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Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1192-1199 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.06.154 Randomized Trial Comparing Iridium Implant Plus External-Beam Radiation Therapy With External-Beam Radiation Therapy Alone in Node-Negative Locally Advanced Cancer of the ProstateFrom McMaster University; Ontario Clinical Oncology Group; and Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada Address reprint requests to Jinka R. Sathya, MD, Hamilton Regional Cancer Centre, 699 Concession St, Hamilton, Ontario, L8V 5C2 Canada; e-mail: Jinka.Sathya{at}hrcc.on.ca
PURPOSE: To determine if iridium implant (IM) and external-beam radiation therapy (EBRT) is better than standard EBRT in locally advanced prostate cancer. METHODS: Patients with T2 and T3 prostate cancer with no evidence of metastatic disease were randomly assigned to EBRT of 66 Gy in 33 fractions during 6.5 weeks or to IM of 35 Gy delivered to the prostate during 48 hours plus EBRT of 40 Gy in 20 fractions during 4 weeks. The primary outcome consisted of biochemical or clinical failure (BCF). BCF was defined by biochemical failure, clinical failure, or death as a result of prostate cancer. Secondary outcomes included 2-year postradiation biopsy positivity, toxicity, and survival. RESULTS: Between 1992 and 1997, 51 patients were randomly assigned to receive IM plus EBRT, and 53 patients were randomly assigned to receive EBRT alone. The median follow-up was 8.2 years. In the IM plus EBRT arm, 17 patients (29%) experienced BCF compared with 33 patients (61%) in the EBRT arm (hazard ratio, 0.42; P = .0024). Eighty-seven patients (84%) had a postradiation biopsy; 10 (24%) of 42 in the IM plus EBRT arm had biopsy positivity compared with 23 (51%) of 45 in the EBRT arm (odds ratio, 0.30; P = .015). Overall survival was 94% in the IM plus EBRT arm versus 92% in the EBRT arm. CONCLUSION: The combination of IM plus EBRT was superior to EBRT alone for BCF and postradiation biopsy. This trial provides evidence that higher doses of radiation delivered in a shorter duration result in better local as well as biochemical control in locally advanced prostrate cancer.
Prostate cancer is the most common cancer affecting North American men older than age 60 years. Patients with palpable cancer involving both sides of the prostate, or extension into the seminal vesicles or periprostatic tissue have locally advanced prostate cancer. Recently, several investigators have combined palpable T stage, pretreatment prostate-specific antigen (PSA), and biopsy Gleason score to stratify patients into low-, intermediate-, and high-risk groups.1–3 These risk groups are better predictors of prognosis and treatment-related outcomes than palpable T stage alone. Patients with intermediate- and high-risk disease are considered to have locally advanced prostate cancer with poor prognosis. External-beam radiation therapy (EBRT) with or without hormonal therapy has been the mainstay of treatment for this condition.4–6 One way of improving the outcome of radiation in patients with prostate cancer is to increase the dose of radiation.7–9 Two randomized trials have studied different radiation dose schedules in prostate cancer. Shipley et al10 compared 66 to 76 Gy with proton beam boost and found no overall difference in local control of disease or survival. However, there was better local control associated with the higher dose of radiation in a subset of patients with poorly differentiated tumors. Recently, in a randomized trial of different doses of EBRT, Pollack et al11 found that a modest increase in dose from 70 to 78 Gy resulted in substantial improvement in freedom from biochemical relapse at 6 years in a subgroup with PSA more than 10 µg/L. Brachytherapy (either temporary or permanent) combined with EBRT (ie, implant plus EBRT) is a means of increasing the dose of radiation to the prostate and periprostatic area. Several case series have reported using a combination of EBRT and brachytherapy, with results ranging from 50% to 90% biochemical and clinical disease-free survival.12–14 We report the results of the first randomized control trial comparing brachytherapy plus EBRT with EBRT alone in node-negative locally advanced prostate cancer.
