- Email: [email protected]
New Treatments for Localized Prostate Cancer
New Treatments for Localized Prostate Cancer Michael Marberger, Peter R. Carroll, Michael J. Zelefsky, Jonathan A. Coleman, Hedvig Hricak, Peter T. Scardino, and Lucien L. Abenhaim Interest in focal therapy for prostate cancer has recently been renewed owing to downward stage migration, improved biopsy and imaging techniques, and the prevalence of either unifocal cancer or a dominant cancer with secondary tumors of minimal malignant potential. Several techniques have potential for focal ablation of prostate cancer. Cryotherapy has been used for some time as primary therapy for complete ablation of the prostate or local recurrence after radiotherapy. Enthusiasm for cryotherapy as the primary therapy has been tempered by the uncertainty about complete ablation of the cancer, the frequent persistence of measurable prostate-specific antigen levels after the procedure, and a high rate of erectile dysfunction. Studies have reported “focal ablation” of prostate cancer with cryotherapy, targeting 1 side of the gland to eliminate a cancer confined to that side with less risk of urinary or sexual complications. Whether cryotherapy has sufficient power to eradicate focal cancer and can be targeted with sufficient accuracy to avoid damage to surrounding structures remains to be demonstrated in prospective clinical trials. High-intensity focused ultrasound (HIFU) has been used widely in Europe for complete ablation of the prostate, especially in elderly men who are unwilling or unable to undergo radical therapy. For low- or intermediate-risk cancer, the short- and intermediate-term oncologic results have been acceptable but need confirmation in prospective multicenter trials presently underway. Whole gland therapy with transrectal ultrasound guidance has been associated with a high risk of acute urinary symptoms, often requiring transurethral resection before or after HIFU. Adverse effects on erectile function seem likely after a therapy that depends on heat to eradicate the cancer, but erectile function after HIFU has not been adequately documented with patient-reported questionnaires. HIFU holds promise for focal ablation of prostate cancer. As with cryotherapy, focal HIFU should reduce the adverse sexual, urinary, and bowel effects of whole gland ablation. New techniques are being developed to allow HIFU treatment under real-time guidance using magnetic resonance imaging, which could improve the precision and reduce the adverse effects further. Another promising technique, currently in clinical trials, is vascular-targeted photodynamic therapy, which has been used for whole gland ablation of locally recurrent cancer after radiotherapy and, more recently, for focal ablation of previously untreated cancer. In combination with a new, systemically administered photodynamic agent, laser light is delivered through fibers introduced into the prostate under ultrasound guidance. This technique does not heat the prostate but destroys the endothelial cells and cancer by activating the photodynamic agent. Damage to surrounding structures appears to be limited and can be controlled by the duration and intensity of the light. We have reviewed the principles of focal therapy and these new therapeutic modalities. UROLOGY 72 (Suppl 6A): 36 – 43, 2008. © 2008 Published by Elsevier Inc.
B
ecause the natural history of prostate cancer is often indolent and the prostate gland is accessible by way of the rectum, urethra, and perineum, interest has been considerable in adapting focal methods of tissue ablation to cure or control prostate cancer. This interest has been recently renewed by the downward stage migration, improved imaging and biopsy techniques, and the high prevalence of either a solitary, unifocal cancer or a dominant, biologically significant tumor associated with disease of minimal malignant poFrom the Department of Urology, Medical University of Vienna, Vienna, Austria (MM); University of California, San Francisco, San Francisco, California (PRC); Memorial Sloan-Kettering Cancer Center, New York, New York (MJZ, HH, PTS); McGill University, Montreal, Canada (LLA). Reprint requests: Michael Marberger, M.D., Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1090 Austria. E-mail: [email protected]
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© 2008 Published by Elsevier Inc.
tential elsewhere in the prostate.1 Organ-sparing treatment might provide satisfactory cancer control for such patients. However, to date, tissue ablation has mostly been used for near-whole gland ablation without taking advantage of accompanying the technological capabilities, particularly imaging.
CRYOTHERAPY Interest in cryosurgery for localized prostate cancer has persisted because of the low morbidity, short hospital stays, and high rates of negative biopsy findings after treatment.2,3 The use of transrectal ultrasonography for real-time monitoring of the freezing process, improved cryoprobes, and a better understanding of cryobiology have all contributed to this continued interest. The 3 treatment parameters that correlate with the likelihood 0090-4295/08/$34.00 doi:10.1016/j.urology.2008.08.506
Table 1. Advantages and disadvantages of cryoablation as focal therapy for prostate cancer Advantages
Disadvantages
Good correlation between ice ball and lesion localization Treated lesion (ice ball) visible in real time on ultrasonography Has been used for hemiablation (one lobe) of prostate Morbidity expected to be lower after focal therapy than after treatment of whole gland Can be repeated Does not preclude subsequent radical therapy, but this could be more difficult
Tissue damage extends beyond limit of tissue destruction (risk to surrounding structures) Probe placement is critical Difficult to treat anterior gland Some risk of erectile dysfunction Lack of data on long-term follow-up Changes morphology of prostate, making follow-up with digital rectal examination or imaging more difficult
of cell destruction are the cooling rate during freezing, the lowest temperature achieved, and the duration of the freeze cycle. Temperatures lower than ⫺40°C are required to completely destroy cells. Cryoablation results in 2 treatment effects: a central zone of complete cellular necrosis and a peripheral zone of cell damage without necrosis. The central zone of complete cellular necrosis can be significantly enlarged by a second freezing cycle. These findings are important to consider during treatment because the hyperechoic leading edge of the ice ball is 0° to ⫺2°C, and the temperatures required for tissue ablation (⫺20° to ⫺40°C) might be ⬎1 cm inside this edge. Therefore, the ice ball must be extended well beyond the borders of the prostate to ensure adequate tissue necrosis. Highly vascular areas, acting as heat sinks, might not achieve the target temperatures even though completely enclosed within the treatment area. Great care must be taken during treatment, because involvement of the external urinary sphincter or rectum can have devastating consequences, including urinary incontinence, loss of erectile function, and rectourethral fistula formation.
