Risk-Adapted Androgen Deprivation and Escalated Three-Dimensional Conformal Radiotherapy for Prostate Cancer: Does Radiation Dose Influence
http://www.100md.com
《临床肿瘤学》
the Department of Radiation Oncology, Hospital Universitario de la Princesa, Madrid
Department of Radiation Oncology, Hospital Puerta de Hierro, Madrid
Department of Radiation Oncology, Hospital Gregorio Mara?ón, Madrid
Department of Radiation Oncology, Hospital Clínico de Valencia, Valencia
Department of Radiation Oncology, Hospital Reina Sofía de Córdoba, Córdoba
Department of Radiation Oncology, Hospital General Vall D'Hebrón, Barcelona
Department of Radiation Oncology, Institut Catalá Oncología, Barcelona, Spain
ABSTRACT
PURPOSE: Multicenter study conducted to determine the impact on biochemical control and survival of risk-adapted androgen deprivation (AD) combined with high-dose three-dimensional conformal radiotherapy (3DCRT) for prostate cancer. Results of biochemical control are reported.
PATIENTS AND METHODS: Between October 1999 and October 2001, 416 eligible patients with prostate cancer were assigned to one of three treatment groups according to their risk factors: 181 low-risk patients were treated with 3DCRT alone; 75 intermediate-risk patients were allocated to receive neoadjuvant AD (NAD) 4-6 months before and during 3DCRT; and 160 high-risk patients received NAD and adjuvant AD (AAD) 2 years after 3DCRT. Stratification was performed for treatment/risk group and total radiation dose.
RESULTS: After a median follow-up of 36 months (range, 18 to 63 months), the actuarial biochemical disease-free survival (bDFS) at 5 years for all patients was 74%. The corresponding figures for low-risk, intermediate-risk, and high-risk disease were 80%, 73%, and 79%, respectively (P = .847). Univariate analysis showed that higher radiation dose was the only significant factor associated with bDFS for all patients (P = .0004). When stratified for treatment group, this benefit was evident for low-risk patients (P = .009) and, more interestingly, for high-risk patients treated with AAD. The 5-year bDFS for high-risk patients treated with AAD was 63% for radiation doses less than 72 Gy and 84% for those 72 Gy (P = .003).
CONCLUSION: The results of combined AAD plus high-dose 3DCRT are encouraging. To our knowledge, this is the first study showing an additional benefit of high-dose 3DCRT when combined with long-term AD for unfavorable disease.
INTRODUCTION
Over the last decade two concepts have emerged to improve local control and outcome for patients with localized prostate cancer: dose escalation with new three-dimensional conformal radiotherapy (3DCRT) technologies and combined modality treatment with hormonal therapy.
A number of institutional and multi-institutional studies of dose escalation with 3DCRT in prostate cancer have consistently reported an improvement in biochemical disease-free survival (bDFS) andlocal control as an increasing dose of radiation is delivered.1-6 This improvement in outcome has been particularly evident for intermediate- and high-risk patients. Recent studies evaluating long-term results have also confirmed the presence of a dose response in early-stage, low-risk prostate cancer patients.7,8
Advances for the treatment of prostate cancer have also focused on combined-modality treatment using androgen deprivation (AD) and radiotherapy (RT).9-12 At the present time, there are considerable data to support the use of AD with RT in selected patients with prostate cancer, particularly those with locally advanced, unfavorable-risk disease.13-18 Because randomized trials showing improved outcome with AD have used exclusively conventional dose levels of 65 to 70 Gy, the question about a potential benefit of higher radiation doses in patients receiving AD have remained unanswered.
A multicenter prospective study of the Spanish Cooperative Group Grupo de Investigación Clínica en Oncología Radioterápica (GICOR 05/99) was conducted to determine the impact on biochemical control, overall survival, and morbidity of risk-adapted AD in combination with high-dose 3DCRT for localized prostate cancer. This is a report on biochemical control.
PATIENTS AND METHODS
Patient Characteristics
Between October 1999 and October 2001, 426 patients with clinically localized prostate cancer were registered from seven institutions in a prospective multicenter trial. Of the 426 patients enrolled, 416 were assessable for this report. All patients had biopsy-proven prostate cancer stages T1-3Nx-N0M0, had pretreatment serum prostate-specific antigen (PSA) testing and Gleason-score evaluation. The 416 patients were prospectively assigned to one of three different treatment groups according to risk factors (PSA level, Gleason score and T stage): low risk (defined as having T1c stage or T2 stage with PSA < 20 ng/mL and Gleason score 6), 181 patients; intermediate risk (T2 stage with PSA 20 to 40 ng/mL or Gleason score of 7), 75 patients; and high-risk (T2 stage with Gleason score > 7 and PSA 20 to 40 ng/mL or T3 stage or Gleason score > 7 or PSA > 40 ng/mL), 160 patients. Low-risk patients were treated with 3DCRT alone, intermediate-risk patients were allocated to receive neoadjuvant AD (NAD) 4 to 6 months before and concomitant with 3DCRT, and high-risk patients received NAD followed by adjuvant AD (AAD) 2 years after 3DCRT (Fig 1). Stratification was performed for treatment/risk group and radiation dose level (group 1, < 72 Gy; group 2, 72 Gy).
Pretreatment diagnostic evaluations included complete blood analysis, PSA and testosterone levels, chest x-ray, computed tomography (CT) scan, and bone scan. Eligible patients also needed to have a Karnofsky performance status higher than 70%. Median patients characteristics were age of 74 years (range, 54 to 88 years) and pretreatment PSA level (determined by radioimmunoassay) of 17.7 ng/mL (range, 2.8 to 206 ng/mL). The distribution of patients according to the 1997 American Joint Committee on Cancer clinical stage was 108 (26%) at T1c; 197 (47%) at T2; 75 (18%) at T3a; and 36 (9%) at T3b. Gleason score was available for all patients: 51% had a Gleason score of 6, 35% had a Gleason score of 7, and 14% had a Gleason score of 8 to 10. The patient characteristics are listed in Table 1.
