PROSTATE CANCER WATCHFUL WAITING

ACTIVE SURVEILLANCE

The Royal Marsden Hospital in Surrey, England runs a program for men diagnosed with early stage prostate cancer. This program does not use conventional treatment and the Royal Marsden does not use the term WW (Watchful Waiting). Instead they call their program AS (Active Surveillance).

A leading British newspaper under a storyline "Is Surgery The Best Cure For Prostate Cancer?" included this paragraph:

"At the Royal Marsden Hospital in London, we have been doing trials since 1993 on almost 200 men. In initial trials of 80 men, only ten of those actively monitored needed to have further treatment in the form of surgery or radiotherapy. Seventy of them had no problems at all, with no spread of cancer and a PSA count that has not risen to dangerous levels. They have been saved unnecessary treatment that can lead to permanent, damaging side effects. In the future, we won't be doing surgery at all. We will monitor PSA levels carefully and eventually we won't even chop out the tigers - we will turn them into pussy cats by dietary intervention. It is important that we seek new ways to provide each man with the most appropriate care, but I think that in 20 years, surgery will be a thing of the past".

Although this is a small trial, it is an important one and it bears out the views of other leading experts - that for the majority of men (87.5% in this case) diagnosed with early stage prostate cancer, conventional treatment is not neccessary. Dr Chris Parker, the man behind the Active Surveillance program recently wrote a paper setting out the rationale for their approach. The initial draft of the paper follows, with Dr Parker's permission. The final published version, in pdf format can be found here: Active Surveillance

ACTIVE SURVEILLANCE: TOWARDS A NEW PARADIGM IN THE MANAGEMENT OF EARLY PROSTATE CANCER

Chris Parker

Senior Lecturer in Clinical Oncology

Institute of Cancer Research and Royal Marsden Hospital

Downs Road Sutton

Surrey SM2 5PT

INTRODUCTION

The annual incidence of prostate cancer in the United States has more than doubled since the introduction of the prostate specific antigen (PSA) test (figure 1).

This rise is consistent with the possibility that most PSA screen detected cases are overdiagnosed, that is, even without treatment, they would not have become symptomatic [1]. However, prostate cancer is by no means a uniformly indolent condition, being responsible for 3% of all male deaths in the US [2]. The challenge of managing early prostate cancer is to distinguish patients with clinically relevant cancers from those whose 'disease' is destined merely to be an incidental histological phenomenon, or, in other words, to tell the 'tigers from the pussy cats'. At present, we cannot accurately predict prostate cancer behaviour in an individual, so a standard approach is to offer curative treatment to all men with localised disease, while acknowledging that this treatment is unnecessary in most cases. This approach is far from ideal, not least because of the significant risks of urinary incontinence and impotence associated with such treatment. This policy of radical treatment for all will become harder to sustain as PSA testing becomes more widespread, and overdiagnosis therefore increases. Active surveillance is an alternative strategy, which aims to individualise therapy by selecting only those men with significant cancers for curative therapy. Patients are closely monitored using serum PSA levels and repeat prostate biopsies. The choice between radical treatment and observation is based on evidence of disease progression during this initial monitoring, with progression defined in terms of the PSA doubling time (PSADT), and 'upgrading' at repeat biopsy. There are no long-term outcome data for active surveillance, but the hope is that compared with a policy of immediate radical treatment in all cases, it will reduce the burden of treatment side effects without compromising survival.

THE RATIONALE FOR ACTIVE SURVEILLANCE OF EARLY PROSTATE CANCER

Some men benefit from radical treatment

Prostate cancer, unlike cancers of other sites, often has a very indolent natural history. So whereas patients with any other curable cancer would automatically be offered radical treatment, 'watchful waiting' has been a recognised approach to managing prostate cancer, with acceptable results in selected patients [3]. In fact, the first good evidence that some men benefit from radical treatment of localised prostate cancer has only recently become available. From 1989 to 1999, The Scandinavian Prostatic Cancer Group Study randomised almost 700 men with localised disease between radical prostatectomy and watchful waiting [4]. At 8 years, the risk of metastatic disease was 13% versus 27% in men randomised to surgery and watchful waiting, respectively (p = 0.03). This is an important endpoint, and no doubt will translate in time to an overall survival benefit for those receiving radical treatment. In the light of these results, it is no longer possible to argue that watchful waiting is the appropriate management for all men with localised prostate cancer. Since we know that some men benefit from radical treatment, the question now is which men benefit?

