HAS THE TIME COME FOR FOCAL THERAPY OF PROSTATE CANCER?
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By: Martin J Weissman, M.D.
Medical Director of the Prostate Cancer Program
St Joseph Hospital of Orange CA

Edited from PCRI Insights May, 2008 v 11.2

“I predict that within ten years, or sooner, lesion-guided focal therapy for prostate cancer will become commonplace, and radical therapies will be reserved for larger volume disease.”

The argument is persuasive. One out of six men are diagnosed with prostate cancer during life. One out of thirty-five men die from the disease. By 2020, about 65 million men will be over age 45 in the US.1 Since prostate cancer becomes more common with advancing age, an absolute increase in the number of men who will be diagnosed with prostate cancer is certainly likely. Do all men diagnosed with prostate cancer need to have radical curative therapy? If so, the result will be a significant associated loss of quality of life (QOL) from the known side-effects of commonly used curative therapies.

Moreover, for men who trip the PSA guideline, there is growing awareness that the current PSA screening and extensive biopsy approach has resulted in the identification of a significant number of small-volume, low-risk prostate cancers. This determination has been made by correlating various patient features with the findings of careful prostate sectioning of radical prostatectomy specimens. The notion of ‘limited cancer’ is based on the concepts of tumor volume and doubling time.

Small-volume prostate cancer is often defined as 0.5cm3 or less in the whole prostate.  Small-volume tumors may still be multifocal and bilateral.2,3 Consider that it takes an estimated total tumor volume of 4cm3 for metastasis and 20cm3 for death. Yet, slowly growing prostate cancers may have a doubling time of 3 to 10 years, or longer. If so, for a tumor to enlarge from 0.5 to 20 cm3, – over five doublings – could take over 30 years. Hence, an elderly man diagnosed with a small, slowly growing prostate cancer would quite likely die from other causes than prostate cancer.

Nevertheless, there are men with apparently low-volume cancer who desire some action to be taken, since they fear doing nothing. And yet, they do not wish to take the risk of experiencing significant degradation in quality of life. The percentage of these men diagnosed with prostate cancer who have minimal disease has been variably estimated to be from 15-40%. To serve their interests, various approaches have been proposed.

1) Active surveillance with delayed definitive therapy includes careful follow-up according to protocol often combined with life-style changes. This includes DRE and PSA testing every six months, along with repeat biopsy regimens at yearly or other intervals to allow timely definitive intervention if there is any indication of progression. Some active surveillance programs have added additional diagnostic testing including MRI and/or high definition ultrasound.4-7

2) Focal therapy attempts to mirror the evolution of breast cancer treatment, which often involves “lumpectomy” as part of the initial management of the disease. An additional model is the focal therapy of skin cancer. However, it is still being debated as to exactly what is focal therapy. A consensus conference report was published in 2006,8 suggesting that focal therapy includes all the approaches which are less than total prostate ablation: from hemi-ablation with or without a “hockey stick” (partial treatment to the opposite side) but with contra-lateral nerve sparing, all the way to lesion-directed therapy. Two excellent discussions of the arguments for and against focal therapy were published in 2007.9,10

As of yet, the focal therapy approach for prostate cancer is in its infancy because of a number of unresolved problems:

a) First, after an initial positive biopsy what steps should be taken to more completely evaluate the prostate for extent of the disease? Today, it is quite clear that routine biopsy regimens which reveal minimal Gleason score 6 disease usually lead to upgrading and upstaging in over 20% of radical prostatectomy specimens. Therefore, deciding on focal therapy may be risky, unless a better means of evaluation is developed.

b) Second, what are appropriate techniques for focal therapy? Currently, hemi-prostate cryotherapy has been done, and there have been proposals for focal seed implantation, or high-dose brachytherapy. Also being investigated is high-intensity focused ultrasound (HIFU), as well as other interesting new approaches including vascular-targeted photodynamic therapy.

c) Finally, after partially treating a prostate, what are appropriate guidelines for follow-up, and what salvage therapies could then be used?

What Steps Should Be Taken To More Completely Evaluate the Prostate

Step-sectioning of prostatectomy specimens often reveals prostate cancer to be multifocal and bilateral.2,3 The concept of the index lesion states that the largest focus usually determines the biology of the disease. In small-volume disease, the additional foci are usually miniscule. Nevertheless, there are reported cases where the metastatic focus originated from a miniscule secondary focus rather than from the index lesion. So, how to determine unifocality or whether significant additional disease is present is important.

