Defining and predicting indolent and low risk prostate cancer

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Abstract

The early detection of asymptomatic prostate cancer has led to the increased incidence of tumours that are unlikely to become symptomatic during life, so called indolent cancers. The prediction of low risk and indolent prostate cancer is needed to avoid overtreatment by unnecessary invasive therapies, and select men for active surveillance. Some of the currently available nomograms predicting these low risk tumours have been validated in independent populations. However, assessment to the compliance with their treatment advises based on the calculation of probability are scarce. The ultimate value of nomograms for the urologic practice can only be assessed by analysing their practical implementation.

Introduction

The incidence of prostate cancer is increasing worldwide [1], likely due to an enhanced awareness of prostate cancer. As the first evidence of a reduction of prostate specific mortality by screening of asymptomatic men between 55 and 70 years old was provided by the population based European Randomized study of Screening for Prostate Cancer (ERSPC) [2], and as in many parts of the world the overall life expectancy increases, individual men consider prostate cancer (PCa) screening for their personal benefit. App. 50% of PCa diagnosed in population based studies show the pathological features of the incidental cancers found at autopsy [3]. This implies that a subset of men diagnosed with prostate cancer do not require any active, invasive treatment during life. In the ERSPC, over 600 men with these clinically and pathologically defined low risk PCa features were observed without primary treatment over a period of ten years [4]. Overall survival was 70%, while none died of PCa.

The diagnosis of these small, well differentiated low risk tumours (i.e. over diagnosis), is the major drawback of screening for prostate cancer and the major barrier to implement population based PCa screening programs. Up to now there still is no parameter that can indicate the risk on an potential low risk cancer adequately before taking a prostate biopsy. For the same lack of strong prognostic markers also over treatment is difficult to avoid.

Various nomograms on the probability of low risk or indolent PCa have been constructed [5], in order to distinguish these cancers from those that are considered relevant at the time of diagnosis [6].

Since tumour monitoring with potentially delayed active invasive therapy (this is: active surveillance (AS)) has been included in the guidelines of PCa treatment, the selection of men suitable for an AS strategy based on accurate risk assessment has become pivotal. Guideline advices might vary substantially, likely related to the literature information they are based upon, and the cultural background of the health system, especially regarding the attitude for lawsuit procedures. While the American Urologic Association (www.auanet.org/guidlines) and the American Cancer Society (www.cancer.org) produced guidelines that define their low risk categories by PSA and Gleason score only, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology 2010 created an extra low risk category in addition to the low risk category adding other histological features, suggesting an extra safety level for the application of active surveillance (www.nccn.org). Offering invasive therapy to all men diagnosed with PCa would be unacceptable in terms of quality of life and cost efficiency [7]. Active Surveillance however becomes increasingly accepted by patients and physicians as a treatment option [8].

In this review the stages of the development and use of nomograms predicting indolent PCa are highlighted.

Section snippets

Various aspects of indolence

The definition of indolence bears various dimensions. While for patients the most important aspect is the absence of symptoms of their prostate tumour over time, the pathologist/biologist will be most interested in the molecular pathways and genomic background of these cancers, in order to understand the processes that make these malignancies within their host into the slow growing tumours they are, with or without latent metastases. From this biological understanding molecular markers and

Current nomograms predicting indolent cancer are integrated in risk assessment strategies

The development of nomograms to predict the outcome of disease treatments has been stimulated by the growth of clinical databases overtime. Nomograms are of interest to inform patients, and support them making treatment choices. Nomograms also classify patients in risk groups that are used to select patients for clinical trials.

