The Prostate 37:195–206 (1998) Review Article Update on the Treatment of Prostate Cancer With External Beam Irradiation Eric M. Horwitz,* Alexandra L. Hanlon, and Gerald E. Hanks Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania BACKGROUND. We review the recent changes in the radiotherapeutic management of clinically localized prostate cancer, including the implementation of three-dimensional (3-D) conformal radiation therapy (3DCRT), biochemical disease-free survival (bNED control) using conventional and 3DCRT techniques, and the morbidity of these treatment strategies. METHODS. The components of 3DCRT are discussed, including patient immobilization, 3-D treatment planning, multileaf collimation, and electronic portal imaging. bNED control rates from institutions using conventional and 3DCRT techniques are compared. The gastrointestinal (GI) and genitourinary (GU) morbidity from prospective trials using conventional doses of radiation are compared to data from 3DCRT series. bNED control rates stratified by pretreatment prostate-specific antigen (PSA) are compared between surgical and radiation series. RESULTS. bNED control rates (3–5 years) for patients treated with conventional and 3DCRT techniques ranged from 44–70% and 30–72% with pretreatment PSA levels 4–10 and 10–20, respectively. Although direct comparisons are difficult between treatment modalities, no difference in bNED control stratified by pretreatment PSA was observed between surgical and radiation patients. CONCLUSIONS. Patients with clinically localized prostate cancer treated with 3DCRT demonstrate durable bNED control at 5 years. Conformal radiation techniques, multileaf collimation, electronic portal imaging, and patient immobilization have reduced acute and chronic GI and GU morbidity while allowing safe dose escalation in an effort to further improve local control and overall survival. Prostate 37:195–206, 1998. © 1998 Wiley-Liss, Inc. INTRODUCTION The American Cancer Society estimates there will be 210,000 new cases of prostate cancer diagnosed in the United States in 1997 [1,2]. For those patients with clinically localized disease, several options for treatment exist, including observation , surgery , radiation therapy , or hormonal manipulation . External beam radiation therapy has been a mainstay in the management of prostate cancer over the last 35 years and continues to treat 29% of all patients receiving definitive therapy . The development of the prostate-specific antigen (PSA) test and its use as a screening tool has increased the number of patients diagnosed and treated with early-stage disease. More importantly, pretreatment PSA levels have been shown to be the strongest independent predictor of treatment outcome after both surgery and radiation, and a rising posttreatment PSA level indicates failure many years before disease becomes clinically detected [8–10]. Proper use of pre© 1998 Wiley-Liss, Inc. treatment categorization of disease and serial posttreatment PSA levels allow an accurate and meaningful assessment of various treatment modalities. The development and clinical testing of threedimensional (3-D) conformal radiation therapy (3DCRT) since 1989 has demonstrated clearly that this technology results in improved outcome compared to conventional treatment techniques [5,11,12]. The use of 3DCRT enables the safe delivery of higher doses of radiation to the prostate with reduced morbidity, especially in patients with pretreatment PSA levels greater than 10 ng/ml . The purpose of this communication is to review the current results with external beam radiation therapy (RT), including results with 3DCRT, and make limited comparisons with results from prostatectomy series. *Correspondence to: Eric M. Horwitz, M.D., Department of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. E-mail: EM Horwitz@fccc.edu Received 22 October 1997; Accepted 7 May 1998 196 Horwitz et al. Fig. 1. Anterior digitally reconstructed radiograph (DRR) treatment portal for 3DCRT. RESULTS 3DCRT vs. Conventional Technique Three-dimensional conformal radiation therapy is external beam irradiation in which the radiation treatment volume closely matches the macroscopic and microscopic tumor volume. The goal of 3DCRT is to better delineate and immobilize the target (prostate), allowing decreased treatment margins and thereby delivering higher doses of radiation to the prostate. This minimizes the volume of normal tissue receiving a clinically significant radiation dose and reduces the probability of normal tissue complications. This is accomplished by 1) immobilizing the patient in the treatment position with a posterior body cast to reduce day-to-day patient motion and positioning error [14,15]; 2) reconstruction of the prostate (target) in three dimensions from a CT scan done with the patient in the treatment cast; 3) directing multiple beams at the target that are shaped to conform