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Carboplatin, Prolongs Survival in Previously Untreated Patients with Advanced Non–Small-Cell Lung Cancer: Preliminary Results from the ECOG 4599 Trial
research in brief
rnb Bevacizumab, when Added to Paclitaxel/Carboplatin, Prolongs Survival in Previously Untreated Patients with Advanced Non–Small-Cell Lung Cancer: Preliminary Results from the ECOG 4599 Trial Rationale ________________________ • Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor receptor (VEGFR), has been shown to increase survival in colorectal cancer patients and now appears to increase survival when combined with chemotherapy for non– small-cell lung cancer (NSCLC). The background for this recent success includes the phase II trial by Johnson et al, which compared chemotherapy plus bevacizumab at 2 dose levels with chemotherapy alone.1 Ninety-nine patients with locally advanced or metastatic NSCLC were randomized to 1 of 3 treatment groups as follows: carboplatin to an area under the curve (AUC) of 6, paclitaxel 200 mg/m2, and bevacizumab 7.5 mg/kg; carboplatin to an AUC of 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg; or carboplatin to an AUC of 6 and paclitaxel 200 mg/m2. The primary objectives were time to tumor progression (TTP) and response rate (RR). Chemotherapy plus bevacizumab (15 mg/kg) significantly prolonged TTP to 7.4 months versus 4.2 months with chemotherapy alone (P = 0.023) and produced a higher RR of 31.5% versus 18.8% with chemotherapy alone. In addition, the overall survival (OS) was prolonged with bevacizumab (15 mg/kg) compared with chemotherapy alone, but it did not reach statistical significance (17.7 months vs. 14.9 months; P = 0.63). • Of concern, a bevacizumab-related toxicity is the occurrence of life-threatening hemoptysis, or pulmonary hemorrhaging, in 6 patients (6%) in this study. Curiously, 5 of Prepared by: Preeta Tyagi, PhD
Reviewed by: Chandra P. Belani, MD
these 6 patients had received the lower dose (7.5 mg/kg) of bevacizumab; however, 4 of 6 had squamous cell carcinoma (SCC). It was concluded that the pulmonary hemorrhages were also linked to centrally located tumors, tumors adjacent to major blood vessels, and tumor cavitation, a disease feature more common in SCC than in any other histologic subtype. • The Eastern Cooperative Oncology Group (ECOG) 4599 trial also compared carboplatin/paclitaxel with or without bevacizumab.2 Based on the results from Johnson et al, bevacizumab 15 mg/kg was used, and the trial specifically excluded patients with squamous cell histology or with a previous history of gross hemoptysis. • The Data Safety and Monitoring Committee allowed the preliminary results from the recent interim analysis of ECOG 45993 to be made public on March 14, 2005, because the trial had met its primary endpoint of improving OS with the addition of bevacizumab to chemotherapy.3
Study Design The ECOG 4599 trial enrolled 878 previously untreated patients with advanced nonsquamous cell NSCLC with histologically or cytologically confirmed stage IIIB (with malignant pleural effusion), stage IV, or recurrent NSCLC with an ECOG performance status of 0/1. No previous systemic chemotherapy was allowed, but other therapies—surgery or biologic, endocrine, or radiation therapy—were allowed if completed ≥ 3 weeks before enrollment. Concurrent use of therapeutic anticoagulators or chronic use of aspirin
(> 325 mg per day), dipyridamole, ticlopidine, clopidogrel, or cilostazol was not permitted. The treatment group receiving bevacizumab could not use concurrent nonsteroidal antiinflammatory agents. Patients with concurrent hypertension were eligible, provided the hypertension was well controlled on a stable regimen of antihypertensive therapy. Preexisting cardiovascular conditions such as symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia were the reasons for ineligibility. Patients must have had no history of gross hemoptysis (defined in the protocol as at least one-half teaspoon of bright red blood). Patients were required to have no known central nervous system metastases as determined by computed tomography scan of the head or magnetic resonance imaging within the 4 weeks before enrollment. Patients were stratified on the basis of measurable disease (presence vs. absence), previous radiation therapy (yes vs. no), weight loss (< 5% vs. ≥ 5%), and disease stage (IIIB vs. IV vs. recurrent; Figure 1) Patients were randomized to paclitaxel 200 mg/m2 administered intravenously (I.V.) over 3 hours followed by I.V. carboplatin to an AUC of 6 over 15-30 minutes on day 1 alone (arm 1) or in combination with I.V. bevacizumab 15 mg/kg (arm 2) over 30-90 minutes on day 1. Treatment was repeated every 3 weeks for a maximum of 6 cycles until disease progression or unacceptable toxicity. After 6 cycles, patients with stable disease or a response to bevacizumab continued to receive bevacizumab on an every-3-week schedule until disease progression or unacceptable toxicity occurred.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Clinical Lung Cancer April 2005
Eligibility criteria: • Previously untreated stage IIIB/IV • Nonsquamous histology • ECOG PS 0/1 Stratification: • Measurable disease (yes vs. no) • Prior radiation therapy (yes vs. no) • Weight loss (< 5% vs. ≥ 5%) • Disease stage (IIIB vs. IV vs. recurrent)
R A N D O M I Z E
Paclitaxel 200 mg/m2 Carboplatin AUC of 6 Placebo every 3 weeks Paclitaxel 200 mg/m2 Carboplatin AUC of 6 Bevacizumab 15 mg/kg every 3 weeks
Abbreviation: PS = performance status
All patients were to be followed up every 3 months for 2 years, and then every 6 months for 3 years. The objectives of ECOG 4599 were to compare the OS, RR, TTP, and toxicity for the paclitaxel/carboplatin regimen with or without bevacizumab. A 25% improvement in OS was required for the success of the trial.
