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Editorial: PCa Prevention – Proof is Elusive

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Prevention is so much better than cure because it saves the labor of being sick. Thomas Adams, 1618

Inferior doctors treat the full blown disease; mediocre doctors treat the disease before evident; superior doctors prevent disease.   Nai Ching, 1st Chinese Medical Text, 2600 BC. 

Enthusiasm for prevention is hundreds, even thousands of years old.  In the field of prostate cancer, profound differences in the regional variation of prostate cancer around the world (highest in Americans and Scandinavians, lowest in Asians) despite the similar incidence of histologic occult prostate cancer, and shifts in the incidence in mortality amongst immigrant populations moving from low to high prostate cancer regions, led to a firm belief that clinical disease was preventable.   This belief was supported by the known long initiation phase for prostate cancer, providing an opportunity over decades for diet and micronutrient intake to influence the likelihood of disease progression.

In addition, many epidemiologic studies pointed to the benefits of fruits and vegetable intake high in Vitamin E, Selenium, Beta Carotene, Lycopene, and other micronutrients, and a diet low in animal fat.

However, recently several pivotal studies have taken the bloom off the rose of prevention.  In particular, the SELECT study demonstrated a 17% increased rate of prostate cancer in men on Vitamin E, and an increase in DM in men on Selenium (1).  The study was resoundingly negative.  In addition, both high intake of multivitamins, and high dairy and calcium intake, have been associated with an increased risk of fatal prostate cancer (2).   Folic acid intake results in an increased incidence of prostate cancer.  Despite the positive PCPC and Reduce trials, the 5 ARIs were not approved for prevention by the FDA due to concerns about an increased risk of high grade prostate cancer, despite the reduction in positive biopsies in men on the drug (mostly due to  a decrease in low grade cancer).

Further, studies of the association between dietary intake of fruits and vegetables and PCa are inconsistent.  For example, one large study of 130,544 men found no significant association between fruit or vegetable intake, including cruciferous vegetables, and prostate cancer. (3)  Another study showed dietary modification, reducing fat and increasing fruits, vegetables, and fiber, had no impact on PSA.  (4).

And yet, despite the negative intervention studies, a lingering spark of hope exists that the many positive population, epidemiologic, and pre- clinical studies supporting dietary prevention will be vindicated.  The study in the current issue of BJU Int on the MEAL study is therefore a laudable and ambitious initiative (5).   Remarkably, 478 men have been randomized to validated dietary counseling intervention vs no intervention.  This paper reports the initial demographics and eligibility data.  It is undoubtedly the first of many publications that will arise from this important trial.

Will this study prove its’ ambitious goal, to demonstrate that prostate cancer progression can be influenced by dietary modification?   While the initiative is laudable, I suspect the hurdles are insurmountable given the sample size and conceptual basis for the study.  The study is being performed in men on active surveillance, and the primary end point will be the risk of disease ‘progression’.  The study references the Redeem study, which showed a 44% reduction in disease ‘progression’ with dutasteride compared to placebo (6).

What we have learned since the Redeem study was initiated more than a decade ago was that the major limitation of conservative management in men diagnosed with low grade prostate cancer on systematic biopsy is not disease progression as it is usually defined (ie, developing worse disease over time); it is grade misattribution, based on sampling and pathologic miss of co-existent higher grade cancer (7).  Higher grade cancer is present in about 30% of men with Gleason 6 cancer on systematic biopsy.  Finding this on subsequent systematic biopsy is largely a matter of luck, location of the cancer, and biopsy strategy and number.    In contrast, true grade progression (from Gleason pattern 3 to pattern 4 or 5) is uncommon, estimated to occur in only 1-2% of patients per year (8).  The adoption of MRI and targeted biopsy into the surveillance algorithm has reduced the misattribution problem.   Thus, the true ‘event rate’ (exclusive of misattribution) is likely to be in the 15% range at 10 years.   A study with the power to detect a 20% relative difference in these events, ie a 3% absolute difference, would require more than a thousand patients followed for 10 years.

In the Redeem study, the reduction in ‘progression’ was entirely related to a decrease in the volume of low grade cancer.  Indeed, the rate of upgrading was 13% in both arms in Redeem.  Therefore the decrease in progression in that study likely reflected the cytoreduction effect of 5 ARIs, and not a real biological effect on cancer progression.

Thus, to be meaningful, prevention studies in men on surveillance should identify, at the very least, a real reduction in grade progression, based on state of the art evaluation at baseline with MRI and targeted biopsies as warranted, and long term follow up.    A decrease in the rate of volume progression of Gleason 6, a major end point of this study, is not meaningful.   In the study as described, which does not explicitly incorporate MRI, an imbalance in the number of patients having off protocol MRI and targeted biopsies between the two arms could significantly bias the outcome.

