Watchful waiting

For men with biopsy-diagnosed prostate cancer, for which patients (based on diagnostic, clinical and other criteria) does watchful waiting achieve equivalent or better outcomes in terms of length and quality of life than definitive treatment? (PICO questionⁱ 11)

For men with biopsy-diagnosed prostate cancer following a watchful waiting protocol, which combination of monitoring tests, testing frequency and clinical or other criteria for intervention achieve the best outcomes in terms of length and quality of life? (PICO question 12)

Conservative strategies for managing prostate cancer are considered when cure is not the goal. A comprehensive approach to managing prostate cancer diagnosed by biopsy after prostate-specific antigen (PSA) testing therefore involves determining:

• appropriate criteria for choosing watchful waiting in preference to definitive treatment
• the optimal monitoring protocol for watchful waiting, including criteria for intervention.

Guidelines developed in partnership with

Cite this guideline

Prostate Cancer Foundation of Australia and Cancer Council Australia PSA Testing Guidelines Expert Advisory Panel. Clinical practice guidelines PSA Testing and Early Management of Test-Detected Prostate Cancer. Sydney: Cancer Council Australia. [Version URL: http://wiki.cancer.org.au/australiawiki/index.php?oldid=122839, cited 2023 Dec 10]. Available from: https://wiki.cancer.org.au/australia/Guidelines:PSA_Testing/Watchful_waiting.

This resource has been developed, reviewed or revised more than five years ago. It may no longer reflect current evidence or best practice.

Published: 2015

National Health and Medical Research Council

These guidelines (recommendations) in the web-version of this guideline were approved by the Chief Executive Officer of the National Health and Medical Research Council (NHMRC) on 2 November 2015 under section 14A of the National Health and Medical Research Council Act 1992 In approving the guidelines (recommendations), NHMRC considers that they meet the NHMRC standard for clinical practice guidelines. This approval is valid for a period of five years. NHMRC is satisfied that the guidelines (recommendations) are systematically derived, based on the identification and synthesis of the best available scientific evidence, and developed for health professionals practising in an Australian health care setting.

This publication reflects the views of the authors and not necessarily the views of the Australian Government.

Background

Watchful waitingⁱⁱ is a conservative strategy for managing prostate cancer that is asymptomatic or for which the man declines intervention. As currently understood, it does not aim to cure prostate cancer, but to delay intervention until clinically warranted to prevent or relieve symptoms caused by the cancer. Watchful waiting involves avoiding treatment until there are symptoms or signs of progressive disease. Treatment, when given, is directed towards slowing the disease’s progression or relieving its symptoms, not to cure.

The decision to undertake watchful waiting is made in agreement with the patient after explaining the available options and discussing their benefits and harms. Reasons for undertaking watchful waiting include the following:

• The cancer has advanced and is not curable with local treatments.

• The patient’s life expectancy is limited and prostate cancer is unlikely to cause significant problems in his lifetime.

• The patient chooses this option – some men may elect to undertake a program of watchful waiting rather than proceed with any of the localised disease management options with curative intent.

Available evidence for the outcomes of watchful waiting, compared with immediate definitive treatment, is from studies that commenced 20–25 years ago and included men with early-stage cancer and a life expectancy of more than 10 years. This group may not now be considered for watchful waiting (except at their choice). Therefore, the outcomes of these trials may not be generalisable to the population of men who would be likely to be offered watchful waiting under present circumstances. The evidence is, however, directly relevant to men with early-stage cancer and a life expectancy of more than 10 years who choose not to have definitive treatment. The outcomes of watchful waiting reported in this body of evidence could also apply to men who have early-stage cancer and a life expectancy of less than 10 years (for reasons other than prostate cancer).

Evidence about the optimal components and frequency of the clinical assessments is lacking. In patients undergoing watchful waiting, clinical assessment is designed to detect symptoms, signs and laboratory tests indicative of progressive prostate cancer that may require treatment. Physical assessment may include a digital rectal examination of the prostate to assess its local extent and progression. Laboratory testing may include serum PSA to assess the rate of progression, serum creatinine to assess renal function, serum alkaline phosphatase to help indicate the likelihood of bone metastases, and a full blood count to assess marrow involvement. Imaging studies may include radionuclide bone scans and computed tomography.