to the shape of the target from each beam’s eye view (BEV) ; 4) using treatment-planning computers with dosimetric algorithms which allow the calculation of dose in three dimensions; 5) using electronic portal imaging devices which allow real-time visualization of the treatment fields to assure proper patient position ; and 6) using multileaf collimation (MLC) in the place of cerrobend blocking [18–20]. With MLC, the treatment field can be adjusted, accommodating both isocenter and field margin changes without moving the patient and introducing additional error. Figures 1 and 2 illustrate conformal treatment portals for an anterior and lateral view, including 1 cm of normal tissue margin around the prostate gland. Our 3-D treatment technique has previously been reported . To summarize briefly, the patient first undergoes a treatment-planning CT while immobilized in a half-body alpha cradle from the waist to the knees. CT slices 3 mm thick are obtained from the top of the sacro-iliac joints through the bottom of the obturator foramen. The gross tumor volume is defined as the entire prostate according to the ICRU 50 report . The seminal vesicles, and periprostatic, obturator, internal, and external iliac lymph nodes are also contoured. Treatment field size and dose guidelines at Fox Chase depend on pretreatment PSA, Gleason score, and clinical T stage. A contour 1.2 cm superior to the apex of the urethrogram contrast defines the inferior most portion of the prostate. The planning target volume (PTV) is defined as the prostate plus 1–1.5 cm in all directions. Conformal blocks are placed around the PTV in all directions, using BEV visualization. Doses range from 68–75 Gy, but currently remain at 70–72 Gy. Since 1993, lateral blocking has been added for the final 10 Gy to reduce the dose to the anterior rectal wall . One endpoint for comparing outcomes between these two RT techniques is to measure 12-month PSA response. The 12-month PSA response was analyzed for 260 patients treated at Fox Chase to determine if External Beam Irradiation of Prostate Cancer 197 Fig. 2. Lateral digitally reconstructed radiograph (DRR) treatment portal for 3DCRT. conformal treatment techniques were superior to conventional techniques. Patients were divided into two groups based on treatment technique (conventional vs. conformal) and 12-month PSA response determined for each group using two definitions (PSA 艋1.5 ng/ml and PSA 艋4.0 ng/ml). The median total dose was the same for both groups (70 Gy). The patients treated with 3DCRT had a statistically significant improvement in the 12-month PSA response compared to the group of patients treated with conventional techniques using both definitions (Table I) . Biochemical Freedom From Disease (bNED Control) Table II shows bNED control rates stratified by pretreatment PSA for patients treated with conventional doses of external beam RT from several institutions from the PSA era. Direct comparison of results is difficult due to different definitions of bNED control used, unequal distribution of critical prognostic factors between series, and unequal lengths of follow-up. However, as pretreatment PSA levels increase, rates of bNED control decrease across institutions using conventional doses of RT. Figure 3 shows the clinical and bNED rates for conventional and 3DCRT patients treated at Fox Chase. A bNED failure was defined as two consecutive rises in the posttreatment PSA which exceeded 1.5 ng/ml. These plots (Fig. 3) compare bNED control for all patients treated with conventional treatment (median dose 69 Gy), for all patients TABLE I. Twelve-Month PSA Response by Treatment Technique and Field Size* Treatment Prostate only 3DCRT Conventional Significance Pelvis and prostate boost 3DCRT Conventional Significance PSA 艋4.0 ng/ml PSA 艋1.5 ng/ml 95/99 (96%) 28/33 (85%) P < 0.03 85/99 (76%) 18/33 (55%) P < 0.02 58/71 (82%) 35/57 (61%) P < 0.01 40/71 (56%) 22/57 (38%) P < 0.05 *Modified with permission from Corn et al. . treated with 3DCRT at doses <71 Gy (median dose 70 Gy), and for all patients treated with 3DCRT with doses >71 Gy (median dose 74 Gy). There was a significant improvement in bNED control for patients treated with 3DCRT compared to conventional techniques, and further improvement with higher doses of 3DCRT . Morbidity of Conventional and 3-D Conformal Radiation Therapy Early data of 1,020 patients treated with conventional techniques and doses of radiation combined from the Radiation Therapy Oncology Group (RTOG) studies 75-06 and 77-06 showed a 3.3% incidence of grade 3 or higher late GI complications. Fewer than 198 Horwitz et al. TABLE II. Rates of bNED Control Stratified by Pretreatment PSA for Conventional RT Series* PSA (ng/ml) <4 4–10 <10 <13 >13 10–20 >20 20–25 >50 EVMS  Mayo Clinic  68% 57% MDACC  MGH  84% 66% 82% 44% Stanford  WBH  90% 54% 65% 92% 58% 56% 20% 49% 11% 30% 72% 8% 0% 28% 17% 27% 14% *EVMS, Eastern Virginia Medical School; MDACC, M.D. Anderson Cancer Center; MGH, Massachusetts General Hospital; WBH, William Beaumont Hospital. Fig. 3. Clinical and biochemical freedom-from-disease rate for conventional and 3DCRT patients. 