Patient Population Patients with histologically proven adenocarcinoma of the prostate with clinical stage T2 or T3, N0, M0 were eligible for the study. Patients had to be fit enough to undergo pelvic lymphadenectomy as a staging procedure. Patients with a prior history of pelvic radiotherapy, radical prostatectomy, androgen ablation, or transurethral resection of prostate and evidence of metastatic disease using a computed tomography (CT) scan and bone scan were excluded from the study. Written informed consent was obtained with the understanding that patients would be excluded from the study if their lymph nodes were positive at the time of pelvic lymphadenectomy. The study protocol was approved by the local hospital's Research Ethics Board. All patients had a complete history and physical examination including a digital rectal examination performed by the urologist as well as the radiation oncologist involved in the care. The clinical stage was assigned using the 1992 TNM system classification.15 All patients had blood tests including CBC, PSA, prostatic acid phosphatase PAP, a CT scan of the abdomen and pelvis, and a bone scan. Patients were randomly assigned to either implant plus EBRT or EBRT alone in a 1:1 ratio using sealed opaque envelopes maintained by the clinical trials department of the Hamilton Regional Cancer Centre. Patients were stratified on palpable tumor stage (T2 or T3).
Study Interventions EBRT. Patients randomly assigned to the EBRT group had conventional four-field box radiation to the prostate and seminal vesicles with a 2-cm margin all around. The dose was specified as 66 Gy to 100% isodose line and was delivered at 2 Gy per fraction over 6.5 weeks. The anteroposterior fields were typically approximately 11 x 11 cm and laterals were approximately 11 x 10 cm. Appropriate shielding was used to protect parts of the bladder and the rectum from the lateral fields. The EBRT was started approximately 3 to 4 weeks after pelvic lymphadenectomy. CT planning was not done on any of the patients. Cystourethrogram, rectal contrast, and diagnostic CT scans were used to define the fields for planning purposes. Brachytherapy. Patients randomly assigned to the implant plus EBRT group had the transperineal iridium implant done at the time of pelvic lymphadenectomy if the lymph nodes were clear on frozen section. A 17-gauge, 20-cm-long stainless steel needle was inserted below the pubic symphysis into the pelvis as per the technique of Syed et al.16 The first needle was guided with the help of the urologist while the abdomen was still open to skim through the anterior aspect of the prostate. The needle was advanced to 2 cm above the most superior aspect of prostate. Syed's template was used to guide the remaining 17 needles, such that they were just inside the prostate capsule. Posterior needles were guided to be just anterior to the rectum. A total of 18 needles were inserted consisting of 12 needles in the outer ring and six needles in the inner ring. Transrectal ultrasound (TRUS) was not used for placement of needles with this technique. After the patient recovered from the anesthetic, a CT scan was obtained for dosimetric planning. A total dose of 30 Gy was prescribed to an isodose line just outside the prostate, with the entire prostate receiving 35 Gy and more than 80% of the prostate receiving 40 Gy in approximately 48 hours. The needles were loaded with iridium wires manually. The activity of the wires in the outer ring was different from the activity of those in the inner ring. The duration of each wire left in was varied to optimize the plan. The patient was required to be on bed rest for the duration of the temporary implant. Adequate analgesia was used to keep the patient comfortable. The implant was removed after approximately 48 hours when the prescribed dose was delivered, and the patient was discharged home. Two weeks later, EBRT of 40 Gy in 20 fractions during 4 weeks was given to the prostate plus seminal vesicles with 2-cm margins all around. The dose was specified at the isocenter. Corner shielding for the lateral fields was allowed as deemed appropriate. The total dose to the prostate with brachytherapy plus EBRT was 75 Gy in 6.5 weeks and more than 80% of the prostate received 80 Gy.