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Evidence

Criteria for selecting watchful waiting

Two randomised controlled trials were identified that reported prostate cancer-specific mortality rate and other relevant outcomes in men with early-stage (T1–2NxM0) prostate cancer randomised to immediate radical prostatectomy or to watchful waiting. Both studies were assessed to have a moderate risk of bias for the outcomes of mortality and development of distant metastases, and a high risk of bias for the outcomes of quality of life and adverse events. The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.

The first, Scandinavian Prostate Cancer Group trial number 4 (SPCG-4), randomised 695 men with early-stage, low-grade or intermediate-grade prostate cancer, diagnosed in Sweden from 1989 to 1999, to immediate radical prostatectomy or to watchful waiting. Of men randomised to radical prostatectomy, 84.7% had radical prostatectomy and of those randomised to watchful waiting, 13.2% had definitive treatment. Intention-to-treat analysis at median 12.8 years’ follow-up favoured radical prostatectomy for the following outcomes:

• all-cause mortality (hazard ratio [HR] 0.75; confidence interval [CI] 0.61–0.92)
• prostate cancer-specific mortality (relative risk [RR] 0.62; CI 0.44–0.87)
• development of distant metastases (RR 0.59; CI 0.45–0.79).

Results were also analysed in strata of age at diagnosis and risk of a poor cancer outcome (low risk defined as PSA < 10 ng/mL and either Gleason score < 7 or World Health Organization [WHO] cancer grade 1). The impact of radical prostatectomy appeared to be limited to, or greater for, men younger than 65 years for all-cause mortality (RR 0.52, compared with RR 0.98 for men older than 65 years), prostate cancer-specific mortality (RR 0.49, compared with RR 0.83 for men older than 65 years), and development of distant metastases (RR 0.47, compared with RR 0.77 for men older than 65 years). The impact of radical prostatectomy also appeared to be greater in men with low-risk cancer for all-cause mortality (RR 0.62), prostate cancer-specific mortality (RR 0.53) and distant metastases (RR 0.43). Results for the subgroup with high-risk cancer were not reported.

While limited to men with well-differentiated or moderately differentiated prostate cancer, this trial appears to have included men with more advanced primary prostate cancer than is usual at diagnosis today:

• It largely excluded patients whose prostate cancer had been detected as a result of PSA testing; only 12% had disease primarily detected by a PSA test (stage T1c).
• Biopsy techniques used (which included aspiration cytology) were less sensitive than those used at present.
• It included men with PSA levels of up to 50 ng/mL.

The second trial, Prostate Cancer Intervention Versus Observation Trial (PIVOT), randomised 731 men with early-stage prostate cancer of any grade, diagnosed in the USA between 1994 and 2002, to immediate radical prostatectomy or to watchful waiting. This trial had difficulty recruiting and was underpowered. Just over 30% of participants were Black Americans. Of men randomised to radical prostatectomy, 77.2% had radical prostatectomy and 85.4% had definitive treatment. Of those randomised to watchful waiting, 10.1% had radical prostatectomy and 20.4% had definitive treatment.

Intention-to-treat analysis at median 10.0 years of follow-up favoured radical prostatectomy for development of bony metastases (HR 0.40; CI 0.22–0.70) and showed statistically non-significant trends in favour of radical prostatectomy for all-cause mortality (HR 0.88; CI 0.71–1.08) and prostate cancer-specific mortality (HR 0.63; CI 0.36–1.09).

Results were also analysed in strata of age at diagnosis, race, comorbidity, performance status, PSA level, Gleason score, and tumour risk (based on PSA, stage and biopsy findings). The impact of radical prostatectomy appeared to be limited to, or greater for, men with PSA > 10 ng/mL for all-cause mortality (HR 0.67, compared with 1.03 for PSA ≤ 10 ng/mL), prostate cancer-specific mortality (HR 0.36, compared with 0.92 for PSA ≤ 10 ng/mL), and bony metastases (HR 0.28, compared with 0.58 for PSA ≤ 10 ng/mL). The impact of radical prostatectomy also appeared to be limited to, or greater in, men with high- or intermediate-risk disease, but this effect may have been due to the inclusion of PSA in the risk algorithm, since there was little difference in radical prostatectomy effect between subgroups with Gleason score categories (< 7, > 7). However, there were differences between histological reporting at participating sites and by a central pathologist that affected risk stratification and, consequently, secondary endpoint results. Using a less predictive pre-2005 International Society of Urological Pathology Consensus Gleason classification, about 25% of patients had Gleason score of 7 or higher reported at the peripheral sites, compared with 48% with Gleason score 7 or higher by a central pathologist.

