Salvage Cryoablation of the Prostate

Introduction

According to data from the Surveillance, Epidemiology, and End Results (SEER) Program, 233,000 estimated new cases of prostate cancer (PCa) will have been diagnosed in the United States in 2014, and approximately 29,480 men will die of this disease. Common treatment options for localized PCa include radical prostatectomy (RP), radiation therapy (RT), or active surveillance. External beam radiation therapy (EBRT) and brachytherapy (BT) have become popular choices for the management of localized PCa with up to one third of patients selecting RT as their primary treatment.

Among patients undergoing RT for localized PCa, some will experience a recurrence of their disease, which is most often detected by a rise in the serum prostate-specific antigen (PSA). One study has shown that among 4839 patients, 1582 (33%) had biochemical failure by PSA criteria (American Society for Therapeutic Radiology and Oncology – ASTRO), while 416 (9%) had local failure and 329 (7%) had distant failure after external beam radiation therapy (EBRT) for clinically localized diseases. Another study using data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database, identified 587 out of 935 patients (63%) to have a rise in their serum PSA within 10 years after RT. Traditionally, these patients receive androgen deprivation therapy (ADT) with only a few being offered salvage treatments.

Potential salvage options for radiorecurrent PCa include salvage RP, BT, high-intensity focused ultrasound, and cryotherapy. A major limitation to all of these therapies has been the morbidity of treatment in the salvage setting, which is compounded on the secondary adverse effects of primary RT. Although salvage RP has the longest history and best likelihood for local control, it is generally more technically challenging due to radiation-induced fibrosis and obliteration of tissue planes. As a result it is associated with worsening urinary incontinence, erectile dysfunction, anastomotic strictures, and rectal injury.

Cryotherapy has emerged as an alternative salvage strategy with more contemporary technologies allowing an improvement in oncological outcomes and complication rates over the past few decades shifting this treatment modality from investigational status to an established therapeutic option. In 2008, the American Urological Association (AUA) Best Practice Consensus Statement recognized cryoablation of the prostate as an established treatment option for men with newly diagnosed or radiorecurrent organ-confined PCa. However, controversy still exists over the selection of appropriate patients to allow maximum likelihood of cure with minimal morbidity. The objective of this chapter is to provide an update on salvage cryotherapy with a focus on patient selection and a discussion of oncological and adverse outcomes.

Detection of radiorecurrent prostate cancer

The two most widely used definitions for failure after primary radiotherapy are the ASTRO definition of three consecutive rises after the PSA nadir and the Phoenix definition of PSA nadir +2 ng/mL. The ASTRO definition has been criticized for being poorly linked to clinical progression, as small consecutive rises in PSA can constitute meeting the definition without showing any significant concern for clinically progressive disease. As a response to this and other deficiencies of the ASTRO criteria, the Phoenix definition was created. The goal of the Phoenix definition is to select patients who are more likely to go on to experience clinical progression rather than just biochemical recurrence alone. Therefore, the threshold to reach this definition is much higher, which results in it having a lower sensitivity and higher specificity for detecting recurrence. Although both definitions are currently used in clinical practice, neither definition can reliably discern between patients with local recurrence, who may benefit from local salvage therapy versus those with systemic progression, who are unlikely to benefit from such treatments.

PSA kinetics continues to be one of the most helpful predictors of outcome after treatment. A pretreatment PSA velocity > 2.0 ng/mL per year in 18 months prior to diagnosis has been found to be associated with prostate-cancer-specific mortality and all-cause mortality after RT or RP. Therefore, patients with a pretreatment PSA velocity > 2.0 ng/mL per year at initial presentation are not the optimal candidates for local salvage therapy at the time of PSA failure due to their high likelihood of having occult micrometastases. Zagars and Pollack observed that a PSA doubling time (PSA-DT) < 8 months had a 7-year actuarial metastatic rate of 54% while patients with a PSA-DT > 8 months had only a 7% metastatic rate. Spiess et al. reported a statistically significant difference in PSA doubling time (12.3 months vs. 5.6 months) for men with lower (<10 ng/mL) versus higher (≥10 ng/mL) PSA level before salvage cryoablation. Izawa et al. reported a 5-year disease-free survival (DFS) of 57% for precryotherapy PSA ≤ 10 ng/mL versus 23% for PSA > 10 ng/mL ( p = 0.004). Although all of these thresholds require further validation in prospective studies, it appears that the best candidates are those with a low serum PSA and a long doubling time prior to salvage therapy. Retrospective studies have suggested the optimal candidates should have a PSA < 10 ng/mL, and a PSA-DT > 8 months, preferably >12 months. However, prospective trials are desperately needed in the salvage setting to help us understand who the best candidates are for local salvage after failed radiation.

The usual response to BCR is to restage the patient and the most commonly used imaging modalities for this purpose are computed tomography (CT) and bone scan. However, molecular imaging modalities, such as positron-emission tomography (PET) CT, are gaining popularity in restaging patients with BCR. Choline is a compound used in phospholipid biosynthesis that shows increased uptake in tumor cells, and it was recently approved by the US Food and Drug Administration for detection of recurrent PCa. Promising results have been obtained with newer PET tracers such as choline and fluoride for the detection of distant disease. Generally, PET provides good sensitivity and specificity in detecting distant or regional PCa recurrence; however, these numbers are highly dependent on the serum PSA level, with better detection at higher PSA levels.

MRI has also gained popularity in PCa detection, localization, and staging. The interpretation of PCa on T2-weighted MR imaging can be affected by false-positive findings such as prostatitis, postbiopsy hemorrhage, and fibrosis. To improve its diagnostic accuracy, functional MR imaging techniques have been developed, such as diffusion-weighted, proton spectroscopic, and dynamic contrast-enhanced MR imaging. The addition of these parameters has enhanced the ability to localize cancer within the prostate allowing improved detection of local recurrences as well as guide biopsy to areas of the gland that are suspicious for recurrence.

Before considering any kind of local salvage therapy, a local recurrence of PCa needs to be confirmed with a prostate biopsy and reviewed by a pathologist with the knowledge of pathological radiation changes in the prostate after RT. The timing of the biopsy can be of significance since some studies have reported that approximately 30% of positive biopsies obtained 12 months after radiation will convert to negative by 24–30 months. Due to the potential morbidity salvage therapy can bring, it becomes crucial to determine the patients who are more likely to acquire a local disease in order to spare unwarranted side effects in those who are unlikely to benefit due to systemic progression. Even with today’s available diagnostic modalities, none of these tools or even the use of all of them can reliably discern between localized versus distant recurrence.