Journal of Clinical Oncology, Vol 21, Issue 21
(November), 2003: 3972-3978
© 2003 American Society for Clinical Oncology
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
Gerald E. Hanks,
Thomas F. Pajak,
Arthur Porter,
David Grignon,
Harmart Brereton,
Varagur Venkatesan,
Eric M. Horwitz,
Colleen Lawton,
Seth A. Rosenthal,
Howard M. Sandler,
William U. Shipley
From the Fox Chase Cancer Center and the Radiation Therapy Oncology Group, Philadelphia, and Mercy Hospital of Scranton, Scranton, PA; Harper Hospital, Wayne State University, Detroit, MI; University of Western Ontario, London, Ontario, Canada; Medical College of Wisconsin, Milwaukee, WI; Radiological Associates of Sacramento, Sacramento, CA; University of Michigan Medical School, Ann Arbor, MI; and Massachusetts General Hospital, Boston, MA.
Address reprint requests to Thomas F. Pajak, PhD, Statistical Department, Radiation Oncology Therapy Group, 1101 Market St, Philadelphia, PA 19107; e-mail: tpajak{at}phila.acr.org.
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ABSTRACT
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Purpose: Radiation Therapy Oncology Group (RTOG) Protocol 92–02 was a randomized trial testing long-term (LT) adjuvant androgen deprivation (AD) after initial AD with external-beam radiotherapy (RT) in patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level less than 150 ng/mL.
Patients and Methods: Patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT. A radiation dose of 65 to 70 Gy was given to the prostate and a dose of 44 to 50 Gy to the pelvic lymph nodes. Patients were randomly assigned to receive no additional therapy (short-term [ST]AD-RT) or 24 months of goserelin (LTAD-RT); 1,554 patients were entered onto the study.
Results: The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P = .73), compared with the STAD-RT arm. In a subset of patients not part of the original study design, with tumors assigned Gleason scores of 8 to 10 by the contributing institutions, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P = .044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P = .037), the cause of which is not clear.
Conclusion: The RTOG 92–02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC. In the exploratory subset analysis of patients with Gleason scores 8 to 10, LT adjuvant AD resulted in a survival advantage.
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INTRODUCTION
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LOCALLY ADVANCED prostate cancer (PC) has been difficult to cure with radiotherapy (RT) alone and has been the subject of randomized trials combining androgen deprivation (AD) with RT in the Radiation Therapy Oncology Group (RTOG) during the last 15 years. The initial trials were conducted in the mid-1980s, before the prostate-specific antigen (PSA) era. In RTOG 86–10, short-term (ST) total AD with goserelin and flutamide plus RT was compared with RT alone.1 The initial analysis showed the combined treatment arm was superior in all outcome end points except overall survival (OS) and was selected as the standard treatment arm for RTOG 92–02. In RTOG 85–31, indefinite AD with goserelin administered immediately after RT was compared with RT given alone with AD at relapse.2,3 Patients with Gleason scores 8 to 10 who were treated with the immediate-treatment arm showed a survival advantage compared with similar patients treated on the delayed-treatment arm. With additional follow-up, this advantage was seen for the entire study population. The adjuvant AD became the investigational arm of RTOG 92–02, in which patients were randomly assigned to receive 24 months of goserelin after receiving the STAD and RT (LTAD-RT).4 Because this trial was performed in the PSA era, pretreatment and posttreatment PSA levels were obtained for the analysis of treatment failure. This article reports outcomes from RTOG 92–02.
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PATIENTS AND METHODS
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Patients
Patients with histologically confirmed adenocarcinoma of the prostate (clinical stage T2c [bilobar] to T4), with no involved nodes in the common iliac or higher node chains, Karnofsky performance score  70, and pretreatment PSA level less than 150 ng/mL, were eligible. Patients with previous or concurrent cancers other than basal cell skin carcinoma were excluded. Clinical stage was based on the 1992 American Joint Committee on Cancer tumor-node-metastasis system. No prior therapy (surgery, hormone therapy, or RT) was allowed. Informed consent was obtained from patients before their participation in the study.
Patient Evaluations
Pretreatment evaluation included medical history, assessment of sexual function, Karnofsky status evaluation, histologic evaluation, chest x-ray, and bone scan. Mandatory laboratory studies were CBC, AST, ALT, serum acid phosphatase, serum testosterone, alkaline phosphatase, PSA, and lymph node evaluation, which was performed by at least one of the following methods: lymphangiogram, computerized tomography of the pelvis and abdomen, or exploratory laparotomy with lymph node biopsy (sampling).
