Some men with low- or intermediate-risk localized prostate cancer will present on MRI imaging with a lesion sufficiently small and apparently well-delineated to warrant targeted focused therapy. This is termed “focal therapy” and can be accomplished with heat probes (laser ablation), radioactive seeds (brachytherapy), freezing (cryotherapy) or highly focused radiation (stereotactic ablative radiotherapy with, i.e., CyberKnife). The goal is total eradication of the cancer with the associated benefit in quality of life by better preservation of erectile function and urinary continence as compared to whole gland treatments. It might be considered a “middle ground” between active surveillance and radical treatment and is particularly appropriate for favorable intermediate-risk cancers.
Currently the mpMRI is the imaging tool to select patients for focal therapy. The concept of focal therapy is the irradiation of the “index” lesion as visualized on the mpMRI. Therefore, the accurate location and definition of intraprostatic cancer is essential. Since disease often extends unseen 5-10 mm beyond the MRI “area of interest,” the fully treated field is often “hemi-gland.” Appropriate candidates for focal therapy are those men with PSA <15ng/mL, clinical/radiological tumor stage limited to 1/2 of the prostate ( < T2b) and Gleason Grades 2-3. A recent study (Geboers et al. BJU Int, Oct. 2023) addressed focal therapy and patient selection and reported that the sensitivity and negative predictive value for MRI imaging for excluding more advanced cancer were 79% and 77%, respectively. Their study found that the addition of a PSMA PET scan for patient selection provided some improvement. However, the major shortcoming of focal therapy is unidentified cancer extending beyond the chosen treatment margins or subtle multifocal disease. These states are the “Achilles heel” that decreases the effectiveness of all forms of focal therapy based on the conventional MRI.
In the 1970s pioneers in the management of breast cancer developed the “lumpectomy” procedure (local excision of cancer with breast preservation) and this strategy has become standard of care in the treatment of early breast cancer. Potentially, focal therapy of prostate cancer could achieve a similar accomplishment.
Two Examples: The two commonest forms of focal therapy for prostate cancer are brachytherapy and cryotherapy.
Focal Prostate Brachytherapy: In 2022 Langley et al. (Brachytherapy) reported the findings of the ‘Hemi-Ablative Prostate Brachytherapy Trial’ comparing low-dose-rate I-125 hemi-gland BT treatment, 30 men, vs 362 men, whole-gland “to control unilateral localized prostate cancer and reduce treatment related toxicity at 2 years post-implant.” Bowel, bladder, erectile function and quality of life was evaluated by a combination of standard questionnaires. Symptoms were significantly less troublesome for men receiving hemi-gland vs whole-gland brachytherapy.
Findings: “The mean time to PSA nadir was 4.2 and 4.8 years in HG and WG, respectively.” Treatment failure occurred in 6.7% HG patients and in 5.5% WG patients. “Five-year relapse-survival was 97% in both groups (P=.07).”
Focal Therapy for Localized Prostate Cancer
Focal Cryotherapy: A small and carefully performed protocol of focal cryotherapy was reported by Tan et al, The Prostate, March 2023. Twenty-eight men were studied, and all underwent a 12-month follow-up biopsy. Patient eligibility required a single MRI lesion with volume < 3 cm or two lesions each < 1.5 cm; PSA < 20 ng/mL; and Gleason Grade Group < 4. The lesions were treated with 5 mm margins. The median PSA at onset was 7.3 ng/mL and was reduced to a median of 4.6 ng/mL, a 60.4% reduction.
Findings: At the 12-month MRI-based biopsy 22 patients (78.6%) had no detectable prostate cancer while 6 men had cancer with < Gleason Grade Group 2. Within the treated field 7.1% were biopsy positive and 10.7% had cancer beyond the treated field; one man had both. Four men had repeat cryotherapy, one surgery and one with low-volume GG2 cancer entered active surveillance.
Urinary and sexual domains both demonstrated “acute deterioration at one month with recovery at 3 months.” “Ablation to the adjacent neurovascular bundle delayed recovery of sexual function for 6 months”, otherwise there was “no deterioration in sexual function.”
Since focal therapy does not ablate the entire prostate, residual serum PSA remains, rendering inapplicable the usual PSA thresholds indicating post-treatment biochemical recurrence. A study of HIFU therapy by Mattlet et al, (Prostate, 2023) of 343 men found a failure rate of 23% based on clinically significant cancer on post-therapy biopsy.
The best criteria for predicting failure were “PSA nadir + 1 ng/mL at 12 months or PSA nadir + 1.5 ng/mL at 24-36 months.”
Artificial Intelligence to treat the “Achilles heel:”
The in-field persistence of disease noted above in both types of focal treatments is likely the result of insufficient radiation dose or inherent resistance of the cancer in the treated focus. But out-of-field untreated disease is due to inaccurate targeting. Avenda Heath, a biotech company, has addressed this deficiency by creating a multimodal AI model, ‘Unfold AI,’ that produces a color enhanced 3-D depiction of the cancer within the prostate. In their article, “Prediction and Mapping of Intraprostatic Tumor Extent with Artificial Intelligence,” Priester, Marks et al, (European Urology Open Science, August 2023) contend that compared to their UnFold model, tumor delineation of intraprostatic tumor based on magnetic resonance imaging (MRI) significantly underestimates the extent of prostate cancer, which “complicates the definition of focal treatment margins.” Their AI-based platform is multimodal in that it combines patient specific data (MRI, PSA, biopsy and pathology) and artificial intelligence to create a “3-D cancer estimation map” showing the cancer’s extent and margins. Based on evaluation of 50 prostatectomy specimens from men with intermediate-risk cancer the mean sensitivity of cancer mapping was higher for AI estimated margins, 97%, than for MRI based contours at 37%. This difference remained significant even when comparing the conventional treatment margins of 10 mm surrounding the MRI identified tumor.
The authors’ conclusion: “This approach could help improve and standardize focal treatment margins, potentially reducing cancer recurrence rates.”
Focal therapy of prostate cancer is increasing. An Artificial Intelligence based model, ‘UnFold’, more accurately defines intraprostatic tumor extent and margins compared to MRI-based estimates and can improve the efficiency of focal treatment.