A further problem with long term studies of dietary intervention relates to the well-known methodological limitations in this area—ensuring long term compliance, recall bias of food intake, and contamination of the control arm.

Nonetheless, the authors deserve strong congratulations for pursuing this major initiative.  We will follow the course of this study with interest.

 

Dr. Laurence Klotz C.M.

Division of Urology, Sunnybrook Health Sciences Centre, 2075 Bayview Ave. #MG408 

Toronto, Ontario M4N 3M5

 

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References

  1. Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011
  2. Lawson KA, Wright ME, Subar A, et al.: Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst 99 (10): 754-64, 2007
  3. Key TJ, Allen N, Appleby P, et al.: Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 109 (1): 119-24, 2004
  4. Shike M, Latkany L, Riedel E, et al.: Lack of effect of a low-fat, high-fruit, -vegetable, and -fiber diet on serum prostate-specific antigen of men without prostate cancer: results from a randomized trial. J Clin Oncol 20 (17): 3592-8, 2002.
  5. BJU-2016-1793.R2 – The Men’s Eating and Living (MEAL) Study (CALGB 70807 [Alliance]): Recruitment Feasibility and Baseline Demographics of a Randomized Trial of Diet in Men on Active Surveillance for Prostate Cancer
  6. Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. 2012;379(9821):1103-1111.
  7. Cooperberg MR, Carroll PR, Klotz L: Active surveillance for prostate cancer: progress and promise. J Clin Oncol 29 (27): 3669-76, 2011. [PubMed]
  8. Lurdes Y.T. Inoue, Bruce J. Trock, Alan W. Partin, H. Ballentine Carter, Ruth Etzioni Modeling Grade Progression In An Active Surveillance Study Stat Med. Author manuscript; available in PMC 2015 Mar 15. Published in final edited form as: Stat Med. 2014 Mar 15; 33(6): 930–939.

 

Article of the Week: Association between T2DM, curative treatment and survival in localized PCa

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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 discussing the paper.

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

Association between type 2 diabetes, curative treatment and survival in men with intermediate- and high-risk localized prostate cancer

Danielle Crawley*, Hans Garmo*, Sarah Rudman†, Par Stattin‡§, Bjorn Zethelius**, Lars Holmberg*, Jan Adolfsson†† and Mieke Van Hemelrijck*

 

*Division of Cancer Studies, Cancer Epidemiology Group, King’s College London, †Guy’s and St Thomas’ NHS Foundation Trust and King’s College London’s Comprehensive Biomedical Research Centre, London, UK, ‡Department of Surgical Sciences, Uppsala University, Uppsala, §Department of Surgical and Peri-operative Sciences, Urology and Andrology, Umea University, Umea, Department of Public Health and Geriatric, Uppsala University, **Medical Products Agency, Uppsala, and ††Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

 

Read the full article

Abstract

Objective

To investigate whether curative prostate cancer (PCa) treatment was received less often by men with both PCa and Type 2 diabetes mellitus (T2DM) as little is known about the influence of T2DM diagnosis on the receipt of such treatment in men with localized PCa.

Subjects and Methods

The Prostate Cancer database Sweden (PCBaSe) was used to obtain data on men with T2DM and PCa (n = 2210) for comparison with data on men with PCa only (n = 23 071). All men had intermediate- (T1–2, Gleason score 7 and/or prostate-specific antigen [PSA] 10–20 ng/mL) or high-risk (T3 and/or Gleason score 8–10 and/or PSA 20–50 ng/mL) localized PCa diagnosed between 1 January 2006 and 31 December 2014. Multivariate logistic regression was used to calculate the odds ratios (ORs) for receipt of curative treatment in men with and without T2DM. Overall survival, for up to 8 years of follow-up, was calculated both for men with T2DM only and for men with T2DM and PCa.

Results

Men with T2DM were less likely to receive curative treatment for PCa than men without T2DM (OR 0.78, 95% confidence interval 0.69–0.87). The 8-year overall survival rates were 79% and 33% for men with T2DM and high-risk PCa who did and did not receive curative treatment, respectively.

Conclusions

Men with T2DM were less likely to receive curative treatment for localized intermediate- and high-risk PCa. Men with T2DM and high-risk PCa who received curative treatment had substantially higher survival times than those who did not. Some of the survival differences represent a selection bias, whereby the healthiest patients received curative treatment. Clinicians should interpret this data carefully and ensure that individual patients with T2DM and PCa are not under- nor overtreated.

