HIGH DOSE RADIATION DELIVERED BY INTENSITY MODULATED CONFORMAL RADIOTHERAPY IMPROVES THE OUTCOME OF LOCALIZED PROSTATE CANCER

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1 /01/ /0 THE JOURNAL OF UROLOGY Vol. 166, , September 2001 Copyright 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC. Printed in U.S.A. HIGH DOSE RADIATION DELIVERED BY INTENSITY MODULATED CONFORMAL RADIOTHERAPY IMPROVES THE OUTCOME OF LOCALIZED PROSTATE CANCER MICHAEL J. ZELEFSKY,* ZVI FUKS, MARGIE HUNT, HENRY J. LEE, DANNA LOMBARDI, CLIFTON C. LING, VICTOR E. REUTER, E. S. VENKATRAMAN AND STEVEN A. LEIBEL From the Departments of Radiation Oncology, Medical Physics, Pathology and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York ABSTRACT Purpose: We present the long-term outcome and tolerance of 3-dimensional (D) conformal and intensity modulated radiation therapy for localized prostate cancer. Materials and Methods: Between October 1988 and December 1998, 1,100 patients with clinical stages T1c-T3 prostate cancer were treated with 3-D conformal or intensity modulated radiation therapy. Patients were categorized into prognostic risk groups based on pretreatment prostate specific antigen (PSA), Gleason score and clinical stage. Sextant biopsies were performed 2.5 years or greater after treatment to assess local control. PSA relapse was defined according to the consensus guidelines of the American Society for Therapeutic Radiation Oncology. Late toxicity was classified according to the Radiation Therapy Oncology Group morbidity grading scale. Median followup was 60 months. Results: At 5 years the PSA relapse-free survival rate in patients at favorable, intermediate and unfavorable risk was 85% (95% confidence interval [CI] 4), 58% (95% CI 6) and 38% (95% CI 6), respectively (p 0.001). Radiation dose was the most powerful variable impacting PSA relapse-free survival in each prognostic risk group. The 5-year actuarial PSA relapse-free survival rate for patients at favorable risk who received 64.8 to 70.2 Gy. was 77% (95% CI 8) compared to 90% (95% CI 8) for those treated with 75.6 to 86.4 Gy. (p 0.05). The corresponding rates were 50% (95% CI 8) versus 70% (95% CI 6) in intermediate risk cases (p 0.001), and 21% (95% CI 8) versus 47% (95% CI 6) in unfavorable risk cases (p 0.002). Only 4 of 41 patients (10%) who received 81 Gy. had a positive biopsy 2.5 years or greater after treatment compared with 27 of 119 (23%) after 75.6, 23 of 68 (34%) after 70.2 and 13 of 24 (54%) after 64.8 Gy. The incidence of toxicity after 3-D conformal radiation therapy was dose dependent. The 5-year actuarial rate of grade 2 rectal toxicity in patients who received 75.6 Gy. or greater was 14% (95% CI 2) compared with 5% (95% CI 2) in those treated at lower dose levels (p 0.001). Treatment with intensity modulated radiation therapy significantly decreased the incidence of late grade 2 rectal toxicity since the 3-year actuarial incidence in 189 cases managed by 81 Gy. was 2% (95% CI 2) compared with 14% (95% CI 2) in 61 managed by the same dose of 3-D conformal radiation therapy (p 0.005). The 5-year actuarial rate of grade 2 urinary toxicity in patients who received 75.6 Gy. or greater 3-D conformal radiation therapy was 13% compared with 4% in those treated up to lower doses (p 0.001). Intensity modulated radiation therapy did not affect the incidence of urinary toxicity. Conclusions: Sophisticated conformal radiotherapy techniques with high dose 3-D conformal and intensity modulated radiation therapy improve the biochemical outcome in patients with favorable, intermediate and unfavorable risk prostate cancer. Intensity modulated radiation therapy is associated with minimal rectal and bladder toxicity, and, hence, represents the treatment delivery approach with the most favorable risk-to-benefit ratio. KEY WORDS: prostate; prostatic neoplasms; radiotherapy, conformal; risk; radiation dosage The frequent persistence of local residual tumor after external beam irradiation for prostate cancer has been a matter of concern. Recent studies have indicated prostate specific antigen (PSA) relapse-free survival in only 65% of patients with stages T1-T2 disease. 1 Biopsy proved local recurrence has been identified in 23% to 65% of patients in whom stages Accepted for publication April 27, Supported in part by Grant CA from the National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland. * Requests for reprints: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, New York T1-T3 disease was treated with conventional radiotherapy doses of 70 Gy. or less. 2 5 While the probability of eradicating prostate cancer increases with increasing dose, 6, 7 classic radiotherapy techniques have failed at doses exceeding 70 Gy. because of high rates of severe rectal and bladder toxicity. 8 Three-dimensional (D) conformal and intensity modulated radiation therapy were developed to address these issues. 9, 10 Three-D conformal and intensity modulated radiation therapy planning use advanced imaging for tumor and normal organ segmentation, new algorithms for dose calculations and computer aided optimization to generate treatment plans that conform the prescribed dose to the prostate, while 876