RT Treatment
All patients were treated with 3DCRT, and the technique varied according to validated institutional protocols. Briefly, patients were CT scanned (with a 0.5- to 0.3-cm step) and treated supine, using an immobilization device for knees and feet and with emptied rectum and full bladder. Depending on the estimated risk of involvement of the seminal vesicles based on Gleason score, PSA level, and tumor stage, the gross tumor volume and clinical target volume incorporated the prostate plus seminal vesicles (85%) or the prostate only (15%). A 1-cm margin was added to define the planning target volume (PTV), reduced to 0.7 cm in the overlap region with the rectum to minimize rectal toxicity. The block edge was placed 0.7 cm circumferentially around the PTV and 1.0 to 1.2 cm in the superior and inferior directions. In general, patients receiving doses 72.0 Gy were treated with a four-field "box" technique, and patients receiving doses 75.6 Gy were treated with a six-field arrangement (opposed laterals and four obliques). Elective pelvic lymph node (LN) irradiation that was left to the criteria of the participant institution was performed in 138 intermediate- and high-risk patients (32%) to a total dose of 45.0 to 50.0 Gy (1.8G to 2.0 Gy per fraction) using a four-field "box" technique.
Radiation prescription dose varied according to the 3DCRT protocol of every institution; the minimal requirement was 64.8 Gy. The homogeneity criteria were 95% to 107% (the minimal dose to PTV was 95% of the prescription dose). The median prostate International Commission on Radiation Units and Measurements (ICRU) reference dose delivered to the isocenter was 72.0 Gy (range, 64.8 to 82.6 Gy), with daily fractions of 1.8 to 2.0 Gy. The ICRU reference dose was less than 72 Gy in 230 (55%) patients (level one) and 72 Gy in 196 (45%) patients (level two). The technical characteristics of RT treatment are summarized in Table 2.
AD
Risk-adapted androgen ablation consisted of a luteinizing hormone-releasing hormone agonist (mainly goserelin acetate in 47% of the patients and leuprolide acetate in 26% of the patients) with a nonsteroidal antiandrogen (flutamide acetate 250 mg tid or bicalutamide 50 mg/d). Patients with high-risk features were subjected to 4 to 6 months of total androgen blockade before, concurrent with, and 2 years after RT (long-term AAD). Patients with intermediate-risk disease received 4 to 6 months of short-term NAD before and concurrent with RT. At baseline and following the administration of AD, a CBC and liver-function tests were obtained during the first month of AD and then in the follow-up visits until the end of hormone treatment. Antiandrogen flutamide was discontinued when a liver test exceeded 2x the upper limit of normal or when the patient developed drug-induced diarrhea.
Follow-Up
All patients were observed periodically after treatment completion, and the follow-up time was calculated from the date of diagnosis. Follow-up visits, including digital rectal examination and PSA determination, occurred first at 4 months, then every 6 months for 5 years, and annually thereafter. Patients in the high-risk group treated with long-term AAD also underwent more extensive evaluation including CT scan, bone scan, and chest x-ray at the end of hormonal therapy. Prostate biopsies were planned at 2 years after completion of RT or for a rising PSA level in one institution as part of an intramural protocol. Acute and late toxicity were scored according to the Radiation Therapy Oncology Group morbidity scoring scale.19
Statistical Analysis
The primary end point was bDFS, which was defined following the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition.20 bDFS was calculated from the date of diagnosis using the Kaplan-Meier method. Differences between groups were compared with the log-rank test, and linear trend was performed when possible. The potential prognostic factors studied in univariate analysis were clinical stage, pretreatment PSA, Gleason score, patient age, risk group, radiation dose, and elective LN RT. DFS was defined as any clinical failure other than biochemical and was measured from the date of diagnosis to the date of an event. Multivariate analysis was performed by using a Cox regression analysis.21 A P < .05 significance level (two-sided) was considered for all statistical tests. Analyses were performed by using SPSS 9.0 software (SPSS Inc, Chicago, IL).
RESULTS
Early Morbidity
Fifty-four patients (14%) had grade 2 acute rectal toxicity, and 73 (19%) had grade 2 bladder toxicity. Few patients (1.3% and 1.8%) experienced grade 3 rectal or bladder toxicity, and there were no grade 4 or 5 toxicities. In multivariate analysis, inclusion of LNs on PTV was the only significant factor associated with higher risk of grade 2 acute rectal toxicity (OR, 2.4; 95% CI, 1.3 to 4.4) and grade 2 acute bladder complications (OR, 2.1; 90% CI, 1.2 to 3.8; Table 3). AD did not show significant impact on rectal or bladder early toxicity in multivariate analysis.
Outcome
Biochemical control. The median follow-up of the entire patient group was 36 months (range, 18 to 63 months) at the time of analysis (May 2004). Forty-four (10%) of 416 patients developed biochemical failure according to ASTRO criteria as the first event, with a median time to PSA relapse of 32 months. Of the 44 patients who experienced biochemical failure, seven had documented clinical disease progression (local, five patients [1%]; metastatic disease, two patients [0.5%]). The actuarial bDFS at 5 years for all patients was 74% (SE, 5.3). The corresponding figures at 5 years for low-, intermediate-, and high-risk patients were 80% (SE, 7.7), 73% (SE, 16), and 79% (SE, 5.7), respectively (P = .847; Fig 2).
Risk factors for biochemical outcome. Univariate analysis for prediction of biochemical outcome was performed for the 416 patients as a whole and stratified by risk subgroups. Clinical and therapeutic variables included in the analysis were patient age, pretreatment PSA, tumor stage, Gleason score, ICRU radiation dose (as a continuous and categoric variable), and the elective irradiation of pelvic LNs. In the global analysis for all patients, no clinical factor was significantly associated with outcome. Only radiation dose, both as continuous (P = .0001) and categoric (levels one and two; P = .0004) variables, was significantly correlated with an improved biochemical disease-free survival (bDFS). Overall, outcome for patients who received higher radiation doses is 90%. Table 4 summarizes the results of the univariate analysis.