On completion of RT, follow-up was scheduled every 3 months during year 1, every 4 months during year 2, every 6 months from years 3 to 5, and annually thereafter. Each follow-up visit included a history, physical examination, Karnofsky performance status evaluation, sexual function assessment, liver function test, CBC, and PSA measurement. In addition, tumor status was evaluated, and toxicity was graded. Measurement of serum testosterone level was repeated at the time of first follow-up. If the result was subnormal, the test was repeated until it returned to the normal range. Serum testosterone level was also measured at termination of goserelin therapy and at 6 and 12 months after discontinuation. Acid phosphatase and alkaline phosphatase were collected yearly. During follow-up, any patient presenting with bone pain not attributable to any intercurrent disease had a bone scan performed. The protocol did not require a bone scan in asymptomatic patients with elevated PSA levels.
RT
All patients received external-beam RT to the whole pelvis followed by a boost to the prostate using a four-field technique with megavoltage machines (> 6 MV). The prescribed dose was recorded at the center of the target volume. The prostate was to receive 65 to 70 Gy for T2c tumors and 67.5 to 70 Gy for T3 to T4 tumors, at 1.8 to 2.0 Gy per day. The regional lymphatics were to receive 44 to 46 Gy in 1.8- to 2.0-Gy fractions. Higher doses, up to 50.0 Gy, were permitted.
Hormone Therapy
Before external-beam RT, all patients received monthly flutamide (Eulexin; Schering Plough, Kenilworth, NJ) 250 mg orally tid with monthly goserelin acetate (Zoladex; AstraZeneca Pharmaceuticals, Wilmington, DE) 3.6 mg subcutaneously until RT was completed. The patients were randomly assigned to receive no further treatment (STAD-RT) or to receive goserelin 3.6 mg subcutaneously monthly for an additional 2 years after the completion of RT (LTAD-RT).
Administration of goserelin and flutamide was suspended only if there was an apparent or suspected reaction to the drug. The adjuvant goserelin was to be terminated if signs of disease progression appeared while the patient was taking it. If gastrointestinal disturbances occurred before the initiation of RT, flutamide was withheld until the side effects subsided and was then reintroduced at a dose of 250 mg/d, increasing the dose to 500 mg/d, then to 750 mg/d as tolerated. If the severity of gastrointestinal disturbances exceeded the level commonly observed during pelvic radiation, the toxicity was ascribed to flutamide and the drug was permanently discontinued. Subsequent hormone treatment was allowed only with evidence of treatment failure.
Study Design
The trial was designed to test for a 10% improvement in disease-free survival (DFS), from 40% to 50%, at 5 years. The sample size was adjusted for possible noncompliance, loss to follow-up, and ineligibility.5 The DFS failure times were assumed to follow an exponential distribution, and a one-sided test with a significance level of .05 and statistical power of .80 was employed. The sample size was targeted at 1,052 men with a projected 4 years of patient accrual and an additional 2 years of follow-up. The protocol analysis plan called for four interim significance tests with the results reported to the RTOG Data Monitoring Committee. When accrual was temporarily discontinued on June 20, 1994, there were 1,168 patients enrolled, of whom 130 were African Americans. The National Cancer Institute agreed to allow RTOG to enroll more patients so that questions about race could be examined with more statistical power. The targeted total sample size was increased to 1,508 men to enroll 175 African Americans onto the study.
Randomization
Randomization was performed before any treatment was initiated (instead of after RT), for patient and clinician ease, given that the dropout rate during the initial RT was exceedingly low in RTOG 86–10. Patients were stratified by clinical stage (T2c v T3 v T4); pretreatment PSA level ( 30 v > 30 ng/mL); tumor grade (well v moderately v poorly differentiated or undifferentiated); nodal status (negative [N0] by surgical sampling v positive [N+] confirmed only by surgical sampling or fine-needle aspiration v not done if negative by imagining methods [NX]). The treatment allocation scheme described by Zelen6 was used because it balances for patient factors other than institution. Gleason scores were provided by the institution whenever possible.
Study End Points
Local progression was assessed by palpation and defined as tumor growth of 25% or local persistence of palpable tumor beyond 18 months. Distant metastasis was defined as the clinical evidence of distant disease (by any method). The American Society for Therapeutic Radiology and Oncology consensus definition of biochemical progression after RT alone was adopted, although it was derived in 1997, long after this study started.7 Failure was defined as three consecutive increases in PSA level, the administration of hormone treatment for an increasing PSA level, or a posttreatment PSA nadir level greater than 4.0 ng/mL. Any death was considered a failure when OS was calculated, but for cause-specific survival (CSS), the failure event was defined as death as a result of PC, treatment-related toxicity, or unknown causes, with reported progressive prostate disease before death. Any patient death reported as resulting from another cancer was considered a failure for CSS if the patient had documented bone metastases attributed to PC before the appearance of the second independent cancer. For DFS, the failure event was defined as the first occurrence of local progression, distant failure, regional failure, biochemical progression, or death as a result of any cause. All time events, with the exception of biochemical progression, were measured from the date of randomization to the date of their occurrence or last follow-up. American Society for Therapeutic Radiology and Oncology consensus guidelines were adopted to calculate the time to biochemical progression.