Follow-up
Outcomes Postradiation biopsy. Recurrent prostate cancer based on a postradiation biopsy undertaken at approximately 2 years after random assignment to treatment was a secondary outcome. Although this was the primary outcome in the original protocol, we chose BCF for the primary analysis on the basis of the emerging literature before analysis. The study pathologist who was blinded to the treatment allocation classified biopsies as positive, negative, or suspicious for cancer. Suspicious biopsies underwent second review by the study pathologist using immunohistochemical staining to determine the status of the biopsy. Patients in the EBRT-alone group had TRUS-guided biopsy, whereas patients in the implant plus EBRT group had a transperineal biopsy performed under general anesthetic by the urologist. TRUS biopsy was not done in the experimental group because of the potential postradiation rectal ulcer complications. Overall survival. An additional secondary outcome was all-cause mortality. This was determined throughout the study duration, with a common date of closeout for all patients who survived. Toxicity. Information on radiation toxicity was recorded on all patients during the radiation treatment phase and on subsequent visits using the National Cancer Institute of Canada Clinical Trials Group Expanded Common Toxicity Criteria. Genitourinary and gastrointestinal toxicity were targeted specifically. Sexual function (erectile function and ability to perform sexual intercourse) was assessed during each visit.
Statistical Analysis
The time from randomization to BCF and to overall survival was summarized separately for each treatment group using Kaplan-Meier methods, and the groups were compared using a two-sided log-rank test stratified on tumor stage (T2, T3). Cox proportional hazards regression models were used to produce the hazard ratio (HR) estimates and their corresponding 95% CIs. The Cox modeling was also used to assess the impact of baseline covariates (age in years and PSA) and factors (Gleason score and tumor stage) on the treatment-BCF relationship. The biopsy positivity proportions were compared using a Mantel-Haenszel
In addition, two a priori subgroups were defined on the basis of risk status: intermediate risk (T2, PSA
Patient Population In total, 138 patients were enrolled onto the study and underwent pelvic lymphadenectomy: 70 were randomly assigned to implant plus EBRT, and 68 were randomly assigned to EBRT alone. Nineteen patients in the implant plus EBRT group and 15 patients in EBRT-alone group were excluded postrandomization because of positive lymph nodes. The analysis was based on the remaining 104 patients: 51 and 53 patients in the implant plus EBRT and EBRT-alone groups, respectively. The patient characteristics at the time of random assignment were comparable (Table 1). The first patient was randomly assigned on May 12, 1992, and the last patient was enrolled on December 8, 1997. Follow-up information was included up to March 14, 2003. Median follow-up was 8.2 years.
BCF During the 10.6 years of the study, 50 of 104 patients experienced BCF: 17 in the implant plus EBRT group compared with 33 in the EBRT-alone group (HR, 0.42; 95% CI, 0.23 to 0.75; P = .0024). The cumulative probability of BCF over time is shown in Fig 1. In every case, the PSA failure was the earliest event. There were 28 patients with clinical failures; 12 in the implant plus EBRT group, and 16 in the EBRT-alone group. At 5 years postrandomization, the probability of BCF was 29% and 61% in the implant plus EBRT and EBRT-alone groups, respectively. The BCF results for all patients with and without adjustment for tumor stage and by risk group are summarized in Table 2. Although the treatment effect appears stronger for intermediate-risk patients, the HRs in the two subgroups were not statistically different (P = .57). In the Cox analysis for all patients, when adjusted for age, baseline PSA, Gleason score, and stage, the treatment effect was more pronounced (HR, 0.31; 95% CI, 0.17 to 0.58; P = .0002).