2 HIGH DOSE RADIATION IMPROVES OUTCOME OF PROSTATE CANCER 877 attempting to exclude maximally the adjacent normal organs. This planning has resulted in a significant decrease in rectal and bladder toxicity, enabling tumor dose escalation to improve local control. 11, 12 Based on these principles and techniques in October 1998 a dose escalation study in patients with localized prostate cancer was initiated at our institution. 13 In a preliminary study of 743 patients we showed the feasibility, safety and preliminary observations of the outcome of dose escalation with 3-D conformal radiation therapy to 81 Gy. 12, 14 However, it became apparent that escalation of the radiation dose to 81 Gy. or greater required enhanced conformality, such as that provided by intensity modulated radiation therapy, to decrease the risk of toxicity. We present an update on the long-term outcome in 1,100 patients treated with 3-D conformal and intensity modulated radiation therapy. To our knowledge we report for the first time preliminary toxicity findings of 86.4 Gy. The data stress the need for high radiation doses for improving the biochemical outcome in prostate cancer with radiation and indicate that intensity modulated radiation therapy represents a safe method for delivering the dose levels required to achieve the maximal rate of local tumor control. MATERIALS AND METHODS An institutional review board approved phases I and II study was initiated in October 1988 to assess the toxicity of dose escalation with 3-D conformal and intensity modulated radiation therapy in prostate cancer. The radiation dose was increased from 64.8 to 86.4 Gy. by increments of 5.4 Gy. in consecutive groups of patients. The 1,100 patients with clinically localized prostate cancer accumulated through December 1998 included 96 (9%) treated with 64.8, 269 (24%) treated with 70.2, 445 (40%) treated with 75.6, 250 (23%) treated with 81 and 40 (4%) treated with 86.4 Gy. Median patient age was 69 years (range 46 to 86). Pretreatment diagnostic evaluations were performed as previously described American Joint Commission on Cancer 1997 clinical stage 16 was T1c in 284 patients (26%), T2a in 354 (32%), T2b in 200 (18%) and T3 in 262 (24%). All patients were histologically diagnosed with prostatic adenocarcinoma classified according to the Gleason grading system. 17 Serum PSA concentration was determined by radioimmunoassay (Tosoh, Foster City, California) with a normal range of 4 ng./ml. or less and a minimal detectable level of 0.02 ng./ml. The techniques for treatment planning and delivering 3-D conformal and intensity modulated radiation therapy have been previously described in detail. 10, 11, 13 15, Three-D conformal radiation therapy was administered in 810 patients to a dose of 64.8 to 75.6 Gy. and the initial 61 received 81 Gy. The subsequent 229 patients received 81 and 86.4 Gy. intensity modulated radiation therapy. Treatment was delivered with 15 mv. x-rays in daily fractions of 1.8 Gy. The radiation dose was prescribed as a minimum tumor dose to the whole prostate and seminal vesicles with a 1 cm. margin except at the prostatorectal interface, where a 0.6 cm. margin was used. A total of 427 patients (39%) with a large volume prostate were given a 3-month course of neoadjuvant complete androgen deprivation to decrease prostate size. 21, 22 This treatment was discontinued at the completion of radiotherapy. Followup evaluations after treatment were performed at 3 to 6-month intervals for 5 years and yearly thereafter. Median followup was 60 months (range 24 to 142) and 339 patients (31%) were followed 7 years or longer. Median followup of patients treated up to 81, 75.6 and 70.2 Gy. or less was 40, 72 and 95 months, respectively. Combined median followup for the high dose group that received 75.6 Gy. or greater was 69 months. Late toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading scale, including grade 1 minimal side effects not requiring medication for symptom control, grade 2 symptoms requiring medication, grade 3 complications requiring minor surgical intervention, such as transurethral resection, laser coagulation or blood transfusion, and grade 4 hospitalization and major intervention. Disease status was determined at analysis in November PSA relapse was defined as 3 successive PSA elevations after a posttreatment nadir was achieved. 