Perineal Prostatectomy, X-Rays, Protons, Neutrons, and Combination Brachytherapy

Therapeutic Strategies for Localized Prostate Cancer II:

10TH INTERNATIONAL PROSTATE CANCER UPDATE Therapeutic Strategies for Localized Prostate Cancer II: Perineal Prostatectomy, X-Rays, Protons, Neutrons, and Combination Brachytherapy Michael D. Weil, MD,* Arthur T. Porter, MA, MBA, MD,† David C. Beyer, MD,‡ Peter S. Albert, MD, FACS,§ Douglas Chinn, MD, Michael J. Harris, MD¶ * University of Colorado Health Sciences Center, Denver; †Detroit Medical Center, Detroit; University of Arizona, Phoenix; §Staten Island University Hospital, Staten Island, NY; Arcadia, Calif; ¶ Northern Institute of Urology and Munson Medical Center, Traverse City, Mich ‡ Application of improved imaging, diagnostic, and computer techniques is beginning to have an impact on the management of localized prostate cancer. It is possible to perform a range of surgical and radiation procedures with less morbidity than in the past. The changes in therapy for patients with localized disease derive from better knowledge of anatomy for invasive procedures and optimization of virtual planning for noninvasive methods. Perineal prostatectomy and combinations of beam and seed radiation offer both patient and physician reasonable therapeutic options. Key words: Prostatic neoplasms • Radiotherapy • Survival analysis S urvival from prostate cancer is strongly determined by the virulence of the tumor at presentation (Table 1).1 In the absence of a prospective, randomized trial in the era of prostate-specific antigen (PSA) testing, there is no evidence that any 1 local treatment is superior, giving unequivocally better cure rates. Nonetheless, better imaging, computer software, and anatomic approaches have clearly decreased morbidity and given patients a wider range of therapeutic options. Perineal Prostatectomy The anatomic radical perineal prostatectomy can be performed with excellent results as a primary procedure or as a salvage procedure following cryotherapy or irradiation. Harris2 at the Northern Institute of Urology recently reported his use of this procedure for 348 patients, with an average follow-up of 3 years. Biochemical freedom from recurrence was 98% for organ-confined disease (60% of cases) and 95% for specimen-confined disease (18% of cases). Half of the patients were continent within the first postoperative month, and 97% were free of pad use by the end of the first year. The remaining patients reported minimal stress incontinence. Nerve preservation in men with unilateral, nonapical tumors resulted in adequate unassisted vaginal penetration in 54% of the patients. The rate of complications, including strictures, was less than 2%, with no deaths. 30 REVIEWS IN UROLOGY Supplement Therapeutic Strategies II The surgery took 90 minutes for the non–nerve-sparing procedure and 120 minutes for the nerve-sparing procedure. Ninety percent of patients were discharged on postoperative day 1 and the remainder on day 2. Catheters were removed on day 10 in patients with intact bladder necks and day 17 in those with repaired bladder necks. The technique appears to be cost-effective, reproducible, and appropriate for localized prostate cancer. Table 1 Chance of Dying of Prostate Cancer Within 15 Years Based on Gleason Score Gleason score 2-4 5 6 7 8 - 10 Mortality (%) 5 10 25 50 75 Adapted from Albertsen PC et al. JAMA. 1998.1 X-Rays Innovations in computer technology and medical imaging have helped to dramatically decrease the side effects of x-rays and increase the chances for cure. An analysis of long-term outcome of patients treated with x-rays only in the Radiation Therapy Oncology Group (RTOG) trials revealed that survival rates were similar to those of patients treated by radical prostatectomy (Table 2).3-5 Toxicity data for older radiation methods are derived from the RTOG trials 7506 and 7706.6 These data demonstrate that rectal and urinary complications of grade 3 or greater occurred in 3% and 8% of patients, respectively. Bowel complications become apparent approximately 1 year after beam treatment, and genitourinary complications develop closer to 3 years after beam treatment.7 Even when a conformal, but not a 3-dimensional (3D), technique is used, grade 3/4 rectal bleeding developed in as many as 5% of patients from 9 to 40 months following irradiation.8 Three-dimensional conformal radiotherapy. Most x-ray therapy for prostate cancer in the United States is done without 3D planning. The 3D planning software available reconstructs 2-dimensional CT images and displays the dose of radiation delivered to a target organ as well as to normal structures. The rectum