Risk-group analysis. Using a stratified analysis separately for each risk group and adjusting by radiation dose (as a continuous and categoric variable), we did not find significant clinical correlations with PSA outcome (Table 5). Only a higher radiation dose was significantly associated with an improved bDFS for low-risk and high-risk patients. Patients with low-risk prostate cancer had an actuarial 5-year bDFS of 66% for level one radiation doses (< 72 Gy) and 96% for level two radiation doses ( 72 Gy; P = .009). Interestingly, patients with high-risk prostate cancer, all of whom were treated with long-term AD, also experienced a significant benefit with the increase of radiation dose (level one, 63%; level two, 84%; P = .003). In the intermediate-risk group of patients, although the figures show better bDFS for higher doses (94% v 56%), the sample was small and the difference was not statistically significant (P = .119; Fig 3).
In the present analysis no significant benefit in bDFS was observed with the elective LN irradiation for intermediate-risk (P = .4843) or high-risk (P = .3799) patients with prostate cancer. Finally, a multivariate analysis was performed separately for intermediate- and high-risk groups, including radiation dose and controlling for elective node irradiation to rule out potential confusion (Table 6). The results confirm an independent benefit of higher radiation dose for high-risk patients (P = .021).
DISCUSSION
With the proven benefit of androgen suppression in high-risk groups, the modern therapeutic scenario generates a growing controversy about the role of AD combined with high-dose RT or the need of dose-escalation RT when using AD in intermediate- and high-risk patients with prostate cancer. The present study was undertaken to determine the impact on biochemical control and disease-specific survival of risk-adapted AD in combination with high-dose 3DCRT for localized prostate cancer. We also tried to determine the potential independent benefit of the higher radiation dose when combined with AD in high-risk patients. The results showed an actuarial bDFS of 74% (SE, 5.3) at 5 years for all 416 patients who were analyzed. The corresponding figure at 5 years for low-risk patients (3DCRT alone) was 80%, for intermediate-risk patients (NAD plus 3DCRT) was 73%, and for high-risk patients (NAD and 3DCRT followed by 2 years AAD) was 79% (P = .847). These results are encouraging and might reflect several relevant treatment-related effects. First, the efficacy of RT alone as definitive therapy for early-stage (low-risk) prostate cancer is proven further. A biochemical control of 80% at 5 years concurs with studies from other major single-institution expert experiences, although the low-risk definition in the present study included higher PSA levels (up to 20 ng/mL).
Second, these preliminary data show the favorable impact of long-term AD combined with high-dose 3DCRT in high-risk patients achieving a PSA outcome similar to that of low-risk patients (Fig 2). Although it is difficult to compare the current experience directly with other treatment regimens because of the potential variation in patient selection, outcome definitions, and treatment schedules (radiation dose and length of AD), the outcomes reported in this study (5-year bDFS of 79%) compare favorably with other treatment reports for high-risk patients.9,14,17,22,23 The heterogeneous definition of intermediate-risk prostate cancer represents a drawback for treatment assignment and comparison of results between trials and institutional experiences.
As hypothesized, the results presently analyzed confirmed a relevant benefit of higher radiation doses in PSA outcome for all 416 patients (P = .0001) and separately by risk subgroup; this benefit was more significant for low- and high-risk patients. Overall, outcomes for patients who received higher radiation doses are excellent. Patients with low-risk disease had an actuarial 5-year bDFS of 66% for radiation doses less than 72 Gy and 96% for doses 72 Gy (P = .009). For the intermediate-risk disease, although the figures showed superior bDFS for higher doses, the difference was not statistically significant (94% v 56%; P = .119). This feature is interpreted as an effect of the small size of this particularly heterogeneous cohort of patients. Interestingly, patients with high-risk prostate cancer, all of whom were treated with long-term AD, consistently experienced a significant benefit from higher radiation doses (63% for < 72 Gy v 84% for 72 Gy; P = .003).
These preliminary results of a multi-institutional radiation-dose–escalation trial are in agreement with the extensively published data from expert authors and centers,3,4,6,8 confirming the need for increased radiation doses to achieve a maximal local cure in prostate cancer, even in high-risk patients treated with hormone therapy. We think that although the length of follow-up is short and results are preliminary, the data derived from univariate and multivariate analyses emphasize that higher doses significantly improve the PSA outcome over conventional dose levels regardless of whether hormone therapy is administered and seem to confirm that the use of AD in high-risk patients does not preclude the need for dose escalation in these patients. However, we should wait for more definitive results with longer follow-up.
We recognize the limitations inherent to this prospective nonrandomized study. One variable to consider is related to the use of hormone treatment, because this therapy gives a temporary advantage to those patients treated with AAD. Furthermore, the applicability of the ASTRO failure definition for patients treated with temporary hormone RT can add some confusion to the results. Finally, another factor is the length of follow-up. To minimize these biases in this preliminary report, a separated and stratified analysis for every risk subgroup was performed, and although the length of follow-up is limited, the outcome data for patients in each risk-related treatment category are dramatically different for each dose level. Results as they are presently reported, showing a significant benefit in biochemical outcome with higher radiation dose even in high-risk patients, seem to indicate an additional benefit of high-dose RT for patients independent of the use of AD. To our knowledge, this is the first published study showing an independent benefit of high-dose CRT when combined with long-term AAD. Results of ongoing randomized trials (European Organisation for Research and Treatment of Cancer 22991, Radiation Therapy Oncology Group [RTOG] 9408, RTOG 9910, and RTOG 9902) with the appropriate patient selection testing this hypothesis will clarify these issues further.