24 The date of failure was considered the midpoint between the last nonincreasing and first increasing PSA value. 1 None of the patients received post-irradiation androgen deprivation or other anti-cancer therapy before documentation of a PSA relapse. To assess the local tumor response to treatment sextant prostate biopsies were performed in patients followed 2.5 years or longer (median 35 months) after the completion of 3-D conformal/intensity modulated radiation therapy. An ongoing attempt was made to biopsy all eligible cases. Of 586 surviving patients meeting the time requirement 252 (43%) underwent this procedure. The remaining patients did not undergo biopsy because of patient or physician refusal, or medical contraindications. The histological diagnosis was classified as positive prostatic adenocarcinoma without typical radiation induced changes, negative no evidence of carcinoma and severe treatment effects such as residual tumor cells showing radiation changes. Histological features of the latter category have been described previously. 25, 26 Since long-term followup has indicated that the histological pattern defined as severe treatment effects does not indicate active relapsing tumor 4, and the PSA outcome in our patients with these changes was similar to that in patients with negative biopsy specimens (data not shown), those with these features were included in the negative biopsy group. Patients were classified into prognostic risk groups according to pretreatment variables that independently affected PSA relapse-free survival. 14 Parameters used to characterize the risk groups included pretreatment PSA 10 ng./ml. or less, stages T1-2 disease and Gleason score 6 or greater (p 0.01). When all 3 indicators were present, the case was classified in a favorable prognosis group. An increase in the value of 1 and 2 or more indicators classified the case in an intermediate and an unfavorable prognosis group, respectively. The distribution of PSA relapse-free survival time was calculated according to the Kaplan-Meier product-limit method. 27 Differences in time adjusted incidence rates were evaluated using the Mantel log rank test for censored data. 28 The relative impact of covariates that affect time adjusted outcome was determined using the stepwise Cox proportional hazards regression model. 29 RESULTS Therapeutic outcome by PSA relapse-free survival. Figure 1 shows the PSA relapse-free survival rate by prognostic risk group. The 5-year actuarial PSA relapse-free survival was 85% (95% confidence interval [CI] 4) for the 279 patients at favorable, 58% (95% CI 6) for the 405 at intermediate and 38% (95% CI 6) for the 416 at unfavorable risk. In addition to pretreatment PSA, Gleason score and T stage, the radiation dose of 70.2 or less versus 75.6 Gy. or greater was a significant independent variable affecting PSA outcome after each type of radiotherapy (table 1). In favorable and intermediate risk cases a significant improvement in PSA outcome was observed after 75.6 Gy. or greater were given compared with lower doses (fig. 2). At analysis we detected no improvement in PSA relapse-free survival for patients at favorable and intermediate risk treated with 81 versus 75.6 Gy. However, in unfavorable risk cases 81 Gy. was associated with improved PSA relapse-free survival compared with 75.6 Gy. and lower doses. In the latter group the 5-year PSA relapse-free survival rate for 81 Gy. was 67% (95% CI 4)

3 878 HIGH DOSE RADIATION IMPROVES OUTCOME OF PROSTATE CANCER FIG. 1. Kaplan-Meier actuarial probability of achieving PSA relapse-free survival in favorable, intermediate and unfavorable prognostic risk subgroups. At 5 years 77, 79 and 41 patients were at risk, respectively. Values in parentheses indicate number of patients per subgroup. TABLE 1. Cox regression analysis of variables affecting PSA relapse-free survival p Value Mean Regression Coefficient ( SE) Regression Coefficient Exponent PSA 10 ng./ml. or less Stage less than T Dose 75.6 Gy. or greater Gleason score 6 or less Androgen deprivation Not significant versus 43% (95% CI 4) for 75.6 and 21% (95% CI 4) for 64.8 to 70.2 Gy. (fig. 3). Therapeutic outcome by post-irradiation biopsy findings. Because radiation was confined to the prostate only, it is reasonable to assume that improved PSA