is the most sensitive structure in the region. By lowering rectal dose (as compared with standard methods), 3D planning lessens symptoms and side effects. Optimization by 3D planning permits delivery of a greater radiation dose to the tumor with less chance of injuring critical organs.9 Patients require no restrictions on activity with 3D conformal radiotherapy (3D CRT). Side effects are usually limited to minimal fatigue, with mild dysuria and frequency, and resolve quickly after therapy. There is no anesthesia risk, and chances of incontinence or bowel injury are very small. The main inconvenience is daily treatments for 2 months. Several studies report the benefit of 3D CRT for prostate cancer.10-12 Zelefsky and associates12 noted a significant benefit with higher radiation to the prostate using 3D CRT, which allows safe escalation of the prostate dose. The study of more than 700 patients with localized disease, with a median follow-up of 3 years, showed that 90% of the patients treated with 75.6 Gy or greater had a PSA nadir of 1 ng/mL or less. Two published, prospective phase III studies13,14 have demonstrated fewer late complications with 3D CRT. A multicenter trial has shown better tolerance of higher doses with 3D CRT.15 Computer modeling has allowed further improvement of the therapeutic ratio of 3D CRT. The use of a noncoplanar, 3-field arc technique (3-FAT) resulted in the lowest doses of radiation to the rectum, bladder, and femoral heads of any geometry.16 Following 3-FAT treatment, 168 patients reported minimal discomfort during therapy and minimal urinary complaints, despite receiving doses comparable with the upper ranges reported elsewhere. The results are consistent with predictions from computer modeling, which limited the high doses to the targeted regions of the prostate and seminal vesicles.17 Intensity-modulated radiation therapy. Using either static or dynamic beams with multileaf collimation, intensity-modulated radiation therapy Table 2 Disease-Free Survival at 4 Years by Pretreatment PSA Level in Patients Receiving X-Ray Therapy Only* PSA (ng/mL) < 10 10 – 20 (Gl ≤ 6) 10 – 20 (Gl > 6) > 20 DFS (%) 80 70 50 30 PSA, prostate-specific antigen; DFS, disease-free survival; Gl, Gleason score. *Biochemical—no evidence of disease (overall), 66%. Adapted from Shipley WU et al. JAMA. 1999.5 Supplement REVIEWS IN UROLOGY 31 Therapeutic Strategies II continued Table 3 Comparison of Costs for Radiation Factor Equipment Protons Linear accelerator High-dose rate temporary seeds Per treatment* Protons Seeds Linear accelerator Cost $80 million $4.5 million $0.8 million $80 thousand $12 thousand $4.5 thousand *Treatment for 10 years, 100 treatments a year. From Weil MD. Unpublished data. (IMRT) is an advancement of 3D CRT. Compared with 3D CRT, IMRT produces better dose distributions in some instances but takes longer. It deposits x-rays tightly in a 3D volume. The dose to normal tissue is minimized by changing the intensity of the beam and shaping the treatment fields.18 Using this approach, it is possible to radiate the prostate with more than 70 Gy and deliver 90 Gy to a dominant intraprostatic lesion, with a lower dose to the rectum than standard 3D CRT.19 The optimization of the therapeutic ratio should allow higher radiation doses with less acute toxicity.20 This technique may offer a marked drop in late complications, compared with even the best 3D CRT. Protons and Neutrons Protons have a potential advantage over other forms of radiotherapy, because the dose expands in a discrete region called the “Bragg Peak.” Parti- cles have different properties than xrays. The costs of equipment and treatment are much greater than those of conventional radiotherapy or seeds (Table 3).21 Neutron beam therapy is indicated for unresectable salivary gland tumors.22 Protons were first used clinically in 1954 in Sweden23 and shortly thereafter at Berkeley for pituitary radiation in patients with metastatic breast cancer.24 In 1961, Kjellberg and associates25 began treating patients using the Harvard cyclotron. His team performed a comprehensive study of arteriovenous malformations and derived the dose effects resulting in radiation necrosis from proton therapy of the brain.26 Kjellberg’s line for radiation necrosis set the standard for modern radiosurgical doses. Protons have been used for chordoma, chondrosarcoma, brain tumors, arteriovenous malformations, uveal melanoma, macular degeneration, retino- Table 4 Disease-Free Survival at 5 Years by Pretreatment PSA Level in Patients Receiving Proton Therapy PSA (ng/mL) 4 – 10 10 – 20 > 20 PSA, prostate-specific antigen; DFS, disease-free survival. Adapted from