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Article of the Month: The PROMEtheuS Project: Bringing PHI to prostate Cancer

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

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

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

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

Clinical performance of Prostate Health Index (PHI) for prediction of prostate cancer in obese men: data from a multicenter European prospective study, PROMEtheuS project

Alberto Abrate, Massimo Lazzeri, Giovanni Lughezzani, Nicolòmaria Buffi, Vittorio Bini*,Alexander Haese†, Alexandre de la Taille‡, Thomas McNicholas§, Joan Palou Redorta¶,Giulio M. Gadda, Giuliana Lista, Ella Kinzikeeva, Nicola Fossati, Alessandro Larcher,Paolo Dell’Oglio, Francesco Mistretta, Massimo Freschi** and Giorgio Guazzoni

Division of Oncology, Unit of Urology, URI, **Department of Pathology, IRCCS Ospedale San Raffaele, UniversitàVita-Salute San Raffaele, Milan, *Department of Internal Medicine, University of Perugia, Perugia, Italy,†Martini-ClinicProstate Cancer Center, University Clinic Hamburg-Eppendorf, Hamburg, Germany,‡Department of Urology, APHPMondor Hospital, Créteil, France,§South Bedfordshire and Hertfordshire Urological Cancer Centre, Lister Hospital,Stevenage, UK, and¶Urologic Oncology Section of the Department of Urology and Radiology Department, FundaciòPuigvert, Barcelona, Spain

OBJECTIVES

To test serum prostate-specific antigen (PSA) isoform [-2]proPSA (p2PSA), p2PSA/free PSA (%p2PSA) and Prostate Health Index (PHI) accuracy in predicting prostate cancer in obese men and to test whether PHI is more accurate than PSA in predicting prostate cancer in obese patients.

PATIENTS AND METHODS

The analysis consisted of a nested case-control study from the pro-PSA Multicentric European Study (PROMEtheuS) project. The study is registered at https://www.controlled-trials.com/ISRCTN04707454. The primary outcome was to test sensitivity, specificity and accuracy (clinical validity) of serum p2PSA, %p2PSA and PHI, in determining prostate cancer at prostate biopsy in obese men [body mass index (BMI) ≥30 kg/m2], compared with total PSA (tPSA), free PSA (fPSA) and fPSA/tPSA ratio (%fPSA). The number of avoidable prostate biopsies (clinical utility) was also assessed. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision-curve analysis.

RESULTS

Of the 965 patients, 383 (39.7%) were normal weight (BMI <25 kg/m2), 440 (45.6%) were overweight (BMI 25–29.9 kg/m2) and 142 (14.7%) were obese (BMI ≥30 kg/m2). Among obese patients, prostate cancer was found in 65 patients (45.8%), with a higher percentage of Gleason score ≥7 diseases (67.7%). PSA, p2PSA, %p2PSA and PHI were significantly higher, and %fPSA significantly lower in patients with prostate cancer (P < 0.001). In multivariable logistic regression models, PHI significantly increased accuracy of the base multivariable model by 8.8% (P = 0.007). At a PHI threshold of 35.7, 46 (32.4%) biopsies could have been avoided.

CONCLUSION

In obese patients, PHI is significantly more accurate than current tests in predicting prostate cancer.

Editorial: Time to replace PSA with the PHI?

Yet more evidence that the PHI consistently outperforms PSA across diverse populations

The Prostate Health Index (PHI) has regulatory approval in >50 countries worldwide and is now being incorporated into prostate cancer guidelines; for example, the 2014 National Comprehensive Cancer Network Guidelines for early prostate cancer detection discuss the PHI as a means to improve specificity, using a threshold score of 35 [1]. The PHI is also discussed in the Melbourne Consensus Statement [2], and it has been incorporated into the multivariable Rotterdam risk calculator smartphone app for use in point-of-care decisions [3].

As the use of this test continues to expand, more data on its performance in specific at-risk populations are of great interest. The investigators from the PROMEtheus multicentre European trial have previously validated the use of the PHI in men with a positive family history of prostate cancer [4]. The new study by Abrate et al. in this issue of BJUI instead addresses another high-risk population – obese men – who have previously been shown to have a greater risk of aggressive prostate cancer [5].