Treatment-related toxicities were scored using the RTOG criteria.8 RT-related toxicities were divided into acute and late effects. Toxicities occurring within 90 days from the start of RT were considered acute. Any toxicities continuing or newly reported after 90 days were considered late. Any late gastrointestinal toxicity (eg, proctitis, bowel obstruction, bleeding) that required surgery, laser treatment, cauterization, or transfusion was scored as grade 3 to 4.
Statistical Methods
All time-related end points were estimated by the Kaplan-Meier method,9 with the log-rank statistic used to test for differences.10 Because CSS, local progression, distant metastasis, and biochemical progression are cause-specific treatment failures and patients could die without experiencing treatment failure, we also performed the cumulative incidence analysis11 and used the Gray’s method to test for differences.12 Because the two approaches yielded remarkably similar results, only the results from the first approach were reported.
For each end point, the two-sided significance levels are reported so that they can be compared easily with other published reports. Because the sample size was modified in the trial, the significance levels and the estimates for efficacy end points are reported for the original sample size (1,052 patients) and for the total entries (1,544 patients). Because the results are the same, the significance levels and the estimates made on the basis of total entries are reported.
Subset analyses were conducted for patients scored by the contributing institutions as Gleason scores 8 to 10 and 2 to 7. After the 61 patients with histologically documented nodal disease were excluded, there were 337 patients in the Gleason scores 8 to 10 subgroup (171 in STAD-RT and 166 in LTAD-RT) and 1,014 patients in the Gleason scores 2 to 7 subgroup (497 in STAD-RT and 517 in LTAD-RT).
The study cochairs (G.H. and A.P.) reviewed the RT and the hormone therapy relative to the protocol prescription for each patient. In particular, patients receiving less than 25% of the assigned protocol hormones were scored as receiving treatment with an unacceptable major deviation. The RT was similarly scored if there was a gross miss of the tumor or if the patient received a total radiation dose to the primary and the nodes that differed from the protocol by approximately 7% to 8%.13 One experienced pathologist (D.G.) reviewed the 1,175 patients with tissue submitted and could assign a Gleason score for 1,124 patients (96%). In the 51 patients (4%) whose Gleason scores could not be assigned, the principal reasons were no tumor on the slide, fine-needle aspirate, and nondiagnostic slide.
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RESULTS
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Patient accession began in June 1992 and was completed in April 1995, with 779 and 775 patients randomly assigned to the STAD-RT and LTAD-RT arm, respectively. Thirty-six patients were ineligible, mostly as a result of staging error, second cancer, and prior treatment, and were excluded from analyses. Four other patients had no follow-up data. The remaining 1,514 patients form the basis of this report. Their median follow-up time was 5.8 years (range, 0.04 to 8.9 years). If only live patients are considered, the median is 6.3 years (range, 0.24 to 8.9 years). There are 73 patients (9%) in the STAD-RT arm and 89 patients (12%) in the LTAD-RT arm alive with less than 5 years of follow-up.
Patient Characteristics
Table 1 lists the distributions of the stratifying and other baseline variables for the two treatment arms. No marked differences were observed. In the subsets examined, the treatment arms were also well balanced. A comparison between the Gleason scores assigned by the institution and the central review is listed in Table 2. Of 257 patients with Gleason scores 8 to 10 as assigned by the participating institutions, the central pathologist concurred in 61% and scored 38% as Gleason score 7.
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Table 2. RTOG 92–02 Gleason Score Provided by Participating Institutions Compared With Gleason Score From Central Review
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Treatment Delivery and Morbidity
Table 3 summarizes by treatment arm the quality-control review and morbidity data for both RT and AD.
AD toxicity was mainly observed in the LTAD-RT arm and was most commonly gastrointestinal or hepatic toxicity commonly ascribed to flutamide. There was one death as a result of liver toxicity. AD quality of delivery was excellent, with lower compliance in the LTAD-RT arm resulting from premature discontinuation of the goserelin.
Radiation-ascribed toxicity was infrequent and similar except for late gastrointestinal toxicity, for which there was a significant increase (P = .037) in the LTAD-RT arm resulting from more grade 3 events than in the STAD-RT arm. At 5 and 8 years, the time-adjusted rates for patients in the LTAD-RT arm were 2.6% and 2.9%, compared with 1.2% and 1.2% for the STAD-RT arm. This increase could not be attributed to radiation dose or technique. When these toxicities were first reported for the 20 LTAD-RT patients, 10 were receiving goserelin, and another three had discontinued goserelin treatment within 50 days. No patients in the STAD-RT arm were receiving goserelin when this toxicity occurred.
