Exploring High-Intensity Focused Ultrasound as an Organ-Sparing Option for Prostate Cancer

The definitive treatment of prostate cancer has historically relied on whole-gland treatment. Advances in surgical techniques and radiation technology have improved upon these therapies, but significant urinary and sexual adverse effects remain. Men continue to seek less morbid and less invasive options.

Organ-sparing surgical treatments are well described and considered standard of care in the treatment of many cancers. Even within urologic oncology, organ-sparing surgeries are offered to patients with renal and bladder malignancies. It begs the question: are there organ-sparing options for men with prostate cancer?

Pushing the Boundries of Prostate Cancer Treatment

The goals of organ-sparing treatment would be to offer long-term oncologic control and minimize the adverse effects of whole-gland treatment. The term to describe this is focal therapy and it puts an emphasis on quality of life. Opponents of this type of therapy have argued that prostate cancer is a multifocal disease and thus organ-sparing treatment is not appropriate. It is true that prostate cancer is multifocal, but it is also true that most men have an index lesion that is larger and higher grade, which drives the overall tumor biology.1 Secondary lesions are small and low grade, and as a result are cancer for which active surveillance is normally offered. Evidence from most studies suggests that at least 30% of men with prostate cancer have unilateral clinically significant disease that would be potentially suitable for focal therapy.

When considering organ-sparing surgeries, accurate tumor location becomes paramount. Advancements in prostate multiparameteric MRI (mpMRI) offer the ability to localize cancers like never before. Using a breast cancer analogy, the mpMRI is akin to mammography, and focal therapy, or prostate lumpectomy, is analogous to partial mastectomy.

Many different techniques are being studied as focal therapy, including high-intensity focused ultrasound (HIFU), cryotherapy, irreversible electroporation, radiotherapy, photodynamic therapy, laser interstitial therapy, gold nanoparticle photothermal, and water vapor.

HIFU has become one of the most adopted focal therapy techniques around the world. The technology gained more initial traction outside the United States, and was not approved by the FDA until 2015 to be used for the destruction of prostate tissue (not specifically prostate cancer). HIFU is an outpatient procedure performed under anesthesia. A transrectal ultrasound is used to map the prostate and plan what area of the prostate to treat. In addition, mpMRI images can be fused with the real-time ultrasound images for more accurate tumor localization. The high-intensity ultrasound waves kill tissue with both thermal and mechanical destruction.

Although HIFU and focal therapy have been studied in all prostate cancer risk groups, most investigators in the field would agree that patients with intermediate-risk prostate cancer are the ideal candidates.

HIFU By the Numbers

Complications are rare but can include urinary retention, dysuria, hematuria, and urinary tract infection. An early study on HIFU focal therapy from France evaluated efficacy and quality-of-life outcomes of 111 patients. In this study, 97% of men remained continent and 78% of men had preserved erectile function.²

Another trial, one of the largest trials of men undergoing HIFU focal therapy, reported on just over 1000 men in the United Kingdom. In this study, 81% of men were free from needing radical treatment at 96 months.³

A randomized trial comparing radical prostatectomy with focal therapy would be ideal to determine long-term efficacy; however, this is a difficult proposition for many reasons. A study such as this would require significant equipoise on the provider’s part, which may be problematic. In addition, based on statistical modeling, to show an overall benefit between the 2 treatments, an estimated 2000 to 8000 patients would need to enroll in such study. Finally, because prostate cancer is typically a slow-growing disease, patients would need to be followed for at least 10 to 15 years.

While the feasibility of a randomized trial is being debated, a propensity score-matched analysis to compare cancer control outcomes of focal therapy with radical prostatectomy has been done.⁴ Patients were matched 1:1 using numerous clinical measures, including year of treatment, age, prostate-specific antigen, Gleason score, stage, and cancer core length. The primary outcome was failure-free survival defined as transition to local salvage therapy or systemic therapy or development of metastases. Investigators reported that in patients with low/intermediate risk prostate cancer, oncological outcomes over 8 years were similar between focal therapy and radical prostatectomy.⁴

The field of focal therapy for prostate cancer has advanced considerably over the last decade. Thus, many new questions have arisen, including the following:

• How do we select appropriate candidates?
• How do we best conduct follow-up to identify persistent or new prostate cancers?
• How do we treat recurrences?

It has created a paradigm shift in our true end point of treatment: preventing the development of nonlocalized disease compared with the historical treatment goal of cure. This provoking thought is perhaps best summarized by the quote from Willet F. Whitmore Jr, MD, who was chairman of the Urology service at Memorial Sloan Kettering Cancer Center in New York, New York, for more than 30 years: “Is cure possible? Is cure necessary? Is cure possible only when it is not necessary?"

References

1. Liu W, Laitinen S, Khan S, et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med. 2009;15(5):559-565. Published correction in Nat Med. 2009;15(7):819.
2. Rischmann P, Gelet A, Riche B, et al. Focal high intensity focused ultrasound of unilateral localized prostate cancer: a prospective multicentric hemiablation study of 111 patients. Eur Urol. 2017;71(2):267-273. doi:10.1016/j.eururo.2016.09.039
3. Stabile A, Orczyk C, Hosking-Jervis F, et al. Medium-term oncological outcomes in a large cohort of men treated with either focal or hemi-ablation using high-intensity focused ultrasonography for primary localized prostate cancer. BJU Int. 2019;124(3):431-440. doi:10.1111/bju.14710
4. Shah TT, Reddy D, Peters M, et al. Focal therapy compared to radical prostatectomy for non-metastatic prostate cancer: a propensity score-matched study. Prostate Cancer Prostatic Dis. 2021;24(2):567-574. doi:10.1038/s41391-020-00315-y