Natural history of prostate cancer, chemoprevention and active surveillance

Prostate cancer is a disease with an extreme span of clinical presentations and consequences. Locally advanced and metastatic disease is a major health concern and cause of death in industrialised countries. However, only a minority of the initial, microscopic foci of cancer cells in prostatic glands progress to symptomatic and potentially lethal disease. Most elderly men harbour such indolent cancer foci and die from other causes unaware of their existence. The risk of progression from microscopic prostate cancer to clinical illness is influenced by environmental and life-style factors, such as diet, interacting with hereditary genetic factors, but the exact biological events and interactions are difficult to unravel [1].

The natural history of prostate cancer

Most often, the natural history of prostate cancer is initially that of a preclinical tumour slowly progressing over decades. Most such preclinical cancer foci do never cause symptoms and remain undetected throughout men's lifetime. The preclinical but potentially detectable phase of prostate cancer is usually very long, compared to other malignant tumours. Many asymptomatic men have palpable prostatic tumours for many years and even more men harbour small cancer foci detectable with systematic prostate biopsies. Whether the more rapidly progressing, poorly differentiated prostate cancers are derived from pre-existing, well differentiated “latent” prostate cancers or develop de novo with a much shorter pre-clinical phase, is still unknown.

When a prostatic tumour has grown to such size that it causes symptomatic infravesical obstruction or invaded adjacent organs producing other local symptoms, cure is commonly not possible. Locally advanced, symptomatic prostate cancer has at the time of diagnosis usually seeded metastases to the regional lymph nodes or distally to the bone marrow or, less commonly, to other organs. The tumour differentiation is highly associated with the progression rate of localised and locally advanced prostate cancer.

There are few studies on the natural history of untreated symptomatic prostate cancer, but the median survival time was considered short before the introduction of endocrine therapy in the 1940s [2]. Untreated, metastatic prostate cancer was a severely disabling disease, usually leading to death within a year or two.

Recent and current research on the natural history of prostate cancer

Research on the natural history of prostate cancer has mainly focused on asymptomatic, localised tumours. Information on prognostic factors is of profound importance when deciding the treatment strategy for a man with recently diagnosed localised prostate cancer. Since the introduction of PSA testing, the detection of small, well differentiated prostate cancers has increased dramatically [3,4]. Most patients with such low-risk tumours do not need any therapy at all. However, no definition of “clinically insignificant” prostate cancer in living men (as opposed to autopsy studies) can predict which cancers will be clinically important and which will not. Since the last WHO consultation on prostate cancer in 2004, active surveillance with selective delayed treatment has evolved to be the method of choice for reducing overtreatment of low-risk prostate cancer. The critical issues which patients should receive treatment and when were outlined by Peter Albertsen at the WHO International Consultation on Prostate Cancer in Stockholm, 8–10 September 2010, and are summarised in this issue of Acta Oncologica [5].

Active surveillance for low-risk prostate cancer

There is no doubt that the adverse effects would vastly overshadow the benefit if all men diagnosed with low-risk tumours were treated with curative intent. Unfortunately, as long as we continue to biopsy palpably benign prostates, we will continue to detect such clinically insignificant prostate cancers in huge numbers. It seems unlikely that research will in the near future lead to methods for accurate prediction of which localised prostate cancers will develop to life-threatening disease and which will not. Thus, the concept of active surveillance with repeated assessments of the tumour and the patient is here to stay. Active surveillance is proven effective for reducing overtreatment, but knowledge is scarce about the risk of missing the window of curability and of issues related to quality of life. We are thus obliged to do further research on which patients should be recommended active surveillance, how it should be performed, and when radical therapy should be initiated – if ever. Some specific areas of uncertainty are listed below:

1. Which criteria define the tumours best managed with active surveillance? The optimal tumour criteria vary with the age and co-morbidity of the patient. The current criteria are based on Gleason score, tumour extent and PSA values, but they are largely arbitrary. Most urologists and oncologists agree that patients with a life expectancy of more than ten years should be recommended immediate treatment if there is a substantial amount of cancer with Gleason pattern 4 or 5 in the prostate biopsies. However, Gleason grading is observer-dependent and the definitions of the Gleason grades vary over time. Also, the prognostic significance of the extent of cancer in the biopsies is not well studied. Sampling of the prostate with transrectal biopsies commonly underestimates the Gleason score and the tumour volume compared to prostatectomy specimens [6,7]. More aggressive tumours in the anterior aspect of the prostate may be missed with routine biopsies [8]. The optimal number of biopsies and the location of these for accurate sampling are still to be defined. The value of the new variants of magnetic resonance imaging for assessing the local tumour in potential candidates for active surveillance is unclear, but recent results are promising. Likewise, the total PSA value, the PSA density and the ratio of free to total PSA are all of importance, but optimal cut-off values for recommending active surveillance are unknown. Hopefully, new biomarkers that add prognostic information will appear on the scene within the next few years.