Slater JD et al. Int J Radiat Oncol Biol Phys. 1998.35 32 REVIEWS IN UROLOGY Supplement DFS (%) 91 79 40 blastoma, and prostate cancer.27 The only established indications are choroidal melanomas and low-grade, skull base chondrosarcomas and chordmas.28 Proton trials. Protons were first used for prostate cancer in the 1970s at Harvard, where Shipley and associates29 treated 17 patients with x-rays and then gave 20 to 25 cobalt Gray equivalent (CGE) by perineal proton boosts for localized prostate cancer. In followup, Suit and colleagues30 reported on treatment with protons only or in combination with x-rays in 317 patients with various lesions, including 65 patients with prostate cancer. No significant increase in complications was noted with protons compared with x-rays, despite a 10% increase in dose.31 With a median follow-up of 5 years, later reports of 189 patients with T3-T4 prostate cancer noted that rectal bleeding correlated with a higher dose to the anterior rectal wall.32 The completed phase III trial compared high-dose treatment with combined x-rays plus photons (75.6 CGE) versus low-dose treatment with x-rays only (67.2 CGE). There was no statistically significant difference in survival or disease-free survival with the addition of proton therapy. There was, however, a significant increase in morbidity in the proton boost arm. This higher-dose group had a higher incidence of rectal bleeding (32% versus 12%) and more urethral strictures (19% versus 8%).32,33 The use of combined x-ray and proton treatment has more recently been evaluated at Loma Linda University Medical Center for locally advanced prostate cancer34 and localized disease.35 The latter study included 643 patients treated with up to 75 CGE from 1991 to 1995. Half of the patients received whole pelvic irradiation with x-rays up to 45 Gy. At 3-year followup, grade 2 radiation proctitis was seen in 21% and grade 3 toxicity in 0.3% of the 643 patients. The 5-year diseasefree survival based on pretreatment PSA levels is shown in Table 4 and is comparable with the results with x- Therapeutic Strategies II rays (Table 2). Neutron trials. Fast neutron radiotherapy is clinically indicated for locally advanced salivary gland tumors and inoperable sarcomas of the bone and soft tissue.36 Two randomized trials comparing neutron radiotherapy with external beam photon radiation for prostate cancer showed better diseasefree survival with use of neutrons.37,38 Between 1977 and 1983, RTOG37 performed a randomized protocol with mixed beams in patients with locally advanced disease. From 1986 to 1990, the Neutron Therapy Collaborative Working Group did a second study with neutrons alone.38 The 10-year results from RTOG showed a significant survival advantage with neutrons (46% versus 29%),37 but there were more severe complications with neutrons (11% versus 3%). Researchers at Wayne State University have continued studying neutrons for the management of prostate cancer, with good results.39 Their reported complications rates have been low, with evidence of good biochemical control. Disease-free survival rates at 4 years, based on initial PSA levels, are shown in Table 5. These numbers resemble the outcomes for x-rays and protons (Tables 2 and 4). Brachytherapy and X-Rays If well tolerated, monotherapy with seeds is clearly a good option for lowrisk patients; that is, those with tumors of stage T2a or lower, Gleason score of 6 or lower, and a PSA level of 10 ng/mL or lower (Tables 6 and 7).40 Problems arise when the prostate gland has a volume greater than 60 g, overlaps the pubic arch, blocks needle placement, and requires hormonal downsizing. The risk of urinary problems is high after implant in patients with American Urological Association scores higher than 20. Treatment with the peripheral loading approach appears to be safe in patients who have previously undergone transurethral resection of the prostate (TURP). Following implants, TURP should not be per- Table 5 Disease-Free Survival at 4 Years by Pretreatment PSA Level in Patients Receiving Neutron Therapy PSA (ng/mL) < 10 10 - 20 > 20 DFS (%) 92 85 38 PSA, prostate-specific antigen; DFS, disease-free survival. Based on data from Forman JD, Porter AT. Semin Urol Oncol. 