Among the 965 participants in the PROMEtheus study, 14.7% were considered obese based on a body mass index ≥30 kg/m2. In this group, 45.8% were diagnosed with prostate cancer from a ≥12-core biopsy, and 67.7% had a Gleason score ≥7. Overall, the PHI significantly outperformed PSA for prostate cancer detection in men with a body mass index ≥30 kg/m2 (area under the curve 0.839 vs 0.694; P < 0.001). At 90% sensitivity, the threshold for PHI in obese men was 35.7, with a specificity of 52.3%. The PHI also had the best performance for the detection of Gleason ≥7 disease, with an area under the curve of 0.89.

These findings add to the highly consistent body of evidence supporting the use of the PHI in early prostate cancer detection and risk stratification. In fact, all published studies to date have shown that the PHI outperforms PSA for detection of overall and high-grade prostate cancer detection on biopsy [6]. Numerous studies have also shown a role for the PHI in patient selection and monitoring during active surveillance [7, 8]. Expanded use of this test is warranted to reduce unnecessary biopsies and better identify cancers with life-threatening potential.

Stacy Loeb
Department of Urology and Population Health, New York University, New York, NY, USA

 

References

1 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prostate Cancer Early Detection Version 2014. https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf.Accessed May 26, 2014

2 Murphy DG, Ahlering T, Catalona WJ et al. The melbourne consensus statement on the early detection of prostate cancer. BJU Int 2014; 113:186–8

3 Roobol M, Salman J, Azevedo N. Abstract 857: The Rotterdam Prostate Cancer Risk Calculator: Improved Prediction with More Relevant Pre-Biopsy Information, Now in the Palm of Your Hand. Stockholm: European Association of Urology, 2014

4 Lazzeri M, Haese A, Abrate A et al. Clinical performance of serum prostate-specific antigen isoform [-2]pr oPSA (p2PS A) and its derivatives, %p2PSA and the prostate health index (PHI), in men with a family history of prostate cancer: results from a multicentre European study, the PROMEtheuS project. BJU Int 2013; 112:313–21

5 Freedland SJ, Banez LL, Sun LL, Fitzsimons NJ, Moul JW. Obese men have higher-grade and larger tumors: an analysis of the duke prostate center database. Prostate Cancer Prostatic Dis 2009; 12: 259–63

6 Filella X, Gimenez N. Evaluation of [-2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med 2013; 51: 729–39

7 Tosoian JJ, Loeb S, Feng Z et al. Association of [-2]proPSA with Biopsy Reclassification During Active Surveillance for Prostate Cancer. J Urol2012; 188: 1131–6

8 Hirama H, Sugimoto M, Ito K, Shiraishi T, Kakehi Y. The impact of baseline [-2]proPSA-related indices on the prediction of pathological reclassification at 1 year during active surveillance for low-risk prostate cancer: the Japanese multicenter study cohort. J Cancer Res Clin Oncol2014; 140: 257–63

 

Video: Clinical performance of PHI for prediction of prostate cancer: data from the PROMEtheuS project

Clinical performance of Prostate Health Index (PHI) for prediction of prostate cancer in obese men: data from a multicenter European prospective study, PROMEtheuS project

Alberto Abrate, Massimo Lazzeri, Giovanni Lughezzani, Nicolòmaria Buffi, Vittorio Bini*,Alexander Haese†, Alexandre de la Taille‡, Thomas McNicholas§, Joan Palou Redorta¶,Giulio M. Gadda, Giuliana Lista, Ella Kinzikeeva, Nicola Fossati, Alessandro Larcher,Paolo Dell’Oglio, Francesco Mistretta, Massimo Freschi** and Giorgio Guazzoni

Division of Oncology, Unit of Urology, URI, **Department of Pathology, IRCCS Ospedale San Raffaele, UniversitàVita-Salute San Raffaele, Milan, *Department of Internal Medicine, University of Perugia, Perugia, Italy,†Martini-ClinicProstate Cancer Center, University Clinic Hamburg-Eppendorf, Hamburg, Germany,‡Department of Urology, APHPMondor Hospital, Créteil, France,§South Bedfordshire and Hertfordshire Urological Cancer Centre, Lister Hospital,Stevenage, UK, and¶Urologic Oncology Section of the Department of Urology and Radiology Department, FundaciòPuigvert, Barcelona, Spain

OBJECTIVES

To test serum prostate-specific antigen (PSA) isoform [-2]proPSA (p2PSA), p2PSA/free PSA (%p2PSA) and Prostate Health Index (PHI) accuracy in predicting prostate cancer in obese men and to test whether PHI is more accurate than PSA in predicting prostate cancer in obese patients.