Most men will not benefit from radical treatment

The improvement in the risk of metastatic disease achieved by surgery was relatively large in the Scandinavian study. Just seven men needed to be treated in order for one to benefit. Unfortunately, however, these results may not be generalisable to the contemporary management of early prostate cancer. In particular, patients with PSA screen detected disease will have a much more favourable outcome, even without treatment, than those diagnosed clinically in Scandinavia in the late 1980's and early 1990's. It is estimated that a PSA screening program will detect prostate cancers an average of 9 years prior to when they would have been diagnosed clinically in the absence of screening [5]. Furthermore, given the often slow natural history of the disease, together with the typical age distribution, early detection using PSA testing risks overdiagnosis, that is death from other causes before the cancer would have become symptomatic. The proportion of cases identified by PSA screening that are overdiagnosed is difficult to establish, and estimates vary between 29% [6] and 84% [7]. The observed geographical variation in prostate cancer incidence provides one indication of the frequency of overdiagnosis. In countries such as Denmark, where PSA screening is uncommon, the estimated age-standardised annual incidence rate for the year 2000 is 31 per 100,000, whereas in the USA, where PSA screening is widespread, the incidence is 104 per 100,000 [8]. If one assumes that there is no difference in the 'real' incidence between these countries, it would suggest that 70% (73/104) of prostate cancers in the USA are overdiagnosed. While current data do not provide an accurate estimate of the risk of overdiagnosis, it is clear that a significant proportion of men with early prostate cancer would never develop symptomatic disease, even in the absence of treatment.

PSA screen detected prostate cancers have only become common in the last ten years or so, and the long-term results of watchful waiting for such cancers are not known. Given the lead time bias and the risk of overdiagnosis discussed above, the outcome will certainly be more favourable than that of watchful waiting for clinically diagnosed cancers. Nicholson and Harland, using the mature outcome data of watchful waiting from the pre-PSA era, together with temporal trends in incidence and mortality since the introduction of PSA testing, have modelled the expected 15-year mortality associated with watchful waiting for screen detected cancers (figure 2) [5]. While the outcome varies both with age at diagnosis, and with Gleason score, it is interesting to note that the predicted 15- year prostate cancer mortality for men with Gleason score 6 cancers is 10% or less, compared with a mortality rate of 40-76% from other causes. These considerations strongly suggest that a policy of immediate radical treatment for all screen-detected cases will, at best, have only a small impact on overall survival. Most men with screen-detected early prostate cancers are destined to die from causes other than prostate cancer. Radical treatment of their prostate cancer may not improve their longevity, but it can have a big impact on their lifestyle.

The morbidity of radical treatment

Overdiagnosis of prostate cancer would not matter if treatment had no morbidity. It would be acceptable, albeit costly, to treat all cases, including those destined never to cause symptoms, if treatment was without problems. However, the side effects of radical prostatectomy and of radical radiotherapy can be considerable. For example, in the Scandinavian study of radical prostatectomy versus watchful waiting, men randomised to surgery had significantly increased rates of urinary incontinence (49% versus 21%) and of impotence (80% versus 45%) [9]. Figures such as these highlight the fact that prostate cancer treatment can significantly impact on a man's lifestyle, and intervention should be restricted to those who need it.

The problem of predicting individual cancer behaviour

Accurate prediction of the natural history of individual cases of prostate cancer would enable radical treatment to be targeted to those men who could benefit from it, while sparing the remainder the risks of treatment side-effects. The established prognostic factors, such as Gleason score, PSA level and T stage, are of some use. For example, the benefits of radical treatment of localised prostate cancer appear to be greater in those cases with a higher Gleason score: A recent Mayo Clinic analysis [10] of long-term outcome following radical prostatectomy was designed to be as comparable as possible to the watchful waiting series reported by Albertsen [3]. Both were based on about 750 men with clinically localised disease, aged between 55 and 74, who were diagnosed between 1971 and 1984. The outcome in terms of 15-year mortality from prostate cancer was derived using the same competing risks methodology, and is shown, for men aged between 60 and 64 at diagnosis, in figure 3. While there are likely to be systematic biases between the two data sets, and while the outcomes for PSA screen detected cases will be much better than these figures, nonetheless, these data suggest that the magnitude of the benefit of radical treatment is greater for higher Gleason scores. Although the established prognostic factors can be useful in this way, they explain only a small proportion of the variation in prostate cancer behaviour [11]. There is a pressing need for better ways of selecting which men stand to benefit from radical treatment.

ACTIVE SURVEILLANCE: A SELECTIVE APPROACH TO RADICAL TREATMENT OF PROSTATE CANCER

The aim of active surveillance of early prostate cancer is to individualise therapy by selecting only those men with significant cancers for curative therapy. Patients with favourable tumour characteristics, in terms of T stage, Gleason score and PSA level, are closely monitored using serum PSA levels and repeat prostate biopsies. The choice between radical treatment and continued observation is based on evidence of disease progression during this initial monitoring, with progression defined in terms of the PSA doubling time (PSADT), and 'upgrading' at repeat biopsy. The use of PSADT to guide management is based on the knowledge that pre-operative serum PSA levels correlate significantly with the volume of prostate cancer in radical prostatectomy specimens [12], and that PSADT varies widely between patients but is constant over time for a given patient [13]. It seems intuitive that PSADT will approximate to the rate of tumour growth. In support of this, PSADT is well established as an important predictor of the risk of metastatic disease [14] and survival [15] in men with PSA failure after radical treatment, and, in a report of 113 men on watchful waiting, McLaren et al. found PSADT to be the strongest predictor of clinical progression [16].

