Cryotherapy for Recurrent Prostate Cancer: A Detailed Guide to Salvage Treatment Options

Table of Contents

• Introduction: Understanding Recurrent Prostate Cancer
• What Is Cryoablation? The Technique Explained
• Cryotherapy Outcomes in Various Salvage Settings
• Treating Recurrence After Radiation Therapy
• The Crucial Role of Imaging and Staging at Recurrence
• Whole-Gland Salvage Cryotherapy: Results and Predictors
• Focal Salvage Cryotherapy: Targeted Treatment
• Functional Outcomes and Complications
• Comparing Cryotherapy to Other Salvage Ablation: HIFU
• Conclusion and Key Takeaways
• Source Information

Introduction: Understanding Recurrent Prostate Cancer

Prostate cancer is the most common non-skin cancer in men. While many newly diagnosed patients with low-risk disease can opt for active surveillance (close monitoring), those with intermediate or high-risk cancer often undergo definitive treatments like radiation therapy or radical prostatectomy (surgical removal of the prostate).

Unfortunately, recurrence is not uncommon. Approximately 32% of patients who undergo radiation therapy and more than 40% of men with intermediate or high-risk prostate cancer who have surgery will experience a biochemical recurrence. This means their Prostate-Specific Antigen (PSA) level begins to rise again, indicating the cancer may have returned.

Effectively treating a local recurrence (cancer that comes back in the prostate area) after radiation is challenging. While salvage prostatectomy (surgery to remove the prostate after prior radiation) can achieve good cancer control, it is associated with significant side effects, including high rates of incontinence and other complications.

This is where salvage cryotherapy comes in. Cryotherapy, also called cryoablation or cryosurgery, involves freezing cancer cells to destroy them. For many patients seeking a less invasive curative treatment for prostate cancer that returns after radiation, salvage cryotherapy may be an effective option that could reduce the risk of side effects like erectile dysfunction and urinary incontinence compared to more extensive surgery.

This article reviews the clinical outcomes of two main approaches: whole-gland (treating the entire prostate) and focal (targeting only the area of recurrence) salvage cryotherapy. We will look at disease-free survival, cancer-specific survival, and overall survival rates. We will also examine the critical role of modern imaging and how cryotherapy compares to other salvage ablation techniques like High-Intensity Focused Ultrasound (HIFU).

What Is Cryoablation? The Technique Explained

Cryoablation is a type of focal therapy, meaning it targets a specific region of the prostate. First performed in the 1960s, early techniques had high complication rates. The modern era began in 1993 when the procedure was reintroduced with real-time monitoring using transrectal ultrasound (TRUS).

One key feature of modern, image-guided focal cryoablation is the use of multiparametric prostate MRI (mpMRI). This special MRI scan helps doctors precisely locate the site of significant cancer, which is confirmed by an MRI-TRUS fusion biopsy. The mpMRI also shows prostate size, cancer regions, and their location relative to critical structures like the bladder neck, urethra, rectum, and neurovascular bundles (which affect erectile function).

Here is how the procedure typically works:

1. Planning & Imaging: Using the mpMRI and fusion software, doctors create a detailed 3D map of the prostate and the tumor.
2. Probe Placement: Hollow needles called cryoprobes are inserted through the skin of the perineum (the area between the scrotum and rectum) into the target locations in the prostate. This is guided by ultrasound and often a brachytherapy grid template.
3. Creating the "Ice Ball": Supercooled gas flows through the probes, creating ice balls that freeze and destroy the targeted tissue. Thermocouples (tiny temperature sensors) are often used to monitor tissue temperature near critical nerves and the urinary sphincter to help prevent damage.
4. Freeze-Thaw Cycles: The standard treatment involves two freeze-thaw cycles to optimize cancer cell destruction.
5. Protecting the Urethra: A urethral warming catheter is used during the procedure to protect the urethra from freezing and potential damage.

The ablation can be customized based on the cancer's location. Patterns include quadrant, hemi-gland (half), "hockey stick," or sub-total ablation. Experts generally agree the ablation zone should extend about 1 cm (0.4 inches) into the healthy tissue surrounding the visible tumor to ensure all cancer cells are eradicated.

Postoperative care is similar to other prostate procedures. Patients typically have a catheter for several days and receive pain control and antibiotics as needed.

Cryotherapy Outcomes in Various Salvage Settings

For patients with recurrent prostate cancer after radiation, salvage cryotherapy can be an effective curative option and may avoid the need for long-term androgen deprivation therapy (ADT) and its associated side effects (like hot flashes, loss of libido, and metabolic changes).

A key 2019 study by Seyaf et al. conducted a retrospective review of 75 men who underwent salvage cryoablation for biopsy-proven recurrence after radiation therapy. In this group, 70 men received whole-gland treatment and 5 underwent hemiablation (treating half the gland).

The study found a powerful predictor of success: the post-cryotherapy PSA nadir (the lowest point the PSA reaches after treatment).

