Appropriate use criteria for imaging evaluation of biochemical recurrence of prostate cancer after definitive primary treatment

Imaging is often used to evaluate men with biochemical recurrence (BCR) of prostate cancer after definitive primary treatment (radical prostatectomy [RP] or radiotherapy [RT]). The goal of imaging is to identify the source of elevated or rising serum prostate-specific antigen (PSA) levels because subsequent management depends on disease location and extent. Salvage therapy (with surgery or radiation) may be considered for select cases with BCR to provide additional potential opportunity for cure. The salvage treatment strategy may be extended to regional adenopathy. Patients with limited distant metastases on imaging, referred to as oligometastatic disease (≤5 demonstrable lesions), may be candidates for close observation, systemic hormonal therapy, or metastases-directed therapies with or without local therapy, depending on sites of recurrence. Patients with metastatic disease are typically treated with systemic therapy. The purpose of this document is to describe the appropriate use of imaging in the diagnostic evaluation of patients with BCR after definitive primary treatment. The imaging modalities that were considered included CT, bone scan, and the U.S. Food and Drug Administration (FDA)-approved PET radiotracers that track malignancy- induced lipogenesis (11C-choline) and amino acid metabolism (18F-fluciclovine). The prostate-specific membrane antigen (PSMA)-targeted monoclonal antibody, 111In-capromab pendetide, is also included for historical perspective because it is neither available nor used clinically. The new class of PSMA-targeted PET radiotracers have generated considerable interest and are discussed briefly, although these agents are currently not approved for routine clinical use in the United States. Moreover, whole-body MRI (WB-MRI), with or without diffusion-weighted imaging, is excluded. Although WB-MRI may have utility in this clinical setting, particularly for the detection of bone metastases, the variability in availability, accessibility, quality, and standardization, as well as the fact that there are no currently established procedural is ≥ 0.2 ng/mL, measured 6-13 wk after surgery, and confirmed by a second determination of a PSA level of > 0.2 ng/mL (7). In patients treated with RT, the ASTRO Phoenix Criteria defines BCR as a rise in PSA level of 2 ng/mL or more above the nadir regardless of androgen deprivation therapy (ADT) (8). The significance of biochemically recurrent disease varies considerably according to individual risk factors. One clinically important prognostic variable is PSA doubling time. For instance, prostate cancer-specific survival is approximately 90% in patients with a PSA doubling time of ≥ 15 mo (highest quartile), whereas it is about 20% for patients with a PSA doubling time of, 3 mo (lowest quartile) (9). In part because of this wide variability in disease aggressiveness, coupled with competing causes of mortality and the typically long time to documented metastatic disease by standard imaging (median metastasis-free survival is 10 y in patients with BCR and no treatment), there is no defined standard management for this patient population (10). The development of metastasis in a patient signals that a change in treatment approach is warranted. Since the 1940s, the foundation of treatment for metastatic prostate cancer has been testosterone-lowering therapy. It is likely that the use of more sensitive imaging techniques will identify patients earlier who are at higher risk of developing overt metastases identified by more commonly used techniques. In some scenarios, earlier intervention in the disease process may result in improved outcomes for patients, as has been seen with postoperative RT (11). RT after a prostatectomy is commonly used to eradicate microscopic residual disease in the prostate bed, thereby reducing the risk of recurrence. Defining who needs postoperative RT is most often based on surgical pathology and postoperative PSA because standard imaging does not have sufficient sensitivity to identify early recurrences in the PSA range where salvage treatment is more likely to be curative. There is growing evidence that genomic biomarkers (e.g., Decipher, GenomeDx Biosciences, San Diego, CA) can have utility in this clinical setting, although it remains unclear as to how this information affects imaging choice (12,13). In the adjuvant setting, pathology (pT3a/b or surgical margins positive for disease) currently drives the addition of RT. In the salvage setting, when men have persistently detectable PSA (PSA persistence) or a delayed rise in PSA level (≥0.2 ng/mL), conventional imaging does not have sufficient sensitivity to identify early recurrences. The ability to detect residual or recurrent disease within the pelvis can affect RT dose and target. In the absence of molecular imaging, the question of whether to include pelvic lymph nodes in the RT field in patients with pathologic node-negative disease is a question that has been studied by the Radiation Therapy Oncology Group (RTOG) 0534 trial and is awaiting final results. The first report from RTOG 0534 (3-arm randomized trial) shows gains in freedom from progression with the addition of short-term (4-6 mo) ADT to prostate bed radiation and further gains with the inclusion of pelvic lymph node RT and short-term ADT over a PSA level of 0.34 ng/mL (14). With the ability to visualize prostate cancer cells, molecular imaging can help define RT treatment fields. Similarly, molecular imaging can identify patients who have early metastatic disease and could avoid RT to the prostate fossa. The use of molecular imaging to identify oligometastatic prostate cancer has allowed for additional treatment strategies in patient care (15). Studies show a benefit (e.g., biochemical progression-free survival, distant progressionfree survival) to metastasis-directed stereotactic body RT in the setting of oligometastatic prostate cancer (16-18). Molecular imaging can enhance the postoperative treatment algorithm for prostate cancer patients by identifying targets for RT. This document is the product of an extensive literature search in combination with expert opinion. Its intent is to provide upto- date information and recommendations for AUC for approved (in the United States) imaging technologies in the setting of BCR of prostate cancer after definitive treatment. We also discuss the outlook for upcoming imaging technologies that are anticipated to be approved in the United States relatively soon.