There was also little evidence that the effect of radical prostatectomy differed by age at diagnosis or any other stratification variable, but competing mortalities exacted a significant toll; 47% of men assigned to prostatectomy died, yet only 5.8% deaths were attributed to prostate cancer. Similarly, 49.9% of men assigned to observation died, yet only 8.4% deaths were attributed to prostate cancer.

Notably, only 10% of participants were younger than 60 years, compared with 20% of men diagnosed with prostate cancer in Australia in 2008. This study was begun in the ‘early PSA era’, but approximately 50% of men had non-palpable cancers.

These two studies are consistent in their evidence that, in men with early-stage prostate cancer, there are higher rates of all-cause mortality, prostate cancer-specific mortality, and development of distant metastases in men randomised to watchful waiting than in men randomised to radical prostatectomy. However, the studies were not consistent in the strata of personal and disease characteristics in which apparently beneficial effects of radical prostatectomy were observed. Whereas SPCG-4 observed an apparently greater reduction in rates of all-cause mortality, prostate cancer-specific mortality, and development of distant metastases in men with low-risk cancer (PSA < 10 ng/mL and either Gleason score < 7 or WHO cancer grade 1) randomised to radical prostatectomy, PIVOT observed an apparently greater reduction in all three of these outcomes in men with a PSA > 10 ng/mL randomised to radical prostatectomy. In addition, these benefits appeared greater in younger men in SPCG-4 but unrelated to age in PIVOT.

These two studies also reported quality-of-life outcomes. In both SPCG-4 (at mean of 4.1 years and median of 12.2 years after randomisation) and PIVOT (approximately 2 years after randomisation), there were significantly greater prevalence rates of urinary incontinence, erectile dysfunction and associated distress in men randomised to radical prostatectomy than in men randomised to watchful waiting. In PIVOT, prevalence of bowel dysfunction was not different between the randomised groups at approximately 2 years after randomisation. In SPCG-4, anxiety, depression, wellbeing and patient assessed quality of life were similar between the two groups at 4.1 years (mean) and 12.2 years (median) after randomisation. These studies provide consistent evidence of greater rates of urinary incontinence and associated distress, and erectile dysfunction and associated distress, in men randomised to radical prostatectomy than in men randomised to watchful waiting – at least up to a mean of 4 years after randomisation. Modification of these effects of treatment type by patient or disease characteristics was not examined.

PIVOT reported on adverse events occurring within 30 days of surgery. Based on cumulative incidences for 280 patients, early procedure-related adverse events included wound infection (4.3%) urinary tract infection (2.5%), requirement for additional surgical repair other than bowel repair (2.5%), bleeding requiring transfusion (2.1%), urinary catheter present at > 30 days (2.1%), bowel injury requiring repair (1.1%), and one death (0.4%).

No studies were identified that compared watchful waiting with definitive treatment in men with advanced prostate cancer.

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Watchful waiting protocols

No randomised controlled trials were found that tested or compared follow-up schedules or strategies for watchful waiting. In the absence of direct evidence, a useful starting point could be the schedules used for the control groups in randomised clinical trials comparing various active treatments with watchful waiting in three different clinical scenarios: locoregional prostate cancer detected by screening, locoregional prostate cancer detected clinically, and advanced prostate cancer with minimal symptoms. The components and frequency of these schedules were carefully specified for these trials, but they were designed primarily to satisfy the needs of research rather than those of routine clinical practice and may, therefore, be more intensive than would be desirable for clinical practice, both with respect to frequency and number and nature of investigations.

In the absence of relevant published evidence on which to base watchful waiting protocols, we adapted selected NICE 2014 recommendations, which were informed by available evidence and represent current international expert consensus.

