Selecting Treatment for High-Risk, Localized Prostate Cancer: The Case for Radiation Therapy

NE W POINT-COUNTERPOINT SE CT IO N Selecting Treatment for HighRisk, Localized Prostate Cancer: The Case for Radiation Therapy Robert Meier, MD,* Michael K. Brawer, MD† *Swedish Cancer Institute at Northwest Hospital, Seattle, WA, and †Northwest Prostate Institute, Seattle, WA Prostate cancers that clinically appear to be localized may nonetheless respond poorly to curative treatment. Pretreatment prostate-specific antigen (PSA) level, biopsy Gleason score, and percentage of positive biopsies are all at least as important as clinical stage in predicting treatment outcome. A patient with a nonpalpable tumor, stage T1c disease, serum PSA of 12 ng/mL, and a Gleason score of 8 to 10 in 2 of 12 biopsy cores has a relatively poor prognosis. In a high-risk patient such as this one, the recommended treatment strategy involves a combination of brachytherapy and conformal external beam radiotherapy. In studies comparing treatments in patients stratified according to a variety of risk measures, this combination has shown biochemical disease-free survival rates superior to those seen following radical prostatectomy. The role of androgen suppression remains unclear. [Rev Urol. 2002;4(3):141–146] © 2002 MedReviews, LLC Key words: Prostate cancer • Radiotherapy • Brachytherapy • Radical prostatectomy • Biochemical disease-free outcome • Gleason score his paper addresses the case of a healthy 70-year-old man presenting with a nonpalpable tumor of the prostate, stage T1c disease, serum PSA of 12 ng/mL, and an adenocarcinoma with a Gleason score of 8 to 10 that is present in 2 of 12 biopsy cores. This case illustrates the therapeutic challenge of high-risk, localized prostate cancer. That is, although these tumors clinically appear to be localized, attempts at curative treatment are at high risk for failure. This patient has clinical stage T1c disease; however, the American Joint Committee on Cancer (AJCC) staging system does not include grade or pretreatment prostate-specific antigen (PSA) and therefore inadequately describes this patient's relatively poor T VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 141 Prostate Cancer Treatment: Radiation Therapy continued prognosis. In patients with clinically localized disease, other clinical and pathologic factors are at least as important as clinical stage in predicting treatment outcomes. Pretreatment PSA, biopsy Gleason score, clinical stage, and percentage of positive biopsies all independently predict recurrence after radical prostatectomy1-6 have been most favorable, in the 60%–80% range.14-16 However, in patients with pretreatment PSA higher than 10 ng/mL, Gleason scores higher than 6, and clinical stage higher than T2a, careful pathologic evaluation of radical prostatectomy specimens revealed a distressingly high rate of extracapsular tumor. In patients with clinically localized disease, other clinical and pathologic factors are at least as important as clinical stage in predicting treatment outcomes. and radiotherapy (RT).7-11 Furthermore, significant cancer volume and percentage of cancer occupied by Gleason grade 4/5 are associated with biochemical progression.12 Although the biopsy material for this patient demonstrates a small amount of cancer, we know that his predominantly grade 4 cancer combined with a pretreatment PSA of 12 ng/mL predict a poor outcome following attempts at curative treatment. Numerous predictive tables, or nomograms, have been devised in an attempt to predict outcome following treatment. In a recent review of the literature, Ross and colleagues identified 42 prostate cancer nomograms.13 Most of these charts have not been validated, and there is no consensus as to a preferred risk stratification system. However, using any of these systems, the patient in our discussion is at high risk for failure following local therapy. Radical Prostatectomy In the 1990s, the use of PSA screening resulted in more early-stage diagnosis of prostate cancer, and radical prostatectomy became increasingly popular. In patients with low-risk cancers (clinical stage T1-T2a, Gleason score < 7, PSA < 10 ng/mL), cure rates following radical prostatectomy 142 VOL. 4 NO. 3 2002 Indeed, radical prostatectomy in patients with these risk factors often fails.17-26 These high failure rates are presumably due to the undetected spread of cancer, either through local extension beyond the capsule, or through metastases to nodal or distant sites. New techniques that treat local spread of disease beyond the capsule of the prostate, and/or effective systemic therapies that eradicate occult distant disease, might improve outcomes in these high-risk patients. Radiotherapy In theory, RT is suited to address both local disease extension beyond the prostate, and occult nodal involvement. Potential subclinical lymph-node metastases can be safely intermediate- and high-risk patients. It therefore comes as no surprise that urologists have been skeptical about the curative potential of RT in prostate cancer. The poor results seen with