Read more articles of the week

Editorial: Selecting patients for PCa treatment: the role of comorbidity

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The risk of dying from prostate cancer is strongly influenced by competing causes related to age and comorbidity. In the past, indiscriminate screening and treatment of prostate cancer in men with limited life expectancy have been heavily criticized. In the SPCG-4 study, Bill-Axelson et al. [1] showed that patient age significantly modified the likelihood of benefit from radical prostatectomy: while patients aged <65 years at the time of treatment saw significantly decreased risk of overall mortality, prostate cancer mortality, and metastases, those aged >65 years did not have a significant improvement in survival, despite significantly decreased risk of metastases [1]. Significant progress has since been made with regard to treatment, in offering surveillance to men unlikely to die from their prostate cancer, either because of indolent disease or competing risks.

In this issue of BJUI, Crawley et al. [2] describe the association between type 2 diabetes and receipt of curative treatment for patients newly diagnosed with intermediate- and high-risk prostate cancer. Using the Prostate Cancer database Sweden (PCBaSE), the authors convincingly show us that patients who received oral therapies or insulin for type 2 diabetes were significantly less likely to undergo curative treatment after a prostate cancer diagnosis compared with men without diabetes. They also demonstrated a gradient of effect, as men treated with insulin (with presumably more severe diabetes) were even less likely to receive curative therapies than those treated with oral agents (odds ratios 0.62 and 0.91, respectively, both compared with men without diabetes). This could have been better assessed with more objective measures of disease severity including micro- and macrovascular complications or glycated haemoglobin levels. Interestingly, the authors found that men with diabetes had more aggressive disease, with higher Gleason scores, a greater proportion of biopsy cores involved with cancer, and higher PSA levels. We therefore must consider the question, is withholding curative therapy from these patients undertreatment or appropriate?

Mortality rates for men with diabetes are significantly higher than for those without. Among men aged ≥50 years, life expectancy is 7.5 years (95% CI: 5.5–9.5) shorter for those with diabetes [3]. The effect of diabetes on mortality is mediated through cardiovascular disease, the leading cause of mortality among men diagnosed with prostate cancer [4]. Thus, competing risks of mortality, rather than prostate cancer mortality, are likely to be the limiters of these patients’ life expectancy.

Interestingly, the authors found that men with diabetes who received pharmacotherapy for dyslipidaemia or cardiovascular disease had a similar likelihood of receiving treatment as men treated for diabetes alone [2].

The authors then assessed whether receipt of curative treatment was associated with overall survival among patients with diabetes. The authors conclude that curative treatment was associated with improved overall survival among these men [2], with differences in both prostate cancer and non-prostate cancer mortality. We should be sceptical of these findings, however, because of significant selection bias and confounding as the authors present only unadjusted results. The greater comorbidity and more aggressive cancers among men with diabetes in this cohort may explain a large portion of the differences in non-prostate cancer mortality and prostate cancer-mortality, respectively, separate from the effect of local treatment. This is supported by the authors’ observation that men with type 2 diabetes treated with curative intent had better overall survival than men with type 2 diabetes without prostate cancer [2]. In fact, non-prostate cancer causes contributed to the majority of deaths in these men with intermediate- and high-risk cancer, regardless of receipt of curative treatment. Lastly, with respect to survival, it should be noted that previous analyses have demonstrated a protective effect of metformin on overall and prostate cancer mortality among men with diabetes [5].

What are we to take from this paper? First, men with diabetes appear to present with more aggressive disease at the time of diagnosis. This may relate to decreased prostate cancer screening, lower PSA levels among screened men leading to a decreased index of suspicion [6], or a lower likelihood of biopsy at a given PSA level. Further, we believe that this paper shows that Swedish urologists are understandably providing curative prostate cancer treatment to men with the potential to benefit from these interventions, while sparing men with significant medical comorbidity the side effects of such therapies which are unlikely to benefit them. Caution should be applied in using these data to reflexively justify more aggressive screening and treatment in all men with diabetes. Individualized decision-making should be made on a case-by-case basis based on the best estimates of risks of prostate cancer and non-prostate cancer mortality.