1997.39 formed, but transurethral incision of the prostate appears to be safe. In higher-risk patients, a potentially straightforward approach to increasing radiation to the prostate, without risking increased morbidity to the surrounding tissue, is to combine beam therapy with transperineal seed implants. The beam can be delivered with conventional or 3D techniques, and the seeds can be temporary or permanent. The permanent seed treatment can be preplanned or distributed in real-time using nomograms. High-dose rate temporary implants can be planned after needle implantation. This combined approach offers a good deal of flexibility and is forgiving of potential technical weakness. It subjects the patient, however, to the inconvenience of daily beam treatments for 5 weeks and invasive seed placement under anesthe- Table 6 Comparison of Surgery, X-Rays, and Seeds by Risk Groups Relative risk* Low Moderate High RP 1 1 1 Treatment RT 1.1 0.8 0.9 PI+H 0.5 1.6 2.2 PI 1.1 3.1 3 *The relative risk of prostate-specific antigen (PSA) failure using radiotherapy (RT), permanent implant plus hormones (PI + H) or implant alone compared with radical prostatectomy (RP, relative risk = 1) in patients with clinically localized prostate cancer. • Low risk (stage T1c, T2a and Gleason score of 6 or lower and a PSA level of 10 ng/mL or lower) • Moderate risk (stage T2b or Gleason score of 7 or a PSA level of 10 or greater and a PSA level of 20 ng/mL or lower) • High risk (stage T2c or Gleason score of 8 or greater or a PSA level greater than 20 ng/mL) Adapted from D’Amico AV et al. JAMA. 1998.40 Table 7 Side Effects of Permanent Seeds Side effect Retention Prostatitis Proctitis Potency Comments Lasts 1 - 3 days 2 - 3 weeks postimplant More frequent bowel movements 80%, but painful ejaculation Supplement REVIEWS IN UROLOGY 33 Therapeutic Strategies II continued sia. It is also very expensive, exceeded only by the cost of proton irradiation for management of prostate cancer. Albert41 at the Staten Island University Hospital recently reported the use of combined radiotherapy following extraperitoneal, endoscopic lymph node biopsy for patients with greater than stage T2a disease, Gleason score of 7 or higher, or PSA level greater than 15 ng/mL, or who were younger than 60 years. They have treated 165 patients with combined radiotherapy with a follow-up of at least 5 years. The freedom from progression rate based on PSA level is 81%. Twentyeight patients (17%) reported rectal bleeding, and 2 patients (1.2%) had more severe rectal complications—fistula and rectal wall necrosis—requiring diverting surgery. These complications led to abandonment of the use of iodine 125 before beam irradiation. In addition, 10 patients (6%) had stress or urgency incontinence, while 8 (5%) had urinary irritative symptoms lasting more than 1 year. In these high-risk patients, the potency rate was 52%. The combined radiotherapy approach is thus a more aggressive regimen to be considered for patients at higher risk for failure. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Range of Options Localized therapy for prostate cancer includes a wider range of less morbid procedures than were available in the past. The patient is presented with many reasonable choices but may have many more questions. Open discussion of the newer approaches is an opportunity for planning customized treatment based on a patient’s concerns as well as medical indications. ■ References 1. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA. 1998; 280:975-980. 2. Harris MJ. Perineal prostatectomy. Paper presented at: 10th International Prostate Cancer Update; February 2-6, 2000; Vail, Colo. 3. Iselin CE, Robertson JE, Paulson DF. Radical perineal prostatectomy: oncological outcome during a 20-year period. J Urol. 1999;161:163-168. 4. Roach M III, Lu J, Pilepich MV, et al. Long-term 34 REVIEWS IN UROLOGY Supplement 16. 17. 18. 19. 20. 21. 22. survival after radiotherapy alone: radiation therapy oncology group prostate cancer trials. J Urol. 1999;161:864-868. Shipley WU, Thames HD, Sandler HM, et al. Radiation therapy for clinically localized prostate cancer. JAMA. 1999;281:1598-1604. Lawton CA, Won M, Pilepich MV, et al. Longterm treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys. 1991;21:935-939. Schultheiss TE, Hanks GE, Hunt MA, Lee WR. Incidence of and factors related to late complications in conformal and conventional radiation treatment of cancer of the prostate. Int J Radiat Oncol Biol Phys. 1995;32:643-649. Hanlon AL, Schultheiss TE, Hunt MA, et al. Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol Biol Phys. 1997;38:59-63. Roach M III, Pickett B, Weil M, Verhey L. The “critical volume tolerance method” for estimating the limits of dose escalation during three-dimensional conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 1996;35:1019-1025. Fukunaga-Johnson N, Sandler HM, McLaughlin PW, et al. Results of 3D conformal radiotherapy in the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys. 1997;38:311-317. Roach M III. Comparison of treatment techniques for conformal radiotherapy of the prostate using dose-volume histograms and normal tissue complication probabilities [letter; comment]. Radiother Oncol. 