Many other questions regarding the use of RT and AD therapy remain open. Among these questions is that of the role of prophylactic pelvic LN irradiation. Elective LN RT in the setting of prostate cancer continues to have a poorly defined role. Although no consistent benefit in recurrence-free survival has been observed, pelvic lymphatic irradiation is associated with a higher risk of complications and higher cost.24 Mixed results in numerous studies (most of them retrospective) that have attempted to identify a specific population that would benefit from pelvic irradiation have led to conflicting recommendations.25-27 This controversy has been confused also by the combined use of hormone therapy in these patients. Most recently, the results from the RTOG 94-13 trial showed a significant benefit in progression-free survival for whole-pelvis RT when combined with NAD versus prostate-only RT.28
As part of this controversy, in the present study we analyzed the potential role of prophylactic LN RT in intermediate- and high-risk patients. The results of univariate and multivariate analyses failed to show any significant benefit in terms of bDFS for pelvic RT versus no pelvic RT (intermediate risk, P = .841; high risk, P = .147). One possible explanation for this finding might be that periprostatic LNs are usually included in the PTV that encompasses seminal vesicles in high-risk patients. More relevant, a synergistic effect beyond prostate of long-term AAD plus high-dose RT has been also reported.28 Because some confusion exists regarding this point, additional specifically designed studies and longer follow-up of ongoing trials are required to determine the definite role of pelvic-node RT and the interaction with AD in prostate cancer.
In conclusion, the preliminary results of the present study show that, in prostate cancer, higher doses using 3DCRT significantly improve the PSA outcome over conventional dose levels regardless of whether hormone therapy is administered and seem to confirm that the use AD in high-risk patients does not preclude the need for dose escalation. To our knowledge, this is the first published study showing an independent benefit of high-dose CRT when combined with long-term AAD. These data indicate that high-dose CRT should be a critical element in additional clinical trials of combined treatment and seem to suggest a synergistic effect of long-term AAD plus high-dose RT. Trials currently underway that have taken these concerns into consideration and are addressing many of these critical issues will further clarify the contribution of RT, AD, and their interaction in clinically localized prostate cancer.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
Scientific supervision was carried out by Grupo de Investigación Clínica Oncología Radioterápica (GICOR).
NOTES
Presented at the 29th European Society for Medical Oncology Congress, October 29 to November 2, 2004, Vienna, Austria; 5th La Federación Espa?ola de Sociedades Oncológicas (FESEO) Congress, November 17-19, 2004, Valencia, Spain.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53:1097-1105, 2002
Zelefsky MJ, Leibel SA, Gaudin PB, et al: Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 41:491-500, 1998
Zelefsky MJ, Fuks Z, Hunt M, et al: High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 166:876-881, 2001
Fiveash JB, Hanks G, Roach M, et al: 3D conformal radiation therapy (3DCRT) for high grade prostate cancer: A multi-institutional review. Int J Radiat Oncol Biol Phys 47:335-342, 2000
Vicini FA, Abner A, Baglan KL, et al: Defining a dose-response relationship with radiotherapy for prostate cancer: Is more really better? Int J Radiat Oncol Biol Phys 51:1200-1208, 2001
Hanks GE, Hanlon AL, Epstein B, et al: Dose response in prostate cancer with 8-12 years' follow-up. Int J Radiat Oncol Biol Phys 54:427-435, 2002
Zietman AL, DeSilvio M, Slater JD et al: A randomized trial comparing conventional dose (70.2 GyE) and high-dose (79.2 GyE) conformal radiation in early stage adenocarcinoma of the prostate: Results of an interim analysis of PROG 95-09. Int J Radiat Oncol Biol Phys 60:131, 2004 (abstr 4)
Kupelian PA, Kuban D, Thames H, et al: Improved biochemical relapse-free survival with increased external radiation doses in patients with localized prostate cancer: The combined experience of nine institutions in patients treated in 1994 and 1995. Int J Radiat Oncol Biol Phys 57:271, 2003 (abstr 269)
Roach M 3rd, Lu J, Pilepich MV, et al: Predicting long-term survival, and the need for hormonal therapy: A meta-analysis of RTOG prostate cancer trials. Int J Radiat Oncol Biol Phys 4:617-627, 2000
Zietman AL, Nakfoor BM, Prince EA, et al: The effect of androgen deprivation and radiation therapy on an androgen-sensitive murine tumor: An in vitro and in vivo study. Cancer J Sci Am 3:31-36, 1997
Joon DL, Hasegawa M, Sikes C, et al: Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation. Int J Radiat Oncol Biol Phys 38:1071-1077, 1997
Pollack A, Salem N, Ashoori F, et al: Lack of prostate cancer radiosensitization by androgen deprivation. Int J Radiat Oncol Biol Phys 51:1002-1007, 2001
Vicini FA, Kini VR, Spencer W, et al: The role of androgen deprivation in the definitive management of clinically localized prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys 43:707-713, 1999
Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomized trial. Lancet 360:103-106, 2002
Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50:1243-1252, 2001
Shipley WU, Lu JD, Pilepich MV, et al: Effect of a short course of neoadjuvant hormonal therapy on the response to subsequent androgen suppression in prostate cancer patients with relapse after radiotherapy: A secondary analysis of the randomized protocol RTOG 86-10. Int J Radiat Oncol Biol Phys 54:1302-1310, 2002
Lawton CA, Winter K, Murray K, et al: Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 49:937-946, 2001
Laverdiere J, Gomez JL, 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 37:247-252, 1997
Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 32:567-576, 1995
American Society for Therapeutic Radiology and Oncology Consensus Panel: Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997
Cox DR: Regression models and life tables. J R Stat Soc B 34:187-220, 1972
Hanks GE, Pajak TF, Porter A, et al: Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 21:3972-3978, 2003
D'Amico AV, Manola J, Loffredo M, et al: 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial. JAMA 292:821-827, 2004
Pan CC, Kim KY, Taylor JM, et al: Influence of 3DCRT pelvic irradiation on outcome in prostate cancer treated with external beam radiotherapy. Int J Radiat Oncol Biol Phys 53:1139-1145, 2002
Seaward SA, Weinberg V, Lewis P, et al: Improved freedom from PSA failure with whole pelvic irradiation for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 42:1055-1062, 1998
Perez CA, Michalski J, Brown KC, et al: Nonrandomized evaluation of pelvic lymph node irradiation in localized carcinoma of the prostate. Int J Radiat Oncol Biol Phys 36:573-584, 1996
Leibel SA, Fuks Z, Zelefsky MJ, et al: The effects of local and regional treatment on the metastatic outcome in prostatic carcinoma with pelvic lymph node involvement. Int J Radiat Oncol Biol Phys 28:7-16, 1994
Roach M 3rd, DeSilvio M, Lawton C, et al: Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 21:1904-1911, 2003(Almudena Zapatero, Franci)
Department of Radiation Oncology, Hospital Puerta de Hierro, Madrid
Department of Radiation Oncology, Hospital Gregorio Mara?ón, Madrid
Department of Radiation Oncology, Hospital Clínico de Valencia, Valencia
Department of Radiation Oncology, Hospital Reina Sofía de Córdoba, Córdoba
Department of Radiation Oncology, Hospital General Vall D'Hebrón, Barcelona
Department of Radiation Oncology, Institut Catalá Oncología, Barcelona, Spain
ABSTRACT
PURPOSE: Multicenter study conducted to determine the impact on biochemical control and survival of risk-adapted androgen deprivation (AD) combined with high-dose three-dimensional conformal radiotherapy (3DCRT) for prostate cancer. Results of biochemical control are reported.
