By: Dan Sperling, MD

A growing number of prostate cancer patients are deliberately pursuing focal treatment. The internet plays a huge role in directing patient attention away from radical prostatectomy (RP), radiation and even active surveillance (AS) despite the recommendations of their own physicians. Patients learn about the application of multiparametric MRI (mpMRI or functional MRI) to image their disease; MRI-guided targeted biopsy as a more accurate alternative to TRUS-guided biopsy; and the use of genomics and biomarker tests to rule out highly aggressive occult (hidden) disease. After gaining a high degree of confidence that they are candidates for focal therapy, they often encounter the objection that “there is no long-term data on focal therapy results.” However, the majority of patients who learn that they qualify for a focal ablation are optimistic about their choice, and proceed with treatment despite naysayers and the often-hefty cost of treatments that are not currently reimbursed by Medicare and private insurance.

A new article (Shah et al., 2015) points out that the attraction of focal therapy lies in its intent to “… treat the index lesion within the prostate whilst leaving behind healthy non-cancerous tissue or non-significant disease.”[i] This has the effect of greatly minimizing the risk of urinary and sexual side effects associated with whole-gland treatments. Patients in the U.S. may be familiar with cryotherapy (freezing), HIFU (high intensity focused ultrasound) and FLA (focal laser ablation) as technologies that can deliver a precisely targeted thermal ablation to the tumor plus a margin of safety. However, U.S. patients may be surprised to learn that there are additional modalities that are either in clinical trial here or abroad, or already in use internationally but not available here (photodynamic and vascular-targeted photodynamic therapy, irreversible electroporation, radiofrequency ablation, magnetic thermotherapy, convective thermal water vapour, injectable toxins and focal brachytherapy. Cryotherapy and HIFU have been in longer use, including use for whole-gland ablation, but there are no large scale Level I published studies to contribute the kind of numbers that professional societies and regulatory bodies require for approving such treatments for focal application.

Obstacles to obtaining long term results

One reason why it’s difficult to assess treatment success is the lack of universal agreement on how best to obtain outcome measures. Standards that are used with RP and radiation translate poorly to focal ablation. After surgery, the PSA blood test is an efficient and inexpensive way to monitor success; since PSA is expected to quickly become undetectable, any subsequent rise to a detectable level (and continued progression, or PSA kinetics) is interpreted as biochemical recurrence, or BCR. However, this criterion will not apply after focal treatment since the remaining healthy gland tissue continues to produce PSA. After radiation, the PSA value will continue to drop slowly until it reaches its lowest level, or nadir (sometimes there is a “bounce” before the PSA settles to nadir); again, PSA kinetics will be interpreted as BCR. In the case of focal ablation, however, the PSA value may drop due to the cancer destruction, but in the majority of cases PSA drops by 80% and stabilizes there. Because of these variables, “Debate is ongoing about the clinical significance of various levels of residual disease after focal therapy and the exact threshold at which to call failure within a patient who has had focal therapy.”

Furthermore, the authors identify the difficulties of obtaining the “more solid endpoints” of metastatic disease and prostate cancer-specific death after focal treatment, which would require

… over a decade of follow-up due to the long natural history of even clinically significant prostate cancer. Insisting on such outcomes for changes in clinical practice or regulatory approvals would inevitably stifle innovation. Not only would these findings have limited external validity, reported after 10–15 years but would be prohibitively expensive and resource heavy.

Therefore, the authors chose post-ablation biopsy (histology) as the best demonstration of focal therapy results. They conducted an extensive review of published literature on biopsies after focal cryotherapy and focal HIFU to determine collective results. Such results are reported because of either follow-up biopsies triggered by rising PSA, or because a study protocol specified biopsies at certain intervals after treatment.

Reason for optimism over focal therapy

The researchers found that in literature reports, about 1 out of 5 post-focal treatment biopsies are positive (roughly 20%) but quickly qualify that number: “… the majority of these seemed to be from the untreated portion of the gland or met criteria for clinically insignificant disease.” They do not find this alarming, but rather liken it to the fact that positive surgical margins after RP do not always lead to disease progression. They conclude that based on post-focal treatment biopsy results which confirm the effectiveness of focal treatment in the “short to medium term,” focal therapies are promising. Further reassurance stems from the minimal side effect risks, and from the possibility of re-treatment if needed.

Implications for FLA

The above research suggests that MRI-guided focal laser ablation is equally promising, if not more so, than existing focal therapies. Early results reveal biopsy-demonstrated effectiveness of 96% with zero impact on urinary and sexual function.[ii] If current patient demand is any indication, men will not wait for the publication of Level I research, but will continue to inform themselves on the success of other therapies, and extrapolate from the existing evidence that they have a justifiable foundation for optimism over FLA. In addition, the growing number of academic centers turning their attention to FLA confirms the sense of professional hope that image-guided focal laser ablation allows them to meet the needs of their patients for cancer control with minimal-to-no side effects while keeping all options  open.

[i] Shah TT, Kasivisvanathan V, Jameson C et al. Histological outcomes after focal high-intensity focused ultrasound and cryotherapy. World J Urol. 2015 May 6. Epub ahead of print. doi: 10.1007/s00345-015-1561-0

[ii] Lepor H, Llukani E, Sperling D, Futterer JJ. Complications, recovery, and early functional outcomes and oncologic control following in-bore focal laser ablation of prostate cancer. Eur Urol. 2015 May 12. pii: S0302-2838(15)00331-0. doi: 10.1016/j.eururo.2015.04.029. [Epub ahead of print]