Christopher J.D. Wallis,*† Raj Satkunasivam,*† and Bimal Bhindi‡
*Division of Urology, Department of Surgery, University of Toronto, †Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada and ‡Department of Urology, Mayo Clinic, Rochester, MN, USA

 

Read the full article

 

References

 

1 Bill-Axelson A, Holmberg L, Garmo H et al. Radical prostatectomy or watchful waiting in early prostate cancer. New Engl J Med 2014; 6: 932–42

 

2 Crawley D, Garmo H, Rudman S et al. Association between type 2 diabetes, curative treatment and survival in men with intermediate and high risk localized prostate cancer. BJU Int 2018; 121: 209–16

 

3 Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W. Associations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease. Arch Intern Med 2007; 167: 1145–51

 

4 Ketchandji M, Kuo YF, Shahinian VB, Goodwin JS. Cause of death in older men after the diagnosis of prostate cancer. J Am Geriatr Soc 2009;57: 24–30

 

5 Margel D, Urbach DR, Lipscombe LL et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol 2013; 31: 3069–75

 

6 Werny DM, Saraiya M, Gregg EW. Prostate-specific antigen values in diabetic and nondiabetic US men, 2001–2002. Am J Epidemiol 2006; 164: 978–83

 

Video: Association between T2DM, curative treatment and survival in localized PCa

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Association between type 2 diabetes, curative treatment and survival in men with intermediate- and high-risk localized prostate cancer

Read the full article

Abstract

Objective

To investigate whether curative prostate cancer (PCa) treatment was received less often by men with both PCa and Type 2 diabetes mellitus (T2DM) as little is known about the influence of T2DM diagnosis on the receipt of such treatment in men with localized PCa.

Subjects and Methods

The Prostate Cancer database Sweden (PCBaSe) was used to obtain data on men with T2DM and PCa (n = 2210) for comparison with data on men with PCa only (n = 23 071). All men had intermediate- (T1–2, Gleason score 7 and/or prostate-specific antigen [PSA] 10–20 ng/mL) or high-risk (T3 and/or Gleason score 8–10 and/or PSA 20–50 ng/mL) localized PCa diagnosed between 1 January 2006 and 31 December 2014. Multivariate logistic regression was used to calculate the odds ratios (ORs) for receipt of curative treatment in men with and without T2DM. Overall survival, for up to 8 years of follow-up, was calculated both for men with T2DM only and for men with T2DM and PCa.

Results

Men with T2DM were less likely to receive curative treatment for PCa than men without T2DM (OR 0.78, 95% confidence interval 0.69–0.87). The 8-year overall survival rates were 79% and 33% for men with T2DM and high-risk PCa who did and did not receive curative treatment, respectively.

Conclusions

Men with T2DM were less likely to receive curative treatment for localized intermediate- and high-risk PCa. Men with T2DM and high-risk PCa who received curative treatment had substantially higher survival times than those who did not. Some of the survival differences represent a selection bias, whereby the healthiest patients received curative treatment. Clinicians should interpret this data carefully and ensure that individual patients with T2DM and PCa are not under- nor overtreated.

View more videos

Article of the Week: Safety and efficacy of 2-weekly cabazitaxel in mCRPC

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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.

Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer

Alice Clement-Zhao* , Marie Auvray*, Hail Aboudagga†, Felix Blanc-Durand*, Antoine Angelergues *, Yann Alexandre Vano*, Florence Mercier‡, Nader El Awadly*, Benjamin Verret*, Constance Thibault* and Stephane Oudard*

 

*Department of Medical Oncology, †Pharmacy Department, Hopital Europeen Georges Pompidou, Paris, and ‡Stat Process Society, Port-Mort, France

 

Read the full article

How to Cite

Clément-Zhao, A., Auvray, M., Aboudagga, H., Blanc-Durand, F., Angelergues, A., Vano, Y. A., Mercier, F., El Awadly, N., Verret, B., Thibault, C. and Oudard, S. (2018), Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer. BJU International, 121: 203–208. doi: 10.1111/bju.13855

Abstract

Objectives

To evaluate the safety and efficacy of a 2-weekly cabazitaxel schedule in patients with metastatic castration-resistant prostate cancer (mCRPC).

Materials and methods

During the period October 2013 to February 2016, 43 patients with mCRPC were treated with cabazitaxel (16 mg/m2, on days 1 and 15 of a 4-week cycle) together with prophylactic granulocyte colony-stimulating factor (G-CSF). The safety profile and efficacy (prostate-specific antigen [PSA] response; biological, clinical or radiological progression-free survival [PFS] and overall survival [OS]) of the treatment were analysed.

Results

All patients had received prior docetaxel and 79.1% abiraterone acetate. At inclusion, 46.5% were aged >70 years and 27.9% had an Eastern Cooperative Oncology Group performance status ≥2. Six patients stopped treatment because of toxicity. Grade ≥3 toxicities were: asthenia (16.3%); neutropenia (11.6%); thrombocytopenia (9.3%); diarrhoea (7%), anaemia (4.7%), febrile neutropenia (4.7%) and haematuria (2.3%). In all, 52.4% achieved a ≥30% PSA response and 40.5% had a ≥50% PSA response. The median OS was 15.2 months.

