Focal therapy as standard of care for prostate cancer


Where did focal therapy find its place in the treatment of prostate cancer? This was discussed at the 2022 meeting of the American Urological Association (AUA) during the plenary lecture entitled “Second opinion cases: Focal therapy for prostate cancer—Should it replace standard of care?” Michael Koch, MD, Indiana University School of Medicine, moderated the session; panelists were Kelly Stratton, MD (University of Oklahoma School of Medicine) and Scott Eggener, MD (University of Chicago School of Medicine).

Dr. Koch began by reviewing the prevalence of prostate cancer in the United States, where nearly 200,000 men continue to be diagnosed each year. The vast majority will survive at least 5 years, and for men with localized prostate cancer, many will live 10-20 years after undergoing treatment. Understanding this is critical when discussing treatment options with patients, as many treatment modalities have consequential permanent side effects. He noted that over the past 10 to 15 years there has been an increase in the use of active surveillance for patients with low-risk disease and an increase in radical therapy for those with a high-risk disease. Trends for treatment of patients with intermediate-risk disease were split between surgery (40%) and radiotherapy (40%), with active surveillance being used for only a small proportion of these patients. Unfortunately, Dr. Koch has painted a picture that shows that for nearly 40 years, there have been no significant changes in the approach to treating patients with intermediate-risk prostate cancer.

The beginnings of focal ablation therapy

A 2017 study that assessed decisional regret after treatment for prostate cancer found that approximately 15% of patients who underwent surgery or radiation therapy had major decisional regret.1 This regret was mostly associated with sexual or gastrointestinal dysfunction. This paved the way for focal therapy, especially if it reduced the side effect profile seen with whole gland therapy. This approach, introduced in 2008, was supported by the results of a small study evaluating focal therapy with a follow-up of nearly 5 years, which reported fairly good oncology and quality of life outcomes.2 That same year, a consensus panel organized by Urology®, the “Gold Journal,” and led by Peter Scardino, MD, of Memorial Sloan Kettering Cancer Center, concluded that focal therapy was a reasonable treatment option that should be explored in clinical trials.

Dr. Koch went on to explain why it took so long for focal ablation therapy to be adopted. Initially, the rationale was that since prostate cancer is a multifocal disease, the idea of ​​treating an index lesion while leaving residual disease was of concern. However, over time we have become more aware that the index lesion determines cancer biology. Additionally, advances in multiparameter magnetic resonance imaging (mpMRI), prostate-specific membrane antigen (PSMA), positron emission tomography (PET) imaging, and ablation technology strengthened the argument for focal therapy. Patients are also increasingly aware of these less morbid approaches and express a desire to pursue them.

The effectiveness of focal therapy

So how effective is focal therapy? The largest cohorts of patients receiving focal therapy ablation are from Europe. A recently published study that included 1400 men, mostly at intermediate risk and some at high risk, attempted to determine which patients did not need whole-gland treatment (failure-free survival). Failure was defined as 2 consecutive increases in prostate specific antigen (PSA) level followed by magnetic resonance imaging (MRI) and biopsy which could then indicate the need for treatment of the entire gland. In the study, 70% of intermediate-risk patients and 30% of high-risk patients were able to avoid whole-gland therapy for 7 years while experiencing minimal complications.3 Other researchers have found that quality of life is maintained in patients undergoing focal therapy, and a conglomeration of 3 studies indicate that erectile function declines initially but returns nearly to baseline 1 year after treatment.4

Dr. Koch concluded that the ideal patient for focal therapy has significant disease but is not a candidate for active surveillance. Prospective patients should not have high-risk disease, where wide resection and/or lymph node dissection would be indicated. The cancer should be confined to only one part of the prostate, not involve the sphincter, and ideally it should be visible on pMRI.

Cryotherapy vs High Intensity Focused Ultrasound

Dr. Koch then introduced Dr. Stratton, who discussed 2 modalities, Cryotherapy and High Intensity Focused Ultrasound (HIFU). Cryotherapy is thermal removal of the prostate by placing treatment probes into the prostate. The needles are placed and create an “ice ball”. During the follow-up mpMRI, the index lesion is erased and a subsequent biopsy would be negative. Limitations to the use of cryotherapy include large prostates (>80g), small prostates, presence of a midlobe, or transurethral anterior resection of the prostate (TURP).