Compliance with the protocol treatment plan with regard to RT or hormone therapy delivery was excellent for both arms. The percentage of patients scored as having an unacceptable major treatment variation ranged from 1.0% to 6.0%. In 78% of patients, the prostate dose was within the stated range of 65 to 70 Gy, with 20% below that range and 2% above. In 70% of patients, the pelvic nodal dose was between 44 and 46 Gy, with 14% below that range and 16% above.
Treatment Efficacy Outcomes
The estimated 5-year rates in various efficacy outcomes by treatment arm are shown in Table 4. The LTAD-RT arm shows a significant advantage for all end points except for OS. The significant DFS advantage for the LTAD-RT arm is illustrated in Figure 1, with a 5-year rate of 46.4% (range, 42% to 50%) as compared with a rate of 28.1% (range, 24% to 32%; P < .0001) for the STAD-RT arm. Figure 2 shows no advantage in OS (P = .73) for the LTAD-RT arm, with a 5-year rate of 80.0% (range, 76% to 83%) versus a rate of 78.5% (range, 75% to 82%) for the STAD-RT arm. However, Figure 3 illustrates the LTAD-RT arm’s advantage in CSS (P = .003), with a 5-year rate of 94.6% (range, 93% to 96%) versus 91.2% (range, 89% to 93%) for the STAD-RT arm. In Table 5, treatment received by patients in the LTAD-RT arm significantly reduced the frequency of PC deaths (38% v 24%, P = .001) but was associated with an absolute increase in the number of deaths as a result of other causes. When other causes of death were classified into cardiovascular, respiratory, neurologic, gastrointestinal or genitourinary, and other, there were no differences in the rates of death by cause. The difference in the LTAD-RT arm appears to be due to a higher percentage of patients entering onto the study with preexisting cardiovascular disease compared with the STAD-RT arm (55% v 44%, respectively). This shows that men with controlled PCs subsequently died as a result of other causes as they aged during follow-up.
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Fig. 1. Disease-free survival for all patients. STAD-RT, androgen suppression with external-beam radiation therapy; LTAD-RT, androgen suppression with external-beam radiation therapy followed by goserelin.
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Fig. 2. Overall survival for all patients. STAD-RT, androgen suppression with external-beam radiation therapy; LTAD-RT, androgen suppression with external-beam radiation therapy followed by goserelin.
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Fig. 3. Cause-specific survival for all patients. STAD-RT, androgen suppression with external-beam radiation therapy; LTAD-RT, androgen suppression with external-beam radiation therapy followed by goserelin.
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Treatment Efficacy Outcomes of Subgroups With Gleason Scores Provided by Institutions
This subset analysis was not part of the original study design. In patients with Gleason scores 8 to 10, a significant advantage for the LTAD-RT arm is seen for every end point (Table 6). OS and CSS are illustrated in Figures 4 and 5. The estimated 5-year rate for OS is 81.0% for LTAD-RT versus 70.7% for STAD-RT (P = .044), and rates for CSS are 93.4% and 82.0% (P = .0078), respectively. In patients with Gleason scores 2 to 7, a significant advantage of the LTAD-RT arm is seen for DFS, with a 5-year rate of 49.4% (range, 44% to 54%) as compared with 31.8% (range, 27% to 36%; P < .0001) for the STAD-RT arm. Both arms had similar OS (P = .52), with a 5-year rate of 80.4% (77% to 84%) v 81.3% (78% to 85%), and CSS (P = .11), with a 5-year rate of 95.8% (94% to 98%) v 95.0% (93% to 97%), respectively.
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Table 6. Outcomes for Institutional Gleason Score 8 Through 10 Tumors at 5 Years, As Provided by Participating Institutions
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Fig. 4. Overall survival for patients with Gleason scores 8 to 10 assigned by participating institutions. STAD-RT, androgen suppression with external-beam radiation therapy; LTAD-RT, androgen suppression with external-beam radiation therapy followed by goserelin.
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Fig. 5. Cause-specific survival for patients with Gleason scores 8 to 10 assigned by participating institutions. STAD-RT, androgen suppression with external-beam radiation therapy; LTAD-RT, androgen suppression with external-beam radiation therapy followed by goserelin.