Conclusion

This prospective pilot study suggests that cabazitaxel 16 mg/m² given 2-weekly has a manageable toxicity profile in docetaxel- and abiraterone acetate-pretreated patients with mCRPC. A prospective phase III trial comparing this regimen with the standard cabazitaxel regimen is planned to confirm these results.

Read more articles of the week

Editorial: Even ‘low-dose’ cabazitaxel requires careful and meticulous patient selection

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In the present issue of BJUI, Clèment-Zhao et al. [1] have evaluated the safety profile of a 2-weekly regime of cabazitaxel (CBZ) at a dose of 16 mg/m2 in 43 patients with progressing, metastatic castration-resistant prostate cancer (mCRPC). Treatment was planned to have been delivered for a total of six cycles, with each cycle consisting of two 2-weekly applications of CBZ. The majority of patients had already received two life-extending systemic therapies, such as docetaxel and abiraterone acetate. Despite the prophylactic use of granulocyte colony-stimulating factor (G-CSF), 11.6% and 4.7% of patients developed grade ≥3 neutropenia or febrile neutropenia, respectively, and one patient even died from treatment-related toxicities. Only 75% of the scheduled six cycles could be delivered, although dose reduction of 20% was carried out in 37.2% of the patients. The authors recommend this type of treatment for elderly and frail patients and they provide the reader with the impression that the delivery of such a toxic regime in elderly and frail patients is accordance with the guidelines [2].

Based on the International Society of Geriatric Oncology (SIOG) guidelines [2], it is evident that the term ‘frailty’ requires a dedicated and sophisticated geriatric assessment using, for example, the G8 questionnaire. If a score <14 is calculated on this questionnaire, and the patients have been identified as having irreversible impairment, an intensive geriatric intervention might be undertaken to correct the underlying comorbidities. Only in the presence of correctable comorbidities should an adapted cancer therapy be initiated, while in their absence best supportive care seems to be the optimal approach. Of the 43 patients in the present phase II trial, none underwent a geriatric assessment and three-quarters of the patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; therefore, only a minority of the treated patients represented frail patients, and conclusions should be drawn with great caution, also considering the relatively low number of patients recruited.

The frequency of 11.6% and 4.7% of grade 3/4 neutropenia and neutropenic fever, respectively, and an overall frequency of 34.9% grade 3/4 treatment-emergent adverse events is still quite high compared with the data from studies on the German Early-Access Programme (EAP) and the European EAP on CBZ, which included 111 and 746 patients with similar disease characteristics, of whom 7.2% and 15%, respectively, developed grade ≥3 neutropenia, despite non-regular use of G-CSF [3, 4].

Several factors might have contributed to the relatively high frequency of treatment-emergent adverse events in the present study. Firstly, the cumulative CBZ dose was 144 mg/m2 in the present study as compared with 100 mg/m2 in the European EAP and 162.5 mg/m2 in the German EAP, so that there was not a significant reduction in dose despite the lower dose delivered at each cycle. This might have contributed to impairment of bone marrow function over time. Secondly, bone marrow reserve appeared to differ among treated patients: ~50% of patients already had neutrophil counts below the normal values. As we have shown recently, neutrophil counts <4 000/mm3 were associated with an odds ratio of 1.73 (95% CI 1.25–2.39; P < 0.001) for developing grade 3/4 neutropenia [4]. Thirdly, age ≥75 years, but not age <75 years or ECOG performance status ≥2, was associated with a 1.66-fold (95% CI 1.09–5.52; P = 0.018) increased risk of significant neutropenia in the above-mentioned studies [3, 4]; however, it is unclear how many patients were aged >75 years in the present study.

As a result of these factors, it is still necessary to carefully select elderly patients with mCRPC prior to the recommendation of cytotoxic CBZ therapy, even at a reduced dose. Despite the fact that there is some weak evidence that severe neutropenia might be associated with a survival benefit, we need to bear in mind that this evidence is from post hoc analysis of fit and non-elderly patients recruited in the TROPIC trial [5]. We have no meaningfuldata from a cohort of elderly and vulnerable/frail patients and we have no data at all on quality of life in these patients; therefore, we should not overtreat and we should only consider frail and elderly patients with mCRPC for CBZ treatment if they have undergone geriatric assessment that has shown correctable comorbidities. Otherwise, there are numerous other treatment options in addition to chemotherapy, including best supportive care [6].

