in imaging, pathology, as well as surgical and non-surgical treatments. The most utopian approach would see these centres also having andrology and continence specialists focused on the management of all postoperative functional consequences, including the ability to undertake penile implant and artificial sphincter surgery as required.

The progress in developing such an infrastructure has been slow. Research on optimising functional recovery has not been as extensive as the focus on diagnosis and treatment in prostate cancer, which can dominate many urology journals and meetings. This imbalance needs to be addressed, to provide not only the best treatment for prostate cancer, but also the best management of the consequences of treatment, aimed at improving quality of life after surgery.

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Majid Shabbir
Guy’s Hospital, London, UK

 

References

 

1 Deveci S, Gotto GT, Alex B, O’Brien K, Mulhall JP. A survey of patient
expectations regarding sexual function following radical prostatectomy. BJU Int 2016; 118: 641–5

 

2 Schroeck FR, Krupski TL, Sun L et al. Satisfaction and regret after open
retropubic or robot-assisted laparoscopic radical prostatectomy. Eur Urol 2008; 54: 785–93

 

3 Crawford ED, Bennett CL, Stone NN et al. Comparison of perspectives
on prostate cancer: analyses of survey data. Urology 1997; 50: 366–72

 

Editorial: HOXB13 mutations and prostate cancer risk

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For the first time, Storebjerg et al. [1] describe the prevalence of the HOXB13 G84E mutation in a Danish population and its association with prostate cancer risk and features indicative of clinically aggressive disease in a cohort of men undergoing radical prostatectomy. In this study, the prostate cancer risk mutation was seen in 0.49% of controls with an ~5-fold increase in risk of prostate cancer among carriers. The homeobox transcription factor gene HOXB13, is located on the long arm of chromosome 17 (17q21), and belongs to a superfamily of genes considered critical to animal embryonic development, characterised by a highly-conserved DNA-binding domain. In 2012, our research team described the association of a rare recurrent HOXB13 mutation, substituting adenine for guanine in the second position of codon 84 resulting in the replacement of glycine by glutamic acid, with prostate cancer and found that the carrier frequency was ~20-times higher among men with early onset disease and multiple affected close relatives compared with men presumed without disease [2]. Since then, numerous studies have confirmed this association with estimates of risk overall varying from ~3 to 9-fold, and generally a greater risk seen among men diagnosed before the age of 60 years and among those with a positive family history of disease among first-degree relatives [3]. The G84E mutation is almost exclusively found in men of Northern European descent with evidence suggesting that it is a relatively recent (circa 1790s) founder mutation in the population, and considered to be of moderate penetrance (estimated lifetime risk among carriers 35–65%) [4]. The same germline mutation has also been preliminarily reported to be associated with cancers of the breast, colon, bladder, and leukaemia, but requires further investigation [5, 6].

The findings from this study [1], both for the prevalence of the mutation, as well as its magnitude of association with prostate cancer, are comparable to prior reports in Northern European populations. Furthermore, among the 995 cases, the mutation frequency was significantly associated with features predictive of progression after surgery (high PSA level, positive surgical margins, higher pathological Gleason score, and non-organ confined disease) suggesting that genetic evaluation of men with a strong family history would identify a subset of men that would benefit from early screening and intervention in the same manner as are male carriers of known founder mutations in BRCA2[7]. The observation between HOXB13 and clinical features indicative of aggressive disease has been less consistent compared with studies of risk overall and the exact mechanism whereby the gene contributes to malignant progression in the prostate is not well-understood. There is some suggestion that the gene may operate both as a tumour suppressor, as early studies reported its suppression of androgen receptor activity, and as an oncogene as HOXB13 overexpression has been seen in androgen-independent tumours [8].

Currently, most countries (including the USA) do not recommend use of PSA screening for men at average risk for prostate cancer. However, given the significant risk of prostate cancer in men carrying a single copy of the HOXB13 G84E allele, should these male mutation carriers be screened for prostate cancer with PSA testing and DRE? If so, how do we identify these men and at what age should testing commence? Unfortunately, many G84E carriers may not be identified by family history, which raises the question about when is the risk of disease significant enough to warrant population level testing? As Nordic countries, including Denmark, have a higher frequency of HOXB13 G84E allele in the general population, research directed toward understanding the benefit of genetic testing followed by prostate cancer early detection strategies should be considered.

