Following up prostate cancer in primary care

In 2009, prostate cancer had the greatest incidence of all cancers in New Zealand, accounting for 16.1% of cancer registrations (30.2% of all male registrations).¹Although prostate cancer is the third most common cause of cancer death in males, it has a favourable survival ratio: between 2004 and 2009, 91.3% of men with prostate cancer survived past five years, compared with 61.8% of people with colorectal cancer.²

There are a number of different options for treatment of localised prostate cancer, that vary depending on the health and age of the patient, the stage of the disease (largely determined by biopsy results and prostate-specific antigen [PSA] level), and personal preference. These options include surgery and/or radiotherapy with intent to cure, hormone treatment or monitoring for progression of disease.

The majority of men with a diagnosis of localised prostate cancer undergo definitive treatment, e.g. radical prostatectomy, external beam radiotherapy or brachytherapy (internal radiotherapy using radioactive “seeds”) with intent to cure.

Follow-up treatment after definitive treatment for localised prostate cancer includes:

• Patient and family/whānau education and psychosocial support
• Clinical assessment for local or distant recurrence, primarily with PSA testing
• Ongoing assessment and treatment of adverse effects secondary to the definitive treatment, such as urinary incontinence, erectile dysfunction
• Monitoring of long-term adverse effects from the definitive treatment

Because prostate cancer is generally slow growing, some patients with low-risk localised cancer may be offered “active surveillance” through regular PSA testing and have definitive treatment only if there is evidence of progression of the cancer. Men are considered to be at low risk if they have a:³

• PSA level of < 10 ug/L, and
• Gleason score (histological grade) of ≤ 6, and
• Clinical stage of T1-T2a (confirmed tumour involving no more than one half of the prostate gland)

A “watchful waiting” approach may be taken in men with prostate cancer who are unsuitable for radical treatment, e.g. those with disseminated disease, co-morbidities precluding radical treatment, or older men with limited life expectancy where the cancer is unlikely to progress significantly over this time.³ If PSA levels begin to rise rapidly, or if symptoms develop, hormonal treatment (e.g. androgen blockade) is the preferred treatment option.³

Androgenic hormones can stimulate prostate cancer growth, therefore androgen deprivation treatment (or androgen blockade) may also be used in various other circumstances, such as an addition to radical radiotherapy, pre- or post- surgery or as a means of treating metastatic prostate cancer.³

Table 1 summarises the follow-up procedures for the different treatment options for men diagnosed with localised prostate cancer.

DRE = Digital rectal examination PSA = Prostate specific antigen

A rise in serum PSA is usually the only indication of a recurrence in men who have been treated for localised prostate cancer with radical prostatectomy or radiotherapy. Although the role of PSA for prostate cancer screening is not clear and often controversial, PSA is a reliable and sensitive tumour marker that increases in the majority of men with recurrent cancer. However, there is little evidence that determines the frequency that PSA should be requested after definitive treatment, and the significance and extent of the increase in the PSA level depends on the type of definitive treatment. Most clinicians are guided by the PSA velocity (the rate of the change) and the grade of the tumour rather than by absolute levels.

PSA testing intervals

Men who have undergone radical prostatectomy or radiotherapy should have their PSA level checked:³

• Six weeks after treatment (unless adjuvant hormonal treatment is being given)
• At least every six months for the first two years
• Then annually

Men in an active surveillance protocol should have their PSA level checked regularly, e.g. every six months, however, the PSA velocity should be used to guide the frequency of testing.

Men who adopt a watchful waiting approach (no intention to cure) should have their PSA measured at least annually, as guided by the velocity of change.³

The significance of an increase in PSA

An increasing PSA level after treatment is regarded as a biochemical recurrence of cancer. Regardless of the initial treatment, it is estimated that one-third to one-half of patients will have a biochemical recurrence.⁵ The significance of this recurrence, however, is not always clear, e.g. it does not necessarily indicate metastatic disease, which is estimated to occur in less than one-third of patients that have rising PSA levels after radical prostatectomy.⁵

Velocity and the PSA doubling time are used to guide further investigation and treatment during monitoring. Velocity refers to the rate of change over time between PSA measurements. The PSA doubling time is the length of time for PSA to double based on an exponential growth pattern. PSA doubling time has been shown to be a strong predictor of clinical progression and cancer mortality.⁵ A man with a PSA level that has doubled slowly, e.g. over 12 months, is more likely to have local recurrence and a less aggressive tumour than a man with a PSA doubling time of less than six months.^5,6

The measurement and use of PSA velocity and doubling time to guide management has been described as “an art, not a science” because the ideal number of times that PSA should be tested and the time period between these tests has not been determined.⁶ NICE guidelines (United Kingdom) recommend that a minimum of three PSA measurements be carried out over a least a six-month period to estimate the PSA doubling time.³

Rises in PSA level must also be interpreted in the context of the specific treatment received. During a radical prostatectomy, almost all the prostate tissue is removed and PSA should become undetectable within three to six weeks. PSA levels > 0.2 ug/L (or > 0.05 ug/L if an ultrasensitive PSA assay is used) after this time, would indicate that there may be residual or recurrent cancer, and this should be discussed with an urologist.^5,7

The fall in PSA levels after radical radiotherapy is much slower, and may take 18 months to four years to reach the lowest point. An increase in PSA level to > 2 ug/L (or any persistently increasing levels) after radical radiotherapy warrants discussion with a radiation oncologist, but this can generally only be assessed two to three years after treatment.^5,7 A further complicating factor is the PSA bounce phenomenon, which is a benign rise in PSA levels in some patients after radiotherapy (most commonly brachytherapy) due to apoptosis (cell death). This tends to resolve spontaneously within 12 months.⁸

N.B. 5α-reductase inhibitors such as finasteride and dutasteride lower PSA levels by approximately 50%. PSA results should be doubled to get an indication of the patient’s true PSA level, if they have been using these medicines.^5,7

The Memorial Sloan-Kettering Cancer Centre has an online nomogram to calculate PSA doubling times, see: http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx

Patients should be referred for an isotope bone scan if symptoms and rising PSA trends are suggestive of metastatic disease.³

Men who report lower gastrointestinal tract symptoms after radiotherapy should be investigated due to the risk of radiation-induced enteropathy or secondary malignancies. The NICE guidelines recommend flexible sigmoidoscopy every five years for men who have previously received radical radiotherapy.³

There are no consistent guidelines in relation to bone mineral density scanning for men using androgen deprivation therapy. A baseline DEXA scan should be performed. In general, the follow-up DEXA scan should occur at 12 months, or earlier (six months) if the baseline DEXA scan suggests pre-existing osteopenia or a borderline result.¹⁰