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DISCUSSION
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RTOG 92–02 has tested the value of LTAD by luteinizing hormone-releasing hormone agonist alone after initial STAD by goserelin and flutamide with RT. The study design was built on unpublished preliminary results from RTOG 86–10 and RTOG 85–31, which showed a dramatic reduction in both local and distant failures for the hormone-containing arm. The study reached its original sample size of 1,052 patients in 2 years, instead of the projected 4 years. The treatment compliance for both arms was excellent. RT-ascribed toxicity was infrequent and similar by arm except for late gastrointestinal grade 3+ toxicity with the LTAD-RT arm (20 v nine patients). The cause of the increase is not entirely clear. Differences in radiation doses or techniques did not account for the difference. The only difference identified was that 10 of the 20 LTAD-RT patients were still receiving goserelin when these toxicities were reported, whereas none of the STAD-RT patients were still receiving goserelin. This issue is the subject of continuing study. A statistically significant OS difference is not yet observed in the trial, with a median follow-up time of 5.8 years. However, all other efficacy end points, including CSS, showed a significant advantage for the LTAD-RT arm. There will be a separate report on racial differences within these outcomes.
The subset analysis of patients with Gleason scores 8 to 10 reported in this article was not part of the initial protocol design and was performed as a follow-up to published results from the RTOG 85–31 trial. It should be viewed as exploratory and interpreted with caution, because the study design and power were not specifically developed to test treatments in this subset. Any results should be then prospectively tested. In RTOG 85–31, Pilepich et al2 reported a significant survival difference with indefinite AD after RT compared with RT alone in the subset of patients with Gleason scores 8 to 10 whose scores were derived only by central pathology review but not by review by the contributing institution. In the RTOG 92–02 study, a significant OS advantage was observed for the LTAD-RT arm among the patients with Gleason score 8 to 10 tumors whose pathology was determined by the contributing institution. There is also a trend favoring the LTAD-RT arm in CSS among the fraction of patients with Gleason score 8 to 10 tumors whose pathology was determined by the central review. The associated hazard ratio was rather high, at 2.12, but there were only 46 PC deaths, which compromised the statistical power to detect a significant difference. These results are important because they support the observation from RTOG 85–31 of a benefit to LTAD over STAD in combination with RT for patients with Gleason score 8 to 10 tumors. In addition, RTOG 92–02 appears to broaden the application of this observation because the Gleason scores were determined by the contributing institution in RTOG, rather than by central review of PC expert pathologists. This suggests the quality of pathologic interpretation of Gleason score 8 to 10 PC is good in the RTOG facilities that contributed patients.
In 1997, the European Organization for Research and Treatment of Cancer (EORTC) trial 22863—a study of 401 locally advanced or high-grade PCs randomized between RT and RT plus 36 months of goserelin—and RTOG trial 85–31 were initially reported.2,14 A recent update of the EORTC trial shows a 16% survival advantage at 5 years for the LTAD-RT arm.15 In 2003, the previously reported survival advantage in the subset of patients with Gleason score 8 to 10 tumors was extended to the entire RTOG 85–31 trial. After 10 years, there is a 9% survival advantage for the arm with the hormones administered immediately after RT.3 On the basis of these results, we expect to see an OS advantage in RTOG 92–02 with longer follow-up.
Is cytoreductive hormone therapy of value before RT? RTOG 92–02 does not help with this question because both arms received 2 months of pre-RT cytoreduction. The EORTC 22863 and RTOG 85–31 studies, which demonstrated a survival advantage, did not use pre-RT cytoreduction. The question remains unanswered until a trial designed to test it is done.
The assessment of PSA failure after AD may be influenced by a delayed recovery of testosterone production in some men. Other investigators, as well as our group, have noted this phenomenon, particularly in elderly men, but currently there are limited data on this issue. We expect that difficulties with a definition of biochemical failure in patients who receive AD would not matter in the overall interpretation of this study, because the important end points, such as metastasis, CSS, and OS, are not affected by errors in the determination of biochemical failure rates. If it is true that some men show a slower recovery of androgen stimulation function after discontinuing luteinizing hormone-releasing hormone agonist, then the actual duration of AD may have been longer than planned in these men.
Research during the last 10 years has produced an abundance of evidence that there is a dose-response relationship for cure of PC with external-beam therapy using three-dimensional conformal techniques.16,17 These single-institution studies indicate that, in the absence of androgen ablation, higher doses of radiation may be required for maximal cure of all patients except those with the most favorable prognosis. In the intermediate and locally advanced group of patients, the 5-year biochemical failure-free advantage from high-dose RT is 20% to 40% higher than that obtained with the 65- to 70-Gy dose used in all currently reported clinical trials, including RTOG 92–02. One retrospective case-matched study has shown an advantage in cause-specific death for high-dose versus low-dose RT18 in the absence of AD. It will be important to extend high-dose RT with three-dimensional conformal or intensity-modulated radiation technology to RTOG and EORTC clinical trials in locally advanced PC when 75 to 80 Gy can be safely delivered with that technology in a large number of institutions.
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
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The authors indicated no potential conflicts of interest.
