Addressing overtreatment following the diagnosis of localized prostate cancer

Prostate cancer overtreatment is a serious dilemma for patients, clinicians and ultimately for health-care systems. Overtreatment is defined as the treatment of a given condition that would not have led to symptoms or death during a patient lifespan. Over-diagnosis is a requirement for overtreatment, although the two should be well distinguished; the latter should not be the direct consequence of the former.

Prostate cancer has some characteristics that have favored the growth of over-diagnosis and overtreatment in the past two decades. Firstly, the prevalence of disease is extremely high with over 50% of men older than 60 years harboring malignant disease; this rate constantly increases with age [1]. Secondly, the indiscriminate spread of formal and informal screening habits by prostate specific antigen (PSA) testing has determined a stage migration towards the detection of more early diseases [2]. Thirdly, most prostate cancers are indolent in nature and most screening-detected tumors would not have been clinically relevant within patients’ lifetime. This is well summarized by the unfavorable incidence to mortality ratio in prostate cancer which is around 8. This compares to an average of 2.8 for all cancers [3].

Various strategies have been employed to estimate over-detection with a range varying between 1.7 and 67% [4]. This wide range is because of different elements: population, screening habits in a given setting as well as research methods to determine over-detection. An important concept in prostate cancer is to distinguish ‘indolent disease’ from ‘insignificant disease’ [5]. Indolent disease is a condition that would never lead to clinical symptoms or death, regardless of the host’s lifetime. Insignificant disease is a condition that would not lead to clinical symptoms or death within a subject lifetime. The difference is of key importance in the context of overtreatment. While indolent disease is always a non-threating condition, insignificant disease is influenced by disease-specific aggressiveness adjusted by patient’s life expectancy.

The concerns about overtreatment have finally led policy-makers to advocate against prostate cancer screening, and criticize the current pathway. Importantly, there is consensus across the board about the effectiveness of screening on cancer progression and disease-specific mortality with a number needed to treat constantly decreasing with prolonged follow-up; however, many argue that this gain is offset by the detrimental impact of screening on many patients’ quality of life [6]. In other words, although experts recognize early detection as an effective tool for prostate cancer, the current therapeutic ratio – benefit to harm ratio – is considered too low and leads to overtreatment at an unacceptable rate.

There are a number of solutions to reverse this therapeutic ratio at different levels. The first change should be at the outset of screening and detection. A one-size-fits-all approach has a detrimental impact in a disease like prostate cancer which has a high rate of indolent and insignificant tumors. Men should be aware of the therapeutic ratio of the prostate cancer pathway at a patient level and the choice to undergo opportunistic PSA should be done after careful consideration of the downstream implications. Clinicians should inform patients of this evidence and consider the actual benefit of PSA testing in a patient, considering his life expectancy.

A key effort should be done at the diagnosis level in order to improve risk stratification. There is level-one evidence that only men with intermediate-to-high risk localized disease benefit from immediate treatment [7]. Standard transrectal ultrasound biopsy have low accuracy to risk-stratify disease, with evidence showing that up to half patients undergoing surgery are misclassified [8]. If we cannot distinguish insignificant from significant cancer at the diagnostic stage, the consequence can only be either overtreatment or under-treatment, accordingly. Most clinicians tend to favor overtreatment, in presence of doubtful diagnosis [9]. Applying a more accurate test to risk-stratify men would increase the therapeutic ratio. Awaiting new biomarkers, this can be done at present using multi-parametric magnetic resonance imaging (MRI) and targeted biopsy [10]. In recent systematic reviews, this approach was proven to detect more men with clinically significant disease as well as less with clinically insignificant disease [11,12]. Furthermore, in light of the high negative predictive value to rule out clinically significant disease (>90%), multiparametric MRI could be employed earlier in the pathway in order to determine the subset of men who need to undergo sampling [13].

We need also to reconsider the current thresholds of significance as they are likely to be set too low. In a recent large multicenter study in which biopsy-naive men with suspected localized disease underwent an accurate test (template prostate mapping), the prevalence of clinically significant disease varied between 30 and 51%, according to commonly employed histological criteria [14]. This extremely high rate does not match the low mortality rate of prostate cancer in men at risk. If the threshold of significance was set higher, the percentage of men requiring treatment would substantially decrease and those undergoing treatment would likely to have a better therapeutic ratio.

Another change should be considered in order to favor tissue preserving approaches, namely active surveillance and focal therapy. Long-term data have shown that active surveillance is a safe option in order to avoid or delay treatment in men with low risk disease and possibly in a subset of men with intermediate risk [15]. While a minority of men choose expectant management at present, this rate is constantly growing in recent years [16]. In parallel, a stage shift to higher risk disease has been noted in surgical series, again pointing at low risk disease being rather watched [17]. Focal therapy is an emerging option for selected men with unifocal significant disease. The rationale is to treat only the component of the gland harboring the most aggressive clone that would determine the natural history of the disease. This approach has been shown to be safe and effective in the mid-term [18]. A matched-controlled study comparing this approach to radical surgery has shown no significant difference in disease control [19]. If this minimally invasive approach could provide same oncological effectiveness while reducing toxicity in the long-term, the therapeutic ratio would be substantially reversed. This shift is not easy. Institutions and clinicians need to make substantial efforts to adopt tissue-preserving approaches and make these available for patients.

Current overtreatment in prostate cancer is a ‘treatable’ condition. Some solutions are already available for institutions, clinicians and for patients and need to be urgently implemented in clinical practice in order to enhance the current poor therapeutic ratio.

Financial and competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Notes on contributors

Thomas Tawadros

Massimo Valerio