With regard to therapeutic efficacy, we always find it difficult to report median overall survival times of 15.2 months when the median follow-up time is only 12.9 months.

Axel Heidenreich and David Pfister
Department of Urology, Uro-Oncology, Robot-Assisted and Reconstructive Urological Surgery, University of Cologne, Cologne, Germany

 

Read the full article

 

References

 

1Clement-Zhao A, Auvray M, Aboudagga H et al. Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer. BJU Int 2018; 121: 203–8

 

2 Droz JP, Aapro M, Balducci L et al. Management of prostate cancer in older patients: updated recommendations of a working group of the International Society of Geriatric Oncology. Lancet Oncol 2014; 15: e404–14

 

3 Heidenreich A, Scholz HJ, Rogenhofer S et al. Cabazitaxel plus prednisone for metastatic castration-resistant prostate cancer progressing after docetaxel: results from the German compassionate-use programme. Eur Urol 2013; 63: 977–82

 

4 Heidenreich A, Bracarda S, Mason M et al. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: results of the European compassionate-use programme. Eur J Cancer 2014; 50: 1090–9

 

5 Meisel A, von Felten S, Vogt DR et al. Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): a post-hoc analysis of the TROPIC phase III trial. Eur J Cancer 2016; 56: 93–100

 

6 Fitzpatrick JM, Bellmunt J, Fizazi K et al. Optimal management of metastatic castration-resistant prostate cancer: highlights from a European Expert Consensus Panel. Eur J Cancer 2014; 50: 1617-27

 

Article of the Month: Does RARP benefit patients with oligometastatic PCa?

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

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

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

Does robot-assisted radical prostatectomy benefit patients with prostate cancer and bone oligometastases?

Won Sik Jang, Myung Soo Kim, Won Sik Jeong, Ki Don Chang, Kang Su Cho, Won Sik Ham, Koon Ho Rha, Sung Joon Hong and Young Deuk Choi

Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea

Read the full article

Abstract

Objective

To investigate the peri-operative and oncological outcomes of robot-assisted radical prostatectomy (RARP) in patients with oligometastatic prostate cancer (PCa).

Patients and Methods

We retrospectively reviewed the records of 79 patients with oligometastatic PCa treated with RARP or androgen deprivation therapy (ADT) between 2005 and 2015 at our institution. Of these 79 patients, 38 were treated with RARP and 41 were treated with ADT without local therapy. Oligometastatic disease was defined as the presence of five or fewer hot spots detected by preoperative bone scan. We evaluated peri-operative outcomes, progression-free survival (PFS), and cancer-specific survival (CSS). We analysed data using Kaplan–Meier methods, with log-rank tests and multivariate Cox regression models.

Results

Patients treated with RARP experienced similar postoperative complications to those previously reported in RP-treated patients, and fewer urinary complications than ADT-treated patients. PFS and CSS were longer in RARP-treated compared with ADT-treated patients (median PFS: 75 vs 28 months, P = 0.008; median CSS: not reached vs 40 months, P = 0.002). Multivariate analysis further identified RARP as a significant predictor of PFS and CSS (PFS: hazard ratio [HR] 0.388, P = 0.003; CSS: HR 0.264, P = 0.004).

Conclusions

We showed that RARP in the setting of oligometastatic PCa is a safe and feasible procedure which improves oncological outcomes in terms of PFS and CSS. In addition, our data suggest that RARP effectively prevents urinary tract complications from PCa. The study highlights results from expert surgeons and highly selected patients that cannot be extrapolated to all patients with oligometastatic PCa; to confirm our findings, large, prospective, multicentre studies are required.

Read more articles of the week

Editorial: Is it time for a more ‘proactive’ approach to metastatic prostate cancer?

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In this issue of BJU International, Jang et al. [1] investigate the perioperative and oncological outcomes of robot-assisted radical prostatectomy (RARP) in oligometastatic prostate cancer. The authors evaluated a retrospective cohort of 79 patients with oligometastatic prostate cancer, defined as up to five bony metastases on bone scan without visceral metastasis on conventional CT, treated either with RARP (n = 38, 48%) or androgen-deprivation therapy (ADT: n = 41, 52%). They found that cytoreductive RARP was associated with longer progression-free survival (PFS) and cancer-specific survival (CSS) relative to the ADT cohort at a median follow-up of 40 months.