PATIENTS AND METHODS

The analysis consisted of a nested case-control study from the pro-PSA Multicentric European Study (PROMEtheuS) project. The study is registered at https://www.controlled-trials.com/ISRCTN04707454. The primary outcome was to test sensitivity, specificity and accuracy (clinical validity) of serum p2PSA, %p2PSA and PHI, in determining prostate cancer at prostate biopsy in obese men [body mass index (BMI) ≥30 kg/m2], compared with total PSA (tPSA), free PSA (fPSA) and fPSA/tPSA ratio (%fPSA). The number of avoidable prostate biopsies (clinical utility) was also assessed. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision-curve analysis.

RESULTS

Of the 965 patients, 383 (39.7%) were normal weight (BMI <25 kg/m2), 440 (45.6%) were overweight (BMI 25–29.9 kg/m2) and 142 (14.7%) were obese (BMI ≥30 kg/m2). Among obese patients, prostate cancer was found in 65 patients (45.8%), with a higher percentage of Gleason score ≥7 diseases (67.7%). PSA, p2PSA, %p2PSA and PHI were significantly higher, and %fPSA significantly lower in patients with prostate cancer (P < 0.001). In multivariable logistic regression models, PHI significantly increased accuracy of the base multivariable model by 8.8% (P = 0.007). At a PHI threshold of 35.7, 46 (32.4%) biopsies could have been avoided.

CONCLUSION

In obese patients, PHI is significantly more accurate than current tests in predicting prostate cancer.

Article of the Week: Better fit than fat when it comes to radical cystectomy for bladder cancer

Every week the Editor-in-Chief selects the 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.

Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy

Thomas F. Chromecki1,2*, Eugene K. Cha1*, Harun Fajkovic1,3, Michael Rink1,4, Behfar Ehdaie1, Robert S. Svatek5, Pierre I. Karakiewicz6, Yair Lotan7, Derya Tilki8, Patrick J. Bastian8, Siamak Daneshmand9,Wassim Kassouf10, Matthieu Durand1, Giacomo Novara11, Hans-Martin Fritsche12, Maximilian Burger12, Jonathan I. Izawa13, Antonin Brisuda14, Marek Babjuk14, Karl Pummer2 and Shahrokh F. Shariat1

1Weill Medical College of Cornell University, New York, NY, USA, 2Medical University Graz, Graz, Austria, 3Landeskrankenhaus St Poelten, St Poelten, Austria, 4University Medical Centre Hamburg-Eppendorf, Hamburg, Germany, 5University of Texas Health Science Center San Antonio, San Antonio, TX, USA, 6University of Montréal, Montréal, QC, Canada, 7University of Texas Southwestern Medical Center, Dallas, TX, USA, 8Ludwig-Maximilians-University Munich, Klinikum Grosshadern, Munich, Germany, 9University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 10McGill University Health Centre, Montréal, QC, Canada, 11University of Padua, Padua, Italy, 12Caritas St Josef Medical Centre, University of Regensburg, Regensburg, Germany, 13University of Western Ontario, London, ON, Canada, and 14Hospital Motol, 2nd Faculty of Medicine, Charles University, Praha, Czech Republic
*These authors contributed equally.

Read the full article
OBJECTIVE

• To investigate the association between body mass index (BMI) and oncological outcomes in patients after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) in a large multi-institutional series.

PATIENTS AND METHODS

• Data were collected from 4118 patients treated with RC and pelvic lymphadenectomy for UCB. Patients receiving preoperative chemotherapy or radiotherapy were excluded.