relapse-free survival according to dose may be largely attributable to improved local control. To explore further this notion sextant prostate biopsies were performed at an interval of 2.5 years or greater after radiotherapy in 252 cases. Overall only 4 of 41 patients (10%) who received 81 Gy. had positive biopsy indicating residual or relapsing disease compared with 27 of 119 (23%) after 75.6, 23 of 68 (34%) after 70.2 and 13 of 24 (54%) after 64.8 Gy. (75.6 or greater versus less than 75.6 Gy. p and 81 versus 75.6 Gy. p 0.07). Table 2 shows the relationships among biopsy findings, prognostic risk groups and dose. Within each risk group a clear trend was observed for a decreasing incidence of positive biopsy with increasing dose. In addition, in each dose bin the rate of positive biopsy increased as the prognostic group became less favorable except for 81 Gy., in which there was no apparent difference in biopsy outcome among the 3 risk groups. These data indicate that the more aggressive biological phenotypes of prostate tumor cells are more radioresistant. However, even for the more favorable phenotypes conventional radiation doses of 65 to 70 Gy. are ineffective for local tumor control. It appears that doses on the order of 81 Gy. may be necessary to achieve maximal local cure. Whether 86.4 Gy. or higher doses would further decrease the risk of local relapse requires further investigation. Late toxicity. The critical attribute of the 3-D conformal paradigm is that it delivers high radiation doses with a minimal concomitant risk of normal tissue toxicity. Table 3 lists the rate of late complications in our cohort of patients. In 12 patients (1%) grade 3 rectal bleeding required 1 or more transfusions, or 1 or more laser cauterization procedures. In a patient (0.09%) with a history of inflammatory bowel disease who was treated with 64.8 Gy. grade 4 rectal toxicity developed. Figure 4 shows the actuarial incidence of rectal toxicity for each dose level. The overall 5-year actuarial likelihood of grade 2 rectal toxicity was 11% (95% CI 2). Doses of 75.6 Gy. or greater 3-D conformal radiation therapy were associated with a 14% (95% CI 2) rate of late grade 2 rectal toxicity compared with 5% (95% CI 2) for lower dose levels (p 0.001). Perhaps the most important observation is that intensity modulated radiation therapy significantly decreased the incidence of late rectal toxicity in patients who received 81 Gy. The overall rate of late grade 2 and 3 rectal toxicity in these cases was 2% and 0.5% compared with 12% and 2%, respectively, in those managed by 3-D conformal radiation therapy (p 0.01). The 3-year actuarial incidence of late grade 2 rectal toxicity in 189 patients treated with 81 Gy. intensity modulated radiation therapy was 2% (95% CI 2) compared with 14% (95% CI 2) in 61 treated at the same dose level with 3-D conformal radiation therapy (p 0.005). Of 17 patients (1.5%) grade 3 urethral stricture required dilation in 15 and grade 3 hematuria developed in 2. The 5-year actuarial rate of grade 2 urinary toxicity was 10%, including 13% (95% CI 2) after 75.6 Gy. or greater and 4% (95% CI 2) after lower dose levels (p 0.001). The rates for 3-D conformal and intensity modulated radiation therapy did not differ significantly (p 0.32). Improved tolerance, as indicated by decreased rectal bleeding, associated with intensity modulated radiation therapy enabled the escalation of treatment dose to 86.4 Gy, representing the latest arm of the phase I dose escalation study. We have followed 40 patients treated at the 86.4 Gy. level with intensity modulated radiation therapy a median of 31 months (range 24 to 40). To date 2 patients (5%) have had late grade 2 rectal and 8 (20%) have had grade 2 urinary toxicity. No grade 3 or higher toxicity has been observed. Together these data further underscore the safety of dose escalation and improved treatment delivery of intensity modulated radiation therapy. DISCUSSION These data indicate that higher than conventional radiation doses are associated with improved local tumor control on posttreatment biopsy as well as with freedom from PSA biochemical relapse. Patients at favorable, intermediate and unfavorable risk benefited from the increased dose. In previous studies we did not show that dose escalation affected the outcome of favorable risk cases. 14 With more patients and a longer observation interval we have now shown improved PSA relapse-free survival in those at favorable risk who received 75.6 Gy. or greater with a 5-year PSA relapse-free survival rate of 90%. This outcome is consistent with that in series of similar patients treated with radical prostatectomy. 