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Evidence summary and recommendations

Evidence summary	Level	References
The studies were inconsistent in patient selection and in their findings on the effects of age and risk of cancer progression (as assessed at diagnosis) on observed differences in rates of all-cause mortality, prostate cancer-specific mortality and prostate cancer metastases, between men offered radical prostatectomy and men offered watchful waiting. In the one study that reported on race, comorbidity and performance status, these factors were not associated with differences in clinical outcomes between treatment groups.	II	,
In men with early-stage prostate cancer of any grade, watchful waiting was associated with higher rates of distant metastases and death due to prostate cancer, compared with radical prostatectomy. However, watchful waiting was associated with lower rates of erectile dysfunction, urinary incontinence and distress than radical prostatectomy. Despite these differences, rates of anxiety and depression, wellbeing, and patient-assessed quality of life did not differ between men who receive watchful waiting and those who receive radical prostatectomy, according to data from follow-up of 4.1 years (mean) and 12.2 years (median) from diagnosis.	II	, , ,
No studies were found that directly compared different watchful waiting protocols.	N/A

N/A: non-applicable

Evidence-based recommendation	Grade
For men with potentially curable prostate cancer who are considering watchful waiting, advise that: the risk of developing more advanced prostate cancer and dying from it is higher with watchful waiting than with immediate definitive treatment watchful waiting is unlikely to diminish wellbeing and quality of life in the medium-to-long term.	C

Consensus-based recommendation
Offer watchful waiting to men diagnosed with potentially curable prostate cancer who, for reasons other than prostate cancer, are unlikely to live for more than another 7 years.

Consensus-based recommendation
Offer watchful waiting to men diagnosed with potentially curable prostate cancer who choose not to accept potentially curative therapy when it is offered to them.

Consensus-based recommendation
For all men choosing watchful waiting, discuss the purpose, duration, frequency and location of follow-up with the man and, if he wishes, with his partner or carers. Source: adapted from [UK] National Collaborating Centre for Cancer. Prostate cancer: diagnosis and treatment. National Collaborating Centre for Cancer; 2014.

Consensus-based recommendation

Specialists should consider referring men without advanced incurable prostate cancer back to their general practitioners for follow-up in primary care according to a protocol the specialist suggests and/or these guidelines. If there is no evidence of significant disease progression (as indicated by 3–4 monthly PSA levels over 1 year and absence of relevant symptoms), continue monitoring by 6-monthly PSA levels. If there is evidence of significant disease progression (that is, relevant symptoms and/or rapidly-rising PSA level), refer to a member of the treating team (urologist, medical oncologist or radiation oncologist) for review.

Practice point

For men whose prostate cancer is advanced and is not curable with local treatments, follow guidelines for the management of locally advanced or metastatic prostate cancer. If no treatment is offered or accepted, monitor clinically and by PSA testing and reconsider androgen deprivation therapy if any of the following occur: symptomatic local disease progression symptomatic or proven metastasis a PSA doubling time of < 3 months, based on at least three measurements over a minimum of 6 months (this should warrant consideration of further clinical investigations).

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Health system implications

Clinical practice

Implementation of this recommendation would not require any changes in the way care is currently organised.

Resourcing

Implementation of this recommendation would have no significant implications for resourcing.

Barriers to implementation

No barriers to the implementation of this recommendation are envisaged.

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Footnotes

ⁱ Clinical questions were translated into the PICO framework: population, intervention, comparator and outcome (see Appendix 3).

ⁱⁱ Watchful waiting is another approach to monitoring a prostate cancer that was found as a result of PSA testing. It is mostly chosen when the cancer is already at an incurable stage, the man is unlikely to live for another seven years regardless of the prostate cancer or the man has decided not to have surgery or radiotherapy under any circumstances. Unlike active surveillance, a man on watchful waiting will generally not be offered potentially curative therapy if the cancer begins to grow. Treatment may be offered, however, to slow the growth of the cancer or to relieve symptoms. Watchful waiting involves regular PSA tests and clinic check-ups. Men with early prostate cancer who choose watchful waiting are more likely to have the cancer spread and are more likely to die of prostate cancer than if they had chosen immediate cancer treatment (e.g. radical prostatectomy or radiotherapy). On the other hand, men who choose immediate treatment are more likely to experience bladder, bowel or sexual problems than those who choose watchful waiting.

References

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Supporting attachments

View technical report pages 979-1063

NHMRC Evidence Statement form