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Kathleen A. Cooney* and Jennifer L. Beebe-Dimmer†

 

*Departments of Internal Medicine and Urology, The University of Michigan, Comprehensive Cancer Center, Ann Arbor, and †Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detro it, MI, USA

 

References

 

1 Storebjerg TM, Høyer S, Kirkegaard P et al. Prevalence of the HOXB13 G84E mutation in Danish men undergoing radical prostatectomy and its correlations with prostate cancer risk and aggressiveness. BJU Int 2016; 118: 646–53

 

2 Ewing CM, Ray AM, Lange EM et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 2012; 366: 141–9

 

3 Beebe-Dimmer JL, Isaacs WB, Zuhlke KA et al. Prevalence of the HOXB13 G84E prostate cancer risk allele in men treated with radical prostatectomy. BJU Int 2014; 113: 830–5

 

4 Chen Z, Greenwood C, Isaacs WB et al. The G84E mutation of HOXB13 is associated with increased risk for prostate cancer: results from the reduce trial. Carcinogenesis 2013; 34: 1260–4

 

5 Alanee S, Couch F, OffitK. Association of a HOXB13 variant with breast cancer. N Engl J Med 2012; 367: 480–1

 

6 Beebe-Dimmer JL, Hathcock M, Yee C et al. The HOXB13 G84E mutation is associated with an increased risk for prostate cancer and other malignancies. Cancer Epidemiol Biomarkers Prev 2015; 24: 1366–72

 

7 National Comprehensive Cancer Network (NCCN), NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-risk Assessment: Breast and Ovarian (Version 2.2015). Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed 12-27-2015

 

8 Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer 2010; 10: 361–71

 

Comment: Immune checkpoint blockade – a treatment for urological cancers?

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Introduction

In the last few years there have been concerted attempts at using the power of the immune system as an effective treatment option for cancer. This has become possible as our understanding of the workings of the immune system has improved. Tumours form because of failure of the organism to destroy a rogue, mutated cell in an appropriate way. Once the tumour is formed it can further develop when the immune system fails to contain and control it and certain equilibrium is lost in favour of the tumour. This is referred to as the immune editing theory. At this point of failure of the immune system, tumour growth and progression become possible and tumours develop various mechanisms to evade the immune systems surveillance. Therefore, a mechanism to restore the lost equilibrium or to tip it in favour of the immune system would be a new modality in anti-cancer treatment. The initial approach was to use stimulators of the immune system systemically such as interleukin 2 and interferon γ i.v. in patients with metastatic cancers including melanoma and renal cancers [1]. A sustained response was shown in 22% of patients with metastatic kidney cancer, lasting for over a year. Although this treatment was not a resounding success, it did highlight an approach that could yield a durable tumour regression in a minority of cases. As our understanding of the immune system–tumour interaction further developed, new research focused on a specific mechanism in the immune system that seems to be exploited by tumours. This is an activation-inhibition mechanism, which controls the extent of adaptive immune response to invading organisms or to mutated cancer cells. In healthy individuals, this mechanism is a ‘safety’ feature allowing cessation of the immune response once it has performed its task. This is controlled by ‘receptor’ molecules at the T-cell surface and their corresponding ‘ligands’ at the surface of the cells interacting with the T-cell, which can be an antigen presenting cell or a tumour cell surface. This mechanism is called the immune checkpoint [2] (Fig. 1). Cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) are the most well-known checkpoints but there are up to 20 others (and counting) [2]. Their main role is to inhibit an immune response by blocking the activation of T-cells when those cells are presented with a foreign antigen or cancer proteins. This inhibition leads to immune ‘tolerance’ of the presence of cancer cells. So the policeman (T cell) is oblivious to the robbery in front of him. Thus an anti-tumour treatment strategy to disrupt the immune checkpoints seems to be a valid one (Table 1).

image

Figure 1. Blocking checkpoint inhibitors with antibodies is the new immunotherapy strategy to unlock T-cell activation and improve anti-tumour immune response. MHC, major histocompatibility complex; PD-L1, programmed death ligand 1; TCR, T-cell antigen receptor.

Table 1. A selected group of trials of immune checkpoint inhibitors in urological cancers
Tumour Phase Treatment N Results Trial.gov identifier

  1. mCRPC, metastatic castrate-resistant prostate cancer; PD-L1, programmed death ligand 1. The total number of current trials of immune checkpoint inhibitors is 46 for lung, breast, ovarian, rectal, prostate, pancreatic, bladder, renal cancers and melanoma.
mCRPC 1 Dendritic cell therapy and ipilimumab 20 Recruiting NCT02423928
All advanced solid tumours 1 Various combinations of ipilimumab, nivolumab and pembrolizumab 122 Recruiting NCT02467361
RCC 3 Nivolumab vs everolimus 822 Recruiting NCT01668784
RCC 3 Atezolizumab (anti PD-L1) 70 Good safety profile with antitumour activity NCT01375842
mCRPC 3 Ipilimumab vs placebo 799 No improvement of survival in treatment group NCT00861614
Urothelial 2 Gemcitabine, cisplatin and ipilimumab combinations 36 Recruiting NCT01524991