Cancer Control The positive biopsy rate after cryoablation has been 8%25% in series for which post-treatment biopsy data were available, a finding that should be interpreted in light of the 61% negative repeat biopsy rate for low-risk cancer in men being considered for active surveillance.3-9 The interpretation of favorable biopsy results has been clouded by tissue sampling errors and the use of neoadjuvant and adjuvant androgen deprivation therapy. A relationship exists, not surprisingly, between the clinical stage and the likelihood of positive biopsy findings after cryotherapy: 9% for clinical Stage T1 or T2 and ⱖ21% for Stage T3 cancer. Persistent or recurrent cancer is also more likely among men with greater cancer grades and serum prostate-specific antigen (PSA) levels.8,10 In earlier series, recurrence was more common with cancers located at the apex (10%) and seminal vesicles (44%) compared with those in the mid-gland (4%) or the base (0%).7 Treatment failure according to biopsy results appears to be lowest for men with a PSA nadir ⬍0.1 ng/mL (1.5%) and ⬍0.4 ng/mL (10%). In contrast, ⱕ55% of patients with a PSA UROLOGY 72 (Supplement 6A), December 2008
nadir ⬎0.5 ng/mL have positive prostate biopsy findings after treatment. Complications and Quality of Life The potential complications of cryotherapy include erectile dysfunction, incontinence, urethral sloughing, and rectal injury.11 The likelihood of such complications has declined with time, reflecting improvements in experience and patient selection, as well as technical advances such as rectal wall and urethral warming devices. Although erectile dysfunction is likely with whole gland ablation (80%-100%), the risk of other complications is lower when cryotherapy is used as the primary therapy, with a risk of incontinence of 3%-5%, persistent rectal pain of 2%-3%, and tissue sloughing with consequent urinary obstruction of 5%. The risk of complications is greater for men treated with cryotherapy after radiotherapy. More recently, some clinicians have performed focal cryotherapy, in which the tissue of a single lobe is frozen.10 Early reports of selected patients have been encouraging. Some have touted such therapy as the “male lumpectomy.” Such a technique might become more widely used if cancer localization methods become more reliable. No formal quality-of-life assessments have been performed with patients treated with cryotherapy; therefore, the effect of cryotherapy on the overall or prostatespecific health of these patients cannot be assessed. The advantages and disadvantages of cryotherapy are listed in Table 1. Summary The European Urological Association guidelines for the treatment of prostate cancer consider that evidence is insufficient to recommend the use of cryosurgical ablation for the treatment of prostate cancer. Consequently, its use for focal therapy should be considered investigational. The American Urological Association recently updated its “AUA Best Practice Policy” and now recognizes cryotherapy as a treatment option for localized prostate cancer but cautions that its use for focal therapy requires study.12,13 Whether cryotherapy will prove to be an effective technology for focal therapy remains to be demonstrated in clinical trials, but it seems less attractive than other alternatives because of the imprecision of the tissue destruction. 37
HIGH-INTENSITY FOCUSED ULTRASOUND High-intensity focused ultrasound (HIFU) is a noninvasive technique that achieves instantaneous and irreversible coagulative necrosis of the targeted structure through hyperthermia (similar to focusing light with a magnifying glass). The energy decreases sharply outside the focal zone; thus, the overlying and surrounding tissues are minimally affected. This creates a sharp border between the targeted and nontargeted tissues. The size of the thermal lesion can be controlled by adjusting the power and duration of the ultrasound pulse.14 Extensive experimental studies have shown that HIFU can induce precise destruction of malignant tissues without increasing the apparent risk of metastatic spread.15-19 Transrectal HIFU is well suited for the anatomic position of the prostate, because the transducer can be introduced into the rectum and brought within 5 cm of the target, no intervening structures are present between the rectum and the prostate, and both can be visualized on ultrasonography. HIFU has been used to treat low- and intermediate-risk cancer. Its major imitations are the difficulty in ablating the entire prostate, especially in a large (⬎40 g) gland and the difficulty in treating anterior tumors. For all systems presently in clinical use, the transducer is covered by a condom or balloon and inserted into the rectum. Degassed, cooled water is circulated within the rectum, cooling the rectal wall and eliminating acoustic interference between the transducer and the rectal mucosa. During treatment, the zone of coagulative necrosis expands toward the transducer and rectum, facilitating treatment to the posterior segments of the prostate. However, destruction of the anterior prostate is less reliable because of interference from the near-field ablated tissue and, in patients with a large gland, the distance from the transducer. Gelet and Chapelon20 pioneered the use of transrectal HIFU for the treatment of localized prostate cancer. They overcame the difficulty of reaching the anterior parts of the prostate by restricting the use of HIFU to patients with prostates ⬍40 cm3 in volume and using an intrarectal condom to flatten the prostate. Others have performed transurethral resection of the transition zone to solve this problem.21,22 Debulking the prostate not only renders the anterior segments more accessible to HIFU, but also reduces the risk of postoperative retention and the need for prolonged catheter drainage or cystostomy, a common complication of whole gland HIFU. Additional technological developments of HIFU could transform the field, with faster lesion creation by rapid cycling of the pulse with shorter off times and, especially, with the capability of real-time magnetic resonance imaging (MRI) thermometry for monitoring the treatment effect.23,24 HIFU ablation is typically performed with the patient under general anesthesia or epidural anesthesia with sedation. A suprapubic cystostomy or urethral catheter is placed for bladder drainage, and a thorough cleansing of 38
the rectum with enemas before the procedure is essential to reduce interference with the transrectal probe. Cancer Control In a prospective study, Madersbacher et al.15 attempted curative therapy for localized prostate cancer using HIFU in selected patients with localized, palpable (Stage T2a or T2b) disease. Altogether, 10 patients with 1 positive biopsy core from a nodule in 1 lobe received treatment to the tumor-bearing lobe. Histologic evaluation after radical prostatectomy showed that, despite adequate targeting of the tumor, complete ablation was evident in only 3 patients. Transrectal HIFU lesions consistently demonstrated sharply delineated intraprostatic coagulative necrosis without skipping within the target zone, and no alterations of the periprostatic structures were identified in the resected specimens. In a multicenter trial reported by Thüroff et al.,25 402 patients with localized cancer were treated with curative intent. Although 28% of the patients required 2 treatment sessions, 87% of the treated patients had negative biopsy findings on follow-up; a median PSA nadir of 0.4 ng/mL was achieved at a minimal follow-up of 6 months. These same investigators later reported a 5-year actuarial negative biopsy rate of 90%.26 Gelet et al.27 assessed the long-term results in patients with low-risk disease (initial PSA level ⬍10 ng/mL, Gleason score ⱕ6). At 5 years, 78% of patients were considered free of disease (stable PSA level according to American Society for Therapeutic Radiology and Oncology criteria) and had negative biopsy results. For those with intermediate- and high-risk cancer, the disease-free rate was 53% and 36%, respectively. In a recent analysis of a large cohort followed up for ⬎6 years, Blana et al.28 treated 140 patients with low- and intermediaterisk cancer with 1-3 sessions using the Ablatherm HIFU device. The actuarial 5-year disease-free (negative biopsy findings and PSA level ⬍2 ng/mL greater than the nadir) probability was only 66%. Some 28% of the low-risk and 40% of the high-risk cases were considered treatment failures.28 Complications and Quality of Life Other than the usual risks related to the duration of the anesthesia, the postoperative morbidity of HIFU is low, provided that the bladder has been sufficiently drained. The main problem arises from swelling of the prostate after treatment, which can require prolonged catheterization or cystostomy drainage. Patients are usually discharged from the hospital without analgesics on the first postoperative day, with a catheter or cystostomy in place. In a multicenter trial, 402 patients treated with the Ablatherm unit retained their catheters for a median of 5 days. Urinary retention was prolonged in 9% of patients, and urethral strictures developed in 4%.25 Uchida et al.,29 reporting on a single-center experience with the Sonoblate 500 device for curative treatment of 181 patients with organ-confined prostate cancer, observed prolonged UROLOGY 72 (Supplement 6A), December 2008
Table 2. Advantages and disadvantages of high-intensity focused ultrasound as focal therapy for prostate cancer Advantages
Disadvantages
Noninvasive (no needles in prostate) With MRI, precise localization of target, real-time monitoring of treatment effects with thermography, documentation of treated area with intravenous contrast Can be repeated Outpatient procedure, with little time lost from normal activities Low morbidity Does not preclude subsequent radical therapy, but this could be more difficult
Heat risks permanent damage to erectile nerves Without MRI, real-time monitoring of treatment effect not possible With MRI, is expensive and requires multidisciplinary collaboration Difficult to reach anterior prostate Changes morphology of prostate, making follow-up with digital rectal examination or imaging more difficult No experience with HIFU for focal therapy
MRI ⫽ magnetic resonance imaging; HIFU ⫽ high-intensity focused ultrasound.