30, 31 An improved PSA outcome is also now apparent in unfavorable risk cases managed by 81 Gy. versus those managed by lower doses. Furthermore, our post-irradiation biopsy findings indicate that a dose of 81 Gy. is associated with the lowest incidence of positive posttreatment biopsy in patients in each prognostic risk group. Previous studies have also shown improved PSA outcome with escalated doses of external beam radiotherapy, although none has reached the high dose levels that we report. Hanks et al observed that increasing the radiation dose from 73 to 78 Gy. achieved 22% to 40% incremental improvement in the 5-year PSA relapse-free survival rate in various subgroups of patients. 32 However, a benefit to dose escalation was not identified in patients with favorable risk features and in those with unfavorable risk features with PSA 20 ng./ml. or greater. Pollack and Zagars observed that the 3-year PSA relapse-free survival rate after doses of 67 or less, greater than 67 to 77 and greater than 77 Gy. were 61%, 74%

4 HIGH DOSE RADIATION IMPROVES OUTCOME OF PROSTATE CANCER 879 FIG. 2. Kaplan-Meier actuarial probability of achieving PSA relapse-free survival according to dose. A, in favorable high and low dose groups at 3 to 5 years 97, 66 and 35, and 70, 58 and 43 patients were at risk, respectively. B, in intermediate high and low dose groups at 3 to 5 years 109, 64 and 33, and 79, 66 and 46 patients were at risk, respectively. Values in parentheses indicate number of patients per subgroup. TABLE 3. Incidence of late treatment related toxicity after 3-D conformational radiation therapy in 1,100 patients No. Urinary (%) No. Rectal (%) None 798 (72.5) 807 (73) Grade: (16) 174 (16) (10) 106 (10) 3 17 (1.5) 12 (1) FIG. 3. Kaplan-Meier actuarial probability of achieving PSA relapse-free survival in unfavorable prognostic risk subgroups according to 3 dose levels. At 3 to 5 years at 81 Gy. 23, 15 and 9, at 75 Gy. 86, 45 and 18, and at 64.8 to 70.2 Gy. 45, 31 and 15 patients were at risk, respectively. Values in parentheses indicate number of patients per subgroup. TABLE 2. Incidence of positive posttreatment prostate biopsy according to prognostic risk group in 252 patients Dose (Gy.) No./Total No. (%) Favorable Intermediate Unfavorable 81 0/7 3/18 (17) 1/16 (6) /18 (11) 8/44 (19) 17/57 (30) /20 (15) 5/21 (24) 15/27 (56) /3 (33) 6/13 (46) 6/8 (75) Totals 6/48 (13) 22/96 (23) 39/108 (37) FIG. 4. Kaplan-Meier actuarial probability of grade 2 or greater late rectal toxicity, that is rectal bleeding, according to dose. At 3 to 5 years at 81 Gy. conventional 3-D and intensity modulated radiation therapy (IMRT) 50, 42 and 33, and 27.3 and 0 patients were at risk, and at 75 and 64.8 to 70.2 Gy. 309, 239 and 142, and 318, 295 and 262 patients were at risk, respectively. At 81 Gy. intensity modulated radiation therapy was associated with lowest incidence of late rectal toxicity. and 96%, respectively. 7 More recently, Pollack et al presented preliminary data on a randomized trial comparing patients treated at the 70 Gy. level with a 4-field technique with those receiving an additional 8 Gy. to a total of 78 Gy. using a 6-field conformal boost. 33 To date a significant improvement in PSA relapse-free survival has been noted in patients with stages T1-T2 disease and PSA greater than 10 ng./ml. who received 78 Gy. Although our dose escalation study was nonrandomized, the data provide additional evidence that higher doses are required to achieve a maximal probability of local tumor cure regardless of the biological phenotype of the tumor. These data further support the notion that high dose radiotherapy given with conformal techniques, such as 3-D conformal and intensity modulated radiation therapy, represents a new gold standard for the optimal outcome of managing localized prostate cancer. In our patients we did not note that androgen ablation administered with either type of radiotherapy further enhanced the biochemical outcome (table 1). However, its administration in the neoadjuvant setting, as in our cases, may not be as effective as in the adjuvant setting. Combining adjuvant androgen deprivation with standard doses of radiotherapy has demonstrated a significant benefit for high grade, locally advanced disease. 35, 36 To our knowledge whether androgen ablation would obviate the need for dose escalation or androgen deprivation may be unnecessary when higher dose levels are administered remains unknown. In some cases combining the 2 approaches may further improve outcome. Clinical trials are needed to resolve these important questions.