In recent years, a plethora of various inhibitors in the form of monoclonal antibodies to the checkpoint molecules were developed and to date three at least have been approved by the USA Food and Drug Administration (FDA) – ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda). They are anti-CTLA4 and anti-PD-1 antibodies. At least another eight checkpoint inhibitors are being developed. These agents have been shown to have survival benefit in some malignancies and limited benefit in others. However, the breakthrough seems to be happening in the treatment of metastatic malignant melanomas where immune checkpoint inhibitors treatment may become the standard of care. Patients with metastatic malignant melanoma who were treated with ipilimumab had a median survival of ~11 months; however, 22% of patients survived for ≥3 years with a plateau in the survival curve and in a subset of patients up to 10 years [3]. This success has not yet been replicated in prostate cancer [4]. In a more recent clinical trial involving patients with melanoma who progressed, nivolumab showed survival benefit of 72% at 1 year as compared with 42% with dacarbazine [5]. The latest approach is to combine anti-CTLA-4 and anti-PD-1 in one treatment regime as they are expected to act synergistically to remove the inhibition to the immune response, and clinical results seem to show survival benefit for combined therapy [6]. Combination of different treatment methods may potentiate the ‘abscopal effect’, which is seen when local radiation therapy can cause regression of tumour distant to the radiation site. This seems to be mediated by the immune system and potentiated by checkpoint inhibitors. Until now checkpoint inhibitors were used in patients with end-stage metastatic cancer, but recently anti-CTLA-4 has been trialled in pre-radical cystectomy patients not as a neoadjuvant therapy but rather to monitor immune response and surgical safety [2]. It is likely that checkpoint inhibitors will have a place in cancer treatment including urological cancers. However, this new class of anti-cancer treatment comes with a price. The emerging risks and side-effect profile of checkpoint inhibitors are completely different from those seen with the conventional chemotherapy and radiotherapy. Those side-effects are related to the activation of the immune system. Although most are not uncommon, they can occasionally have devastating effect on the patients. These side-effects include autoimmune conditions like dermatitis, mild colitis, and occasionally hepatitis. A severe form of colitis resulting in perforation has been reported. Unfortunately, the rate of adverse effects seems to correlate with positive clinical response. A list of some of the side-effects is summarised in Table 2. Treatment is usually with steroids, and clinicians are starting to develop strategies to minimise those risks.

Table 2. Autoimmune-based adverse effects that are associated with immune checkpoint inhibitors treatment. Most are tolerated. Severe ones are rare but can be devastating. Treatment is usually with steroids [2, 5, 6]
Adverse effects
Common Rare
Diarrhoea Severe colitis – colonic perforation
Pruritus/dermatitis Adrenal insufficiency
Rash Panhypopituitarism
Colitis Hepatitis
Fatigue Uveitis
Decreased appetite Temporal arteritis

The cost of checkpoint inhibitors remains relatively high and a full treatment course of ipilimumab costs >£18 000. One dose of pembrolizumab can cost >£3 500. However, the National Institute for Health and Care excellence (NICE) in the UK deemed this to be cost-effective and approved it for patients with metastatic melanoma that has progressed despite ipilimumab treatment.

Will the 21st century be the era for immunotherapy? It is still too early to tell. At present it remains rather expensive and beyond the means of many patients with cancer.

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Oussama Elhage*, Christine Galustian* and Prokar Dasgupta*,†

 

*Medical Research Council (MRC) Centre for Transplantation, and †National Institute for Health Research (NIHR) Biomedical Research Centre, King’s Health Partners, King’s College London and Guy’s Hospital, London, UK

 

References
1 Rosenberg SA, Lotze MT, Yang JC et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 1989; 210: 474–85

 

2 Allison JP, Freeman GJ, Gotwals P. Targeting cancer pathways: understanding immune checkpoints. Science Webinar Series. Science 2016; 351: 303

 

3 Schadendorf D, Hodi FS, Robert C et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015; 33: 1889–94

 

4 Mataraza J, Gotwals P. Recent advances in immuno-oncology and its application to urological cancers. BJU Int 2016; 118: 506–14

 

5 Robert C, Long GV, Brady B et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372: 320–30

 

6 Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373: 23–34

 

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