1% of patients experienced obstruction or perforation which required surgery to correct. Seventy-nine patients (7.7%) experienced grade 3 or higher late GU complications, and only 0.5% experienced toxicity which required major surgery to correct. Only the total dose of >70 Gy significantly predicted late GU complications. No factor significantly predicted late GI complications . Data from the early National Patterns of Care Study on 1,293 patients showed a 92% 5-year actuarial rate free of complications. Sixty-eight patients experienced serious complications defined as those requiring hospitalization. One third of serious complications required surgical repair. Variables associated with a significant difference in major complica- tions also included dose >70 Gy. Patients treated with a two-field technique showed a trend towards increased complications compared to patients treated with four fields [25–27]. The acute morbidity of 3DCRT was assessed by the number of patients requiring medication for GI or GU symptoms during the course of radiation treatment [28,29]. Table III shows grade 2 and higher rates of GU and GI morbidity for patients stratified by treatment technique and field size. Statistically significant differences were observed in morbidity rates between treatment techniques. The greatest difference was noted for GI morbidity rates for patients treated with small-field 3DCRT (P < 0.001). External Beam Irradiation of Prostate Cancer TABLE III. Acute Morbidity (⭓Grade 2) Based on Treatment Technique and Field Size* GU All patients Small field Large field GI All patients Small field Large field GU/GI All patients Small field Large field 3DCRT Conventional Significance 189/668 (28%) 64/233 (27%) 125/435 (29%) 35/93 (38%) 20/49 (41%) 15/44 (34%) 0.044 0.048 0.28 163/668 (24%) 81/233 (35%) 82/435 (19%) 42/93 (45%) 28/49 (57%) 14/44 (32%) <0.001 <0.001 0.037 299/668 (45%) 120/233 (52%) 179/435 (41%) 63/93 (68%) 38/49 (78%) 25/44 (57%) <0.001 <0.001 0.033 *3DCRT, three-dimensional conformal radiation therapy; Small field, prostate only; Large field, pelvis and prostate boost. The late GI and GU complications following treatment with conventional or 3-D conformal external beam RT were recently reported. Seven hundred twelve patients treated between 1986–1994 with conventional (150 patients) or conformal (562 patients) techniques were analyzed for factors using a modified RTOG/SWOG scoring system which predicted late GI (rectal bleeding requiring 艌3 procedures to correct or proctitis) and GU (cystitis or stricture) morbidity. One hundred fifteen patients experienced grade 2 or higher GI toxicity a mean 13.7 months after treatment. Fifteen of these patients experienced grade 3 or 4 toxicity. Forty-three cases of grade 2 or higher late GU toxicity were observed a mean of 22.7 months after treatment. Only a central axis dose (>74 Gy isocenter) significantly predicted late grade 3 GI toxicity on multivariate analysis. Central axis dose, use of increased rectal shielding, androgen deprivation therapy before RT, history of obstructive symptoms, and acute GU symptoms significantly predicted for late grade 2 GU toxicity on multivariate analysis. After the presence of minor rectal bleeding was noted in 1993, techniques were developed to reduce the radiation dose to the anterior rectal wall. The necessity of multiple coagulations was reduced from 5% to 2% at 75–76 Gy . Data from other institutions which treat patients with 3DCRT show similar reductions in morbidity at high doses of radiation compared with patients treated using conventional techniques. Sandler et al.  reviewed the University of Michigan experience and analyzed 712 patients treated with 3DCRT for late GI effects. Using the RTOG grading system, only 14 grade 3 or 4 complications were observed. Only increasing dose was significantly predictive of late GI effects on univariate and multivariate analysis (includ- 199 ing treatment technique, boost technique, age, and T stage) . Early data from a phase 1 dose escalation study of 432 patients with clinically localized prostate cancer from the Memorial Sloan-Kettering Cancer Center showed 15% grade 2 acute GI toxicity. No grade 3 or 4 toxicities were noted. Forty percent of patients experienced acute grade 2 GU toxicity. The risk of late grade 2 GI or GU complications was 11% and 5%, respectively, for patients who received 75.6– 81 Gy. Three patients experienced grade 3 or 4 late GI or GU complications. The 2-year actuarial rate of impotency was 29% among those patients who were sexually active prior to treatment, and no dose response was observed . Dose Escalation With 3DCRT Between March 1989–October 1992, we conducted