2. What parameters should be followed during active surveillance? The monitoring of the cancer must herald progression before the disease becomes incurable. Most likely, the chance for cure is decreased substantially when tumour progression is obvious with digital rectal examination or transrectal ultrasound. We know little of the risks for tumour dedifferentiation over time or for that poorly differentiated areas of cancer are not sampled at the initial biopsies. Repeat biopsies are incorporated in most follow-up schedules for active surveillance, but how they should be performed and how the results should be interpreted is not studied systematically. Increasing PSA is the most common reason for initiating deferred treatment [9]. One problem with PSA as a marker of tumour progression is that poorly differentiated tumours produce less PSA than slowly growing, well-differentiated tumours. Another problem is that many patients with low-risk localised prostate cancer also have benign prostatic hyperplasia, which may contribute to most of the PSA measured in blood serum. A small, but comparatively rapidly progressing cancer in a large gland may therefore not give rise to a short PSA doubling time before metastases occur. Furthermore, PSA may fluctuate for various reasons which may lead to unnecessary intervention or anxiety. The PCPT and REDUCE studies indicate that 5-alpha-reductase inhibitors may be used to stabilise the PSA derived from the benign hyperplasia and enhance the utility of PSA to detect progressive cancer [10,11], but their role during active surveillance remains to be defined.

3. What is the optimal assessment interval during active surveillance? For the majority of patients tumour progression is very slow and biannual or even annual assessment is probably adequate. The crucial issue is, however, how short the intervals must be to detect more rapid progression during the “window of curability” for the small minority of patient that harbour lethal tumours. Our knowledge on the biology of disease progression from localised prostate cancer to metastatic diseases is still poor.

4. Can the risk of disease progression be reduced? Several pharmacological and non-pharmacological interventions, such as physical activity and dietary modification, are theoretically interesting, but randomised studies are necessary for their evaluation. The potential role of 5-alpha-reductase inhibitors is discussed later in this issue by Roger Rittmaster [12].

5. How does active surveillance affect quality of life? What is the psychological impact of having an untreated cancer, of slowly rising or fluctuating PSA values, and of the uncertainty of what the next scheduled visit will lead to? Is delayed treatment associated with more side-effects than immediate curative treatment? Delayed treatment may decrease the chance for nerve-sparing surgery and include adjuvant therapy because of a more advanced tumour stage. How are patients affected when deferred treatment with curative intent turns out to be initiated too late, at a time when the disease has already spread?

Chemoprevention

Large, randomised studies of chemoprevention with vitamins and trace elements have reported negative results and one study with an anti-inflammatory drug was terminated prematurely because of toxicity [12]. It may be questioned if it is the right way forward to initiate further studies on chemoprevention for prostate cancer targeting men in the general population. Selecting high-risk populations by the family history of prostate cancer, genetic testing or other biomarkers may be more efficient.

Primary chemoprevention of prostate cancer must start decades before the age at which symptomatic disease becomes common in the male population. Even secondary chemoprevention, e.g. for patients on active surveillance for low-risk tumours, must most likely include prolonged treatment before positive effects are clinically apparent. It is therefore essential that studies on chemoprevention do not focus on “prostate health” only. For the average middle-aged man there are many more threats to future health than prostate cancer, of which cardiovascular diseases are the most important. Smoking men with a low-risk prostate cancer will probably increase their chance of longevity more by stopping smoking than by subjecting themselves to a radical prostatectomy. Any intervention that reduce prostate cancer risks but have negative effects on cardiovascular morbidity or mortality may cause more harm than good. It is therefore of major interest that cholesterol-synthesis inhibiting statins, widely used to prevent cardiovascular disease, also may reduce the risk of prostate cancer [13]. Randomised studies of statins with prostate cancer as the primary endpoint are still lacking, though.

As Roger Rittmaster points out in his review later in this issue of Acta Oncologica, the term chemoprevention implies that a disease is being prevented [12]. For a disease like prostate cancer with its abundant preclinical form, preventing disease progression to clinical disease may be as important as preventing cancer initiation. The 5-alpha-reductase inhibitors finasteride and dutasteride reduced the detection of prostate cancer in two large, randomised trials [14,15]. Their effect on the poorly differentiated cancers with the highest potential of becoming life-threatening is, however, at best small. On the other hand, reducing the detection and progression of low-risk tumours may still be beneficial to the patients, since a cancer diagnosis per se and the side-effects of (unnecessary) radical treatment may reduce their quality of life. Which patient groups that could be recommended 5-alpha-reductase inhibitors for such risk reduction was discussed at the WHO meeting, but no consensus was reached.

Conclusions

The natural history of small prostate cancers is usually very protracted and most of them will never become clinically important. There is no need to diagnose cancers that will never lead to symptoms. Unfortunately, prostate cancer is commonly incurable when it has progressed to a stage that is obviously clinically significant. At present and most likely for decades to come, early detection of asymptomatic tumours followed by curative treatment is and will be the most effective measure for reducing morbidity and mortality of prostate cancer. Research on prognostic factors and strategies that reduce overtreatment of clinically insignificant cancers is therefore essential. Pharmacological risk-reduction and active surveillance with selective delayed intervention for low-risk tumours are two very important research fields. An expert session was devoted to these topics at the WHO International Consultation on Prostate Cancer in Stockholm, 8–10 September 2010. Summaries from this session are published in this issue of Acta Oncologica [5,12].

Declaration of interest: Ola Bratt is a member of an advisory board for and has received lecture fees from GlaxoSmithKline, the manufacturer of dutasteride.