urinary retention in only 0.6% of patients. However, 22% of the patients required periodic urethral dilation caused by strictures near the verumontanum, and 6% of patients experienced epididymitis. In the series reported by Blana et al.,28 94% of patients recovered normal urinary continence, 14% had urinary obstruction associated with strictures, 6% complained of pelvic pain for ⱕ6 months, and 26% of previously potent patients developed severe erectile dysfunction. Severe incontinence was rare at 0.6%-1.6%.25 Rectourethral fistulas occurred in 1% of patients.25,28 Thüroff et al.26 published an update of their experience with 1000 HIFU treatments.26 The most serious complication was rectourethral fistulas in 3% of patients, specifically those treated more than once with HIFU and those treated for local recurrence after radical prostatectomy or radiotherapy. In 2 series of patients, erectile function was maintained in 20% and 46% of those who were potent before HIFU, provided treatment was strictly limited to the prostate and only 1 HIFU session was performed.25,28 The use of integrated Doppler ultrasonography to visualize the neurovascular bundles during treatment has been reported to improve this outcome.30 No formal quality-of-life questionnaires were included in any of these trials; therefore, the consequences of HIFU on quality of life— especially sexual, urinary, and bowel function—and on the overall health of these patients remains poorly documented. Summary Transrectal ultrasound-guided HIFU is a promising treatment of prostate cancer, but the approach requires additional study. The current guidelines appropriately consider HIFU an investigational approach. In patients with localized cancer in small prostates, the reported longterm outcomes of whole gland HIFU seem reasonable for men who are not candidates for radical prostatectomy, although cancer control and morbidity might be better with modern radiotherapy. The advantages and disadvantages of whole gland HIFU are listed in Table 2. HIFU seems particularly promising for focal ablation, given the precision of targeting, its low morbidity, and the ability to use magnetic resonance thermography to monitor the temperature in the rectum, urinary sphincter, and neurovascular bundles during treatment. UROLOGY 72 (Supplement 6A), December 2008
VASCULAR-TARGETED PHOTODYNAMIC THERAPY Photodynamic therapy (PDT) enables destruction of targeted tissues using a light-sensitive agent (photosensitizer) and laser light of a specific wavelength in the presence of oxygen. The photosensitizer absorbs the light and transfers the energy to adjacent oxygen molecules, creating reactive oxygen species that trigger cell destruction.31,32 Because the light is produced by a laser and delivered using illuminating optical fibers, this technique can be used to treat the target tissue with limited collateral damage. PDT is currently used in the treatment of recurrent and primary malignancies of the skin, bladder, lung, esophageal, and head and neck and in the treatment of eye diseases such as age-related macular degeneration. The development of new photosensitizers has permitted further improvements in PDT.33-35 Recent research on molecules derived from naturally occurring chlorophyll has led to the synthesis of a new generation of photosensitizers with greater stability, shorter half-lives with faster metabolism, and negligible skin photosensitization problems. TOOKAD (WST09: padoporfin; palladium bacteriopheophorbide) and its water-soluble derivative, WST11 (padeliporfin; palladium bacteriopheophorbide monolysotaurine) made by Steba Biotech (The Netherlands), are the most widely used of this new generation of photosensitizers.36 Both induce irreversible damage to cell membranes37 and largely affect the small and immature arterioles, blocking the supply of blood and nutrients to tumors. Because WST09 preferentially targets blood vessels,36-41 the technique based on its use is known as vascular-targeted photodynamic therapy (VTP).42,43 Both WST09 and WST11 have also been observed to have extensive effects on the vascular networks of tumors in various in vivo models.36,38-41 The drug takes advantage of the tumor vasculature’s sensitivity to stress; thus, damage to the vascular endothelium is quickly followed by a cascade of events, including platelet aggregation, blood stasis, and vessel occlusion, leading finally to tumor necrosis.36,44-48 In this respect, VTP differs from antiangiogenic therapies that aim to prevent the formation and growth of new blood vessels. Vascular injury has been 39
previously observed in many studies of PDT, and it is considered primarily responsible for the overall PDT effect.49,50 Another feature of this photodynamic agent is its long absorption wavelength, with maximal light energy absorption in the visible/near-infrared wavelength at 763 nm.51,52 The long absorption wavelength improves light penetration into the tissues, allowing for treatment of solid tumors ⱕ4 cm in diameter.51,52 This agent has been tested in several cancer models,36-41,48,51-56 and the use of VTP with WST09 has been evaluated for salvage therapy for local recurrence after radiotherapy, and studies of WST11 as focal therapy for previously untreated prostate cancer are in progress. Tissue Effects In preclinical animal models, VTP has been effective in complete eradication of tumor or an increased time to tumor regrowth.36,38-41,44-48,52-56 The use of imaging to assess tissue destruction in the prostate was studied in normal dogs.40,41,53,54 MRI of the prostate performed 1 week after VTP treatment was compared with the histologic results of tissue samples. A reasonable correlation was found between the imaging evidence of hypoperfusion and tissue necrosis visible on histologic examination.57 A dog model was then developed to investigate the effects of VTP on previously irradiated prostatic tissue.41,54-56 The dogs were subjected to radiation of the prostate at levels consistent with cytotoxic treatment 5-6 months before VTP. Histologic examination of the prostate performed 1 week after VTP identified tissue lesions (necrosis and hemorrhage) identical to those observed in nonirradiated canine prostates. The lesions were confined solely to the gland, with no observed lesions or clinically manifest damage to the urethra or surrounding tissues (ie, bladder, colon, and rectum). Thus, VTP can reliably create a zone of ablation within the target tissue with minimal collateral effects on surrounding tissues. The treatment effect can be adequately assessed with MRI 7 days after the procedure.57,58 Cancer Control PDT for prostate cancer is performed with ultrasoundguided, transperineal placement of illuminating laser fibers using an approach similar to that of interstitial brachytherapy. Two multisite proof-of-concept trials were conducted in men presenting with recurrent localized prostate cancer (Stage T1 or T2) after external beam radiotherapy.42,43,59-64 In the first trial, MRI evidence of prostate hypoperfusion was observed at a drug dose of 1 mg/kg and a light dose of 100 J/cm, although the treatment parameters of 2 mg/kg and 360 J/cm demonstrated more reliable hypoperfusion of lesions encompassing ⬎63% of the prostate. Of the 12 patients treated with 2 mg/kg of WST09, MRI 7 days later showed prostate hypoperfusion in 10 men, and the serum PSA level decreased to ⬍1 ng/mL in 4 men. For all patients, the 6-month 40
biopsy findings were positive; however, the men who had received the greatest doses of WST09 and for whom MRI revealed evidence of hypoperfusion had a 44% reduction in the number of positive biopsy cores. A second trial used treatment-planning software to determine the optimal illuminating fiber placement, energy levels, treatment times, and effective ablation volumes for each patient.43,63,64 The patients who met the selection criteria were treated and followed up for 1 year. The drug and light dose was maximized at 2 mg/kg and 360 J/cm, respectively. Imaging data after treatment for 25 patients indicated prostate necrosis involving ⱕ80% of the gland. Treatment with 360 J/cm of the illuminating fiber yielded an average ablation volume of 18 cm3 at the 1-week MRI scan, corresponding to about 50% of the total prostate volume. The serum PSA level decreased to ⬍2 ng/mL in 83% of men and to ⬍1 ng/mL in 50%. The biopsy data were as yet under investigation, although some patients had negative biopsy findings. The procedure was well tolerated; the noted adverse effects included transient, moderate local urinary discomfort.60 Retreatment with VTP has been offered to some of these patients, with minimal additional complications. A Phase I trial of VTP for localized prostate cancer in untreated patients previously followed up with observational management is underway in England.65,66 Clinicians used escalating energy doses with a fixed dose of WST09 (2 mg/kg). The initial analysis of 14 patients by MRI 1 week after treatment confirmed that the volume of prostate necrosis correlates positively with the light energy applied; safe treatment with acceptable effects has been observed at 200 J/cm and 150 mW/cm. These parameters have been used for an additional 24 patients in the second part of this trial. A large, international, multisite trial for clinically localized prostate cancer has been started with the water-soluble form of TOOKAD, WST11.