On the other hand, HIFU allows precise delimitation of an ablation zone. Again, post-treatment mpMRI would show obliteration of the index lesion. Challenges with HIFU technology include a rigid probe focal length, which means the prostate must be manipulated to ensure the focal length is correct. Limitations of use include prostate height, enlarged prostate (>40g), and apical tumors. Other limitations include prostate calcifications and brachytherapy seeds, as they inhibit high intensity ultrasound. Cryotherapy and HIFU have similar efficacy in the treatment of prostate base tumours. However, if the index tumor is more apical, there may be a higher risk of recurrence with the use of HIFU. Dr. Stratton concluded that focal therapy can be considered the standard of care for patients with intermediate-risk prostate cancer.

Dr. Koch then introduced Dr. Eggener, who discussed MRI-guided laser ablation and ultrasonic transurethral ablation. MRI-guided laser ablation uses transperineal access and is done with real-time MRI feedback. It is best used to treat small visible lesions seen on mpMRI. Data on its effectiveness are limited. The largest study included a population in which a third of patients had Gleason 3+3 disease. Patients were followed up and had a follow-up biopsy at 1 year after treatment. However, only a third of the patients in this study received a follow-up biopsy. Of those who underwent a biopsy, almost 40% of patients still had relevant type 4 disease. Side effects included hematuria (7.4%), erectile dysfunction (5%) and urinary retention (4.1%), and, notably, 2 patients developed a rectourethral fistula.5

MRI-guided transurethral ultrasound ablation differs from HIFU in that it works by emitting ultrasound waves radially. Initially it was only available for whole gland therapy, but now it can also be used for focal therapy. It is able to treat both large and small prostates. In a phase 2 multicenter trial evaluating 115 patients, two-thirds of whom had intermediate-risk disease, the primary endpoints were safety and changes in PSA level.6 In patients who underwent whole gland therapy, the median reduction in PSA was 95% and mean gland size decreased significantly (from 37 g to 3 g).

Post-treatment results

Post-treatment biopsy at 1 year showed that 75% to 80% of patients had less or similar level of disease, compared to baseline biopsy, while 65% of patients had no signs of disease. At 3-year follow-up, about 13% of men needed additional treatment. The side effect profile was quite favorable in this patient population and, compared to traditional treatment approaches, there was a better toxicity profile. A small percentage of patients experienced adverse effects of treatment, including worsening of urinary symptoms, such as irritative urination symptoms or urinary incontinence. Additionally, 25% of patients experienced erectile dysfunction, although many of these patients responded successfully to oral pharmaceutical treatment for erectile dysfunction.

Dr. Eggener concluded that although only very short-term follow-up and early outcome data are available for these focal therapy technologies, it is reasonable to consider them for the treatment of highly selected patients. These patients may benefit from the significant improvement in treatment-related toxic effects. It is important to keep in mind that these technologies require the use of an MRI machine and a qualified radiology team, can be expensive and can lead to out-of-pocket expenses for patients.

David Ambinder, MD is a Urology Resident at New York Medical College/Westchester Medical Center. His interests include surgical education, GU oncology, and technological advancements in urology. A significant portion of his research has focused on litigation in urology.

References

  1. Hoffman RM, Lo M, Clark JA, et al. Treatment decision regret in long-term survivors of localized prostate cancer: results from the prostate cancer outcome study. J Clin Oncol. 2017;35(20):2306-2314. doi: 10.1200/JCO.2016.70.6317
  2. Onik G, Vaughan D, Lotenfoe R, Dineen M, Brady J. “Male lumpectomy”: focal therapy of prostate cancer by cryoablation shows results in 48 patients with at least 2 years follow-up. Urol Oncol. 2008;26(5):500-505. do I: 1016/j.urolonc.2008.03.004
  3. Reddy D, Peters M, Shah TT, et al. Outcomes of cancer control after focal therapy using high-intensity focused ultrasound in 1379 men with non-metastatic prostate cancer: a 15-year multi-institute experience. Eur Urol. 2022;81(4):407-413. do I: 1016/j.eururo.2022.01.005
  4. Yap T, Ahmed HU, Hindley RG, et al. The effects of focal therapy for prostate cancer on sexual function: a combined analysis of three prospective trials. Eur Urol. 2016;69(5):844-851. do I: 1016/j.eururo.2015.10.030
  5. Walser E, Nance A, Ynalvez L, et al. Focal laser ablation of prostate cancer: results in 120 patients with low to intermediate risk disease. J Vasc Interv Radiol. 2019;30(3):401-409.e2. do I: 1016/j.jvir.2018.09.016
  6. Klotz L, Pavlovich CP, Chin J, et al. Magnetic resonance imaging guided transurethral ultrasound ablation of prostate cancer. J Urol. 2021;205(3):769-779. do I: 1097/JU.0000000000001362
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