Prostate Biopsy Although all patients were required to undergo a postradiation biopsy at 24 months after completion of radiation, 87 (84%) of 104 patients complied. In the implant plus EBRT group, 42 of 51 patients had a biopsy performed between 21 and 29 months (median, 26 months) postrandomization. Reasons given for noncompliance for the nine patients were the patient was receiving anticoagulants and was considered at high risk for bleeding (n = 3); the patient had severe endogenous depression and could not give consent for the biopsy (n = 1); the patient had obvious metastatic disease and therefore, biopsy was believed to be unnecessary (n = 3); and patient refusal (n = 2). Forty-five of 53 patients in the EBRT-alone group had a biopsy performed between 19 and 31 months (median, 27 months). Six patients did not have biopsy for the following reasons: patient refusal (n = 2), patient was receiving anticoagulants (n = 1), and patient had obvious disease progression with metastatic disease (n = 3). In the implant plus EBRT group, 10 (24%) of 42 patients had a positive result, whereas 23 (51%) of the 45 patients in the EBRT-alone group had positive biopsies (OR, 0.30; 95% CI, 0.12 to 0.75; P = .015). The biopsy positivity results for all patients with and without adjustment for tumor stage and by risk group are summarized in Table 3. The six patients with metastatic disease who did not undergo biopsy are not included in these results. Although the treatment effect appears stronger for intermediate-risk patients, compared with high-risk patients, the ORs in the two subgroups were not statistically different (P = .51).
Overall Survival During the study period, 17 patients died: 10 in the implant plus EBRT arm, and seven in the EBRT group (HR, 1.36; 95% CI, 0.50 to 3.65; P = .54). The earliest death occurred more than 3 years postrandomization. Eight patients died as a result of prostate cancer (four in each arm). At 5 years, the probability of survival was 94% in the experimental arm and 92% in the control arm. The survival curves are shown in Figure 2.
Toxicity Toxicity during treatment and during the 18 months postrandomization was similar in the two treatment groups (Table 4). Beyond 18 months, there were more patients with gastrointestinal toxicity in the implant group (seven v two patients); however, the difference was not statistically significant (P = .09). In addition, sexual function was similar in the two arms.
This is the first randomized study evaluating the combination of temporary iridium implant and EBRT compared with EBRT alone in the management of locally advanced prostate cancer. In this study the combination of implant plus EBRT was associated with improved outcomes, including biochemical failure and postradiation biopsy, compared with EBRT alone. With a median follow-up of 8.2 years, no difference in survival has been detected between treatment groups. However, there have been relatively few deaths to date and a survival difference may be seen with longer follow-up. In our trial, the number of patients with long-term grade 3 and 4 toxicities were higher with the combination treatment compared with standard arm alone, although this was not statistically significant. The technique of prostate implant used in this study has undergone several improvements to reduce potential toxicity since we completed the trial. TRUS-guided placement of needles and computerized planning that minimizes the dose to the rectum, urethra, and bladder neck will likely reduce these complications. Our study has a number of strengths. The groups are well balanced with regard to pretreatment prognostic indicators such as PSA level, Gleason score, and stage. The study population is unique because patients were all surgically staged. Most patients in studies of radiation in prostate cancer have not been staged surgically. Lymph node metastasis is a powerful independent predictor for distant failure and poor survival. In our group, 25% of patients had lymph node metastasis and therefore were excluded from the study. If these node-positive patients were included, most of these patients would have developed BCF with distant metastasis. Therefore, it would have been more difficult to evaluate the true effect of local radiation therapy. In 1990, when the trial was designed, prognostic factors such as Gleason score, PSA, and clinical stage as predictors of lymph node metastasis were not well defined. Therefore, pelvic lymphadenectomy was part of the protocol to exclude patients with positive lymph nodes. At present, patients with low- and intermediate-risk prostate cancer have less than a 5% probability of lymph node metastases, and are comparable to our group of patients. Although 13% of patients failed to have the planned post-treatment biopsy, only five of the 17 who did not undergo biopsy were patients who refused. The other 12 patients had either metastatic disease or were not medically fit for biopsy. This high rate of biopsy acceptance likely eliminates any potential bias caused by the post-treatment biopsy being performed only in patients with clinically suspected local recurrence. An expert pathologist unaware of treatment allocation reviewed all biopsies. None of the patients were treated with hormone therapy after a positive biopsy. The salvage intervention was undertaken subsequently only if