5 880 HIGH DOSE RADIATION IMPROVES OUTCOME OF PROSTATE CANCER The success of dose escalation for prostate cancer may be directly attributed to the emergence of advanced, computer aided technologies that enable the delivery of heretofore unprecedented radiation doses with minimal toxicity. The risk of radiation induced complications to the rectum depends on the dose and on the rectal volume included in the high dose region. 37 The critical contribution of 3-D conformal and intensity modulated radiation therapy in the modern management of prostate cancer appears to be reduction of the volume of the anterior rectal wall included in the planned target volume carried to high radiation doses. 20 Based on our dose escalation studies we have recommended that the rectal dose should be limited to a maximum of 75.6 Gy. delivered to no more than 30% of the rectal wall. 21, 22 With similar dose volume restrictions others have also observed a low rate of rectal complications. 38 The advantage of intensity modulated over 3-D conformal radiation therapy is that this goal may be achieved with tumor doses of 81 Gy. or greater. In fact, the development of intensity modulated radiation therapy was required to enable safe escalation of the dose to 86.4 Gy. In conclusion, low radiation doses should no longer be considered adequate and patients should be appropriately counseled to seek treatment at centers with experience in the planning and delivery of high dose radiation, preferably by intensity modulated radiation therapy. REFERENCES 1. Shipley, W. U., Thames, H. D., Sandler, H. M. et al: Radiation therapy for clinically localized prostate cancer: a multiinstitutional pooled analysis. JAMA, 281: 1598, Scardino, P. T., Frankel, J. M., Wheeler, T. M. et al: The prognostic significance of post-irradiation biopsy results in patients with prostatic cancer. J Urol, 135: 510, Sewell, R. A., Braren, V. and Wilson, S. K.: Extended biopsy followup after full course radiation for resectable prostatic carcinoma. J Urol, 113: 371, Crook, J. M., Perry, G. A., Robertson, S. et al: Routine prostate biopsies following radiotherapy for prostate cancer: results for 226 patients. Urology, 45: 624, Laverdiere, J., Gomez, J. L., Cusan, L. et al: Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer. Int J Radiat Oncol Biol Phys, 37: 247, Hanks, G. E., Martz, K. L. and Diamond, J. J.: The effect of dose on local control of prostate cancer. Int J Radiat Oncol Biol Phys, 15: 1299, Pollack, A. and Zagars, G. K.: External beam radiotherapy doseresponse of prostate cancer. Int J Radiat Oncol Biol Phys, 39: 1011, Smit, W. G., Helle, P. A., van Putten, W. L. et al: Late radiation damage in prostate cancer patients treated by high dose external radiotherapy in relation to rectal dose. Int J Radiat Oncol Biol Phys, 18: 23, Leibel, S. A., Zelefsky, M. J., Kutcher, G. J. et al: The biological basis and clinical application of three-dimensional conformal external beam radiation therapy in carcinoma of the prostate. Semin Oncol, 21: 580, Zelefsky, M. J., Leibel, S. A., Kutcher, G. J. et al: Threedimensional conformal radiotherapy and dose escalation: where do we stand? Semin Radiat Oncol, 8: 107, Zelefsky, M. J., Leibel, S. A., Kutcher, G. J. et al: The feasibility of dose escalation with three-dimensional conformal radiotherapy in patients with prostatic carcinoma. Cancer J Sci Am, 1: 42, Zelefsky, M. J., Cowen, D., Fuks, Z. et al: Long term tolerance of high dose three dimensional conformal radiotherapy in patients with localized prostate cancer. Cancer, 85: 2460, Leibel, S. A., Zelefsky, M. J., Kutcher, G. J. et al: Threedimensional conformal radiation therapy in localized carcinoma of the prostate: Interim report of a phase I doseescalation study. J Urol, part 2, 152: 1792, Zelefsky, M. J., Leibel, S. A., Gaudin, P. B. et al: Dose escalation with three dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys, 41: 491, Zelefsky, M. J., Fuks, Z., Wolfe, T. et al: Locally advanced prostatic cancer: long-term toxicity after three-dimensional conformal radiation therapy a dose-escalation study. Radiology, 209: 169, Fleming, I. D., Cooper, J. S., Henson, D. E. et al: Prostate. In: American Joint Committee on Cancer. Cancer Staging Manual, 5th ed. Philadelphia: Lippincott-Raven, p. 181, Gleason, D. F.: Histologic grading and clinical staging of prostatic carcinoma. In: Urologic Pathology: The Prostate. Edited by M. Tannenbaum. Philadelphia: Lea & Febiger, Chapt. 