1996;40:85-87. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys. 1998;41:491500. Nguyen LN, Pollack A, Zagars GK. Late effects after radiotherapy for prostate cancer in a randomized dose-response study: results of a self-assessment questionnaire. Urology. 1998;51:991-997. Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet. 1999;353:267-272. Michalski JM, Prudy JA, Winter K, et al. Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406. Proceedings of the American Society for Therapeutic Radiology and Oncology. Phoenix: Elsevier; 1998. Weil MD, Pickett B, Kuerth S, Roach M III. A three-field arc technique (3-FAT) for treating prostate cancer. Int J Radiat Oncol Biol Phys. 1998;40:733-738. Hartford AC, Zietman AL. Prostate cancer. Who is best benefited by external beam radiation therapy? Hematol Oncol Clin North Am. 1996;10:595610. Verhey LJ. Comparison of three-dimensional conformal radiation therapy and intensity-modulated radiation therapy systems. Semin Radiat Oncol. 1999;9:78-98. Pickett B, Vigneault E, Kurhanewicz J, et al. Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys. 1999;44:921-929. Zelefsky MJ, Cowen D, Fuks Z, et al. Long term tolerance of high-dose three-dimensional conformal radiotherapy in patients with localized prostate carcinoma. Cancer. 1999;85:2460-2468. Orecchia R, Zurlo A, Loasses A, et al. Particle beam therapy (hadrontherapy): basis for interest and clinical experience. Eur J Cancer. 1998;34: 459-468. Fleurette F, Charvet-Protat S. Proton and neutron 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. radiation in cancer treatment: clinical and economic outcomes. Bull Cancer Radiother. 1996;83 (suppl):223s-227s. Larsson B, Leksell L, Rexed B, et al. The high energy proton beam as a neurosurgical tool. Nature. 1958;182:1222-1223. Tobias C, Lawrence J, Born J, et al. Pituitary irradiation with high-energy proton beams: a preliminary report. Cancer Res. 1958;18:121-134. Kjellberg R, Shintani A, Frantz AG, Kliman B. Proton-beam therapy in acromegaly. N Engl J Med. 1968;278:689-695. Kjellberg RN, Hanamura T, Davis KR, et al. Braggpeak proton-beam therapy for arteriovenous malformations of the brain. N Engl J Med. 1983;309: 269-274. Krengli M, Liebsch NJ, Hug EB, Orecchia R. Review of current protocols for proton therapy in USA. Tumori. 1998;84:209-216. Habrand JL, Schlienger P, Schwartz L, et al. Clinical applications of proton therapy: experiences and ongoing studies. Radiat Environ Biophys. 1995;34:41-44. Shipley WU, Tepper JE, Prout GR Jr, et al. Proton radiation as boost therapy for localized prostatic carcinoma. JAMA. 1979;241:1912-1915. Suit H, Goitein M, Munzenrider J, et al. Evaluation of the clinical applicability of proton beams in definitive fractionated radiation therapy. Int J Radiat Oncol Biol Phys. 1982;8:2199-2205. Duttenhaver JR, Shipley WU, Perrone T, et al. Protons or megavoltage x-rays as boost therapy for patients irradiated for localized prostatic carcinoma: an early phase I/II comparison. Cancer. 1983;51:1599-1604. Benk VA, Adams JA, Shipley WU, et al. Late rectal bleeding following combined X-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma. Int J Radiat Oncol Biol Phys. 1993;26:551-557. Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys. 1995;32:3-12. Yonemoto LT, Slater JD, Rossi CJ Jr, et al. Combined proton and photon conformal radiation therapy for locally advanced carcinoma of the prostate: preliminary results of a phase I/II study. Int J Radiat Oncol Biol Phys. 1997;37:21-29. Slater JD, Yonemoto LT, Rossi CJ Jr, et al. Conformal proton therapy for prostate carcinoma. Int J Radiat Oncol Biol Phys. 1998;42:299-304. Laramore GE. The use of neutrons in cancer therapy: a historical perspective through the modern era. Semin Oncol. 1997;24:672-685. Laramore GE, Krall JM, Thomas FJ, et al. Fast neutron radiotherapy for locally advanced prostate cancer: final report of Radiation Therapy Oncology Group randomized clinical trial. Am J Clin Oncol. 1993;16:164-167. Russell KJ, Caplan RJ, Laramore GE, et al. Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: results of a randomized prospective trial. Int J Radiat Oncol Biol Phys. 1994;28:47-54. Forman JD, Porter AT. The experience with neutron irradiation in locally advanced adenocarcinoma of the prostate. Semin Urol Oncol. 1997; 15:239-243. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-974. Albert PS. High dose combination radiation therapy in localized prostate cancer. Paper presented at: 10th International Prostate Cancer Update; February 2-6, 2000; Vail, Colo.