patients developed biochemical or clinical recurrences. Patients enrolled onto the trial were observed for a long time with no hormonal intervention for a clinically insignificant increasing PSA. The hormonal intervention was undertaken only if there was definite clinical failure or the PSA was more than 20 µg/L. This allowed us to review a lengthy PSA profile before defining PSA failures. Three radiation oncologists blinded to treatment arm adjudicated this outcome. Our trial has some limitations. It is a single-institution study with one radiation oncologist performing all of the implants and EBRT. Therefore, the generalizability of the study may be limited. The technique of implant was current at the time of the study, but subsequently has undergone many modifications. These modifications and new developments will reduce long-term toxicity as may well allow even higher doses of radiation to be delivered. The means of obtaining biopsies and number of biopsy specimens per patient were different for the two groups, making it difficult to rule out the potential for sampling bias. The EBRT group had TRUS-guided sextant biopsies, in which six biopsy samples were obtained. The implant plus EBRT group could not be put through TRUS-guided biopsy because of the potential risk of a postbiopsy radiation rectal ulcer. These patients underwent transperineal biopsy under anesthetic by the urologist. The number of biopsy samples obtained varied between two and four only because it was sometimes difficult to feel any residual prostate in some of these patients. Because of this issue and the uncertainty surrounding the predictive value of post-treatment biopsy, we used BCF as the primary end point before analysis was undertaken. The dose of 66 Gy prescribed in our standard arm would be considered a suboptimal dose by current standards of treatment. Three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT), which allow the delivery of higher doses of radiation to the target site without increasing toxicity, were not used in our trial because they were unavailable during this period. There are several case series using 3D-CRT18,19 and IMRT9 reporting favorable results. However, long-term results of these treatments are not available at this time. In addition, none of the patients had CT planning, which increases the possibility of a geographic miss. However, our results with EBRT of 66 Gy are similar to published reports for the unfavorable group with comparable radiation dose schedules.7,8,20 The optimal treatment approach for intermediate- and high-risk patients is evolving. Short-term neoadjuvant hormone therapy combined with standard-dose EBRT is now commonly used to treat intermediate-risk patients. Long-term adjuvant hormonal therapy combined with EBRT is emerging as standard therapy for high-risk patients. However, hormonal therapy is associated with risk of osteoporosis, sexual dysfunction, anemia, and unfavorable body composition, which adversely affect quality of life.21,22 To avoid the use of hormonal therapy, optimization of modern radiotherapy techniques and dose escalation to achieve better local and biochemical control are being explored. In our study, we were unable to show a statistically significant difference between the two subgroups characterized by risk status. Although we did observe a greater treatment effect in intermediate-risk patients compared with high-risk patients for both BCF and biopsy positivity, definite conclusions could not drawn because of the small numbers. The effectiveness of dose escalation in a shorter delivery time is the main question that was addressed in our study. We used temporary iridium implant combined with EBRT as means of achieving this goal. There are several case series published using this method; however, none of them are randomized studies. Currently, higher doses of radiation above 78 Gy are considered to be the standard treatment. This is based on several well-documented case series18,20,23 and one randomized study by Pollock et al11 from M.D. Anderson Cancer Center (Houston, TX). The superior results seen in our study with implant plus EBRT may be due to a combination of higher total dose as well as radiobiological factors associated with shorter duration required to deliver this dose. The total dose of radiation delivered with implant plus EBRT was 75 Gy, with the majority of the prostate receiving 80 Gy in 6.5 weeks. Therefore, the overall treatment is significantly shorter compared with conventional radiation schedules. This may result in significantly better tumoricidal effect because of greater radiobiological effects. Future trials comparing this combination treatment to 3D-CRT or IMRT may answer the question about whether higher doses per se or better radiobiological effects resulting from the shorter duration of treatment are responsible for the better results. In conclusion, our randomized trial provides evidence that dose escalation by the combination of implant plus EBRT is superior to EBRT alone for BCF and postradiation biopsy outcomes in node-negative intermediate- and high-risk prostate cancer patients, suggesting that this should be presented as one of the treatment options to this group of patients. Future studies comparing this treatment with 3D-CRT and/or IMRT, in which dose escalation is possible, should be undertaken.