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ACKNOWLEDGMENTS
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This study is a testimony to the more than 100 radiation oncology facilities that contributed their efforts and patients to advance our knowledge about PC. We are grateful for the valuable contributions of Bernadine Dunning, Elaine Motyka-Welsh, Sheryl Mitnick, and Kateri Heydon at RTOG headquarters.
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NOTES
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Supported by National Cancer Institute grant CA-21661 and National Institutes of Health grant CA-32115. Presented at the Annual Meetings of the American Society of Clinical Oncology, May 2000, and the American Society of Therapeutic Radiation Oncology, October 2000.
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REFERENCES
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1. Pilepich MV, Krall JM, Al-Sarraf M, et al: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: A randomized comparative trial of the Radiation Therapy Oncology Group. Urology 45:616–623, 1995[CrossRef][Medline]
2. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserelin in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of RTOG 85-31. J Clin Oncol 15:1013–1021, 1997[Abstract/Free Full Text]
3. Pilepich M, Winter K, Lawton C, et al: Phase III trial of androgen suppression adjuvant to definitive radiotherapy: Long term results of RTOG study 85-31. J Clin Oncol 22:281, 2003
4. Hanks G, Lu J, Machtay M, et al: RTOG Protocol 92-02: A phase III trial of the use of long-term total androgen suppression following neoadjuvant cytoreduction and radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 48:112, 2000[CrossRef]
5. Lachin JM, Foulkes MA: Evaluation of sample size and power for analyses of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics 42:507–519, 1986[CrossRef][Medline]
6. Zelen M: The randomization and stratification of patients to clinical trials. J Chronic Dis 27:365–375, 1974[CrossRef][Medline]
7. Cox J, Grignon D, Kaplan R, et al: Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 37:1035–1041, 1997[CrossRef][Medline]
8. 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[CrossRef][Medline]
9. Kaplan, EL, Meier P: Non parametric estimation from incomplete observations. J Am Stat Assoc 53:447–457, 1958
10. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170, 1966[Medline]
11. Kalbfleish JD, Prentice RL: The statistical analysis of failure times data. New York, NY, John Wiley, 1980
12. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141–1154, 1988
13. Pajak TF, Laramore GE, Marcial VA, et al: Elapsed treatment days: A critical item for radiotherapy quality control review in head and neck trials—RTOG report. Int J Radiat Oncol Biol Phys 20:13–20, 1991[Medline]
14. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295–300, 1997[Abstract/Free Full Text]
15. 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 randomised trial. Lancet 360:103–106, 2002[CrossRef][Medline]
16. Hanks G, Hanlon A, Pinover W, et al: Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys 46:823–832, 2000[CrossRef][Medline]
17. Pollack A, Zagars G: External beam radiotherapy dose response of prostate cancer. Int J Radiat Oncol Biol Phys 39:1011–1018, 1997[CrossRef][Medline]
18. Hanks G, Hanlon A, Pinover W et al: Survival advantage for prostate cancer patients treated with high dose 3D conformal radiation. Cancer J Sci Am 5:152–158, 1999[Medline]
Submitted November 6, 2002;
accepted August 11, 2003.
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J. A. Efstathiou, K. Bae, W. U. Shipley, G. E. Hanks, M. V. Pilepich, H. M. Sandler, and M. R. Smith
Cardiovascular Mortality After Androgen Deprivation Therapy for Locally Advanced Prostate Cancer: RTOG 85-31
J. Clin. Oncol.,
January 1, 2009;
27(1):
92 - 99.
[Abstract]
[Full Text]
[PDF]
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Y.-N. Wong, S. Freedland, B. Egleston, G. Hudes, J. S. Schwartz, and K. Armstrong
Role of Androgen Deprivation Therapy for Node-Positive Prostate Cancer
J. Clin. Oncol.,
January 1, 2009;
27(1):
100 - 105.
[Abstract]
[Full Text]
[PDF]
|
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M. R. Smith, K. Bae, J. A. Efstathiou, G. E. Hanks, M. V. Pilepich, H. M. Sandler, and W. U. Shipley
Diabetes and Mortality in Men With Locally Advanced Prostate Cancer: RTOG 92-02
J. Clin. Oncol.,
September 10, 2008;
26(26):
4333 - 4339.
[Abstract]
[Full Text]
[PDF]
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E. M. Horwitz, K. Bae, G. E. Hanks, A. Porter, D. J. Grignon, H. D. Brereton, V. Venkatesan, C. A. Lawton, S. A. Rosenthal, H. M. Sandler, et al.
Ten-Year Follow-Up of Radiation Therapy Oncology Group Protocol 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally Advanced Prostate Cancer
J. Clin. Oncol.,
May 20, 2008;
26(15):
2497 - 2504.