• For patients whose PSA nadir was ≤ 0.5 ng/mL, the biochemical progression-free survival (BPFS) was 79.7% at 3 years and 64.7% at 5 years.
• For those with a PSA nadir > 0.5 ng/mL, the BPFS plummeted to 5.6% at 3 years and 0% at 5 years. This difference was statistically highly significant (p < 0.0001).

The researchers concluded that the PSA level after salvage treatment was the strongest predictor of long-term success without biochemical progression.

It's important to understand how success is measured. The criteria often used (Phoenix criteria—a PSA rise of 2 ng/mL above the nadir) were originally designed for radiation therapy, which works differently than ablation. Cryotherapy is an ablative (tissue-destroying) modality. While the PSA nadir is linked to success, some experts argue that follow-up with mpMRI or even biopsy might provide a more accurate picture of treatment success than PSA alone, especially after focal therapy where PSA drops can be variable.

To put cryotherapy in context, other salvage options exist. Androgen deprivation therapy (ADT) is often used. A 2008 study using a large database found that salvage therapy (mostly ADT) was not successful for 68% of men who had recurrence after initial prostatectomy and 74% of men after initial radiation. Those for whom salvage therapy failed had a higher overall death rate (24.8% vs. 6.9%). However, patients selected for ADT often have more advanced disease, so this comparison has inherent bias.

Treating Recurrence After Radiation Therapy

When prostate cancer returns after radiation therapy, patients have several options. Many receive systemic androgen deprivation therapy (ADT) without any local salvage treatment. For men with a very slow-rising PSA, watchful waiting may even be appropriate due to low prostate cancer-specific mortality.

The modern era has revolutionized how we stage recurrent disease. Traditional imaging (CT and bone scans) has limited sensitivity for locating recurrent prostate cancer. Today, staging increasingly involves prostate-specific membrane antigen positron emission tomography (PSMA PET) scans, which are far more sensitive for detecting and locating recurrence within the prostate, in pelvic lymph nodes, or at distant sites.

The success of any local salvage treatment, including cryotherapy, absolutely depends on the recurrence being localized to the prostate area and not regional or metastatic. Therefore, accurate imaging is critical for selecting the right patients.

The Crucial Role of Imaging and Staging at Recurrence

a. PSMA PET Scans
Recent research shows PSMA PET scans have higher detection rates for recurrent prostate cancer after radiation therapy compared to conventional imaging. Detection rates also correlate strongly with rising PSA levels.

• A 2017 Australian study of 419 men treated with radiation found that of those with biochemical failure, only 17% had isolated local recurrence in the prostate. The majority had distant failure (52%) or a combination of local and distant disease (31%). Higher initial PSA (>10 ng/mL) and higher Gleason scores (≥8) predicted biochemical failure.
• A similar 2017 study by Einspieler et al. of 118 men found PSMA detection rates increased with PSA: 81.8% for PSA 2-<5 ng/mL, 95.3% for PSA 5-<10 ng/mL, and 96.8% for PSA ≥10 ng/mL.
• The large 2021 CONDOR phase 3 study showed detection rates ranging from 36.2% (for PSA <0.5 ng/mL) to 96.7% (for PSA ≥5 ng/mL). The scan's accuracy (positive predictive value) was high, ranging from 75-83% for detecting recurrence in the prostate itself.

These studies highlight a crucial point: only a minority of patients (roughly 17-40%) have disease recurrence confined solely to the prostate. This makes accurate PSMA PET staging essential to avoid offering local salvage therapy like cryotherapy to patients who actually have metastatic disease.

b. Multiparametric MRI (mpMRI)
After initial therapy, mpMRI is invaluable for visualizing normal treatment changes versus residual or recurrent disease. It combines anatomical imaging with functional sequences that can suggest aggressive cancer. While PSMA PET is excellent for finding disease anywhere in the body, mpMRI provides exquisite detail about the prostate itself and is key for planning a targeted focal cryoablation procedure.

Whole-Gland Salvage Cryotherapy: Results and Predictors

Whole-gland salvage cryotherapy aims to treat the entire prostate. Studies have identified several factors that predict better outcomes:

• Pre-Salvage PSA Level: A PSA level below 10 ng/mL before salvage cryotherapy is consistently associated with better outcomes. Some studies suggest an even lower threshold of 4-6 ng/mL is ideal.
• PSA Doubling Time (PSADT): A longer PSADT (slower PSA rise) predicts better results. A PSADT of > 16 months is favorable.
• Post-Treatment PSA Nadir: As highlighted earlier, achieving a PSA nadir of ≤ 0.5 ng/mL is a very strong predictor of long-term success.
• Initial Cancer Grade: A lower initial Gleason score (≤7) is associated with better outcomes after salvage.