The usual prostate biopsy regimen is performed by transrectal ultrasound guidance after local periprostatic anesthetic injection. A novel ultrasound setup – Targetscan™ – has been introduced to reproducibly determine three-dimensional location of positive biopsies.11

It has become acceptable to perform biopsy regimens taking 18 or more cores in the office. This technique may still not be accurate in fully assessing all areas of the prostate for small additional lesions. For this reason, three-dimensional transperineal prostate mapping approaches have been described – generating 60 or more cores.12,13 Performed under general anesthesia, with careful labeling of specimen containers, this procedure may well provide the ultimate in biopsy approach. Apparently, the performance of radical prostatectomy after this biopsy approach is somewhat more difficult, but it can be done. There should be less interference with non-surgical approaches. And, for men with a rising PSA and several negative biopsies, this approach has also been proposed as the definitive way to rule out cancer, especially in the anterior prostate, which is often poorly sampled by the transrectal approach.

Non-biopsy approaches to gain further information include use of MRI with endorectal coil and spectroscopy. Recent reports have suggested that lesion size discrimination is not adequate until 3-Tesla coils are used. Several institutions are working with this. In the absence of 3-Tesla MRI and endorectal coils, use of contrast-enhanced pelvic MRI may provide some information about the anterior prostate.14-18 The use of color-flow Doppler with high-resolution US has also been reported to improve the finding of cancer.6 Additionally, microbubble contrast agents may improve the resolution.19 However, the likelihood of finding minute low-grade disease with these approaches is low. On the other hand, there is ongoing debate as to whether low-grade small foci need to be found and treated.

Finally, more tumor markers are being sought which would give some accuracy as to the extent or riskiness of disease.20 A significant amount of research is ongoing in this area. First, such markers may reduce the performance of a prostate biopsy, perhaps sparing some men from the discovery of a minimal low-grade cancer. This may well be a beneficial change. Additionally being studied are various markers that can be applied to positive biopsy specimens in order to better predict aggressiveness.

Potential Techniques for Focal Therapy

Cryotherapy

The freezing of the prostate by cryoprobes inserted into the prostate using transrectal ultrasound guidance is already a common procedure, performed all over the world. While it is typically used for whole prostate treatment, there are early reports of prostate hemi-ablation. Steps are taken to preserve at least one neurovascular bundle.21-23 However, prostate hemi-ablation is not truly focal therapy.

HIFU

This therapy involves the use of a generator of high intensity ultrasound, applied transrectally and focused by a diagnostic ultrasound transducer on the prostate. It has been used on thousands of patients in Europe, Canada and Asia, but is not yet FDA-approved in the US. Typically, it has been used for total prostate ablation with some reports of hemi-ablation. However, it is an energy source that is quite usable for focal therapy. It also can and has been repeated. As yet, however, there are no published outcome reports for its focal use. The technology is undergoing continuing rounds of automation and safety improvement.24-29

Photodynamic therapy

This involves intravenous infusion of a photo-sensitizer (Tookad) and the transrectal ultrasound-guided transperineal insertion of laser fiber carriers for specific wavelength energy. The treatment appears to be vascular endothelium specific, rather than prostate cancer-specific. The production of lesions is not heat-related. Clinical application of this approach in a small number of patients (including some patients as primary therapy) has been reported in Canada and Europe.30-32 There are no long-term outcome reports, but the approach is being pursued. This type of therapy has also been used in other areas of the body.

Indigo Laser

Dr. Trachtenberg, at the University of Toronto, reported treating eight patients with low-risk prostate cancer by transrectal ultrasound-guided transperineal Indigo Optima laser application.32-33 Using a perineal grid, similar to that used for brachytherapy, laser treatment fibers are placed into the known coordinates of the prostate tumor. This laser technology produces a heat lesion, which is monitored by thermistors.

Laser Activated Nanoparticles

Taking advantage of the ‘leakiness’ of tumor vasculature, gold-coated silica nanoshells have been manufactured and tested in laboratory use. The properties of the particle are such that it intensely absorbs near-infrared energy, applied by laser, causing focal heating and destruction of tissue. Thus far, the research has been restricted to animal models. It is hoped that the future will bring clinical applications of this promising approach.34,35

Focal Brachytherapy

Transrectal ultrasound-guided transperineal brachytherapy is already a common approach for total prostate treatment. It would be feasible to modify the approach to produce focal or hemi-ablation, but studies have not yet been reported. Similarly, high-dose rate brachytherapy could be applied focally.

Other modalities

Other modalities that have been briefly reported include: (1) ultrasound-guided transperineal injection of magnetic nanoparticles into a known area of prostate cancer with subsequent heating within a supermagnet to produce focal lesions36 and (2) transperineal ultrasound-guided injection of absolute alcohol into a known area of prostate cancer.