• Univariable and multivariable models tested the effect of BMI on disease recurrence, cancer-specific mortality and overall mortality.

• BMI was analysed as a continuous and categorical variable (<25 vs 25–29 vs 30 kg/m2).

RESULTS

• Median BMI was 28.8 kg/m2 (interquartile range 7.9); 25.3% had a BMI <25 kg/m2, 32.5% had a BMI between 25 and 29.9 kg/m2, and 42.2% had a BMI 30 kg/m2.

• Patients with a higher BMI were older (P < 0.001), had higher tumour grade (P < 0.001), and were more likely to have positive soft tissue surgical margins (P = 0.006) compared with patients with lower BMI.

• In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI >30 was associated with higher risk of disease recurrence (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.46–1.91, P < 0.001), cancer-specific mortality (HR 1.43, 95% CI 1.24–1.66, P < 0.001), and overall mortality (HR 1.81, CI 1.60–2.05, P < 0.001). The main limitation is the retrospective design of the study.

CONCLUSIONS

• Obesity is associated with worse cancer-specific outcomes in patients treated with RC for UCB.

• Focusing on patient-modifiable factors such as BMI may have significant individual and public health implications in patients with invasive UCB.

 

Read Previous Articles of the Week

Editorial: Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy

Michael R. Abern, Stephen J. Freedland and Brant A. Inman

Division of Urologic Surgery, Duke University Medical Center, Durham, NC, USA

Obesity is a worldwide epidemic: it is estimated over 300 million adults are obese and over 1 billion are overweight. As obesity is a risk factor for cancers and is modifiable, the authors of this report retrospectively analyse the association between body mass index (BMI) and outcomes in a large multinational cohort of bladder cancer patients that underwent radical cystectomy. They found that obese patients were older and more likely to have high-grade tumours. Furthermore, obese patients received inferior lymphadenectomies, had more positive margins, and were less likely to receive adjuvant chemotherapy. The end result is an association between obesity and bladder cancer recurrence, and both cancer-specific and overall mortality.

Although these data suggest that obesity is associated with poor radical cystectomy outcomes, this contrasts with evidence showing no link between obesity and bladder cancer mortality in population-based trials such as the Cancer Prevention Study II, which prospectively followed over 900 000 participants. Why the discrepancy? One possible explanation is the presence of confounding factors and one possible confounder is the presence of type 2 diabetes. In population-based studies that considered both BMI and diabetes, people with diabetes were noted to have an increased risk of developing bladder cancer independent of BMI, whereas the converse was not true. Additionally, diabetes has been associated with recurrence and progression of non-muscle invasive bladder cancer whereas obesity has not. The impact of diabetes was not adequately addressed in the current study.

Other limitations also probably affect the results. In the current study, overweight patients (BMI 25–30) had significantly better cancer-specific survival (hazard ratio 0.80, P = 0.01) than those of ‘normal’ weight (BMI < 25). However, a threshold BMI ≥ 30 has been shown to have poor sensitivity for obesity in elderly populations, with over 25% of patients with BMI under 30 qualifying as obese based on body fat. This may result in an overstatement of the effect of obesity. Conversely, the inclusion of underweight patients (BMI < 18.5) in the ‘normal’ group may underestimate the effect between obesity and outcome, as cachexia may be associated with poor outcomes. Another factor mentioned by the authors is the inferior lymphadenectomies performed in obese patients, which introduces a detection bias for lymph node positivity, the strongest predictor after advanced stage for all of their tested outcomes on multivariate analysis (hazard ratio 2.01–2.33, P < 0.001).

Although the true effect of obesity may be hard to quantify with these data, all would agree that maintaining a non-obese bodyweight will help many disease states with little apparent harm. Patients undergoing neoadjuvant chemotherapy before radical cystectomy have a 3-month window to lose weight and exercise more. This could improve surgical outcomes, and possibly tolerance of chemotherapy. Furthermore, if we can prove that obesity leads to increased bladder cancer recurrence or progression, a window of opportunity may exist when a low-risk tumour is diagnosed. Otherwise, we are left with the eighteenth century wisdom of Benjamin Franklin: ‘An ounce of prevention is worth a pound of cure.’

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