Complications and Quality of Life WST09 has rapid vascular distribution and is cleared from the circulation quickly, allowing sufficient time for a 2- or 3-hour procedure. In addition, because of the fast kinetics, the phototoxicity and skin photosensitization, the main toxic effects from current PDT treatment, have not been observed with VTP in animal or human studies.67,68 Patients are typically discharged from the hospital the day after the procedure. Intraoperative hypotension, which has been observed in several cases after beginning intravenous injection of WST09, can be successfully prevented with preemptive intravenous hydration. A transient increase in hepatic enzymes has been seen within 1 week of treatment without clinical signs of liver toxicity. Localized grade 1 and 2 toxicities, including dysuria and perineal discomfort, have been reported after the procedure and have responded to conservative treatment. Repeat procedures have been well tolerated. The most serious adverse effects observed after WST09UROLOGY 72 (Supplement 6A), December 2008
Table 3. Advantages and disadvantages of vascular-targeted photodynamic therapy Advantages
Disadvantages
Outpatient procedure with minimal capital expense (setup similar to that for brachytherapy) Does not change morphology of prostate Good tissue penetration (treatment of relatively large tumor volume) Low morbidity Compared with previous photodynamic agents, WST09 is rapidly metabolized and eliminated, resulting in no photosensitivity issues Can be repeated Does not preclude subsequent radical therapy, but this could be more difficult
Difficult to treat anterior gland Limited clinical experience, lack of data on long-term outcomes Photodynamic agent may be thrombogenic, requires prophylactic heparin for procedure Novel technology requires specific equipment
VTP have been rectourethral fistulas in 3 patients treated after definitive radiotherapy and thromboembolic complications, with thrombophlebitis and paradoxical cerebral emboli (in 2 cases in which patients had atrial septal defects). These complications are thought to be related to the formulation of WST09. Experience with the water-soluble form, WST11, has not yet identified thromboembolic complications; thus, this newer formulation of the photodynamic agent has been substituted for WST09 in all ongoing VTP therapy trials. Summary The experience with VTP for prostate cancer suggests that it has potential for the treatment of localized prostate cancer. The procedure is reasonably brief and feasible for ambulatory use. VTP uses perineal access to the prostate with a guidance system similar to that used for brachytherapy. To date, VTP appears to be reasonably safe. Phase II clinical studies have been initiated with WST11, the watersoluble WST09 derivative, to confirm the efficacy of VTP and validate its safer toxicity. The advantages and disadvantages of VTP are listed in Table 3.
that engages in studies for a large number of pharmaceutical firms, including Steba Laboratories. Acknowledgments: The members of the International Task Force on Prostate Cancer and the Focal Lesion Paradigm are particularly indebted to the following people for their guidance and support: Pierre Dussault, Aurélie Hubert, Stéphanie Adam, and Karyn Wagner from the task force scientific support team in Montreal, Canada. We are grateful to the following people for their scientific contributions: Fernando J. Bianco, MD, of The George Washington University Cancer Institute, Washington, DC, USA; Mark Emberton, MD, of University College London, London, United Kingdom; Avigdor Scherz, PhD, of the Weizmann Institute of Science, Rehovot, Israel; and John Trachtenberg, MD, of Princess Margaret Hospital, University Health Network, Toronto, Canada. We would also like to thank the medical editors from Memorial Sloan-Kettering Cancer Center, New York, NY, USA, for bibliographic, editorial, and writing assistance: Susan Aiello, DVM, ELS; Melissa Bogen, ELS; Barbara Kristaponis; Hope J. Lafferty, ELS; Michael McGregor, MA; Peggy McPartland; and Jennifer Swartz-Turfle. The task force was made possible in part with financial support from Steba Biotech.
References
AUTHOR DISCLOSURES Michael Marberger, MD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this article. Peter R. Carroll, MD, has received an honorarium from Astra Zeneca for a speaking engagement, and he receives research support as an investigator from the National Cancer Institute and Tap Pharmaceuticals. Michael J. Zelefsky, MD, serves as a consultant to Core Oncology. Jonathan A. Coleman, MD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this article. Hedvig Hricak, MD, PhD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this article. Peter T. Scardino, MD, has served as a consultant for Steba Biotech. Lucien L. Abenhaim, MD, is an Honorary Professor at the London School of Hygiene & Tropical Medicine and the President of LA Risk Consultants LLP, a company UROLOGY 72 (Supplement 6A), December 2008
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In: Ter Haar GR, Rivens I, eds. Fourth ISTU Symposium. Melville, NY: American Institute of Physics; 2005;3:23-26. Brown SB, Brown EA, Walker I. The present and future role of photodynamic therapy in cancer treatment. Lancet Oncol. 2004;5: 497-508. Vogl TJ, Eichler K, Mack MG, et al. Interstitial photodynamic laser therapy in interventional oncology. Eur Radiol. 2004;14:10631073. Martin NE, Hahn SM. Interstitial photodynamic therapy for prostate cancer: a developing modality. Photodiagn Photodyn Ther. 2004; 1:123-136. Detty MR, Gibson SL, Wagner SJ. Current clinical and preclinical photosensitizers for use in photodynamic therapy. J Med Chem. 2004;47:3897-3915. Muschter R. Photodynamic therapy: a new approach to prostate cancer. Curr Urol Rep. 2003;4:221-228. Salomon Y, Gross S, Gilead A, et al. Eradication of melanoma tumors by anti vascular photodynamic therapy (PDT) with TOOKAD, a pd-bacteriochlorophyll derivative: if you can’t fight them, starve them. Presented at the 18th International Pigment Cell Conference, September 9-13, 2002, Egmond aan Zee, The Netherlands. Vakrat-Haglili Y, Weiner L, Brumfeld V, et al. The microenvironment effect on the generation of reactive oxygen species by Pdbacteriopheophorbide. J Am Chem Soc. 2005;127:6487-6497. Borle F, Radu A, Fontolliet C, et al. Selectivity of the photosensitiser TOOKAD for photodynamic therapy evaluated in the Syrian golden hamster cheek pouch tumour model. Br J Cancer. 2003;89:2320-2326. Garbo GM, KiK PK, Harrison LT, et al. Differential vascular response and relationship to tumor response with photodynamic therapy using WST-09 (TOOKAD). In: Kessel D, ed. Proceedings of SPIE (5315). Bellingham, WA: International Society for Optical Engineering; 2004:18-26. Huang Z, Chen Q, Luck D, et al. Studies of a vascular-acting photosensitizer, Pd-bacteriopheophorbide (Tookad), in normal canine prostate and spontaneous canine prostate cancer. Lasers Surg Med. 2005;36:390-397. Hetzel FW, Chen Q, Luck D, et al. Preclinical studies of vascular acting photosensitizer bacteriopheophorbide for the treatment of prostate cancer. In: Kessel D, ed. Proceedings of SPIE (5315). Bellingham, WA: International Society for Optical Engineering; 2004:27-32. Trachtenberg J, Bogaards A, Haider M, et al. Vascular targeted photodynamic with WST09 (WST09-VTP) for locally recurrent prostate cancer following radiation therapy. BJU Int. 2004;94(suppl 2):57. Trachtenberg J, Bozaards A, Weersink RA, et al. Vascular targeted photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response. J Urol. 2007; 178(5):1974-9. Schreiber S, Gross S, Brandis A, et al. Local photodynamic therapy (PDT) of rat C6 glioma xenografts with Pd-bacteriopheophorbide leads to decreased metastases and increase of animal cure compared with surgery. Int J Cancer. 2002;99:279-285. Koudinova NV, Pinthus JH, Brandis A, et al. Photodynamic therapy with Pd-bacteriopheophorbide (TOOKAD): successful in vivo treatment of human prostatic small cell carcinoma xenografts. Int J Cancer. 2003;104:782-789. Kelleher DK, Thews O, Scherz A, et al. Perfusion, oxygenation status and growth of experimental tumors upon photodynamic therapy with Pd-bacteriopheophorbide. Int J Oncol. 2004;24:1505-1511. Plaks V, Koudinova N, Nevo U, et al. Photodynamic therapy of established prostatic adenocarcinoma with TOOKAD: a biphasic apparent diffusion coefficient change as potential early MRI response marker. Neoplasia. 2004;6:224-233.