PATIENTS AND METHODS: Between October 1999 and October 2001, 416 eligible patients with prostate cancer were assigned to one of three treatment groups according to their risk factors: 181 low-risk patients were treated with 3DCRT alone; 75 intermediate-risk patients were allocated to receive neoadjuvant AD (NAD) 4-6 months before and during 3DCRT; and 160 high-risk patients received NAD and adjuvant AD (AAD) 2 years after 3DCRT. Stratification was performed for treatment/risk group and total radiation dose.
RESULTS: After a median follow-up of 36 months (range, 18 to 63 months), the actuarial biochemical disease-free survival (bDFS) at 5 years for all patients was 74%. The corresponding figures for low-risk, intermediate-risk, and high-risk disease were 80%, 73%, and 79%, respectively (P = .847). Univariate analysis showed that higher radiation dose was the only significant factor associated with bDFS for all patients (P = .0004). When stratified for treatment group, this benefit was evident for low-risk patients (P = .009) and, more interestingly, for high-risk patients treated with AAD. The 5-year bDFS for high-risk patients treated with AAD was 63% for radiation doses less than 72 Gy and 84% for those 72 Gy (P = .003).
CONCLUSION: The results of combined AAD plus high-dose 3DCRT are encouraging. To our knowledge, this is the first study showing an additional benefit of high-dose 3DCRT when combined with long-term AD for unfavorable disease.
INTRODUCTION
Over the last decade two concepts have emerged to improve local control and outcome for patients with localized prostate cancer: dose escalation with new three-dimensional conformal radiotherapy (3DCRT) technologies and combined modality treatment with hormonal therapy.
A number of institutional and multi-institutional studies of dose escalation with 3DCRT in prostate cancer have consistently reported an improvement in biochemical disease-free survival (bDFS) andlocal control as an increasing dose of radiation is delivered.1-6 This improvement in outcome has been particularly evident for intermediate- and high-risk patients. Recent studies evaluating long-term results have also confirmed the presence of a dose response in early-stage, low-risk prostate cancer patients.7,8
Advances for the treatment of prostate cancer have also focused on combined-modality treatment using androgen deprivation (AD) and radiotherapy (RT).9-12 At the present time, there are considerable data to support the use of AD with RT in selected patients with prostate cancer, particularly those with locally advanced, unfavorable-risk disease.13-18 Because randomized trials showing improved outcome with AD have used exclusively conventional dose levels of 65 to 70 Gy, the question about a potential benefit of higher radiation doses in patients receiving AD have remained unanswered.
A multicenter prospective study of the Spanish Cooperative Group Grupo de Investigación Clínica en Oncología Radioterápica (GICOR 05/99) was conducted to determine the impact on biochemical control, overall survival, and morbidity of risk-adapted AD in combination with high-dose 3DCRT for localized prostate cancer. This is a report on biochemical control.
PATIENTS AND METHODS
Patient Characteristics
Between October 1999 and October 2001, 426 patients with clinically localized prostate cancer were registered from seven institutions in a prospective multicenter trial. Of the 426 patients enrolled, 416 were assessable for this report. All patients had biopsy-proven prostate cancer stages T1-3Nx-N0M0, had pretreatment serum prostate-specific antigen (PSA) testing and Gleason-score evaluation. The 416 patients were prospectively assigned to one of three different treatment groups according to risk factors (PSA level, Gleason score and T stage): low risk (defined as having T1c stage or T2 stage with PSA < 20 ng/mL and Gleason score 6), 181 patients; intermediate risk (T2 stage with PSA 20 to 40 ng/mL or Gleason score of 7), 75 patients; and high-risk (T2 stage with Gleason score > 7 and PSA 20 to 40 ng/mL or T3 stage or Gleason score > 7 or PSA > 40 ng/mL), 160 patients. Low-risk patients were treated with 3DCRT alone, intermediate-risk patients were allocated to receive neoadjuvant AD (NAD) 4 to 6 months before and concomitant with 3DCRT, and high-risk patients received NAD followed by adjuvant AD (AAD) 2 years after 3DCRT (Fig 1). Stratification was performed for treatment/risk group and radiation dose level (group 1, < 72 Gy; group 2, 72 Gy).
Pretreatment diagnostic evaluations included complete blood analysis, PSA and testosterone levels, chest x-ray, computed tomography (CT) scan, and bone scan. Eligible patients also needed to have a Karnofsky performance status higher than 70%. Median patients characteristics were age of 74 years (range, 54 to 88 years) and pretreatment PSA level (determined by radioimmunoassay) of 17.7 ng/mL (range, 2.8 to 206 ng/mL). The distribution of patients according to the 1997 American Joint Committee on Cancer clinical stage was 108 (26%) at T1c; 197 (47%) at T2; 75 (18%) at T3a; and 36 (9%) at T3b. Gleason score was available for all patients: 51% had a Gleason score of 6, 35% had a Gleason score of 7, and 14% had a Gleason score of 8 to 10. The patient characteristics are listed in Table 1.