Active surveillance must be distinguished from watchful waiting, which for decades has described a policy of observation with the use of palliative treatment for symptomatic progression. Put another way in order to emphasise the differences between these two contrasting approaches, whereas watchful waiting involves relatively lax observation with late, palliative treatment for those who develop symptoms of progressive disease, active surveillance involves close monitoring with early, radical treatment in those with signs of progression (table 1).

Preliminary outcome data for active surveillance

The concept of active surveillance was formally described for the first time in 2001 by Richard Choo from Toronto, in a report of the preliminary findings from a prospective single-arm study, started in 1995, of a 'watchful observation protocol with selective delayed intervention for clinical, histologic, or PSA progression' [17]. Eligibility was restricted to men with untreated, localized, favorable grade prostate adenocarcinoma (T1b-T2b N0 M0, Gleason Score < 7, and PSA < 15 ng/mL). Men were followed every 3 months for the first 2 years and then at six-month intervals, with digital rectal examination and PSA testing on each visit. PSA doubling time (PSADT) was estimated from linear regression of ln(PSA) against time. Repeat prostate biopsy was performed at 18 months. Indications for treatment were PSA progression, defined as a PSA doubling time < 2 years and a final PSA > 8 ng/ml; histologic progression, defined as upgrading to Gleason score > 8 on re-biopsy; or clinical progression. By the time of the latest update [18], 206 men had entered the study. They ranged in age from 49 to 84 with a median of 70 years. Median initial PSA was 6.5 ng/ml. One hundred and sixty-three patients (79%) had a biopsy Gleason score < 6, and 130 (64%) had a stage T1 tumour. At a median follow-up of 29 months, 137 men remain on observation within the surveillance program, 48 have received radical treatment, 17 have changed to a watchful waiting program (ie. no longer appropriate for radical treatment) and 4 have died of unrelated causes. Of the 48 men who have had radical treatment, 29 had met the criteria for disease progression, while the other 19 elected or were advised to have treatment without having met the criteria. The actuarial probability of freedom from disease progression was 67% (+/- 12%) at 4 years, suggesting that up to two thirds of men could be spared radical treatment using this protocol. Of note, 42% of cases had a PSADT of > 10 years, suggesting a particularly indolent course in these patients.

A different surveillance policy, based largely on repeat biopsies, has been desribed by Carter et al. from Johns Hopkins [19]. Eighty-one men with a median age of 65 years who had T1c disease, a PSA density of less than 0.15 ng/ml/cm3, and favourable needle biopsy findings (defined as Gleason score < 6, no Gleason grade 4 or 5 cancer, fewer than 3 cores involved, and less than 50% of any one core involved) were followed with PSA and digital rectal examination at six-monthly intervals, and annual prostate biopsies. Radical treatment was recommended for disease progression defined as unfavorable repeat biopsy findings (any Gleason pattern 4 or 5, greater than 2 biopsy cores involved, greater than 50% involvement of any core). At a median follow-up of 23 months, 25 (31%) had disease progression.

Optimising the active surveillance protocol

Comparison of these two reports of active surveillance shows that there is no consensus on the criteria used to define disease progression requiring radical treatment. In particular, the Johns Hopkins criteria are based on the results of repeat biopsies alone [19], whereas the Toronto group also uses PSADT and clinical criteria [17]. Although both groups use repeat biopsies, they differ with respect to the both the frequency of the procedure, and the findings which merit intervention. At present there is insufficient evidence to determine an optimum active surveillance protocol. However, some general points can be made. Initial analyses have shown that the variation in the findings between initial and repeat biopsies, at least within the first few years of surveillance, reflect the limitations of sampling, rather than tumour evolution [20] [21]. That is, cancers are downgraded on repeat biopsy as often as they are upgraded. If one accepts the presence of high grade cancer as an indication for radical treatment, then there is an argument for a more extensive initial biopsy procedure with at least, say, 12 needle cores to minimise sampling error. If initial sampling error can be reduced in this way, subsequent repeat biopsies could then be performed less frequently.