[Abstract]
[Full Text]
[PDF]
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P. L. Nguyen and A. V. D'Amico
Targeting Pelvic Lymph Nodes in Men With Intermediate- and High-Risk Prostate Cancer Despite Two Negative Randomized Trials
J. Clin. Oncol.,
April 20, 2008;
26(12):
2055 - 2056.
[Full Text]
[PDF]
|
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M. Roach III, K. Bae, J. Speight, H. B. Wolkov, P. Rubin, R. J. Lee, C. Lawton, R. Valicenti, D. Grignon, and M. V. Pilepich
Short-Term Neoadjuvant Androgen Deprivation Therapy and External-Beam Radiotherapy for Locally Advanced Prostate Cancer: Long-Term Results of RTOG 8610
J. Clin. Oncol.,
February 1, 2008;
26(4):
585 - 591.
[Abstract]
[Full Text]
[PDF]
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E. S. Antonarakis, A. L. Blackford, E. Garrett-Mayer, and M. A. Eisenberger
Survival in Men With Nonmetastatic Prostate Cancer Treated With Hormone Therapy: A Quantitative Systematic Review
J. Clin. Oncol.,
November 1, 2007;
25(31):
4998 - 5008.
[Abstract]
[Full Text]
[PDF]
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H. K. Tsai, A. V. D'Amico, N. Sadetsky, M.-H. Chen, and P. R. Carroll
Androgen Deprivation Therapy for Localized Prostate Cancer and the Risk of Cardiovascular Mortality
J Natl Cancer Inst,
October 17, 2007;
99(20):
1516 - 1524.
[Abstract]
[Full Text]
[PDF]
|
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A. A. Patel, M.-H. Chen, A. A. Renshaw, and A. V. D'Amico
PSA Failure Following Definitive Treatment of Prostate Cancer Having Biopsy Gleason Score 7 With Tertiary Grade 5
JAMA,
October 3, 2007;
298(13):
1533 - 1538.
[Abstract]
[Full Text]
[PDF]
|
|
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|
|
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A. Chakravarti, M. DeSilvio, M. Zhang, D. Grignon, S. Rosenthal, S. O. Asbell, G. Hanks, H. M. Sandler, L.-Y. Khor, A. Pollack, et al.
Prognostic Value of p16 in Locally Advanced Prostate Cancer: A Study Based on Radiation Therapy Oncology Group Protocol 9202
J. Clin. Oncol.,
July 20, 2007;
25(21):
3082 - 3089.
[Abstract]
[Full Text]
[PDF]
|
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R. R. Rajendran and G. D. Kao
"No Turning Bax" in the Combined Battle against Prostate Cancer:
Clin. Cancer Res.,
June 15, 2007;
13(12):
3435 - 3438.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Y. Khor, J. Moughan, T. Al-Saleem, E. H. Hammond, V. Venkatesan, S. A. Rosenthal, M. A. Ritter, H. M. Sandler, G. E. Hanks, W. U. Shipley, et al.
Bcl-2 and Bax Expression Predict Prostate Cancer Outcome in Men Treated with Androgen Deprivation and Radiotherapy on Radiation Therapy Oncology Group Protocol 92-02
Clin. Cancer Res.,
June 15, 2007;
13(12):
3585 - 3590.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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A. V. D'Amico, J. W. Denham, J. Crook, M.-H. Chen, S. Z. Goldhaber, D. S. Lamb, D. Joseph, K.-H. Tai, S. Malone, C. Ludgate, et al.
Influence of Androgen Suppression Therapy for Prostate Cancer on the Frequency and Timing of Fatal Myocardial Infarctions
J. Clin. Oncol.,
June 10, 2007;
25(17):
2420 - 2425.
[Abstract]
[Full Text]
[PDF]
|
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F. H Schroder
Early versus delayed endocrine therapy for prostate cancer
Endocr. Relat. Cancer,
March 1, 2007;
14(1):
1 - 11.