Guidelines for Follow-Up

How should follow-up be performed for focal or hemi-prostate treatment? Repeating the transperineal mapping biopsy is feasible. If other state-of-the-art technologies, such as MRI with spectroscopy, are available they would be used. Research into molecular diagnostics and isotope scanning compounds are underway. Will PSA dynamics be adequate for follow-up? The answers to these questions are not yet clear.

After focal therapy, the patient should take the same steps as a patient on active surveillance. This should include the additional components of diet and life-style change which have already been proposed for active surveillance programs.

Observations

  1. There is a need for some reasonable middle ground between not treating prostate cancer after it is found and performing traditional curative therapy.
  2. Techniques are needed for more complete mapping of the sites of cancer within the prostate.
  3. Techniques are also needed for more accurate prediction of the biologic potential of prostate cancer, after it is found.
  4. Techniques for ‘focal’ therapy of prostate cancer are either available or being developed. Whether or not it is reasonable to use these approaches needs to be proven by longer-term follow-up including survival data and QOL data.
  5. The ideal approach for focal therapy is not yet clinically available. This approach would target prostate cancer focally in the prostate without having to know where it is located, and without any QOL degradation from treatment. Short of that, a combination of prostate cancer mapping by biopsy and other diagnostic studies will allow truly focal ‘lumpectomy’ using either currently available technologies such as HIFU, photodynamic therapy or nanoparticle therapy, or using techniques now being developed.
  6. The project to develop and prove the effectiveness of ‘focal’ therapy of prostate cancer has been joined by excellent researchers. Several international conferences have been held. Surprising developments are likely to come in the next several years.

Conclusions

I predict that within ten years, or sooner, lesion-guided focal therapy for prostate cancer will become commonplace, and radical therapies will be reserved for larger volume disease. The elements needed to bring this about are clear, but they are not yet fully developed. Molecular diagnostic tests are actively being developed, more accurate radiologic and ultrasound technologies are already being used, and exciting focal therapies are actively being pursued and used. What remains is to prove the benefit of these approaches to life-extension and quality-of-life maintenance. The motivation to make this happen is huge.

References:

  1. Projected population of the United States, by age and sex: 2000 to 2050; http://www.census.gov/population/projections/SummaryTabB2.pdf
  2. Cheng L, et al: Anatomic distribution and pathologic characterization of small-volume prostate cancer (<0.5 ml) in whole-mount prostatectomy specimens. Modern Pathology 18, 1022-1026, 2005
  3. Meiers I: Preoperative prediction of multifocal prostate cancer and application of focal therapy: review 2007. Urology (Suppl 6A), 3-8, 2007
  4. Chinn D: Notes from Annual EAU Congress, March 2007. PCRI Insights V10 No3: 12, 2007
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  8. various authors: Consensus conference on focal treatment of prostate carcinoma Celebration, Florida, February 24, 2006. Urology 70 (6A): 42-44, 2007
  9. Ahmed HU, et al. Will focal therapy become a standard of care for men with localized prostate cancer?. Nature Clinical Practice Oncology 4(11): 632-642,2007
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  19. Halpern EJ. Contrast-enhanced ultrasound imaging of prostate cancer. Review in Urology, Vol 8 Suppl 1, 29-37,2006
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  22. Lambert EH, et al: Focal cryosurgery: encouraging health outcomes for unifocal prostate cancer. Urology 69: 1117-1120, 2007
  23. Ellis DS, et al: Focal cryosurgery followed by penile rehabilitation as primary treatment for localized prostate cancer: initial results. Urology 70 (Suppla 6A): 9-15, 2007
  24. Chinn, DO: Transrectal HIFU: the Next Generation. PCRI Insights Vol 8 No 1: 9-13, 2005.
  25. Rewcastle, JC: High intensity focused ultrasound for prostate cancer: a review of the scientific foundation, technology and clinical outcomes. Technology in Cancer Research and Treatment Vol 5 No 6, 619-625, 2006
  26. Vallancien, G: Treatment of localized prostate cancer with transrectal high-intensity focused ultrasound. Business Briefing: European Kidney and Urologic Disease: 61-62, 2006
  27. Azzouz, H, et al: HIFU: local treatment of prostate cancer. EAU-EBU Update Series 4, 62-70, 2006
  28. Israeli, RS: HIFU for prostate cancer. Contemporary Urology Oct 1, 2007
  29. Koch, MO, et al: Phase I/II trial of high intensity focused ultrasound for the treatment of previously untreated localized prostate cancer. The Journal of Urology 178, 2366-2371, 2007
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