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48. Woodhams JH, MacRobert AJ, Novelli M, et al. Photodynamic therapy with WST09 (Tookad): quantitative studies in normal colon and transplanted tumours. Int J Cancer. 2006;118:477-482. 49. Krammer B. Vascular effects of photodynamic therapy. Anticancer Res. 2001;21:4271-4277. 50. Dolmans DE, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nat Rev Cancer. 2003;3:380-387. 51. Weersink RA, Wilson BC, Patterson MS. Determination of the peak absorption wavelength and disaggregation kinetics of TOOKAD in vivo using dynamic, spatially resolved diffuse reflectance spectroscopy in a rabbit model. In: Alfano RR, ed. Proceedings of SPIE (5315). Bellingham, WA: International Society for Optical Engineering; 2002:135-142. 52. Gross S, Gilead A, Scherz A, et al. Monitoring photodynamic therapy of solid tumors online by bold-contrast MRI. Nat Med. 2003;9:1327-1331. 53. Chen Q, Huang Z, Luck D, et al. Preclinical studies in normal canine prostate of a novel palladium-bacteriopheophorbide (WST09) photosensitizer for photodynamic therapy of prostate cancers. Photochem Photobiol. 2002;76:438-445. 54. Chen Q, Huang Z, Luck D, et al. Effects of TOOKAD-PDT on canine prostates pre-treated with ionizing radiation. In: Kessel D, ed. Proceedings of SPIE (4952). Bellingham, WA: International Society for Optical Engineering; 2003:115-124. 55. Huang Z, Chen Q, Brun PH, et al. Studies of a novel photosensitizer Pd-bacteriopheophorbide (Tookad) for the prostate cancer PDT in canine model. In: Hwu J, ed. Proceedings of SPIE (5254) 2003. Bellingham, WA: International Society for Optical Engineering; 2004:83-90. 56. Huang Z, Chen Q, Trncic N, et al. Effects of Pd-bacteriopheophorbide (TOOKAD)-mediated photodynamic therapy on canine prostate pretreated with ionizing radiation. Radiat Res. 2004;161:723-731. 57. Huang Z, Haider MA, Kraft S, et al. Magnetic resonance imaging correlated with the histopathological effect of Pd-bacteriopheophorbide (Tookad) photodynamic therapy on the normal canine prostate gland. Lasers Surg Med. 2006;38:672-681. 58. Huang Z, Chen Q, Dole KC, et al. The effect of Tookad-mediated photodynamic ablation of the prostate gland on adjacent tissues—in vivo study in a canine model. Photochem Photobiol Sci. 2007;6:1318-1324.
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59. Trachtenberg J, Weersink RA, Davidson SR, et al. Vascular-targeted photodynamic therapy (Padoporfin, WST09) for recurrent prostate cancer after failure of external beam radiotherapy: a study of escalating light doses. BJU Int. 2008;102(5):556-62. 60. Pinthus JH, Bogaards A, Weersink R, et al. Photodynamic therapy for urological malignancies: past to current approaches. J Urol. 2006;175:1201-1207. 61. Weersink RA, Wilson B, Bogaards A, et al. Vascular-targeted photodynamic of prostate cancer with Tookad for recurrent prostate cancer following radiation therapy: initial clinical studies. In: Kessel D, ed. Proceedings of SPIE (6424). Bellingham, WA: International Society for Optical Engineering; 2007:1-10. 62. Trachtenberg J, Bogaards A, Weersink RA, et al. Vascular targeted photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response. J Urol. 2007;178:1974-1979. 63. Haider MA, Davidson SR, Kale AV, et al. Prostate gland: MR imaging appearance after vascular targeted photodynamic therapy with palladium-bacteriopheophorbide. Radiology. 2007;244:196-204. 64. Trachtenberg J, Weersink RA, Davidson SRH, et al. TOOKAD (Padoporfin, WST09) for recurrent prostate cancer after EBRT failure: a light-dose escalating study. BJU Int. Epub 2008 May 19. 65. Moore C, Hoh I, Mosse CA, et al. Vascular-targeted photodynamic therapy in organ-confined prostate cancer—report of a novel photosensitiser. Eur Urol Suppl. 2006;5:131. 66. Pendse D, Allen C, Moore C, et al. Dynamic contrast-enhanced magnetic resonance imaging after vascular targeted photodynamic therapy with TOOKAD in the primary treatment of prostate cancer. Presented at the Annual Meeting of the American Urological Association (AUA), May 19-24, 2007, Anaheim, CA, Poster presentation 1694. 67. Brun PH, Bucking M, DeGroot JL, et al. Neutron activation and liquid scintillation analysis of tissue samples containing palladium bacteriochlorophyll derivative, a potential photochemotherapeutic agent. Can J Anal Sci Spectrosc. 2004;49:55-63. 68. Weersink RA, Forbes J, Bisland S, et al. Assessment of cutaneous photosensitivity of TOOKAD (WST09) in preclinical animal models and in patients. Photochem Photobiol. 2005;81:106-113.
43
B
ecause the natural history of prostate cancer is often indolent and the prostate gland is accessible by way of the rectum, urethra, and perineum, interest has been considerable in adapting focal methods of tissue ablation to cure or control prostate cancer. This interest has been recently renewed by the downward stage migration, improved imaging and biopsy techniques, and the high prevalence of either a solitary, unifocal cancer or a dominant, biologically significant tumor associated with disease of minimal malignant poFrom the Department of Urology, Medical University of Vienna, Vienna, Austria (MM); University of California, San Francisco, San Francisco, California (PRC); Memorial Sloan-Kettering Cancer Center, New York, New York (MJZ, HH, PTS); McGill University, Montreal, Canada (LLA). Reprint requests: Michael Marberger, M.D., Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1090 Austria. E-mail: [email protected]
36
© 2008 Published by Elsevier Inc.
tential elsewhere in the prostate.1 Organ-sparing treatment might provide satisfactory cancer control for such patients. However, to date, tissue ablation has mostly been used for near-whole gland ablation without taking advantage of accompanying the technological capabilities, particularly imaging.