[Abstract]
[Full Text]
[PDF]
|
|
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A. V. D'Amico
Toward the Optimal Use of Androgen Suppression Therapy in the Radiotherapeutic Management of Prostate Cancer
J. Clin. Oncol.,
January 1, 2007;
25(1):
8 - 9.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Heymann, M. C. Benson, K. M. O'Toole, B. Malyszko, R. Brody, D. Vecchio, P. B. Schiff, M. M. Mansukhani, and R. D. Ennis
Phase II Study of Neoadjuvant Androgen Deprivation Followed by External-Beam Radiotherapy With 9 Months of Androgen Deprivation for Intermediate- to High-Risk Localized Prostate Cancer
J. Clin. Oncol.,
January 1, 2007;
25(1):
77 - 84.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. L. Keating, A. J. O'Malley, and M. R. Smith
Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy for Prostate Cancer
J. Clin. Oncol.,
September 20, 2006;
24(27):
4448 - 4456.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Speight and M. Roach III
Radiotherapy in the Management of Clinically Localized Prostate Cancer: Evolving Standards, Consensus, Controversies and New Directions
J. Clin. Oncol.,
November 10, 2005;
23(32):
8176 - 8185.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hashine, K. Numata, K. Azuma, Y. Sumiyoshi, and M. Kataoka
Long-term Outcomes of 60 Gy Conventional Radiotherapy Combined with Androgen Deprivation for Localized or Locally Advanced Prostate Cancer
Jpn. J. Clin. Oncol.,
November 1, 2005;
35(11):
655 - 659.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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A. Zapatero, F. Valcarcel, F. A. Calvo, R. Algas, A. Bejar, J. Maldonado, and S. Villa
Risk-Adapted Androgen Deprivation and Escalated Three-Dimensional Conformal Radiotherapy for Prostate Cancer: Does Radiation Dose Influence Outcome of Patients Treated With Adjuvant Androgen Deprivation? A GICOR Study
J. Clin. Oncol.,
September 20, 2005;
23(27):
6561 - 6568.
[Abstract]
[Full Text]
[PDF]
|
|
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|
|
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T. M. Pisansky
External Beam Radiotherapy as Curative Treatment of Prostate Cancer
Mayo Clin. Proc.,
July 1, 2005;
80(7):
883 - 898.
[Abstract]
[PDF]
|
|
|
|
|
|
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J. L. Gulley, P. M. Arlen, A. Bastian, S. Morin, J. Marte, P. Beetham, K.-Y. Tsang, J. Yokokawa, J. W. Hodge, C. Menard, et al.
Combining a Recombinant Cancer Vaccine with Standard Definitive Radiotherapy in Patients with Localized Prostate Cancer
Clin. Cancer Res.,
May 1, 2005;
11(9):
3353 - 3362.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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J. R. Sathya, I. R. Davis, J. A. Julian, Q. Guo, D. Daya, I. S. Dayes, H. R. Lukka, and M. Levine
Randomized Trial Comparing Iridium Implant Plus External-Beam Radiation Therapy With External-Beam Radiation Therapy Alone in Node-Negative Locally Advanced Cancer of the Prostate
J. Clin. Oncol.,
February 20, 2005;
23(6):
1192 - 1199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. V. D'Amico, M. Loffredo, J. Manola, A. DellaCroce, A. A. Renshaw, and P. W. Kantoff
Androgen Suppression Plus Radiation Therapy for Prostate Cancer--Reply
JAMA,
November 3, 2004;
292(17):
2085 - 2085.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Horwitz, S. J. Feigenberg, A. Pollack, G. E. Hanks, and R. G. Uzzo
Androgen Suppression Plus Radiation Therapy for Prostate Cancer
JAMA,
November 3, 2004;
292(17):
2084 - 2085.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. V. D'Amico, J. Manola, M. Loffredo, A. A. Renshaw, A. DellaCroce, and P. W. Kantoff
6-Month Androgen Suppression Plus Radiation Therapy vs Radiation Therapy Alone for Patients With Clinically Localized Prostate Cancer: A Randomized Controlled Trial
JAMA,
August 18, 2004;
292(7):
821 - 827.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. L. DeWeese
Radiation Therapy and Androgen Suppression as Treatment for Clinically Localized Prostate Cancer: The New Standard?
JAMA,
August 18, 2004;
292(7):
864 - 866.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pollack, M. DeSilvio, L.-Y. Khor, R. Li, T.I. Al-Saleem, M.E. Hammond, V. Venkatesan, C.A. Lawton, M. Roach III, W.U. Shipley, et al.
Ki-67 Staining Is a Strong Predictor of Distant Metastasis and Mortality for Men With Prostate Cancer Treated With Radiotherapy Plus Androgen Deprivation: Radiation Therapy Oncology Group Trial 92-02
J. Clin. Oncol.,
June 1, 2004;
22(11):
2133 - 2140.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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M. Roach III
In Reply:
J. Clin. Oncol.,
June 1, 2004;
22(11):
2255 - 2257.
[Full Text]
[PDF]
|
|
|
|
|
|
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P. Kumar, M. Perrotti, R. Weiss, M. Todd, S. Goodin, K. Cummings, and R. S. DiPaola
Phase I Trial of Weekly Docetaxel With Concurrent Three-Dimensional Conformal Radiation Therapy in the Treatment of Unfavorable Localized Adenocarcinoma of the Prostate
J. Clin. Oncol.,
May 15, 2004;
22(10):
1909 - 1915.
[Abstract]
[Full Text]
[PDF]
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TOP
ABSTRACT
INTRODUCTION