conventional-dose RT led to the development of new strategies to improve its efficacy. Two approaches have proven beneficial: combining RT with androgen suppression, and dose escalation. Several randomized trials have shown that RT plus androgen ablation (AA) is superior to conventional-dose RT in locally advanced prostate cancer,29-35 with improvements in both local control and disease-free survival. Since the patients in these studies were all treated with conventional doses, AA may compensate for inadequate dose to the primary site, or it may be treating regional or distant metastases. The role of AA with dose-escalated RT, and the optimum duration of AA, remain unclear. Dose Escalation Dose escalation has markedly improved outcomes following RT. In conventional external beam RT, a relatively large portion of the rectum and bladder receives the dose prescribed to the prostate, thus the maximum safe dose is limited to about 70 Gy. It is now clear that 65–70 Gy, the previously accepted dose for Dose escalation has markedly improved outcomes following radiotherapy. addressed with moderate doses of pelvic RT. Also, since external beam portals or radioactive prostate implants can deliver the dose beyond the immediate confines of the prostate gland, RT could address local extracapsular disease extension. Yet despite these potential advantages, the results of conventional-dose RT have been disappointing,27,28 particularly in REVIEWS IN UROLOGY prostate cancer, is inadequate. Techniques have therefore been developed that deliver escalated doses to the prostate while limiting the dose to these surrounding organs. These approaches include conformal external beam RT and brachytherapy. Conformal external beam RT. Conformal external beam RT, including three-dimensional conformal RT Prostate Cancer Treatment: Radiation Therapy Table 1 Disease-Free Survival Rates Following Three Prostate Cancer Treatments Type of Treatment Authors Zelefsky et al 199839 Conformal doseescalated external beam radiotherapy Hanks et al 199838 Pollack et al 2000 Critz et al 2000 37 40 Number of Patients 94 Years of Follow-up 4 High (2 risk factors) 98 4 50 PSA 10–19.9 ng/mL 28 5 73 PSA ≥ 20 ng/mL 26 5 36 PSA > 10 ng/mL 53 5 75 PSA > 20 ng/mL 44 4 69 126 4 82 28 4 67 124 6 75 59 6 51 Stages Included Intermediate (1 risk factor) Gleason 7 Gleason 8–10 45-Gy external beam plus seed Lederman et al 200142 Intermediate (1 risk factor) High (2 risk factors) implant Merrick et al 200147 Blasko 200043 D'Amico et al 199844 Seed implant alone Zelefsky et al 200041 Disease-free Survival Rates, % 79 Intermediate (1 risk factor) 165 5 96 High (2 risk factors) 100 5 80 Intermediate (1 risk factor) 115 5 85 High (2 risk factors) 65 5 60 Intermediate (1 risk factor) 15 2 32 High (2 risk factors) 19 2 22 Intermediate (1 risk factor) 85 5 77 High (2 risk factors) 17 5 38 PSA indicates prostate-specific antigen. (3D CRT) and intensity-modulated RT, have permitted escalation of external beam doses to 75–81 Gy. The use of computed tomography (CT)–based target localization and treatment planning, improved patient immobilization, and more sophisticated treatment-field configurations have successfully limited the amount of radiation that reaches the surrounding organs. Rectal complication rates of 8%–10% with 3D CRT have been reported,36 a reduction compared with those seen with conventional techniques. Brachytherapy. Brachytherapy, or the placement of radioactive sources directly in the prostate, is another method to achieve dose conformality. Modern prostate brachytherapy uses a percutaneous transperineal approach, and ultrasound or CT guidance allows sources to be precisely placed in or near the prostate. Since the dose falls off rapidly short distances from these sources, brachytherapy allows very implants, radioactive I-125 or Pd-103 “seeds" are placed in the prostate, and the radiation dose is delivered over a period of weeks, as the isotopes decay. Patients with low-risk, organconfined prostate cancers can be treated with an implant alone, while Since the dose falls off rapidly short distances from these sources, brachytherapy allows very high doses to be given to the target, with minimal exposure to the adjacent bladder and rectum. high doses to be given to the target, with minimal exposure to the adjacent bladder and rectum. Prostate brachytherapy involves either permanent or temporary implants. In permanent those with intermediate- and highrisk cancers receive 45 Gy of external beam prior to the implant. Seed implants give the prostate the radiobiologic equivalent of more than 100 Gy. VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 143 Prostate Cancer Treatment: Radiation Therapy continued In temporary implants, afterloading catheters are placed through the perineum into the prostate, and these catheters are temporarily loaded with the radioactive sources. This procedure usually involves a high-dose-rate (HDR) delivery system, in which case it is called an HDR implant. Typically, HDR implants are combined with 45 Gy of external beam RT, and the prostate receives the radiobiologic