CRYOTHERAPY Interest in cryosurgery for localized prostate cancer has persisted because of the low morbidity, short hospital stays, and high rates of negative biopsy findings after treatment.2,3 The use of transrectal ultrasonography for real-time monitoring of the freezing process, improved cryoprobes, and a better understanding of cryobiology have all contributed to this continued interest. The 3 treatment parameters that correlate with the likelihood 0090-4295/08/$34.00 doi:10.1016/j.urology.2008.08.506
Table 1. Advantages and disadvantages of cryoablation as focal therapy for prostate cancer Advantages
Disadvantages
Good correlation between ice ball and lesion localization Treated lesion (ice ball) visible in real time on ultrasonography Has been used for hemiablation (one lobe) of prostate Morbidity expected to be lower after focal therapy than after treatment of whole gland Can be repeated Does not preclude subsequent radical therapy, but this could be more difficult
Tissue damage extends beyond limit of tissue destruction (risk to surrounding structures) Probe placement is critical Difficult to treat anterior gland Some risk of erectile dysfunction Lack of data on long-term follow-up Changes morphology of prostate, making follow-up with digital rectal examination or imaging more difficult
of cell destruction are the cooling rate during freezing, the lowest temperature achieved, and the duration of the freeze cycle. Temperatures lower than ⫺40°C are required to completely destroy cells. Cryoablation results in 2 treatment effects: a central zone of complete cellular necrosis and a peripheral zone of cell damage without necrosis. The central zone of complete cellular necrosis can be significantly enlarged by a second freezing cycle. These findings are important to consider during treatment because the hyperechoic leading edge of the ice ball is 0° to ⫺2°C, and the temperatures required for tissue ablation (⫺20° to ⫺40°C) might be ⬎1 cm inside this edge. Therefore, the ice ball must be extended well beyond the borders of the prostate to ensure adequate tissue necrosis. Highly vascular areas, acting as heat sinks, might not achieve the target temperatures even though completely enclosed within the treatment area. Great care must be taken during treatment, because involvement of the external urinary sphincter or rectum can have devastating consequences, including urinary incontinence, loss of erectile function, and rectourethral fistula formation.
Cancer Control The positive biopsy rate after cryoablation has been 8%25% in series for which post-treatment biopsy data were available, a finding that should be interpreted in light of the 61% negative repeat biopsy rate for low-risk cancer in men being considered for active surveillance.3-9 The interpretation of favorable biopsy results has been clouded by tissue sampling errors and the use of neoadjuvant and adjuvant androgen deprivation therapy. A relationship exists, not surprisingly, between the clinical stage and the likelihood of positive biopsy findings after cryotherapy: 9% for clinical Stage T1 or T2 and ⱖ21% for Stage T3 cancer. Persistent or recurrent cancer is also more likely among men with greater cancer grades and serum prostate-specific antigen (PSA) levels.8,10 In earlier series, recurrence was more common with cancers located at the apex (10%) and seminal vesicles (44%) compared with those in the mid-gland (4%) or the base (0%).7 Treatment failure according to biopsy results appears to be lowest for men with a PSA nadir ⬍0.1 ng/mL (1.5%) and ⬍0.4 ng/mL (10%). In contrast, ⱕ55% of patients with a PSA UROLOGY 72 (Supplement 6A), December 2008
nadir ⬎0.5 ng/mL have positive prostate biopsy findings after treatment. Complications and Quality of Life The potential complications of cryotherapy include erectile dysfunction, incontinence, urethral sloughing, and rectal injury.11 The likelihood of such complications has declined with time, reflecting improvements in experience and patient selection, as well as technical advances such as rectal wall and urethral warming devices. Although erectile dysfunction is likely with whole gland ablation (80%-100%), the risk of other complications is lower when cryotherapy is used as the primary therapy, with a risk of incontinence of 3%-5%, persistent rectal pain of 2%-3%, and tissue sloughing with consequent urinary obstruction of 5%. The risk of complications is greater for men treated with cryotherapy after radiotherapy. More recently, some clinicians have performed focal cryotherapy, in which the tissue of a single lobe is frozen.10 Early reports of selected patients have been encouraging. Some have touted such therapy as the “male lumpectomy.” Such a technique might become more widely used if cancer localization methods become more reliable. No formal quality-of-life assessments have been performed with patients treated with cryotherapy; therefore, the effect of cryotherapy on the overall or prostatespecific health of these patients cannot be assessed. The advantages and disadvantages of cryotherapy are listed in Table 1. Summary The European Urological Association guidelines for the treatment of prostate cancer consider that evidence is insufficient to recommend the use of cryosurgical ablation for the treatment of prostate cancer. Consequently, its use for focal therapy should be considered investigational. The American Urological Association recently updated its “AUA Best Practice Policy” and now recognizes cryotherapy as a treatment option for localized prostate cancer but cautions that its use for focal therapy requires study.12,13 Whether cryotherapy will prove to be an effective technology for focal therapy remains to be demonstrated in clinical trials, but it seems less attractive than other alternatives because of the imprecision of the tissue destruction. 37
HIGH-INTENSITY FOCUSED ULTRASOUND High-intensity focused ultrasound (HIFU) is a noninvasive technique that achieves instantaneous and irreversible coagulative necrosis of the targeted structure through hyperthermia (similar to focusing light with a magnifying glass). The energy decreases sharply outside the focal zone; thus, the overlying and surrounding tissues are minimally affected. This creates a sharp border between the targeted and nontargeted tissues. The size of the thermal lesion can be controlled by adjusting the power and duration of the ultrasound pulse.14 Extensive experimental studies have shown that HIFU can induce precise destruction of malignant tissues without increasing the apparent risk of metastatic spread.15-19 Transrectal HIFU is well suited for the anatomic position of the prostate, because the transducer can be introduced into the rectum and brought within 5 cm of the target, no intervening structures are present between the rectum and the prostate, and both can be visualized on ultrasonography. HIFU has been used to treat low- and intermediate-risk cancer. Its major imitations are the difficulty in ablating the entire prostate, especially in a large (⬎40 g) gland and the difficulty in treating anterior tumors. For all systems presently in clinical use, the transducer is covered by a condom or balloon and inserted into the rectum. Degassed, cooled water is circulated within the rectum, cooling the rectal wall and eliminating acoustic interference between the transducer and the rectal mucosa. During treatment, the zone of coagulative necrosis expands toward the transducer and rectum, facilitating treatment to the posterior segments of the prostate. However, destruction of the anterior prostate is less reliable because of interference from the near-field ablated tissue and, in patients with a large gland, the distance from the transducer. Gelet and Chapelon20 pioneered the use of transrectal HIFU for the treatment of localized prostate cancer. They overcame the difficulty of reaching the anterior parts of the prostate by restricting the use of HIFU to patients with prostates ⬍40 cm3 in volume and using an intrarectal condom to flatten the prostate. Others have performed transurethral resection of the transition zone to solve this problem.21,22 Debulking the prostate not only renders the anterior segments more accessible to HIFU, but also reduces the risk of postoperative retention and the need for prolonged catheter drainage or cystostomy, a common complication of whole gland HIFU. Additional technological developments of HIFU could transform the field, with faster lesion creation by rapid cycling of the pulse with shorter off times and, especially, with the capability of real-time magnetic resonance imaging (MRI) thermometry for monitoring the treatment effect.23,24 HIFU ablation is typically performed with the patient under general anesthesia or epidural anesthesia with sedation. A suprapubic cystostomy or urethral catheter is placed for bladder drainage, and a thorough cleansing of 38