9, p. 171, Ling, C. C., Burman, C., Chui, C. S. et al: Conformal radiation treatment of prostate cancer using inversely planned intensity-modulated photon beams produced with dynamic multileaf collimation. Int J Radiat Oncol Biol Phys, 35: 721, Burman, C., Chui, C. S., Kutcher, G. J. et al: Planning, delivery, and quality assurance of intensity-modulated radiotherapy using dynamic multileaf collimator: a strategy for large-scale implementation for the treatment of carcinoma of the prostate. Int J Radiat Oncol Biol Phys, 39: 863, Zelefsky, M. J., Fuks, Z., Happersett, L. et al: Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radiother Oncol, 55: 241, Zelefsky, M. J., Leibel, S. A., Burman, C. M. et al: Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys, 29: 755, Zelefsky, M. J. and Harrison, A.: Neoadjuvant androgen ablation prior to radiotherapy for prostate cancer: reducing the potential morbidity of therapy. Urology, suppl., 49: 38, Lawton, C. A., Won, M., Pilepich, M. V. et al: Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and Int J Radiat Oncol Biol Phys, 21: 935, Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys, 37: 1035, Crook, J. M., Bahdur, Y. A., Robertson, S. J. et al: Evaluation of radiation effect, tumor differentiation and prostate specific antigen staining in sequential prostate biopsies after external beam radiotherapy for patients with prostate carcinoma. Cancer, 79: 81, Gaudin, P. B., Zelefsky, M. J., Leibel, S. A. et al: Histopathologic effects of three dimensional conformal external beam radiation therapy on benign and malignant prostate tissues. Am J Surg Pathol, 23: 1021, Kaplan, E. L. and Meier, P.: Nonparametric estimation from incomplete observations. J Am Stat Assoc, 53: 457, Mantel, N.: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Reports, 50: 163, Cox, D. R.: Regression models and life tables. J R Stat Soc, 34: series B, 187, Kupelian, P., Katcher, J., Levin, H. et al: External beam radiotherapy versus radical prostatectomy for clinical stage T1 2 prostate cancer: therapeutic implications of stratification by pretreatment PSA levels and biopsy Gleason scores. Cancer J Sci Am, 3: 78, D Amico, A. V., Whittington, R., Kaplan, I. et al: 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, 37: 1053, Hanks, G. E., Hanlon, A. L., Pinover, W. H. et al: Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys, 46: 823, Pollack, A., Zagars, G. K., Smith, L. G. et al: Preliminary results of a randomized radiotherapy dose escalation study comparing 70 Gy to 78 Gy for prostate cancer. J Clin Oncol, 18: 3904, Lyons, J. A., Kupelian, P. A., Mohan, D. S. et al: Importance of high radiation doses (72 Gy or greater) in the treatment of stage T1 T3 adenocarcinoma of the prostate. Urology, 55: 85, Bolla, M., Gonzalez, D., Warde, P. et al: Improved survival in

6 HIGH DOSE RADIATION IMPROVES OUTCOME OF PROSTATE CANCER 881 patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med, 337: 295, Pilepich, M. V., Caplan, R., Byhardt, R. W. et al: Phase III trial of androgen suppression using goserelin in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol J Clin Oncol, 15: 1013, Skwarchuk, M. W., Jackson, A., Zelefsky, M. J. et al: Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys, 47: 103, Storey, M. R., Pollack, A., Zagars, G. et al: Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys, 48: 635, 2000 EDITORIAL COMMENT Ten years ago the debate was framed by the question, radical prostatectomy or radiation? Now the debate must be extended to reflect developments in radiation oncology. Which type of radiation: brachytherapy or external? Three-D conformal or intensity modulated? Conventional dose, high dose or ultra high dose? These authors have long recommended radiation dose escalation and this study as well as others recently published appears to vindicate their approach. In the early 1990s they reacted to new data on PSA in followup and prostate re-biopsy showing that the outcome after conventional radiation therapy was far from optimal. Radiation oncologists had previously ascribed failure to bad disease