If PSADT is a potentially useful measure of the rate of cancer progression, what is the appropriate cut point to use as an indication for radical treatment? Once again, it is not possible to make an evidence-based recommendation. The choice of PSADT cut point is necessarily somewhat arbitrary. A shorter cut point will spare more men the side-effects of radical treatment, but if the cut-point is too short one might merely be identifying those men who already have metastatic disease. On the other hand, a longer cut point, while making it more likely that men who stand to benefit from radical intervention will be treated appropriately, necessarily means that fewer men are spared treatment side-effects. The Royal Marsden policy is to use an individualised cut point for each patient, depending on absolute PSA level and life expectancy, and assuming that low grade prostate cancer seldom becomes symptomatic before the serum PSA level reaches 50 ng/ml. For example, a man with a PSA level of 6 ng/ml needs three PSA doublings before his PSA will reach 50 ng/ml. If his life expectancy is 10 years, then his PSADT cut point will be around 3 years. On the other hand, if his life expectancy is 20 years, then a cut point of 7 years would be more appropriate.

Another issue related to the use of PSADT as an indication for treatment relates to the uncertainty as to the number of PSA levels, and the duration of PSA monitoring, required before one can confidently estimate an individual's 'true' PSADT. Gerber et al, in a study of 37 men managed by watchful waiting [22], reported a poor correlation between initial PSADT, calculated in the first 9 months after diagnosis, with overall PSADT using all available values (Pearson correlation coefficient 0.42). However, PSA testing was performed at six-month intervals, and it is possible that with more frequent testing, the strength of this correlation would improve [23]. An ongoing study at the Royal Marsden, using monthly PSA levels in men on active surveillance, aims to determine the optimum frequency of PSA testing, and the number of observations needed to make an accurate estimate of long term PSADT.

THE POTENTIAL OF ACTIVE SURVEILLANCE FOR EARLY PROSTATE CANCER

Active surveillance may spare two-thirds of men with early prostate cancer the side effects of treatment, without compromising their survival. This is an attractive prospect, not just for patients, but also for health economists, because it would save valuable resources that are currently spent on 'unnecessary' radical treatment. While the initial experience with active surveillance demonstrates its feasibility, long-term outcome data will be required to establish its efficacy. A randomised study of active surveillance versus immediate radical treatment, the ProtecT study, is underway in the North of England, and a similar study is planned by the National Cancer Institute of Canada.

The true worth of active surveillance may prove to be not as just an attractive alternative to immediate radical treatment, but also as a step towards a whole new paradigm for prostate cancer management. Active surveillance provides an ideal opportunity for us to improve our understanding of the basis for the extraordinary variation in prostate cancer behavior. If patients receive immediate radical treatment, only 15-25% of them will develop recurrence, which typically is detected years later. Long-term follow-up of large numbers is therefore needed to obtain outcome data to evaluate the utility of candidate biomarkers, and it is impossible to distinguish insignificant cancers from those that were significant but were treated successfully. In contrast, outcome in terms of PSADT is available for all men on active surveillance within a matter of months, so that candidate biomarkers can be evaluated rapidly in a relatively modest number of patients. At the Royal Marsden Hospital and the Institute of Cancer Research, together with our collaborators, we are studying the relationship between PSADT and potential markers of prostate cancer behaviour, including tumour gene expression profiles, serum proteomics, tumour oxygenation, cytokine profiles and functional imaging. A better understanding of the determinants of prostate cancer behaviour would not only enable us to identify which cases needed treatment, but, perhaps more importantly, would also indicate potential targets for the development of novel therapeutic strategies.

Active surveillance could also provide an attractive setting for the evaluation of therapeutic agents. Cancer prevention trials typically require tens of thousands of healthy subjects, at low risk of developing cancer, followed up for decades. Men with early prostate cancer on active surveillance could take part in trials of 'prevention' strategies, with the aim being the prevention of clinically significant disease. Prevention strategies could be rapidly tested in relatively small numbers of patients, with early endpoints based on PSADT, functional imaging and repeat biopsies. This novel approach to clinical trials could accelerate progress towards a future in which the management of early prostate cancer was based on observation, with the selective use of therapies designed, not to eradicate the disease, but to alter its natural history. To return to the feline metaphor for the different types of prostate cancer, we would no longer need to shoot the tigers, if we could train them to behave like pussy cats.

CONCLUSIONS

Active surveillance may spare two-thirds of men with early prostate cancer the side effects of treatment, without compromising their survival. Ongoing studies seek to identify the optimum schedule of PSA testing and repeat biopsies, the appropriate indications for intervention, and the long-term efficacy of surveillance in comparison with immediate radical treatment. Active surveillance provides excellent opportunities to identify markers of prostate cancer behaviour, and to test novel therapeutic strategies. Active surveillance may prove to be the start of a paradigm-shift in the management of early prostate cancer.

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RATIONALE: PSA 101: MY EXPERIENCE: MY PSA: OBJECTIFIED OBSERVATION: CLIPPINGS