the rectum with enemas before the procedure is essential to reduce interference with the transrectal probe. Cancer Control In a prospective study, Madersbacher et al.15 attempted curative therapy for localized prostate cancer using HIFU in selected patients with localized, palpable (Stage T2a or T2b) disease. Altogether, 10 patients with 1 positive biopsy core from a nodule in 1 lobe received treatment to the tumor-bearing lobe. Histologic evaluation after radical prostatectomy showed that, despite adequate targeting of the tumor, complete ablation was evident in only 3 patients. Transrectal HIFU lesions consistently demonstrated sharply delineated intraprostatic coagulative necrosis without skipping within the target zone, and no alterations of the periprostatic structures were identified in the resected specimens. In a multicenter trial reported by Thüroff et al.,25 402 patients with localized cancer were treated with curative intent. Although 28% of the patients required 2 treatment sessions, 87% of the treated patients had negative biopsy findings on follow-up; a median PSA nadir of 0.4 ng/mL was achieved at a minimal follow-up of 6 months. These same investigators later reported a 5-year actuarial negative biopsy rate of 90%.26 Gelet et al.27 assessed the long-term results in patients with low-risk disease (initial PSA level ⬍10 ng/mL, Gleason score ⱕ6). At 5 years, 78% of patients were considered free of disease (stable PSA level according to American Society for Therapeutic Radiology and Oncology criteria) and had negative biopsy results. For those with intermediate- and high-risk cancer, the disease-free rate was 53% and 36%, respectively. In a recent analysis of a large cohort followed up for ⬎6 years, Blana et al.28 treated 140 patients with low- and intermediaterisk cancer with 1-3 sessions using the Ablatherm HIFU device. The actuarial 5-year disease-free (negative biopsy findings and PSA level ⬍2 ng/mL greater than the nadir) probability was only 66%. Some 28% of the low-risk and 40% of the high-risk cases were considered treatment failures.28 Complications and Quality of Life Other than the usual risks related to the duration of the anesthesia, the postoperative morbidity of HIFU is low, provided that the bladder has been sufficiently drained. The main problem arises from swelling of the prostate after treatment, which can require prolonged catheterization or cystostomy drainage. Patients are usually discharged from the hospital without analgesics on the first postoperative day, with a catheter or cystostomy in place. In a multicenter trial, 402 patients treated with the Ablatherm unit retained their catheters for a median of 5 days. Urinary retention was prolonged in 9% of patients, and urethral strictures developed in 4%.25 Uchida et al.,29 reporting on a single-center experience with the Sonoblate 500 device for curative treatment of 181 patients with organ-confined prostate cancer, observed prolonged UROLOGY 72 (Supplement 6A), December 2008
Table 2. Advantages and disadvantages of high-intensity focused ultrasound as focal therapy for prostate cancer Advantages
Disadvantages
Noninvasive (no needles in prostate) With MRI, precise localization of target, real-time monitoring of treatment effects with thermography, documentation of treated area with intravenous contrast Can be repeated Outpatient procedure, with little time lost from normal activities Low morbidity Does not preclude subsequent radical therapy, but this could be more difficult
Heat risks permanent damage to erectile nerves Without MRI, real-time monitoring of treatment effect not possible With MRI, is expensive and requires multidisciplinary collaboration Difficult to reach anterior prostate Changes morphology of prostate, making follow-up with digital rectal examination or imaging more difficult No experience with HIFU for focal therapy
MRI ⫽ magnetic resonance imaging; HIFU ⫽ high-intensity focused ultrasound.
urinary retention in only 0.6% of patients. However, 22% of the patients required periodic urethral dilation caused by strictures near the verumontanum, and 6% of patients experienced epididymitis. In the series reported by Blana et al.,28 94% of patients recovered normal urinary continence, 14% had urinary obstruction associated with strictures, 6% complained of pelvic pain for ⱕ6 months, and 26% of previously potent patients developed severe erectile dysfunction. Severe incontinence was rare at 0.6%-1.6%.25 Rectourethral fistulas occurred in 1% of patients.25,28 Thüroff et al.26 published an update of their experience with 1000 HIFU treatments.26 The most serious complication was rectourethral fistulas in 3% of patients, specifically those treated more than once with HIFU and those treated for local recurrence after radical prostatectomy or radiotherapy. In 2 series of patients, erectile function was maintained in 20% and 46% of those who were potent before HIFU, provided treatment was strictly limited to the prostate and only 1 HIFU session was performed.25,28 The use of integrated Doppler ultrasonography to visualize the neurovascular bundles during treatment has been reported to improve this outcome.30 No formal quality-of-life questionnaires were included in any of these trials; therefore, the consequences of HIFU on quality of life— especially sexual, urinary, and bowel function—and on the overall health of these patients remains poorly documented. Summary Transrectal ultrasound-guided HIFU is a promising treatment of prostate cancer, but the approach requires additional study. The current guidelines appropriately consider HIFU an investigational approach. In patients with localized cancer in small prostates, the reported longterm outcomes of whole gland HIFU seem reasonable for men who are not candidates for radical prostatectomy, although cancer control and morbidity might be better with modern radiotherapy. The advantages and disadvantages of whole gland HIFU are listed in Table 2. HIFU seems particularly promising for focal ablation, given the precision of targeting, its low morbidity, and the ability to use magnetic resonance thermography to monitor the temperature in the rectum, urinary sphincter, and neurovascular bundles during treatment. UROLOGY 72 (Supplement 6A), December 2008
VASCULAR-TARGETED PHOTODYNAMIC THERAPY Photodynamic therapy (PDT) enables destruction of targeted tissues using a light-sensitive agent (photosensitizer) and laser light of a specific wavelength in the presence of oxygen. The photosensitizer absorbs the light and transfers the energy to adjacent oxygen molecules, creating reactive oxygen species that trigger cell destruction.31,32 Because the light is produced by a laser and delivered using illuminating optical fibers, this technique can be used to treat the target tissue with limited collateral damage. PDT is currently used in the treatment of recurrent and primary malignancies of the skin, bladder, lung, esophageal, and head and neck and in the treatment of eye diseases such as age-related macular degeneration. The development of new photosensitizers has permitted further improvements in PDT.33-35 Recent research on molecules derived from naturally occurring chlorophyll has led to the synthesis of a new generation of photosensitizers with greater stability, shorter half-lives with faster metabolism, and negligible skin photosensitization problems. TOOKAD (WST09: padoporfin; palladium bacteriopheophorbide) and its water-soluble derivative, WST11 (padeliporfin; palladium bacteriopheophorbide monolysotaurine) made by Steba Biotech (The Netherlands), are the most widely used of this new generation of photosensitizers.36 Both induce irreversible damage to cell membranes37 and largely affect the small and immature arterioles, blocking the supply of blood and nutrients to tumors. Because WST09 preferentially targets blood vessels,36-41 the technique based on its use is known as vascular-targeted photodynamic therapy (VTP).42,43 Both WST09 and WST11 have also been observed to have extensive effects on the vascular networks of tumors in various in vivo models.36,38-41 The drug takes advantage of the tumor vasculature’s sensitivity to stress; thus, damage to the vascular endothelium is quickly followed by a cascade of events, including platelet aggregation, blood stasis, and vessel occlusion, leading finally to tumor necrosis.36,44-48 In this respect, VTP differs from antiangiogenic therapies that aim to prevent the formation and growth of new blood vessels. Vascular injury has been 39