RT Treatment
All patients were treated with 3DCRT, and the technique varied according to validated institutional protocols. Briefly, patients were CT scanned (with a 0.5- to 0.3-cm step) and treated supine, using an immobilization device for knees and feet and with emptied rectum and full bladder. Depending on the estimated risk of involvement of the seminal vesicles based on Gleason score, PSA level, and tumor stage, the gross tumor volume and clinical target volume incorporated the prostate plus seminal vesicles (85%) or the prostate only (15%). A 1-cm margin was added to define the planning target volume (PTV), reduced to 0.7 cm in the overlap region with the rectum to minimize rectal toxicity. The block edge was placed 0.7 cm circumferentially around the PTV and 1.0 to 1.2 cm in the superior and inferior directions. In general, patients receiving doses 72.0 Gy were treated with a four-field "box" technique, and patients receiving doses 75.6 Gy were treated with a six-field arrangement (opposed laterals and four obliques). Elective pelvic lymph node (LN) irradiation that was left to the criteria of the participant institution was performed in 138 intermediate- and high-risk patients (32%) to a total dose of 45.0 to 50.0 Gy (1.8G to 2.0 Gy per fraction) using a four-field "box" technique.
Radiation prescription dose varied according to the 3DCRT protocol of every institution; the minimal requirement was 64.8 Gy. The homogeneity criteria were 95% to 107% (the minimal dose to PTV was 95% of the prescription dose). The median prostate International Commission on Radiation Units and Measurements (ICRU) reference dose delivered to the isocenter was 72.0 Gy (range, 64.8 to 82.6 Gy), with daily fractions of 1.8 to 2.0 Gy. The ICRU reference dose was less than 72 Gy in 230 (55%) patients (level one) and 72 Gy in 196 (45%) patients (level two). The technical characteristics of RT treatment are summarized in Table 2.
AD
Risk-adapted androgen ablation consisted of a luteinizing hormone-releasing hormone agonist (mainly goserelin acetate in 47% of the patients and leuprolide acetate in 26% of the patients) with a nonsteroidal antiandrogen (flutamide acetate 250 mg tid or bicalutamide 50 mg/d). Patients with high-risk features were subjected to 4 to 6 months of total androgen blockade before, concurrent with, and 2 years after RT (long-term AAD). Patients with intermediate-risk disease received 4 to 6 months of short-term NAD before and concurrent with RT. At baseline and following the administration of AD, a CBC and liver-function tests were obtained during the first month of AD and then in the follow-up visits until the end of hormone treatment. Antiandrogen flutamide was discontinued when a liver test exceeded 2x the upper limit of normal or when the patient developed drug-induced diarrhea.
Follow-Up
All patients were observed periodically after treatment completion, and the follow-up time was calculated from the date of diagnosis. Follow-up visits, including digital rectal examination and PSA determination, occurred first at 4 months, then every 6 months for 5 years, and annually thereafter. Patients in the high-risk group treated with long-term AAD also underwent more extensive evaluation including CT scan, bone scan, and chest x-ray at the end of hormonal therapy. Prostate biopsies were planned at 2 years after completion of RT or for a rising PSA level in one institution as part of an intramural protocol. Acute and late toxicity were scored according to the Radiation Therapy Oncology Group morbidity scoring scale.19
Statistical Analysis
The primary end point was bDFS, which was defined following the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition.20 bDFS was calculated from the date of diagnosis using the Kaplan-Meier method. Differences between groups were compared with the log-rank test, and linear trend was performed when possible. The potential prognostic factors studied in univariate analysis were clinical stage, pretreatment PSA, Gleason score, patient age, risk group, radiation dose, and elective LN RT. DFS was defined as any clinical failure other than biochemical and was measured from the date of diagnosis to the date of an event. Multivariate analysis was performed by using a Cox regression analysis.21 A P < .05 significance level (two-sided) was considered for all statistical tests. Analyses were performed by using SPSS 9.0 software (SPSS Inc, Chicago, IL).
RESULTS
Early Morbidity
Fifty-four patients (14%) had grade 2 acute rectal toxicity, and 73 (19%) had grade 2 bladder toxicity. Few patients (1.3% and 1.8%) experienced grade 3 rectal or bladder toxicity, and there were no grade 4 or 5 toxicities. In multivariate analysis, inclusion of LNs on PTV was the only significant factor associated with higher risk of grade 2 acute rectal toxicity (OR, 2.4; 95% CI, 1.3 to 4.4) and grade 2 acute bladder complications (OR, 2.1; 90% CI, 1.2 to 3.8; Table 3). AD did not show significant impact on rectal or bladder early toxicity in multivariate analysis.
Outcome
Biochemical control. The median follow-up of the entire patient group was 36 months (range, 18 to 63 months) at the time of analysis (May 2004). Forty-four (10%) of 416 patients developed biochemical failure according to ASTRO criteria as the first event, with a median time to PSA relapse of 32 months. Of the 44 patients who experienced biochemical failure, seven had documented clinical disease progression (local, five patients [1%]; metastatic disease, two patients [0.5%]). The actuarial bDFS at 5 years for all patients was 74% (SE, 5.3). The corresponding figures at 5 years for low-, intermediate-, and high-risk patients were 80% (SE, 7.7), 73% (SE, 16), and 79% (SE, 5.7), respectively (P = .847; Fig 2).
Risk factors for biochemical outcome. Univariate analysis for prediction of biochemical outcome was performed for the 416 patients as a whole and stratified by risk subgroups. Clinical and therapeutic variables included in the analysis were patient age, pretreatment PSA, tumor stage, Gleason score, ICRU radiation dose (as a continuous and categoric variable), and the elective irradiation of pelvic LNs. In the global analysis for all patients, no clinical factor was significantly associated with outcome. Only radiation dose, both as continuous (P = .0001) and categoric (levels one and two; P = .0004) variables, was significantly correlated with an improved biochemical disease-free survival (bDFS). Overall, outcome for patients who received higher radiation doses is 90%. Table 4 summarizes the results of the univariate analysis.
