Salvage Therapy for Locally Recurrent Prostate Cancer After External Beam Radiation Therapy

Introduction

External beam radiation therapy (EBRT) is a commonly applied treatment modality for patients with localized prostate cancer, with up to 35% of patients with prostate cancer undergoing EBRT as first-line therapy. EBRT is associated with excellent outcomes for patients with localized disease, and outcomes associated with the use of EBRT in this patient population are generally thought to be equivalent to those achieved with radical prostatectomy (RP). Following definitive EBRT, patients typically undergo routine disease surveillance with serial digital rectal exams and prostate-specific antigen (PSA) screening. The majority of disease recurrences are detected by a rising serum PSA – biochemical recurrence (BCR) or failure. For patients who are treated with EBRT or brachytherapy, BCR is defined either as three consecutive serum PSA increases after achievement of a nadir (the American Society for Radiation Oncology [ASTRO] definition) or a PSA value of nadir plus 2 ng/mL (the Phoenix definition). Regardless of which definition is used, several disease factors are known to predict for BCR, including clinical T stage, biopsy Gleason score, and the PSA doubling time.

While most patients undergoing primary EBRT for prostate cancer achieve long-term clinical disease-free survival and biochemical relapse-free survival (BRFS), about 35–50% of patients with high-risk disease, 25–45% of patients with intermediate-risk disease, and 20–30% of patients with low-risk disease will experience a BCR within 10 years after treatment. In the setting of post-EBRT prostate cancer recurrence, it is common practice to prescribe long-term systemic androgen deprivation therapy (ADT) in the form of luteinizing hormone releasing hormone (LHRH) agonists and/or androgen receptor blockers. However, as distant metastasis only develops in a small subset of patients with BCR, many patients may be eligible for local salvage therapy, either with or without concomitant ADT. This chapter will review the evaluation of post-EBRT patients with BCR, the indications and options for local salvage therapy, and published outcomes and toxicities of each local salvage therapy modality.

Although BCR is known to predict for inferior survival, the time interval between biochemical failure and the development of distant metastasis is generally fairly lengthy. In a study from Johns Hopkins University describing the outcomes of patients with biochemical failure after radical prostatectomy who received no salvage therapy, only 34% of patients developed distant metastatic disease within the study period (median follow up of 5.3 years). In patients who did develop distant metastases, the median time to development of metastatic disease was 8 years. Similarly, in a recently published randomized trial by the Radiation Therapy Oncology Group (RTOG), the 10-year rate of BCR was 26% in patients receiving EBRT with concurrent ADT, with a corresponding 10-year rate of distant metastasis of only 6%. Finally, in a study of 151 men who had undergone definitive EBRT for prostate cancer and were found to have a rising PSA with no salvage therapy, there was a median interval of 3 years between biochemical progression and clinical recurrence. The results of these studies suggest that in patients with BCR of prostate cancer, there may be a window of opportunity in which local salvage therapy may eliminate the focus of recurrent disease before distant metastatic disease has a chance to develop. Therefore, aggressive local salvage therapy may be indicated in a potentially large proportion of these patients. Nonetheless, while the inference that a significant portion of patients with recurrent prostate cancer after EBRT may be candidates for local salvage therapy, the adoption of local salvage therapy in this setting has not been widely adopted. A recent analysis of the British Columbia Tumor Registry found that only 2% of patients who were eligible for post-EBRT local therapy between 1999 and 2000 received local salvage treatment, suggesting that local salvage therapy is underutilized for localized prostate cancers after EBRT. As more data become available describing outcomes and toxicities associated with local salvage therapy, however, it is conceivable that this approach may become more widely utilized.

For patients with BCR after primary EBRT, there is no standard of care for local salvage treatment. Although several modalities have been utilized in this setting, the published literature for local salvage therapy is somewhat sparse, and the majority of reports are single institution retrospective series. For any patient who is being considered for local salvage therapy after prostate EBRT, the choice of a salvage modality should be made after a careful consideration of several patient and disease factors that may influence the oncologic and functional outcomes as well as the toxicities associated with salvage treatment.

Evaluation

In patients being considered for local salvage therapy after EBRT, it is critical to exclude the presence of distant or regional metastatic disease prior to committing to definitive local therapy. Therefore, all patients should undergo imaging of the skeletal system with a bone scan (although this test is thought to be fairly insensitive if the PSA level is less than 20 ng/mL ) and evaluation of the pelvic lymph nodes using either computed tomography (CT) or magnetic resonance imaging (MRI). As MRI is more sensitive than CT for imaging of the prostate gland and seminal vesicles (with up to 97% sensitivity for prostate cancer localization within the peripheral zone of the prostate), it may be considered the preferred modality for imaging the pelvis in this setting. Finally, all patients being considered for local salvage therapy should have a prostate biopsy performed. The purpose of the biopsy is not only to confirm the presence of locally recurrent disease within the prostate but also to garner important pathologic details, such as Gleason score, that will provide important oncologic prognostic information, helping to guide treatment decision-making for definitive local salvage therapy.

Local salvage treatment options

In patients with biopsy-proven localized recurrence who qualify for local salvage therapy, the treatment options include RP, cryotherapy, or brachytherapy. The choice of salvage modality should incorporate each individual patient’s risk of disease progression, the risks and toxicities of each modality, and the patient’s individual preferences. Furthermore, in patients with a short life expectancy, long PSA doubling time, or significant medical comorbidities, it may be most appropriate to opt for a course of disease surveillance.