a dose escalation study in 232 consecutive patients treated with 3DCRT. Dose was increased from 66 to 79 Gy, and all patients were monitored continuously. The median follow-up now exceeds 60 months, and 5-year actuarial bNED control rates are now available . We observed a significant dose response effect for patients with pretreatment PSA levels greater than 10 ng/ml. Figure 4 illustrates the biochemical failure observed with high-dose (艌71 Gy) and low-dose (<71 Gy) radiation for patients with pretreatment PSA levels between 10–19.9 ng/ml. At 5 years, there was almost a 30% difference in bNED control for these T1 and T2 patients. These curves continue to separate as longer follow-up is obtained. This difference in bNED control has emphasized the need for higher dose levels in these patients. Figure 5 illustrates the same effect for patients with pretreatment PSA levels of 20 ng/ml and greater. A significant difference in 5-year bNED control rates was noted between patients treated with high-dose (36%) and low-dose (17%). Five-year rates of grade 2 and 3/4 GI toxicity were 33% and 8%, respectively, at doses of 75–76 Gy. When anterior rectal wall shielding was used to keep the dose at <72 Gy to this structure, the 5-year rates of grade 2 and 3/4 GI toxicity were reduced to 11% and 2%, respectively. Results from other institutions using 3DCRT demonstrate similar bNED results when patients are stratified by pretreatment PSA [12,34,35]. At the University of Michigan, the 5-year actuarial rates of bNED were 88%, 72%, 43%, and 30%, respectively, for patients with pretreatment PSA values <4, 4–10, 10–20, and >20 ng/ml. Pretreatment PSA, T stage, Gleason score, total dose, pelvic field treated, surgical status, and favorable grouping were all statistically significant on univariate analysis. However, only pretreatment PSA, T 200 Horwitz et al. Fig. 4. bNED control for patients with pretreatment PSA levels of 10– 19.9 ng/ml, treated with low- and high-dose 3DCRT. Fig. 5. bNED control for patients with pretreatment PSA levels >20 ng/ ml, treated with low- and high-dose 3DCRT. stage, and Gleason score remained independent predictors on multivariate analysis . Roach et al.  reported the UCSF experience of treating 50 patients with high-grade (Gleason score 8–10) prostate cancer using 3DCRT. Patients treated with >71 Gy had 4-year rates of bNED control of 83% vs. 0% for those patients treated with conventional doses of radiation (<71 Gy) . bNED Outcome for External Beam and Retropubic Prostatectomy Patients Table IV compares bNED results in selected external beam RT series with selected retropubic prostatectomy (RP) series at 5 years [4,5,12,34,36,37]. When patients were stratified by pretreatment PSA, no significant difference in outcome was noted at 5 years External Beam Irradiation of Prostate Cancer TABLE IV. Rates of bNED Control Stratified by Pretreatment PSA for Selected Surgical and Radiation Series* Surgery PSA (ng/ml) <4 4–10 <10 <7.5 >7.5 <15 >15 10–20 艋20 >20 UP  BUMC  3DCRT JHU  FCCC  92% 83% 80% UM  UCSF/UCD  88% 72% 85% 74% 49% 55% 25% 56% 56% 66% 43% 83% (>71 Gy) 20% 45% 33% 30% *3DCRT, three-dimensional conformal radiation therapy. UP, University of Pennsylvania: 347 patients, median follow-up 18 months, 2-years actuarial rate. bNED failure defined as detectable PSA (>0.2 ng/ml) >4 weeks postoperatively. BUMC, Boston University Medical College: 62 patients, median follow-up 18 months, 4-year actuarial rate. bNED failure defined as detectable PSA (>0.2 ng/ml) >4 weeks postoperatively. JHU, Johns Hopkins University: 1,354 patients, median follow-up 60 months, 8-year actuarial rate. bNED failure defined as detectable PSA (>0.2 ng/ml) postoperatively. FCCC, Fox Chase Cancer Center: 456 patients, median follow-up 40 months, 5-year actuarial rate. bNED failure defined as clinical evidence of disease or a serum prostate-specific antigen (PSA) 艌1.5 ng/ml and rising on two consecutive occasions. UM, University of Michigan: 707 patients, median follow-up 36 months, 5-year actuarial rate. bNED failure defined as two consecutive PSA rises >2 ng/ml if nadir PSA 艋2 ng/ml, or two consecutive PSA rises if nadir PSA 艌2 ng/ml, or initiation of hormonal therapy after RT. UCSF/UCD, University of California, San Francisco/Univeristy of California, Davis: 50 patients, median follow-up 24 months, 4-year actuarial rate. bNED failure defined as a PSA rise >0.5 ng/ml/year, rise of PSA >1.0 ng/ml, or a positive biopsy. comparing the treatment in surgical series with selected patients and radiation series with unselected patients. Two groups recently reported treatment outcome within institutions comparing similarly grouped patients treated with conventional doses of external beam RT or RP. Keyser et al.  reported the Cleveland Clinic experience of treating 607 patients (RP, 354; RT, 253). The 5-year bNED control rate was 76% and 75% for RP and RT patients, respectively (P = 0.09). On multivariate analysis, only pretreatment PSA and Gleason score were significant predictors of bNED control. Other factors, including treatment type, were not statistically significant . Similar conclusions were reached by D’Amico et al. . Patients treated with conventional doses of RT at the Joint Center for Radiation Therapy were compared with pa- 201 tients treated with RP at the University of Pennsylvania. As with the Cleveland Clinic series, pretreatment PSA, Gleason score, and clinical T stage were independent predictors of bNED control. No statistically significant difference was noted in 2-year bNED control rates for low-risk (98% vs. 92%, P = 0.45), intermediate-risk (77% vs. 81%, P = 0.86), and high-risk (51% vs. 53%, P = 0.48) patients treated with RP or RT, respectively . Comparisons between treatment modalities are difficult due to significant differences in how patients were grouped by pretreatment serum PSA levels, the unequal distribution of prognostic factors from series to series (e.g., Gleason score, clinical vs. pathological stage, age), the variability of how bNED control was defined, the substantial differences in length of followup, and the variety of study designs. In both the surgery and radiation series, the definition of bNED control varied. This was especially true in the radiation literature. As has recently been shown, depending upon which definition of bNED control is used (based upon definitions from several academic radiation oncology departments), statistically significant differences in treatment outcome are obtained attributable only to the definition chosen . In an effort to develop a unified definition of PSA cure for reporting successes or failures following irradiation, the American Society for Therapeutic Radiology and Oncology (ASTRO) recently convened a panel of prostate cancer experts to establish a standard definition of biochemical cure after RT. The consensus definition defines biochemical failure as three consecutive increases in posttreatment PSA after achieving a nadir. Biochemical failure is defined as the time midway between the nadir and first increase in PSA . It should also be noted that the statistical methodology used to estimate probability of bNED control should take into account competing risks. Specifically, cumulative incidence methods should be employed to account for differing age distributions (i.e., different percentages in death due to causes other than prostate cancer). The Kaplan-Meier method does not adjust for competing risks, and the bias increases with the percent of failures due to competing risks. Treatment Results in Selected Groups of Patients Treated With Radiation Results in younger men. Table V lists the 5-year outcomes for T1 and T2 patients with pretreatment PSA less than 10 ng/ml who were age 65 years or younger at time of treatment. This illustrates an extremely favorable outcome for this group with low morbidity, a low rate of incontinence, and a high rate of 5-year bNED control. Figure 6 illustrates the durability of 202 Horwitz et al. TABLE V. Five-Year Outcomes in Patients Age <65 Years With Pretreatment PSA Levels <10 ng/ml, T1–2, and Gleason Score < 7 Parameter Five-year rate Actuarial bNED control RTOG GI grade 3/4 RTOG GU grade 3/4 Potency preservationa 87% <1% <1% 73% a Percentage of mean potent pretreatment able to have sexual intercouse posttreatment. bNED control for this group of patients with available pretreatment PSAs and more than 5 years of follow-up . Similar results in outcome were reported by Poen et al.  for 396 patients treated at Stanford University. No statistically significant differences in causespecific survival and distant metastases-free survival were observed between patients age 60 years and less and those older. Patients age 60 years and less had statistically significant improvements in median survival, local control, and disease-free survival . Results in patients with stage T1c cancer. The 5-year bNED control for 176 patients with clinical stage T1c cancer who had pretreatment PSA levels <20 ng/ml treated with 3DCRT was 85% (Fig. 7). The 5-year rate of bNED control compared favorably to surgical patients with similar pretreatment prognostic variables, and results were durable for the complete length of follow-up . Results in patients with stage T2a cancer. The bNED control rate for 76 patients with clinical stage T2a cancer who had pretreatment PSA levels <10 ng/ml treated with 3DCRT was 77% at 8 years (Fig. 8). As with the T1c patients, the bNED control rate was excellent and the results were durable during the entire period of observation. For comparison with prostatectomy results, data from Johns Hopkins University for clinical stage T2a demonstrate 85% bNED control at 5 years and 68% bNED control at 8 years . Although difficult to compare directly, these results appear equivalent based upon similar pretreatment