The Scandinavian prostate cancer group study: the case for conservative management


  • Chris Parker

    Corresponding author
    1. Academic Unit of Radiotherapy & Oncology, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK
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Unlike other types of cancer, a significant proportion of prostate cancers will behave in an indolent fashion, with no effect either on health or longevity, even in the absence of treatment. Partly for this reason it has been difficult to establish whether the radical treatment of prostate cancer improves survival, and if so, by how much. The Scandinavian Prostatic Cancer Group Study Number 4, which opened in 1989, is the first good quality randomized controlled trial to compare the outcome of radical treatment with that of conservative management [1,2], and its results were recently updated [3].

The trial randomized 695 men with localized disease between radical prostatectomy (RP) and watchful waiting. Patients had a mean age of 65 years, a mean PSA level of 13 ng/mL, and the grade mix was 68% Gleason score <7, 26% of 7 and 6% of 8–10. At a median follow-up of 8.2 years, randomization to RP was associated with a benefit both in terms of disease-specific mortality (hazard ratio 0.56, 95% CI 0.36–0.88, P = 0.01) and overall mortality (0.74, 0.56–0.99; P = 0.04). This translated into a 10-year overall survival of 73% vs 68% (P = 0.04) for RP vs watchful waiting, respectively. This is a very important result and shows beyond doubt that some patients with localized prostate cancer benefit from surgery, as opposed to traditional watchful waiting. Indeed, if the crossover from one arm of the trial to the other is taken into account, and the lack of postoperative radiotherapy, it is quite possible that the Scandinavian trial underestimates the true benefit of radical treatment. However, there are at least three reasons why immediate radical treatment should not be uncritically accepted as the standard of care for all men with localized prostate cancer.

The choice of treatment depends on personal values. The survival benefit in the Scandinavian trial provides a powerful argument for choosing radical treatment in preference to traditional watchful waiting. However, patients need to weigh the survival benefit against the risk of adverse consequences of treatment. The 5% absolute improvement in 10-year survival was achieved at the expense of a 35% absolute increase in the risk of erectile dysfunction and a 28% absolute increase in the risk of urinary leakage [2]. Faced with these results some patients would choose surgery, but many would choose conservative management [4]. An individual's treatment decision depends not only on trial results, but also on his personal values, and in particular the relative importance he places on prolonging life vs preserving lifestyle.

The results may not be applicable to screen-detected prostate cancer. Only 12% of patients in the Scandinavian trial had stage T1c disease, and as many as 19% of patients had a PSA level of >20 ng/mL. How can the outcome data, based largely on clinically detected prostate cancer, be applied to men with screen-detected disease? PSA screening results in over-detection (of cases that would not otherwise have been detected within the patient's lifetime) and introduces a lead time (the time difference between screen-detection and clinical detection in the absence of screening), which may be ≥ 10 years [5]. It follows that, in the absence of treatment, the natural history of screen-detected prostate cancer will be more favourable than that of clinically detected prostate cancer. This is an important consideration for men faced with the choice between conservative management and curative treatment. In comparison with clinically detected disease, men with screen-detected cancers will have longer to endure any adverse effects of curative treatment, and longer to wait for any beneficial effect on survival to emerge. At present, insufficient time has elapsed to observe the natural history of screen-detected prostate cancer, but it is interesting to compare the 10-year prostate cancer-specific mortality rate of 14.9% for watchful waiting reported by Bill-Axelson et al.[3] with the 15-year rate predicted by Nicholson and Harland [6] for screen-detected disease, of 7.4–11.6%. Given the more favourable natural history of screen-detected disease, it seems likely that the absolute survival benefit of treatment will be less than for treatment of clinically detected prostate cancer. There are two ongoing randomized trials that will address this issue [7,8]. The results of these trials will be important in helping to define the magnitude of the survival benefit for the radical treatment of screen-detected, rather than clinically detected, prostate cancer.

Watchful waiting is not the same as active surveillance. In terms of 10-year freedom from distant metastasis, the absolute benefit of surgery vs watchful waiting was 10% (84.8% vs 74.6%, P = 0.004) [3]. So it could be argued that 90% of patients did not benefit significantly from RP. Is it possible to identify these patients before surgery? One approach to this problem is active surveillance, in which radical treatment is targeted to those patients with biochemical or histological progression during a period of close observation [9]. This is by contrast to traditional watchful waiting, as specified in the Scandinavian trial, according to which palliative treatment is given to those with symptomatic progression. Klotz et al.[10,11] reported the updated results of the Toronto experience of active surveillance, which is the largest such study to date. In all, 299 patients with favourable-risk, localized prostate cancer were closely monitored with 3-monthly PSA level tests and a repeat prostate biopsy at 18 months. About 20% of the patients received radical treatment because of a rapid PSA doubling time, 10% because of ‘progression’ on repeat biopsy, and 10% because of patient preference, so that the remaining 60% avoided the risk of treatment-related morbidity. Encouragingly, the 8-year disease-specific mortality was just 1% (in comparison with 10-year disease-specific mortality of 14.9% for watchful waiting in the Scandinavian trial). It is possible that targeted radical treatment, based on an active surveillance strategy, will be as effective, and considerably less morbid, than radical treatment for all cases. An intergroup phase III trial will soon start that will compare the long-term outcomes of active surveillance with those of immediate radical treatment, and will aim to recruit ≈ 1500 patients.

The Scandinavian trial has finally resolved one of the key issues in localized prostate cancer; we now know that radical treatment can improve overall survival. However, the trial leaves several important questions unanswered. How large is the survival benefit for treating screen-detected prostate cancer? Is active surveillance, with radical treatment targeted to those with disease progression, as effective as a blanket policy of radical treatment for all? For the present, a patient's decision whether or not to have radical treatment for localized prostate cancer remains a value judgement, weighing the risk of treatment-related morbidity against the possible survival benefit.