The authors exclusively use the robotic approach for RP in the metastatic prostate cancer setting. Overall, they should be commended for demonstrating the feasibility of RARP in the metastatic setting, with a median operating room time of 147 min and complication rate of ~15%. This is in the same range as the 164 min operative time and 20% complication rate reported in a recent multi-institutional cytoreductive RP (cRP) series, consisting of both open and robotic approaches [2]. However, it is important to note that Jang et al. [1] had a 79% positive margin rate compared to 54% for Sooriakumaran et al. [2]. Furthermore, Jang et al. [1] had a median hospital stay of 5 days compared to 2–3 days in the USA centres [2]. These findings underscore the significant difficulty often encountered in metastatic cases, despite robotic assistance. Thus, we believe the age-old debate of open vs robotic prostatectomy is perhaps less relevant in the cytoreductive setting, where surgeon experience and expertise may be more critical drivers of outcome.

Although there is some evidence in favour of cRP compared to the standard of care, selection bias, limited collection and analysis of much clinical data, and short follow-up often plague most series. Understandably, the current manuscript by Jang et al. [1] also suffers from some of these limitations and leaves some questions unanswered. For instance, did the number of bone metastases, PSA doubling time at diagnosis, and distribution of lymphadenopathy (pelvic vs extra-pelvic) differ between cRP and ADT groups and thus confound the impact of cRP on survival? In addition, the authors may wish to report overall survival, so that their series can be more readily compared to the existing literature. Moreover, the median CSS was only 40 months in the ADT group, whereas it was not even reached in the low-volume arm of the ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) [3], suggesting that the control group in the current manuscript may have had higher volume metastatic disease. Lastly, there is no evaluation of the impact of adjuvant ADT and radiation therapy on CSS, and further studies may wish to explore if such multi-modal approaches may yield a benefit in the cytoreductive setting.

The existing literature on cRP remains in the nascent stage and is conflicting. The first large studies to suggest a benefit for cRP were retrospective series based on large cancer databases. Subsequently, Heidenreich et al. [4] explored the role of cRP in a case-control study, which found a significantly longer PFS and CSS in a group of 23 men undergoing neoadjuvant ADT + cRP compared to 38 men treated with ADT alone. On the other hand, a prospective investigation comparing 43 men with low-volume bone metastasis treated with cRP to 38 men treated with ADT did not show a benefit for time-to-castration-resistance or overall survival [5]. Moschini et al. [6] also found no survival benefit for cRP with 5-years of follow-up relative to a cohort of ADT patients with CSS more consistent with randomised data from the CHAARTED [3]. The present study by Jang et al. [1] adds to the growing body of retrospective series advocating cRP in select patients.

Whilst a full discussion of the putative biological mechanisms proposed to explain a potential survival benefit of cRP is beyond this editorial, they can be broadly grouped into the following: removal of the primary source of circulating tumour cells, reducing the number of cells that can develop resistant mechanisms for systemic therapy, removal of immunosuppressive cytokines, abscopal effects, and decreasing tumour-growth promoting factors. Ultimately, the ‘proof is in the pudding’, and the results of several randomised trials (Testing radical prostatectomy in men with oligometastatic prostate cancer that has spread to the bone [TRoMbone], NCT01751438, and NCT02454543) are eagerly awaited to determine if cRP can benefit patients.

Matteo Soligo, Vidit Sharma and R. Jeffrey Karnes
Mayo Clinic Urology, Rochester, MN, USA

 

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References

 

1 Jang WS, Kim MS, Jeong WS et al. Does robot-assisted radical prostatectomy benefit prostate cancer patients and bone oligometastases? BJU Int 2018; 121: 225–31

 

2 Sooriakumaran P, Karnes J, Stief C et al. A multi-institutional analysis of perioperative outcomes in 106 men who underwent radical prostatectomy for distant metastatic prostate cancer at presentation. Eur Urol 2016; 69:788–94

 

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

 

4 Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. J Urol 2015; 193: 832–8

 

5 Steuber T, Budaus L, Walz J et al. Radical prostatectomy improves progression-free and cancer-specific survival in men with lymph node positive prostate cancer in the prostate-specific antigen era: a confirmatory study. BJU Int 2011; 107: 1755–61

 

6 Moschini M, Morlacco A, Kwon E, Rangel LJ, Karnes RJ. Treatment of M1a/M1b prostate cancer with or without radical prostatectomy at diagnosis. Prostate Cancer Prostatic Dis 2017; 20: 117–21

 

Article of the Week: Oncological outcomes and toxicity for LDR prostate brachytherapy

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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.