The authors indicated no potential conflicts of interest.
We thank Sarah Bouma and Rana Riaz for manuscript preparation; and Drs Jim Wright, Ian Poon, and Tim Whelan for their assistance with this study.
Supported through the Ontario Clinical Oncology Group and the Clinical Trials Department of the Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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6. Hanks G, Pajak T, 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 7. 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[CrossRef][Medline] 8. Pollack A, Smith LG, von Eschenback AC: External beam radiotherapy dose-response characteristics of 1127 men with prostate cancer treated in the PSA era. Int J Radiat Oncol Biol Phys 48:507–512, 2000[CrossRef][Medline] 9. 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[CrossRef][Medline] 10. Shipley WU, Verhey LJ, Munzenrider JE, et al: Advanced prostate cancer: The results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys 32:3–12, 1995[CrossRef][Medline]
11. Pollack A, Zagars GK, Smith LG, et al: Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol 18:3904–3911, 2000 12. Martinez AA, Gustafson G, Gonsalez J: Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer. Int J Radiat Oncol Biol Phys 53:316–327, 2002[Medline] 13. Syed AM, Puthawala A, Sharma A: High-dose-rate brachytherapy in the treatment of carcinoma of the prostate. Cancer Control 8:511–521, 2001[Medline] 14. Radge H, Elgamal A, Snow PB: Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma. Cancer 83:989–1001, 1998[CrossRef][Medline] 15. American Joint Committee on Cancer: Manual for Staging of Cancer. Philadelphia, PA, JB Lippincott, 1992 16. Syed AM, Puthawala AA, et al: Temporary iridium/G2 implantation in the management of carcinoma of the prostate. Cancer 69:2515–2524, 1992[CrossRef][Medline] 17. 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[CrossRef][Medline] 18. Hanks GE, Hanlon AL, Schultheiss TE, et al: Dose escalation with 3D conformal treatment: Five year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 41:501–510, 1998[CrossRef][Medline] 19. Fiveash JB, Hanks G, Roach M: 3D conformal radiation therapy (3DCRT) for high-grade prostate cancer: A multi institutional review. Int J Radiat Oncol Biol Phys 47:335–342, 2000[CrossRef][Medline] 20. Lyons JA, Kupelian PA, Mohan DS, et al: Importance of high radiation doses (72 Gy or greater) in the treatment of stage T1–T3 adenocarcinoma of the prostate. Urology 55:85–90, 2000[CrossRef][Medline] 21. Basaria S, Lieb J, Tan AM, et al: Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin Endocrinol (Oxf) 56:779–786, 2002[CrossRef][Medline] 22. Padula GD, Zelefsky MJ, Venkatraman ES, et al: Normalization of serum testosterone levels in patients treated with neoadjuvant hormonal therapy and three-dimensional conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 52:439–443, 2002[CrossRef][Medline] 23. Hanks GE, Hanlon AL, Pinover WH, et al: Survival advantage for prostate cancer patients treated with high-dose three-dimensional conformal radiotherapy. Cancer J Sci Am 5:152–158, 1999[Medline] Submitted June 22, 2004; accepted November 22, 2004. This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test stratified on tumor stage; summary odds ratios (ORs) and their corresponding 95% CIs were estimated using logistic regression. The two-sided Fisher's exact test was used to compare the toxicity outcomes. In all analyses, patients in the EBRT-alone treatment arm were used as the referent group. 
20 µg/L, and Gleason score 
8). The treatment effects within subgroups were compared using the likelihood ratio test for the treatment-by-group interaction within the Cox regression model for the time-to-event outcomes, and using logistic regression modeling for the binary outcomes. Statistical analyses were performed in the coordinating and methods center of the Ontario Clinical Oncology Group. 