Reported cancer control rates vary across studies but demonstrate the potential efficacy of this approach:

• A 2008 study by Izawa et al. reported 5-year biochemical disease-free survival rates of 50-60% for carefully selected patients.
• A 2012 study by Spiess et al. found 10-year cancer-specific survival of 80% and overall survival of 60%.
• Larger, more recent analyses, like a 2013 study by Kongnyuy et al., reported pooled 5-year biochemical failure-free survival of 54-64%.

Focal Salvage Cryotherapy: Targeted Treatment

Focal salvage cryotherapy treats only the area of recurrence within the prostate, sparing as much healthy tissue as possible. The goal is to maintain cancer control while potentially reducing side effects on urinary and sexual function compared to whole-gland treatment.

Studies on focal salvage cryotherapy are promising but often involve smaller numbers of patients and shorter follow-up times than whole-gland studies.

• A 2016 study by Lagos et al. of 25 men reported a 2-year disease-free survival of 80%.
• A 2020 study by Tan et al. of 50 men showed a 3-year failure-free survival of 68.2%.
• Notably, a 2018 study by van Son et al. that included 100 men treated with either focal or hemi-gland ablation reported a 5-year metastasis-free survival of 91% and a 5-year cancer-specific survival of 98%.

Predictors of success for focal therapy are similar to whole-gland and heavily emphasize proper patient selection using advanced imaging (mpMRI and PSMA PET) to confirm the recurrence is truly localized and suitable for a targeted approach.

Functional Outcomes and Complications

While potentially less morbid than salvage prostatectomy, salvage cryotherapy still carries risks. A 2022 systematic review by Chin and Lynn assessed complications:

• Erectile Dysfunction: Reported rates ranged widely, from 25.0% to 86.2%. The risk is generally higher for whole-gland therapy than focal therapy.
• Urinary Retention (inability to urinate): Ranged from 2.13% to 25.3%.
• Rectourethral Fistula (an abnormal connection between the rectum and urethra): A rare but serious complication, ranging from 1.27% to 3.7%.
• Pelvic or Perineal Pain: Ranged from 10.71% to 31.25%.
• Other potential complications include incontinence, urethral sloughing (passing of dead tissue), and urinary tract infections.

The use of urethral warming catheters and precise image-guidance has helped reduce the rates of some of these complications, particularly fistula formation, compared to earlier cryotherapy techniques.

Comparing Cryotherapy to Other Salvage Ablation: HIFU

High-Intensity Focused Ultrasound (HIFU) is another minimally invasive, focal ablation technique that uses sound waves to heat and destroy cancer cells. Directly comparing salvage cryotherapy and salvage HIFU is difficult due to differences in studies, but some insights can be drawn.

A 2020 systematic review by Albisinni et al. that compared the two found:

• Both modalities showed similar mid-term cancer control rates.
• The review suggested salvage HIFU might have a lower complication profile, particularly regarding urinary incontinence and rectourethral fistula, based on the analyzed studies. However, the authors noted significant variability and bias in the available data.
• They concluded that both are valid options, with the choice often depending on surgeon expertise, available technology, and specific patient anatomy.

Ultimately, the decision between cryotherapy, HIFU, or other salvage options should be made through detailed discussion with a multidisciplinary team of urologic oncologists and radiation oncologists, considering all patient-specific factors.

Conclusion and Key Takeaways

Salvage cryotherapy is a well-established and effective treatment option for localized recurrence of prostate cancer following prior radiation therapy. Its success is highly dependent on careful patient selection.

Key points for patients to understand:

1. Imaging is Paramount: Modern PSMA PET scanning is essential to confirm the recurrence is truly localized to the prostate or prostate bed before considering local salvage therapy like cryotherapy.
2. PSA Nadir Predicts Success: Achieving a very low PSA (≤ 0.5 ng/mL) after cryotherapy is the strongest predictor of long-term success without further recurrence.
3. Two Main Approaches: Whole-gland therapy treats the entire prostate and has longer-term outcome data. Focal therapy targets only the recurrent tumor, aiming to spare healthy tissue and potentially reduce side effects, though long-term data is still maturing.
4. Understand the Risks: While less invasive than salvage surgery, cryotherapy carries risks, including erectile dysfunction, urinary problems, and rare serious complications like fistula. Focal therapy may lower some of these risks.
5. It's One of Several Options: Cryotherapy should be compared with other salvage options like HIFU, salvage prostatectomy, or systemic therapies in the context of your specific case, cancer characteristics, and personal priorities regarding cancer control versus quality of life.

The field continues to evolve with better imaging and more refined techniques, improving the ability to select the right patients and deliver effective, targeted treatment for recurrent prostate cancer.

Source Information

Original Article Title: The Role of Whole-Gland and Focal Cryotherapy in Recurrent Prostate Cancer
Authors: Faozia Pio, Andeulazia Murdock, Renee E. Fuller, and Michael J. Whalen
Publication: Cancers 2024, 16, 3225.
This patient-friendly article is based on the peer-reviewed research review cited above. It is intended for educational purposes to help patients understand complex medical information and should not replace personalized advice from a qualified healthcare professional.