Abstract & commentary
Synopsis: Salvage therapy options for locally recurrent prostate cancer following radiotherapy failure include radical prostatectomy, brachytherapy, and cryotherapy. This study describes the results of the first effort at implementing percutaneous transperineal interstitial photodynamic therapy (PDT) and concludes that local control may be achievable with PDT if better light dosimetry is developed.
Source: Nathan TR, et al. J Urol. 2002;168:1427-1432.
Between 1996 and 1999, Nathan and colleagues at the University College London Hospitals enrolled 14 patients in a Phase I-II study to assess the safety and efficacy of percutaneous interstitial photodynamic therapy (PDT) for local failures following radiotherapy for prostate cancer. Patients were identified for the study based on 2 or more consecutive rises in PSA at follow-up, and eligibility was confirmed based on a positive biopsy. No patient was suitable for surgery. Patients with "locally advanced" or extraprostatic disease were excluded. Median age was 70 years (range, 58-77). Median time from radiotherapy was 42 months (range, 22-108).
Each patient was given 0.15 mg/kg of meso-tetrahydroxyphenyl chlorin, a photosensitizer, intravenously. Following 3 days under low lighting, a series of 2-8 15-cm, 19-gauge needles was placed transperineally under MRI or ultrasound guidance with the patients under sedation. Depending upon the location of the positive biopsies, 1 or both prostate lobes were targeted. Since this study was the first attempt at applying this technology in humans to kill cancer, no attempt was made to treat the entire gland. The peripheral zone of the affected lobe was treated from base to apex at 1-cm intervals up to 4 positions per needle as each needle was withdrawn. A median of 4 laser fibers (range, 2-8) was used per patient. A diode laser was used to deliver 652-nm red light along 0.4-mm diameter laser fibers. In an effort to proceed cautiously, the first 5 patients received 20 J light dose based on earlier canine experiments. Four of these initial 5, along with 9 more patients, were then treated with "at least 50 J." Some poor responders underwent repeat treatment. Only results from the higher light dose were reported.
Follow-up biopsies were obtained several days after treatment and again at 1-4 months post-PDT. Serial PSA and MRI or CT scans were done a few days after treatment and again at 2 months. Flexible sigmoidoscopy was done pretreatment and 2-5 days posttreatment.
PSA levels dropped in 9 of the 13 patients treated, and 5 patients had negative post-PDT biopsies. Two patients maintained undetectable PSA levels, the longest being 26 months. Post-PDT CT scans in 10 patients showed a median 81% increase in prostate volume 2-5 days after PDT (range, 14-161%). If 1 lobe was treated, up to 49% of the prostate tissue was necrotic, and if both lobes were treated, up to 91% of the CT cross-sectional area was necrotic. In all cases, PSA eventually began to rise again, and 13/14 patients were started on antiandrogen therapy at a median of 10 months (range, 3-38).
Side effects included mild-to-moderate perineal discomfort, irritative urinary symptoms lasting up to 1 month, and acute retention/dribbling. While 6/14 patients’ AUA scores normalized by 3 months, 8/14 continued to deteriorate. Four patients developed incontinence, including 2 with occasional leakage and 2 with troublesome stress incontinence. Four of 7 with residual sexual function post-RT suffered irreversible declines in sexual function. Two patients were noted to have superficial rectal ulcers, including 1 who underwent an ill-advised rectal biopsy and subsequently developed a urethrorectal fistula.
Nathan and colleagues concluded that PDT reduced the cancer burden in patients with localized recurrent prostate cancer with a side-effect profile that compared favorably with salvage cryotherapy or surgery. Given improvements in light dosimetry, this minimally invasive procedure is a new option for organ-confined recurrences following failed radiotherapy. If necessary, PDT can be applied 1 or more times to previously irradiated tissue without cumulative toxicity.
Comment by Edward J. Kaplan, MD
Thomas Dougherty at the Roswell Park Cancer Institute in Buffalo, NY, developed photodynamic therapy, which relies on the creation of reactive oxygen species for its cytotoxic effect, 30 years ago. It has been used for a variety of tumors, including bladder, larynx, lung, biliary, naso- and oropharyngeal, and brain cancers.1 Nathan et al are the first group to publish their experience using an interstitial approach for prostate cancer. In this country, Dr. Eli Glatstein’s group at the University of Pennsylvania has been investigating interstitial PDT for prostate cancer using a different photosensitizing agent, motexafin lutetium. So far in the United States, the FDA has approved only porfimer sodium for use. Other photosensitizers being evaluated for use in prostate cancer include tin ethyl etiopurpurin2 and liposomal benzoporphyrin derivative monoacid ring A.3
Tissue penetration is greatest in the red part of the spectrum. Despite this, there can be significant individual variability in light penetration. Lee and associates, in their study of light fluence in 7 prostate cancer patients subjected to PDT, noted that hemorrhage around the light source was a significant, yet unpredictable, impediment to light diffusion into the prostate.4 Successful PDT is not only dependent upon sufficient light, but also adequate photosensitizer levels and good tissue oxygenation. Tumor hypoxia can hamper the effectiveness of PDT, while hyperbaric oxygen during PDT has been shown to improve PDT results in murine mammary tumor models.5
It seemed surprising to me that there had never been a clinical report on PDT for prostate cancer, since I have known about PDT since the days of my Masters degree studies at Roswell Park in the early 1980s. This study was actually brought to my attention by several patients. After reading the paper, I can understand my patients’ enthusiasm, but unfortunately the reality is that light dosimetry, including fractionation issues and interpatient variability in light diffusion, remains a challenge. Clearly, advancement of this technology for clinical use depends upon overcoming the same sorts of issues that have kept cryotherapy and radiofrequency microwave heating from gaining widespread popularity.
Dr. Kaplan is Acting Chairman for the Department of Radiation Oncology at Cleveland Clinic Florida in Ft. Lauderdale FL as well as Medical Director for Boca Raton Radiation Therapy Regional Center in Deerfield Beach, FL.
1. McBride G. J Nat Cancer Inst. 2002;94:1740-1742.
2. Selman SH, et al. J Urol. 2001;165:1795-1801.
3. Momma T, et al. Cancer Res 1998;58:5425-5431.
4. Lee LK, et al. Br J Urol Int. 1999;84:821-826.
5. Chen Q, et al. Photochem Photobiol. 2002;76:197-203.