Long-term oncological outcomes and toxicity in 597 men aged ≤60 years at time of low-dose-rate brachytherapy for localised prostate cancer

Stephen E. M. Langley, Ricardo Soares, Jennifer Uribe, Santiago Uribe-Lewis, Julian Money-Kyrle, Carla Perna, Sara Khaksar and Robert Laing

 

St Luke’s Cancer Centre, Guildford, Surrey, UK

 

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Objectives

To report oncological and functional outcomes of men treated with low-dose-rate (LDR) prostate brachytherapy aged ≤60 years at time of treatment.

Patients and Methods

Of 3262 patients treated with LDR brachytherapy at our centre up to June 2016, we retrospectively identified 597 patients aged ≤60 years at treatment with ≥3-years post-implantation follow-up and four prostate-specific antigen (PSA) measurements, of which one was at baseline. Overall survival (OS), prostate cancer-specific survival (PCSS) and relapse free survival (RFS) were analysed together with prospectively collected physician-reported adverse events and patient-reported symptom scores.

Results

The median (range) age was 57 (44-60) years, follow-up was 8.9 (1.5-17.2) years, and PSA follow-up 5.9 (0.8-15) years. Low-, intermediate- and high-risk disease represented 53%, 37% and 10% of the patients, respectively. At 10 years after implantation OS and PCSS were 98% and 99% for low-risk, 99% and 100% for intermediate-risk, and 93% and 95% for high-risk disease, respectively. At 10 years after implantation RFS, using the PSA level nadir plus 2 ng/mL definition, was 95%, 90% and 87% for low-, intermediate-, and high-risk disease, respectively. Urinary stricture was the most common genitourinary adverse event occurring in 19 patients (3.2%). At 5 years after implantation erectile function was preserved in 75% of the patients who were potent before treatment.

Conclusion

LDR brachytherapy is an effective treatment with long-term control of prostate cancer in men aged ≤60 years at time of treatment. It was associated with low rates of treatment-related toxicity and can be considered a first-line treatment for prostate cancer in this patient group.

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Editorial: LDR prostate brachytherapy in younger men

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Langley et al.1 report on the oncological and functional outcomes of men treated with low dose rate (LDR) prostate brachytherapy in men 60 years old or younger. 597 patients with a median (range) age of 57 (44-60) years had a median follow-up of 8.9 (1.5-17.2) years. The 10- year post-implant relapse free survival using the Phoenix definition for biochemical failure (nadir plus 2 ng/ml) was 95%, 90% and 87% for low, intermediate and high-risk disease, respectively. Potency was preserved in 75% of men potent before treatment. The authors concluded that LDR brachytherapy is an efficacious treatment with excellent long-term control of prostate cancer in men ≤60 years at time of treatment. While the results from this investigation are encouraging, enthusiasm should be tempered given the short follow up, long natural history of prostate cancer and the long-life expectancy for these younger patients.

Although the overall median follow-up was 8.9 years, the calculation of PSA-free failure was derived from a median follow-up of 5.9 years. As this investigation did not identify men who may also be at risk of failure because of a rising PSA and who have not yet reached the Phoenix threshold, I anticipate longer-follow up will further reduce their favorable results. Of the 597 men, 6 (1%) died from prostate cancer. The low incidence of prostate cancer mortality, while impressive, also reflects the short follow-up. Our group has previously reported that PCSM substantially increases between the 10th and 15th year post treatment. The experience of these physicians in prostate brachytherapy is demonstrated in their favorable dosimetry outcomes-the median D90 was 106.4% of the prescription (145 Gy). These results (median D90 154.3 Gy), which were determined and computed on the day of the implant would be 10-15% higher had the CT scans been done on day 30 as most centers do. We and others have reported that patients receiving higher dose implants have improved biochemical and cancer-specific outcomes. While these data help explain their favorable oncological outcomes, they should also serve as a guide to other brachytherapy programs where implant quality should be a primary objective. Erectile function was preserved in 75% of men. These data are consistent with other reports of younger men who were treated for prostate cancer with surgery or radiation. Because this was not a randomized study, it is not possible to make direct comparisons between surgery and brachytherapy. The selection of an IIEF score of > 11 as potent might be challenged as the 12-16 group is considered to have mild to moderate ED. Nonetheless, these data are still encouraging for younger men who are considering treatment for localized prostate cancer where sexual function preservation is important.

Nelson Stone

Mount Sinai Medical Center – Urology 350 E 72nd Street, New York, New York 10021 United States

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Reference

  1. Langley SM, Soares R, Uribe J, et al. Long-term oncological outcomes and toxicity in 597 men ≤60 years of age at time of low dose rate brachytherapy for localised prostate cancer. BJU Int 2017

 

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