PSA and T stage. DISCUSSION External beam irradiation remains a mainstay in the treatment of patients with prostate cancer. Current results of treatment with conventional doses of radiation (<70 Gy) show similar rates of bNED control when patients are stratified by pretreatment PSA levels [35,40,45–48]. However, as pretreatment PSA levels increase, rates of bNED control decrease. The implementation of new technologies, including patient immobi- lization devices, CT treatment planning, beam eye view visualization and planning, dose calculation in 3-D, multileaf collimation, and electronic portal imaging, has improved the radiotherapeutic management of prostate cancer, resulting in increased radiation dose to the prostate. Simultaneously, these techniques have allowed the reduction in volume of normal tissue which receives clinically significant doses of radiation, resulting in the reduction in complication rates . In addition to the utilization of these new technologies, better understanding of tumor biology and prognostic factors, including pretreatment PSA level, Gleason score, and clinical T stage, is allowing better patient selection. Multiple studies in both the radiation and surgical literature have demonstrated that the pretreatment PSA level is the single most important independent prognostic variable to predict and assess treatment efficacy [4,36,40,49–51]. Results of treatment with 3DCRT with long-term (>5 years) PSA follow-up are becoming available which demonstrate superior bNED control rates using this new technique. Data from several institutions demonstrate that when the volume of normal tissue is reduced, the total dose to the prostate can be safely increased, resulting in improved bNED control. Data from our institution demonstrate that this is particularly pronounced for patients with intermediate levels of pretreatment PSA . Extensive long-term data on the GI and GU morbidity of external beam RT using conventional doses of radiation have been available for more than a decade. Data from several large national studies have shown consistently that the dose of radiation (>70 Gy) and the technique used contribute significantly to normal tissue complication rates [24,25]. Now data are becoming available from several institutions treating patients with 3DCRT that GI and GU morbidity is not significantly worsened despite the increased doses of radiation used [30,31]. Because higher doses of radiation can be delivered to the prostate (without substantially higher rates of normal tissue complications) using 3DCRT, evidence demonstrates that bNED control rates are significantly improved. Five to seven-year actuarial data from several institutions, including Fox Chase and the University of Michigan, show increased rates of bNED control, especially for patients with pretreatment PSA levels >10 ng/ml (a group that does not have durable bNED control rates with conventional RT). For patients with pretreatment PSA levels between 10—20 ng/ml, the advantage of 3DCRT was evident, with an almost 30% difference in bNED control at 5 years [5,12]. A major task for the radiation oncology community in the future is to expand the use of 3DCRT External Beam Irradiation of Prostate Cancer 203 Fig. 6. bNED control for T1/T2 patients <65 years old, with pretreatment PSA <10 ng/ml. Fig. 7. bNED control for clinical T1c patients treated with 3DCRT. technology beyond the limited numbers of expert facilities currently utilizing this treatment program. CONCLUSIONS Prostate cancer patients need to be well-informed of the results and morbidities of the various treatment options available so that they can make an informed decision regarding treatment modality. Using known prognostic factors including pretreatment PSA, Gleason score, and T stage to categorize patients into similar prognostic groups, patients with clinically localized prostate cancer can effectively be treated with high-dose 3-D conformal radiation therapy with mini- 204 Horwitz et al. Fig. 8. bNED control for clinical T2a patients treated with 3DCRT. mal long-term GI and GU toxicity. The results presented in this communication of conventional and 3-D conformal radiation therapy provide some basis for patient and physician choice. REFERENCES 1. Parker SL, Tong T, Bolden S, Wingo PA: Cancer Statistics. CA 1997;46:5–27. 2. Wingo PA, Landis S, Ries LAG: An adjustment to the 1997 estimate for new prostate cancer cases. CA 1997;47:239–242. 3. Johansson J-E, Holmberg L, Johansson S, Bergstrom R, Adami H-O: Fifteen-year survival in prostate cancer: A prospective, population based study in Sweden. JAMA 1997;277:467–471. 4. Pound CR, Partin AW, Epstein JI, Walsh PC: PSA following anatomical radical retropubic prostatectomy: An interim report. Urol Clin North Am 1997;24:395–406. 5. Hanks GE, Hanlon AL, Schultheiss TE, Freedman GM, Hunt M, Pinover WH, Movsas B: Conformal external beam treatment of prostate cancer. Urology 1997;50:87–92. 6. Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, Hanks GE, Coughlin CT, Porter A, Shipley WU, Grignon D: Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of RTOG Protocol 85-31. J Clin Oncol 1997;15:1013–1021. 7. Mettlin CJ, Menck HR, Winchester DP, Murphy GP: A comparison of breast, colorectal, lung, and prostate cancers reported to the National Cancer Data Base and the Surveillance, Epidemiology, and End Results Program. Cancer 1997;79:2052–2061. 8. Lee WR, Hanks GE, Hanlon A: Increasing prostate-specific antigen profile following definitive radiation therapy for localized prostate cancer: Clinical observations. J Clin Oncol 1997;15:230– 238. 9. Shipley WU, Prout GR, Coachman NM, McManus PL, Healey EA, Althausen AF, Heney NM, Parkhurst EC, Young HH, Shipley JW, Kaufman SD: Radiation therapy for localized prostate carcinoma: Experience at the Massachusetts General Hospital (1973–1981). NCI Monogr 1988;7:67–74. 10. Zagars GK, von Eschenbach AC: Prostate-specific antigen: An important marker for prostate cancer treated by external beam radiotherapy. Cancer 1993;72:538–548. 11. Corn BW, Hanks GE, Schultheiss TE, Hunt MA, Lee WR, Coia LR: Conformal treatment of prostate cancer with improved targeting: Superior prostate-specific antigen response compared to standard treatment. Int J Radiat Oncol Biol Phys 1995;32:325– 330. 12. Fukunaga-Johnson N, Sandler HM, McLaughlin PW, Strawderman MS, Grijalva KH, Kish KE, Lichter AS: Results of 3D conformal radiotherapy in the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys 1997;38:311–317. 13. Hanks GE, Lee WR, Hanlon AL, Hunt M, Kaplan E, Epstein BE, Movsas B, Schultheiss TE: Conformal technique for dose escalation for prostate cancer: Biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen 艌10 ng/ml. Int J Radiat Oncol Biol Phys 1996;35:861–868. 14. Bentel GC, Marks LB, Sherhouse GW, Spencer DP, Anscher MS: The effectiveness of immobilization during prostate irradiation. Int J Radiat Oncol Biol Phys 1994;31:143–148. 15. Soffen EM, Hanks GE, Hwang CC, Chu JCH: Conformal static field therapy for low volume, low grade prostate cancer with rigid immobilization. Int J Radiat Oncol Biol Phys 1991;20:141– 146. 16. McShan DL, Fraass BA, Lichter AS: Full integration of the beam’s eye view concept into computerized treatment planning. Int J Radiat Oncol Biol Phys 1990;18:1485–1494. 17. Boyer AL, Antonuk L, Fenster A, van Herk M, Meertens H, External Beam Irradiation of Prostate Cancer 205 Munro P, Reinstein LE, Wong JW: A review of electronic portal imaging devices (EPIDs). Med Phys 1992;19:1–61. formal radiotherapy in patients with prostatic carcinoma. Cancer J Sci Am 1995;1:142–150. 18. Frazier AJ, Du M, Wong JW, Vicini FA, Taylor R, Yu C, Matter RC, Martinez AA, Yan D: Dosimetric evaluation of the conformation of the multileaf collimator to irregularly shaped fields. Int J Radiat Oncol Biol Phys 1995;33:1229–1238. 33. Hanks GE, Hanlon AL, Schultheiss TE, Pinover WH, Movsas B, Epstein BE, Hunt MA: Dose escalation with 3D conformal treatment: Five year outcomes, treatment optimization and future directions. Int J Radiat Oncol Biol Phys 1998;41:501–510. 19. Frazier AJ, Yan D, Du M, Wong JW, Vicini FA, Matter RC, Joyce M, Martinez AA: Effects of treatment setup variation on the beam’s eye view dosimetry for radiation therapy using the multileaf collimator versus the cerrobend block. Int J Radiat Oncol Biol Phys 1995;33:1247–1256. 34. Roach M III, Meehan S, Kroll S, Weil M, Ryu J, Small EJ, Margolis LW, Presti J, Carroll PC, Phillips TL: Radiotherapy for high grade clinically localized adenocarcinoma of the prostate. J Urol 1996;156:1719–1723. 20. LoSasso T, Chui CS, Kutcher GJ, Leibel SA, Fuks Z, Ling CC: The use of a multileaf collimator for conformal radiotherapy of carcinomas of the prostate and nasopharynx. Int J Radiat Oncol Biol Phys 1993;25:161–170. 21. International Commission on Radiation Units and Measurements: ‘‘ICRU Report 50: Prescribing, Recording, and Reporting Photon Beam Therapy.’’ Bethesda, MD: International Commission on Radiation Units and Measurements, 1993. 22. Lee WR, Hanks GE, Hanlon AL, Schultheiss TE, Hunt MA: Lateral rectal shielding reduces late rectal morbidity following high dose three-dimensional conformal radiation therapy for clinically localized prostate cancer: Further evidence for a significant dose effect. Int J Radiat Oncol Biol Phys 1996;35:251–257. 23. Hanks GE, Lee WR, Schultheiss TE: Clinical and biochemical evidence of control of prostate cancer at 5 years after external beam radiation. J Urol 1995;154:456–459. 24. Lawton CA, Won M, Pilepich MV, Asbell SO, Shipley WU, Hanks GE, Cox JD, Perez CA, Sause WT, Doggett RLS, Rubin P: Long-term 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. 25. Hanks GE: External-beam radiation therapy for clinically localized prostate cancer: Patterns of care studies in the United States. NCI Monogr 1988;7:75–84. 