equivalent of about 75 to 85 Gy. Dose Escalation: Treatment Outcomes Dose escalation through conformal external beam RT has yielded improved outcomes in localized prostate cancer. As long-term biochemical disease-free survival (bDFS) data emerge, a clear benefit over conventional-dose RT is seen (see Table 1). A randomized trial at the University of Texas MD Anderson Cancer Center37 compared conventional-dose RT (70 Gy) with 3D CRT (78 Gy) in patients with presenting PSA of greater than 10 ng/mL. Fiveyear bDFS was significantly better in the dose-escalated patients (75% vs 48%, P = .011). Long-term bDFS data are limited for conformal external beam RT, but for high-risk patients, such as the one described in this paper, 4- to 5-year bDFS appears to be in the 36%–50% range.38,39 Results with brachytherapy are even more encouraging. The several large, retrospective series from experienced institutions report 4- to 6-year bDFS in the 51%–80% range for high-risk patients.40-43 Two brachytherapy series have reported less favorable outcomes in high-risk patients: 22% bDFS at the University of Pennsylvania44 and 38% bDFS at Memorial Sloan-Kettering Cancer Center.41 However, contrary to common practice, patients in these series received implants alone, without supplemental external beam pelvic RT. Also, poorer outcomes may be a result of clinicians' limited experience, as the learning curve in prostate brachytherapy is well documented, and bDFS depends on adequate dose delivery.45 Radical Prostatectomy Versus Radiotherapy: Treatment Outcomes Since randomized data are lacking, comparisons of radical prostatectomy with modern RT necessitates comparing treatment outcomes from different institutions. The inherent pitfalls of such analysis are minimized by comparing similar pre-treatment groups. Several surgical series stratify patients by the pretreatment parameters of clinical stage, Gleason score, PSA level, and/or risk group. High-risk patients (defined as PSA > 20 ng/mL, Gleason score > 7, or 1992 AJCC stage T2c) undergoing radical prostatectomy at the Hospital of the University of Pennsylvania and at Brigham and Women's Hospital had 5-year bDFS of 32% and 28%, respectively.46 Using a similar risk stratification system, brachytherapy plus pelvic RT series yielded superior bDFS: 51%,42 60%,43 and 80%.47 In the large radical prostatectomy series from Johns Hopkins,16 patients were stratified according to pretreatment PSA level. Patients with pretreatment PSA of 10–20 ng/mL and those with pretreatment PSA greater than 20 ng/mL showed 5-year bDFS of 73% and 60%, respectively. Brachytherapy series using a comparable stratification system have demonstrated superior results, with 5-year bDFS of 76%–90% for pretreatment PSA levels of 10–20 ng/mL, and 65%–83% for levels greater than 20 ng/mL.41,40,43,47,48 Finally, for patients with Gleason scores of 8 to 10, the radical prostatectomy series from Johns Hopkins reported 5-year bDFS of 44%, whereas two brachytherapy series reported 5-year bDFS of 91%46 and 67%.40 Whether stratified by risk group, PSA level, or Gleason score, high-risk patients treated with combined brachytherapy/external beam RT have better relapse-free outcomes than those treated with radical prostatectomy. Conclusion The best opportunity for control of disease in the patient with high-risk, Main Points • Prostate cancers that appear to be clinically localized may nonetheless have a relatively poor prognosis. • In treating high-risk, localized prostate cancer, a combination of brachytherapy and conformal external beam radiotherapy offers the best opportunity for control of the disease. • Both brachytherapy and conformal external beam radiotherapy allow delivery of escalated doses of radiation to the prostate while limiting exposure to surrounding organs. • This combination treatment has shown biochemical disease-free survival rates superior to those seen with radical prostatectomy. • The use of androgen suppression remains controversial. 144 VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY Prostate Cancer Treatment: Radiation Therapy localized prostate cancer is found with brachytherapy plus pelvic RT. Given the high failure rates associated with either radical prostatectomy, brachytherapy, or external beam RT alone, we encourage a combined approach in this patient. Our preferred strategy is to perform a limited pelvic lymph-node dissection either laparoscopically or through a “Mini Lap" approach. If the lymph nodes are negative, we proceed with pelvic radiotherapy and provide a brachytherapy boost. The use of androgen suppression in these patients in a neoadjuvant or adjuvant setting remains controversial. However, the encouraging data associated with the bicalutamide neoadjuvant trial (unpublished data) and data from other studies demonstrating a benefit of hormone suppression combined with external beam RT have led to increased use of hormonal suppression paired with RT.49–51 We generally use 1 to 2 years of LRHR agonist or an anti-androgen in combination with the above-mentioned regimen. 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