Early Stage Prostate Cancer: Biochemical Relapse

21 Early Stage Prostate Cancer: Biochemical Relapse

Andrew Jackson and Teresa Gray Hayes

INTRODUCTION

After definitive treatment of localized prostate cancer, routine monitoring of serum prostate-specific antigen (PSA) for early detection of relapse of disease is common practice. This frequently results in finding a rising PSA in the absence of detectable local or distant disease, which is termed biochemical relapse. Evaluation and subsequent management of rising PSA after treatment of localized prostate cancer is dependent on the original treatment modality.

BIOCHEMICAL RELAPSE AFTER RADICAL PROSTATECTOMY

After radical prostatectomy, all prostate tissues should have been removed and therefore PSA should not be detectable in the serum postoperatively. The American Urological Association (AUA) defines biochemical recurrence as serum PSA of greater than 0.2 ng/mL after prostatectomy in the absence of systemic disease (1). In cases where the postprostatectomy serum PSA does not decrease to undetectable levels or cases of early biochemical relapse with rapid PSA rise, one should suspect systemic disease rather than biochemical-only recurrence.

BIOCHEMICAL RELAPSE AFTER RADIATION THERAPY

Defining biochemical recurrence after radiation therapy (RT) is more challenging. Serum PSA levels slowly decrease after completing RT for localized prostate cancer. The nadir 22serum PSA level is expected at 18 months or more posttreatment (2). While lower nadir PSA levels have better prognosis, there is no absolute or relative PSA nadir that is associated with definitive treatment success. It is therefore necessary to define recurrence relative to the PSA nadir for each individual patient. The American Society for Radiation Oncology (ASTRO) defines biochemical relapse as a serum PSA 2 ng/mL greater than the nadir PSA level (3). This measurement should be repeated to confirm the level and to exclude a PSA bounce. PSA bounce is a phenomenon wherein the serum PSA level rises transiently between 12 and 18 months after radiation treatment but is not associated with relapse or failure of the primary treatment (4).

MANAGEMENT OF PSA INCREASE

While biochemical recurrence is common, it is not necessarily predictive of development of metastatic disease or of cancer-specific mortality. Initial management of PSA increase should include serial PSA monitoring, evaluation for local and distant disease with imaging, and prostate bed or other biopsies as guided by imaging results. Many patents will have biochemical evidence of disease with an indolent course. Thus, risk stratification is important in counseling patients in these clinical situations. PSA doubling time and Gleason score have been demonstrated to be independent predictors of prognosis in the event of biochemical relapse. Individuals with a PSA doubling time greater than 12 to 15 months are more likely to have an indolent course, whereas those with PSA doubling times less than 3 months are at 20-fold higher risk of cancer-related death compared to those with longer doubling times. The Gleason score from initial diagnosis or prostatectomy remains a significant prognostic factor in biochemical relapse. Men with biochemical relapse and Gleason scores of less than 7 are at lower risk of developing metastatic disease and cancer-related death compared to those with scores of 7 to 10 (5,6). Additionally, it is important to take into account the age of the patient, comorbid medical conditions, and personal preferences when counseling regarding management of biochemical recurrence.

23SALVAGE THERAPY AFTER RADICAL PROSTATECTOMY

In men with biochemical relapse after radical prostatectomy and no evidence of metastatic disease, consideration of salvage external beam radiation therapy (EBRT) is recommended. While there are no randomized studies of salvage EBRT versus observation, several retrospective studies support prolonged disease-free survival in patients who received salvage EBRT (7). For men with particularly high-risk disease at the time of initial surgery—Gleason score 8 or more, seminal vesicle invasion, preoperative PSA more than 20—it is worth considering EBRT with concurrent androgen deprivation therapy (ADT) for 6 months (8). ADT, is appropriate for men who are not candidates for, or do not want, salvage EBRT but warrant treatment. Alternately, in older men or men with severe comorbidities, observation is a reasonable option.

SALVAGE THERAPY AFTER DEFINITIVE RADIATION THERAPY

There are several options for local salvage therapy of biochemical relapse after definitive RT, including radical prostatectomy, cryotherapy, and brachytherapy. No prospective clinical trials have evaluated local salvage therapies versus observation, and thus, biopsy-proven local recurrence and selection of appropriate patients is critical when considering local salvage therapy after definitive RT. Men who had earlier stage, lower risk disease (T1 or T2, Gleason score less than 8) at the time of diagnosis have been shown to have better outcomes relative to men with high-risk disease at diagnosis (9). Additionally, men with serum PSA levels less than 10 ng/mL at the time of salvage surgery have better outcomes (10). Men with high-risk disease at the time of initial diagnosis are less likely to benefit from local salvage therapies for treatment of biochemical relapse after RT, as they are more likely to progress to systemic disease. Such patients do better with ADT or observation. In appropriately selected men with biochemical relapse after definitive RT who have a life expectancy of more than 10 years, it is reasonable to consider salvage radical prostatectomy (11). Cryotherapy and brachytherapy are also reasonable salvage options. However, these are less well studied than salvage radical prostatectomy. Given the lack of clinical evidence comparing local salvage therapies to one another or to observation, it is important to take into account available expertise and experience when discussing salvage treatment options with patients (Figure 3.1).