and high rates of occult metastasis. However, re-biopsy data made it evident that local control was as great if not a greater issue and increasing the delivered dose to the prostate was the intuitive answer. Unfortunately radiation doses in excess of 72 Gy. cannot be given using conventional techniques without unacceptable morbidity. These authors were among the first to apply the new strategy of 3-D conformal radiation to decrease the volume of normal tissue irradiated and, thus, allow the dose to the prostate to be increased. Since then, they have been escalating the dose progressively in prospective studies and now they have data sufficiently mature to warrant close attention. The results seem to show that in all prognostic groups there is an advantage in terms of biochemical control to dose escalation beyond 75 Gy. This result is in keeping with and even goes beyond an interim report of a randomized trial comparing 70 with 78 Gy. 1 This trial shows in some subgroups a 5-year outcome advantage in the higher dose arm. The data presented are at first glance powerful but they are somewhat weakened by biases inherent in the use of American Society for Therapeutic Radiation Oncology criteria for PSA failure. These criteria mandate 3 successive increases before failure is considered, making outcome particularly sensitive to the duration of followup. 2 Such a bias is especially true in the low and intermediate prognosis subgroups, in which patients mostly experience a third increase 4 or more years after treatment, a time at which patients are often only monitored yearly. In this study median followup in the 81, 75.6 and less than 70.2 Gy. groups was 40, 72 and 95 months, respectively. While these differences are probably insufficient to erase the advantage of 75.6 Gy. over lower doses, they are of sufficient magnitude that we cannot conclude that 81 Gy. is definitely superior to 75.6 Gy. This distinction is important since doses of 75.6 Gy. are readily achieved by widely available 3-D conformal techniques. However, these authors argue that doses of 81 Gy. or higher mandate much more sophisticated technology, such as intensity modulated radiation therapy or proton beam. These technologies are currently only available at a limited number of major centers and the implication is that only these centers are of sufficient quality to treat effectively and safely. However, their data show that ultra high dose radiation may be given relatively safely via the 3-D conformal approach, although a higher rate of grade 2 rectal bleeding must be tolerated than with intensity modulated radiation therapy (14% versus 2% at 81 Gy.). No grade 3 morbidity was noted. If dose escalation to 81 Gy. proved to be essential for cancer control in a randomized trial, I believe that patients would be prepared to accept a 14% risk of mild rectal bleeding in exchange for an increased likelihood of cure if intensity modulated radiation therapy were not locally available. This study strongly affirms the trend toward higher dose in radiation therapy and redefines the acceptable standard dose somewhere above 75 Gy. It does not yet set an upper level at which the law of diminishing returns takes over. Their early results suggest that 81 to 86 Gy. may be tolerable with intensity modulated radiation therapy but they may only be considered preliminary. While the rectum and bladder are largely spared the maximum doses, the urethra and bladder neck are not. Dose limiting toxicity is likely to involve these structures and to manifest late. Therefore, high dose radiation has become acceptable but ultra high dose radiation needs mature randomized study before it may also be regarded as necessary or safe. These trials are soon to open. Anthony L. Zietman Department of Radiation Oncology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts 1. Pollack, A., Zagars, G. K., Smith, L. G. et al: Preliminary results of a randomized dose-escalation study comparing 70 Gy. to 78 Gy. for the treatment of prostate cancer. Int J Radiat Oncol Biol Phys, Suppl. 45: 146, abstract 4, Vicini, F. A., Kestin, L. L., and Martinez, A. A.: The importance of adequate followup in defining treatment success after external beam irradiation for prostate cancer. Int J Radiat Oncol Biol Phys, 45: 553, 1999