26. Hanks GE, Teshima T, Pajak TF: 20 years of progress in radiation oncology: Prostate cancer. Semin Radiat Oncol 1997;7:114– 120. 27. Leibel SA, Hanks GE, Kramer S: Patterns of care outcome studies: Results of the national practice in adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1984;10:401–409. 28. Hanks GE, Schultheiss TE, Hunt MA, Epstein B: Factors influencing incidence of acute grade 2 morbidity in conformal and standard radiation treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1995;31:25–29. 29. Soffen EM, Hanks GE, Hunt MA, Epstein BE: Conformal static field radiation therapy treatment of early prostate cancer versus non-conformal techniques: A reduction in acute morbidity. Int J Radiat Oncol Biol Phys 1992;24:485–488. 30. Schultheiss TE, Lee WR, Hunt MA, Hanlon AL, Peter RS, Hanks GE: Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1997;37:3–11. 31. Sandler HA, McLaughlin PW, TenHaken RK, Addison H, Forman J, Lichter AS: Three dimensional conformal radiotherapy for the treatment of prostate cancer: Low risk of chronic rectal morbidity observed in a large series of patients. Int J Radiat Oncol Biol Phys 1995;33:797–801. 32. Zelefsky MJ, Leibel SA, Kutcher GJ, Kelson S, Ling CC, Fuks Z: The feasibility of dose escalation with three-dimensional con- 35. Zagars GK, Pollack A: Radiation therapy for T1 and T2 prostate cancer: Prostate-specific antigen and disease outcome. Urology 1995;45:476–483. 36. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Schnall M, Tomaszewski JE, Wein A: A multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol 1995;154:131–138. 37. Zietman AL, Edelstein RA, Coen JJ, Babayan RK, Krane RJ: Radical prostatectomy for adenocarcinoma of the prostate: The influence of preoperative and pathologic findings on biochemical disease-free outcome. Urology 1994;43:828–833. 38. Keyser D, Kupelian PA, Zippe CD, Levin HS, Klein EA: Stage T1–2 prostate cancer with pretreatment prostate-specific antigen level 艋10 ng/ml: Radiation therapy or surgery? Int J Radiat Oncol Biol Phys 1997;38:723–729. 39. D’Amico AV, Whittington R, Kaplan I, Beard C, Jiroutek M, Malkowicz SB, Wein A, Coleman CN: Equivalent biochemical failure-free survival after external beam radiation therapy or radical prostatectomy in patients with a pretreatment prostate specific antigen of >4–20 ng/ml. Int J Radiat Oncol Biol Phys 1997;37:1053–1058. 40. Horwitz EM, Vicini FA, Ziaja EL, Gonzalez J, Dmuchowski CF, Stromberg JS, Brabbins DS, Hollander J, Chen PY, Martinez AA: Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control. Int J Radiat Oncol Biol Phys 1996;36:565– 571. 41. American Society for Therapeutic Radiology and Oncology Consensus Panel: Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37: 1035–1041. 42. Freedman GM, Hanlon AL, Lee WR, Hanks GE: Young patients with prostate cancer have an outcome justifying their treatment with external beam radiation. Int J Radiat Oncol Biol Phys 1996; 35:243–250. 43. Poen J, Hancock SL, Cox RS, Bagshaw MA: Early stage prostatic cancer in younger men: Durable tumor control and favorable prognosis after external beam irradiation at age 60 or less. Int J Radiat Oncol Biol Phys [Suppl] 1995;32:190. 44. Horwitz EM, Hanlon AL, Pinover WH, Hanks GE: The treatment of nonpalpable PSA-detected adenocarcinoma of the prostate with 3-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 1998;41:519–523. 45. Kuban DA, El-Mahdi AM, Schellhammer PF: Prostate-specific antigen for pretreatment prediction and posttreatment evaluation of outcome after definitive irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 1995;32:307–316. 46. Pisansky TM, Cha SS, Earle JD, Durr ED, Kozelsky TF, Wieand HS, Oesterling JE: Prostate-specific antigen as a pre-therapy prognostic factor in patients treated with radiation therapy for 206 Horwitz et al. clinically localized prostate cancer. J Clin Oncol 1993;11:2158– 2166. 47. Zietman AL, Coen JJ, Shipley WU: Radical radiation therapy in the management of prostatic adenocarcinoma: The initial prostate specific antigen value as a predictor of treatment outcome. J Urol 1994;151:640–645. 48. Kaplan ID, Cox RS, Bagshaw MA: Prostate specific antigen after external beam radiotherapy for prostatic cancer: Followup. J Urol 1993;149:519–522. 49. Lee WR, Hanks GE, Schultheiss TE, Corn BW, Hunt MA: Localized prostate cancer treated by external-beam radiotherapy alone: Serum prostate-specific antigen-driven outcome analysis. J Clin Oncol 1995;13:464–469. 50. Schellhammer PF, El-Mahdi AM, Kuban DA, Wright GL: Prostate-specific antigen after radiation therapy. Prognosis by pretreatment level and posttreatment nadir. Urol Clin North Am 1997;24:407–414. 51. Zagars GK, Pollack A, von Eschenbach AC: Prognostic factors for clinically localized prostate carcinoma: Analysis of 938 patients irradiated in the prostate specific antigen era. Cancer 1997;79:1370–1380.