Risk-group analysis. Using a stratified analysis separately for each risk group and adjusting by radiation dose (as a continuous and categoric variable), we did not find significant clinical correlations with PSA outcome (Table 5). Only a higher radiation dose was significantly associated with an improved bDFS for low-risk and high-risk patients. Patients with low-risk prostate cancer had an actuarial 5-year bDFS of 66% for level one radiation doses (< 72 Gy) and 96% for level two radiation doses ( 72 Gy; P = .009). Interestingly, patients with high-risk prostate cancer, all of whom were treated with long-term AD, also experienced a significant benefit with the increase of radiation dose (level one, 63%; level two, 84%; P = .003). In the intermediate-risk group of patients, although the figures show better bDFS for higher doses (94% v 56%), the sample was small and the difference was not statistically significant (P = .119; Fig 3).
In the present analysis no significant benefit in bDFS was observed with the elective LN irradiation for intermediate-risk (P = .4843) or high-risk (P = .3799) patients with prostate cancer. Finally, a multivariate analysis was performed separately for intermediate- and high-risk groups, including radiation dose and controlling for elective node irradiation to rule out potential confusion (Table 6). The results confirm an independent benefit of higher radiation dose for high-risk patients (P = .021).
DISCUSSION
With the proven benefit of androgen suppression in high-risk groups, the modern therapeutic scenario generates a growing controversy about the role of AD combined with high-dose RT or the need of dose-escalation RT when using AD in intermediate- and high-risk patients with prostate cancer. The present study was undertaken to determine the impact on biochemical control and disease-specific survival of risk-adapted AD in combination with high-dose 3DCRT for localized prostate cancer. We also tried to determine the potential independent benefit of the higher radiation dose when combined with AD in high-risk patients. The results showed an actuarial bDFS of 74% (SE, 5.3) at 5 years for all 416 patients who were analyzed. The corresponding figure at 5 years for low-risk patients (3DCRT alone) was 80%, for intermediate-risk patients (NAD plus 3DCRT) was 73%, and for high-risk patients (NAD and 3DCRT followed by 2 years AAD) was 79% (P = .847). These results are encouraging and might reflect several relevant treatment-related effects. First, the efficacy of RT alone as definitive therapy for early-stage (low-risk) prostate cancer is proven further. A biochemical control of 80% at 5 years concurs with studies from other major single-institution expert experiences, although the low-risk definition in the present study included higher PSA levels (up to 20 ng/mL).
Second, these preliminary data show the favorable impact of long-term AD combined with high-dose 3DCRT in high-risk patients achieving a PSA outcome similar to that of low-risk patients (Fig 2). Although it is difficult to compare the current experience directly with other treatment regimens because of the potential variation in patient selection, outcome definitions, and treatment schedules (radiation dose and length of AD), the outcomes reported in this study (5-year bDFS of 79%) compare favorably with other treatment reports for high-risk patients.9,14,17,22,23 The heterogeneous definition of intermediate-risk prostate cancer represents a drawback for treatment assignment and comparison of results between trials and institutional experiences.
As hypothesized, the results presently analyzed confirmed a relevant benefit of higher radiation doses in PSA outcome for all 416 patients (P = .0001) and separately by risk subgroup; this benefit was more significant for low- and high-risk patients. Overall, outcomes for patients who received higher radiation doses are excellent. Patients with low-risk disease had an actuarial 5-year bDFS of 66% for radiation doses less than 72 Gy and 96% for doses 72 Gy (P = .009). For the intermediate-risk disease, although the figures showed superior bDFS for higher doses, the difference was not statistically significant (94% v 56%; P = .119). This feature is interpreted as an effect of the small size of this particularly heterogeneous cohort of patients. Interestingly, patients with high-risk prostate cancer, all of whom were treated with long-term AD, consistently experienced a significant benefit from higher radiation doses (63% for < 72 Gy v 84% for 72 Gy; P = .003).
These preliminary results of a multi-institutional radiation-dose–escalation trial are in agreement with the extensively published data from expert authors and centers,3,4,6,8 confirming the need for increased radiation doses to achieve a maximal local cure in prostate cancer, even in high-risk patients treated with hormone therapy. We think that although the length of follow-up is short and results are preliminary, the data derived from univariate and multivariate analyses emphasize that higher doses significantly improve the PSA outcome over conventional dose levels regardless of whether hormone therapy is administered and seem to confirm that the use of AD in high-risk patients does not preclude the need for dose escalation in these patients. However, we should wait for more definitive results with longer follow-up.
We recognize the limitations inherent to this prospective nonrandomized study. One variable to consider is related to the use of hormone treatment, because this therapy gives a temporary advantage to those patients treated with AAD. Furthermore, the applicability of the ASTRO failure definition for patients treated with temporary hormone RT can add some confusion to the results. Finally, another factor is the length of follow-up. To minimize these biases in this preliminary report, a separated and stratified analysis for every risk subgroup was performed, and although the length of follow-up is limited, the outcome data for patients in each risk-related treatment category are dramatically different for each dose level. Results as they are presently reported, showing a significant benefit in biochemical outcome with higher radiation dose even in high-risk patients, seem to indicate an additional benefit of high-dose RT for patients independent of the use of AD. To our knowledge, this is the first published study showing an independent benefit of high-dose CRT when combined with long-term AAD. Results of ongoing randomized trials (European Organisation for Research and Treatment of Cancer 22991, Radiation Therapy Oncology Group [RTOG] 9408, RTOG 9910, and RTOG 9902) with the appropriate patient selection testing this hypothesis will clarify these issues further.
Many other questions regarding the use of RT and AD therapy remain open. Among these questions is that of the role of prophylactic pelvic LN irradiation. Elective LN RT in the setting of prostate cancer continues to have a poorly defined role. Although no consistent benefit in recurrence-free survival has been observed, pelvic lymphatic irradiation is associated with a higher risk of complications and higher cost.24 Mixed results in numerous studies (most of them retrospective) that have attempted to identify a specific population that would benefit from pelvic irradiation have led to conflicting recommendations.25-27 This controversy has been confused also by the combined use of hormone therapy in these patients. Most recently, the results from the RTOG 94-13 trial showed a significant benefit in progression-free survival for whole-pelvis RT when combined with NAD versus prostate-only RT.28
As part of this controversy, in the present study we analyzed the potential role of prophylactic LN RT in intermediate- and high-risk patients. The results of univariate and multivariate analyses failed to show any significant benefit in terms of bDFS for pelvic RT versus no pelvic RT (intermediate risk, P = .841; high risk, P = .147). One possible explanation for this finding might be that periprostatic LNs are usually included in the PTV that encompasses seminal vesicles in high-risk patients. More relevant, a synergistic effect beyond prostate of long-term AAD plus high-dose RT has been also reported.28 Because some confusion exists regarding this point, additional specifically designed studies and longer follow-up of ongoing trials are required to determine the definite role of pelvic-node RT and the interaction with AD in prostate cancer.