previously observed in many studies of PDT, and it is considered primarily responsible for the overall PDT effect.49,50 Another feature of this photodynamic agent is its long absorption wavelength, with maximal light energy absorption in the visible/near-infrared wavelength at 763 nm.51,52 The long absorption wavelength improves light penetration into the tissues, allowing for treatment of solid tumors ⱕ4 cm in diameter.51,52 This agent has been tested in several cancer models,36-41,48,51-56 and the use of VTP with WST09 has been evaluated for salvage therapy for local recurrence after radiotherapy, and studies of WST11 as focal therapy for previously untreated prostate cancer are in progress. Tissue Effects In preclinical animal models, VTP has been effective in complete eradication of tumor or an increased time to tumor regrowth.36,38-41,44-48,52-56 The use of imaging to assess tissue destruction in the prostate was studied in normal dogs.40,41,53,54 MRI of the prostate performed 1 week after VTP treatment was compared with the histologic results of tissue samples. A reasonable correlation was found between the imaging evidence of hypoperfusion and tissue necrosis visible on histologic examination.57 A dog model was then developed to investigate the effects of VTP on previously irradiated prostatic tissue.41,54-56 The dogs were subjected to radiation of the prostate at levels consistent with cytotoxic treatment 5-6 months before VTP. Histologic examination of the prostate performed 1 week after VTP identified tissue lesions (necrosis and hemorrhage) identical to those observed in nonirradiated canine prostates. The lesions were confined solely to the gland, with no observed lesions or clinically manifest damage to the urethra or surrounding tissues (ie, bladder, colon, and rectum). Thus, VTP can reliably create a zone of ablation within the target tissue with minimal collateral effects on surrounding tissues. The treatment effect can be adequately assessed with MRI 7 days after the procedure.57,58 Cancer Control PDT for prostate cancer is performed with ultrasoundguided, transperineal placement of illuminating laser fibers using an approach similar to that of interstitial brachytherapy. Two multisite proof-of-concept trials were conducted in men presenting with recurrent localized prostate cancer (Stage T1 or T2) after external beam radiotherapy.42,43,59-64 In the first trial, MRI evidence of prostate hypoperfusion was observed at a drug dose of 1 mg/kg and a light dose of 100 J/cm, although the treatment parameters of 2 mg/kg and 360 J/cm demonstrated more reliable hypoperfusion of lesions encompassing ⬎63% of the prostate. Of the 12 patients treated with 2 mg/kg of WST09, MRI 7 days later showed prostate hypoperfusion in 10 men, and the serum PSA level decreased to ⬍1 ng/mL in 4 men. For all patients, the 6-month 40
biopsy findings were positive; however, the men who had received the greatest doses of WST09 and for whom MRI revealed evidence of hypoperfusion had a 44% reduction in the number of positive biopsy cores. A second trial used treatment-planning software to determine the optimal illuminating fiber placement, energy levels, treatment times, and effective ablation volumes for each patient.43,63,64 The patients who met the selection criteria were treated and followed up for 1 year. The drug and light dose was maximized at 2 mg/kg and 360 J/cm, respectively. Imaging data after treatment for 25 patients indicated prostate necrosis involving ⱕ80% of the gland. Treatment with 360 J/cm of the illuminating fiber yielded an average ablation volume of 18 cm3 at the 1-week MRI scan, corresponding to about 50% of the total prostate volume. The serum PSA level decreased to ⬍2 ng/mL in 83% of men and to ⬍1 ng/mL in 50%. The biopsy data were as yet under investigation, although some patients had negative biopsy findings. The procedure was well tolerated; the noted adverse effects included transient, moderate local urinary discomfort.60 Retreatment with VTP has been offered to some of these patients, with minimal additional complications. A Phase I trial of VTP for localized prostate cancer in untreated patients previously followed up with observational management is underway in England.65,66 Clinicians used escalating energy doses with a fixed dose of WST09 (2 mg/kg). The initial analysis of 14 patients by MRI 1 week after treatment confirmed that the volume of prostate necrosis correlates positively with the light energy applied; safe treatment with acceptable effects has been observed at 200 J/cm and 150 mW/cm. These parameters have been used for an additional 24 patients in the second part of this trial. A large, international, multisite trial for clinically localized prostate cancer has been started with the water-soluble form of TOOKAD, WST11.
Complications and Quality of Life WST09 has rapid vascular distribution and is cleared from the circulation quickly, allowing sufficient time for a 2- or 3-hour procedure. In addition, because of the fast kinetics, the phototoxicity and skin photosensitization, the main toxic effects from current PDT treatment, have not been observed with VTP in animal or human studies.67,68 Patients are typically discharged from the hospital the day after the procedure. Intraoperative hypotension, which has been observed in several cases after beginning intravenous injection of WST09, can be successfully prevented with preemptive intravenous hydration. A transient increase in hepatic enzymes has been seen within 1 week of treatment without clinical signs of liver toxicity. Localized grade 1 and 2 toxicities, including dysuria and perineal discomfort, have been reported after the procedure and have responded to conservative treatment. Repeat procedures have been well tolerated. The most serious adverse effects observed after WST09UROLOGY 72 (Supplement 6A), December 2008
Table 3. Advantages and disadvantages of vascular-targeted photodynamic therapy Advantages
Disadvantages
Outpatient procedure with minimal capital expense (setup similar to that for brachytherapy) Does not change morphology of prostate Good tissue penetration (treatment of relatively large tumor volume) Low morbidity Compared with previous photodynamic agents, WST09 is rapidly metabolized and eliminated, resulting in no photosensitivity issues Can be repeated Does not preclude subsequent radical therapy, but this could be more difficult
Difficult to treat anterior gland Limited clinical experience, lack of data on long-term outcomes Photodynamic agent may be thrombogenic, requires prophylactic heparin for procedure Novel technology requires specific equipment
VTP have been rectourethral fistulas in 3 patients treated after definitive radiotherapy and thromboembolic complications, with thrombophlebitis and paradoxical cerebral emboli (in 2 cases in which patients had atrial septal defects). These complications are thought to be related to the formulation of WST09. Experience with the water-soluble form, WST11, has not yet identified thromboembolic complications; thus, this newer formulation of the photodynamic agent has been substituted for WST09 in all ongoing VTP therapy trials. Summary The experience with VTP for prostate cancer suggests that it has potential for the treatment of localized prostate cancer. The procedure is reasonably brief and feasible for ambulatory use. VTP uses perineal access to the prostate with a guidance system similar to that used for brachytherapy. To date, VTP appears to be reasonably safe. Phase II clinical studies have been initiated with WST11, the watersoluble WST09 derivative, to confirm the efficacy of VTP and validate its safer toxicity. The advantages and disadvantages of VTP are listed in Table 3.
that engages in studies for a large number of pharmaceutical firms, including Steba Laboratories. Acknowledgments: The members of the International Task Force on Prostate Cancer and the Focal Lesion Paradigm are particularly indebted to the following people for their guidance and support: Pierre Dussault, Aurélie Hubert, Stéphanie Adam, and Karyn Wagner from the task force scientific support team in Montreal, Canada. We are grateful to the following people for their scientific contributions: Fernando J. Bianco, MD, of The George Washington University Cancer Institute, Washington, DC, USA; Mark Emberton, MD, of University College London, London, United Kingdom; Avigdor Scherz, PhD, of the Weizmann Institute of Science, Rehovot, Israel; and John Trachtenberg, MD, of Princess Margaret Hospital, University Health Network, Toronto, Canada. We would also like to thank the medical editors from Memorial Sloan-Kettering Cancer Center, New York, NY, USA, for bibliographic, editorial, and writing assistance: Susan Aiello, DVM, ELS; Melissa Bogen, ELS; Barbara Kristaponis; Hope J. Lafferty, ELS; Michael McGregor, MA; Peggy McPartland; and Jennifer Swartz-Turfle. The task force was made possible in part with financial support from Steba Biotech.
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AUTHOR DISCLOSURES Michael Marberger, MD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this article. Peter R. Carroll, MD, has received an honorarium from Astra Zeneca for a speaking engagement, and he receives research support as an investigator from the National Cancer Institute and Tap Pharmaceuticals. Michael J. Zelefsky, MD, serves as a consultant to Core Oncology. Jonathan A. Coleman, MD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this article. Hedvig Hricak, MD, PhD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this article. Peter T. Scardino, MD, has served as a consultant for Steba Biotech. Lucien L. Abenhaim, MD, is an Honorary Professor at the London School of Hygiene & Tropical Medicine and the President of LA Risk Consultants LLP, a company UROLOGY 72 (Supplement 6A), December 2008
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