Current nomograms for predicting indolent cancer (at the time cancer has been diagnosed) are based on the histological evaluation of step-sectioned radical prostatectomy

The use of nomograms in the setting of the host

The use of nomograms has been evaluated by Cooperberg, who reported on the existence of over one hundred of predicting tools in the field of Urology [32]. On their implementation in the daily practice it is quoted ‘…Clearly, no risk instrument should be used in isolation to direct patients towards or away from treatment alternatives…’ This is a serious warning to incorporate various host related factors to take clinical decisions. Factors not measured by current models are for example: baseline

The implementation phase of nomograms

In order to implement nomograms into the daily urological routine, a series of validations needs to be followed after the initial construction phase. Traditionally, a nomogram would be tested on an independent but relevant population set, such as has been performed for the predictive ERSPC risk calculator [35]. Next, an evaluation of the implementation should take place to analyze the impact of the instrument as a decision tool on the actions taken by patients and physicians. This phase is

Improving nomograms

Current nomograms on the presence of low risk or indolent disease still lack the long term clinical follow-up on surveillance. With time, the current AS programs [20], [37], [38], [39], [40] will provide this information, improving the accuracy of predictions. New prognostic parameters related to the low volume low grade tumours found by radical prostatectomy will be validated and incorporated in the nomograms. Candidate markers at presence are the kallikreins [41] proPSA [42], PCA3 [43], or

Conclusions

Nomograms provide us with tools to inform patients and physicians more objectively with information on present conditions and future events. They allow us to take a step back and review the experience of many observers, independent on the recent individual impressions on a disease. When complex decisions have to be made using various parameters, nomograms can support balancing the weight of each individual parameter. However, the definition of thresholds for treatment advises is still heavily

Conflict of interest

None.

Reviewers

Michael W. Kattan, Ph.D., School of Medicine, Case Western Reserve University, Department of Epidemiology and Biostatistics, Center for Clinical, Cleveland, OH, United States.

James A. Eastham, MD, FACS, Chief, Urology Service, Memorial Sloan-Kettering Cancer Center, Urology Service, Surgery, 1275 York Avenue, New York, NY 10065, United States.

Chris H. Bangma (born 4th January, 1959) was nominated Professor and Chairman of the Department of Urology at Erasmus University Medical Centre in Rotterdam, The Netherlands, in 2002. He wrote his Ph.D. thesis on ‘Prostate Specific Antigen and ultrasonography in detection and follow-up of prostate cancer’ in 1995, and completed his professional urologic training at the same institute in 1997. He was granted a research fellowship on gene therapy for prostate cancer by the Dutch Cancer Society,

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    Chris H. Bangma (born 4th January, 1959) was nominated Professor and Chairman of the Department of Urology at Erasmus University Medical Centre in Rotterdam, The Netherlands, in 2002. He wrote his Ph.D. thesis on ‘Prostate Specific Antigen and ultrasonography in detection and follow-up of prostate cancer’ in 1995, and completed his professional urologic training at the same institute in 1997. He was granted a research fellowship on gene therapy for prostate cancer by the Dutch Cancer Society, and spent a two-year period at Baylor College of Medicine, Houston, USA, with Prof Timothy Thompson and Peter Scardino, and afterwards at the oncology lab of Prof. Bob Pinedo at the Free University in Amsterdam. Chris Bangma participated in the European Fifth Framework Program from 2000 onwards on the preclinical development of gene therapeutic vectors, followed by coordinating the clinical application in the GIANT consortium within the European Sixth Framework Program. He has participated to the European Randomized study on Screening of Prostate Cancer ERSPC from its start in 1992 as a board member, and has coordinated the P-Mark consortium since 2004 till 2008 under the umbrella of the Sixth Framework Program for the search and validation of prognostic serum markers for prostate cancer. Furthermore, he is PI of the PRIAS (Prostate Cancer International Study of Active Surveillance), PROCABIO (Prostate Cancer Biomarker research in clinical setting of Active Surveillance, a European initiative to develop tailored treatment of prostate cancer by biomarkers), ZonMw Translationeel Gentherapeutisch Onderzoek (Oncolytic adenovirus therapy as a neoadjuvant treatment for prostate cancer), PRO-NEST (Prostate Research Organizations-Network of Early Stage Training, 7th Framework EC, Peoples Pogram), and PCMM (Prostate Cancer Molecular Medicine, the Dutch integrated academia–industry program) programs/studies. Chris has contributed to over 150 peer reviewed papers predominantly in the field of prostate and bladder carcinoma. Currently he is president of the Dutch Urologic Society.

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