In conclusion, the preliminary results of the present study show that, in prostate cancer, higher doses using 3DCRT significantly improve the PSA outcome over conventional dose levels regardless of whether hormone therapy is administered and seem to confirm that the use AD in high-risk patients does not preclude the need for dose escalation. To our knowledge, this is the first published study showing an independent benefit of high-dose CRT when combined with long-term AAD. These data indicate that high-dose CRT should be a critical element in additional clinical trials of combined treatment and seem to suggest a synergistic effect of long-term AAD plus high-dose RT. Trials currently underway that have taken these concerns into consideration and are addressing many of these critical issues will further clarify the contribution of RT, AD, and their interaction in clinically localized prostate cancer.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
Scientific supervision was carried out by Grupo de Investigación Clínica Oncología Radioterápica (GICOR).
NOTES
Presented at the 29th European Society for Medical Oncology Congress, October 29 to November 2, 2004, Vienna, Austria; 5th La Federación Espa?ola de Sociedades Oncológicas (FESEO) Congress, November 17-19, 2004, Valencia, Spain.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53:1097-1105, 2002
Zelefsky MJ, Leibel SA, Gaudin PB, et al: Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 41:491-500, 1998
Zelefsky MJ, Fuks Z, Hunt M, et al: High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 166:876-881, 2001
Fiveash JB, Hanks G, Roach M, et al: 3D conformal radiation therapy (3DCRT) for high grade prostate cancer: A multi-institutional review. Int J Radiat Oncol Biol Phys 47:335-342, 2000
Vicini FA, Abner A, Baglan KL, et al: Defining a dose-response relationship with radiotherapy for prostate cancer: Is more really better? Int J Radiat Oncol Biol Phys 51:1200-1208, 2001
Hanks GE, Hanlon AL, Epstein B, et al: Dose response in prostate cancer with 8-12 years' follow-up. Int J Radiat Oncol Biol Phys 54:427-435, 2002
Zietman AL, DeSilvio M, Slater JD et al: A randomized trial comparing conventional dose (70.2 GyE) and high-dose (79.2 GyE) conformal radiation in early stage adenocarcinoma of the prostate: Results of an interim analysis of PROG 95-09. Int J Radiat Oncol Biol Phys 60:131, 2004 (abstr 4)
Kupelian PA, Kuban D, Thames H, et al: Improved biochemical relapse-free survival with increased external radiation doses in patients with localized prostate cancer: The combined experience of nine institutions in patients treated in 1994 and 1995. Int J Radiat Oncol Biol Phys 57:271, 2003 (abstr 269)
Roach M 3rd, Lu J, Pilepich MV, et al: Predicting long-term survival, and the need for hormonal therapy: A meta-analysis of RTOG prostate cancer trials. Int J Radiat Oncol Biol Phys 4:617-627, 2000
Zietman AL, Nakfoor BM, Prince EA, et al: The effect of androgen deprivation and radiation therapy on an androgen-sensitive murine tumor: An in vitro and in vivo study. Cancer J Sci Am 3:31-36, 1997
Joon DL, Hasegawa M, Sikes C, et al: Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation. Int J Radiat Oncol Biol Phys 38:1071-1077, 1997
Pollack A, Salem N, Ashoori F, et al: Lack of prostate cancer radiosensitization by androgen deprivation. Int J Radiat Oncol Biol Phys 51:1002-1007, 2001
Vicini FA, Kini VR, Spencer W, et al: The role of androgen deprivation in the definitive management of clinically localized prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys 43:707-713, 1999
Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomized trial. Lancet 360:103-106, 2002
Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50:1243-1252, 2001
Shipley WU, Lu JD, Pilepich MV, et al: Effect of a short course of neoadjuvant hormonal therapy on the response to subsequent androgen suppression in prostate cancer patients with relapse after radiotherapy: A secondary analysis of the randomized protocol RTOG 86-10. Int J Radiat Oncol Biol Phys 54:1302-1310, 2002
Lawton CA, Winter K, Murray K, et al: Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 49:937-946, 2001
Laverdiere J, Gomez JL, 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 37:247-252, 1997
Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 32:567-576, 1995
American Society for Therapeutic Radiology and Oncology Consensus Panel: Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997
Cox DR: Regression models and life tables. J R Stat Soc B 34:187-220, 1972
Hanks GE, Pajak TF, Porter A, et al: Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 21:3972-3978, 2003
D'Amico AV, Manola J, Loffredo M, et al: 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial. JAMA 292:821-827, 2004
Pan CC, Kim KY, Taylor JM, et al: Influence of 3DCRT pelvic irradiation on outcome in prostate cancer treated with external beam radiotherapy. Int J Radiat Oncol Biol Phys 53:1139-1145, 2002
Seaward SA, Weinberg V, Lewis P, et al: Improved freedom from PSA failure with whole pelvic irradiation for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 42:1055-1062, 1998
Perez CA, Michalski J, Brown KC, et al: Nonrandomized evaluation of pelvic lymph node irradiation in localized carcinoma of the prostate. Int J Radiat Oncol Biol Phys 36:573-584, 1996
Leibel SA, Fuks Z, Zelefsky MJ, et al: The effects of local and regional treatment on the metastatic outcome in prostatic carcinoma with pelvic lymph node involvement. Int J Radiat Oncol Biol Phys 28:7-16, 1994
Roach M 3rd, DeSilvio M, Lawton C, et al: Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 21:1904-1911, 2003(Almudena Zapatero, Franci)