Results From July 2001 to April 2004, a total of 878 previously untreated patients with advanced nonsquamous cell NSCLC were enrolled in this study. Patients receiving carboplatin/paclitaxel/ bevacizumab had a statistically prolonged median OS of 12.5 months compared with patients treated with carboplatin/paclitaxel alone, who had a median OS of 10.2 months. Of note, even after strict patient selection, the median OS of 10.2 months for the control arm in the ECOG 4599 trial was similar to the historic OS of 10.4 months in a previous trial that included 31% of patients with squamous cell histology.4 Although infrequent, the most significant adverse event was life-threatening/ fatal bleeding, primarily from the lungs, which was reported in more patients treated with the bevacizumab-containing regimen than those treated with chemotherapy alone.5 Three patients experienced grade 3 hemorrhages on either arm, but fatal grade 5 hemorrhages were reported in 3 patients on the bevacizumab-only arm. A single incident of grade 3 thrombosis was reported in the bevacizumab group compared with none in the chemotherapy-only arm. Grade 4 neutropenia was reported by 24%
of patients treated with bevacizumab in combination with paclitaxel/carboplatin, compared with 17% of patients treated with carboplatin/paclitaxel alone. The detailed results from ECOG 4599 will be presented at the 41st Annual Meeting of the American Society of Clinical Oncology in May 2005 in Orlando, FL.
Conclusion Significantly prolonged median OS in favor of chemotherapy/bevacizumab compared with chemotherapy alone is a tremendous step forward in lung cancer treatment. To date, ECOG 4599 is the first trial in lung cancer to show a survival advantage for a triplet (third agent not being a traditional chemotherapeutic agent) over a doublet regimen in first-line treatment of NSCLC. These results are similar to the first-line efficacy data of bevacizumab in combination with
chemotherapy for colorectal cancer, in which the median OS was significantly improved by almost 5 months with the addition of bevacizumab (P < 0.001).6 These data from 2 different tumor types validate the previously unsupported hypothesis that adding a targeted agent to chemotherapy would result in improved survival. Further efficacy and safety data from this trial are awaited. It is hoped that ECOG 4599 will mark the start of a new paradigm in lung cancer treatment that results in significantly improved survival for patients. Additional small-molecule VEGFR tyrosine kinase inhibitors, such as ZD6474 and SU11248, and targeted approaches will be added to chemotherapy for evaluation in advanced NSCLC. A phase II trial is currently evaluating ZD6474 in combination with carboplatin/paclitaxel for first-line treatment of advanced NSCLC.7 Eligible patients are required to have histologically or cytologically confirmed stage IIIB (with pleural effusion), stage IV, or previously resected stage I-III disease that relapsed in a nonresected metastatic site. This is a 2-part, randomized study, the first part of which recommended a safe ZD6474 dose of 150 mg orally every day to be used with the chemotherapy regimen. In the second part, patients will be randomized to 1 of 3 treatment arms: ZD6474 150 mg alone orally once daily, ZD6474 150 mg in combination with paclitaxel 200 mg/m2 and carboplatin to an AUC of 6, or paclitaxel/carboplatin at the same dosages with-
research in brief
Figure 1: Treatment Schema of the ECOG 4599 Trial: Bevacizumab in First-Line Treatment of NSCLC
Figure 2: Treatment Schema of ZD6474 in First-Line Treatment of NSCLC ZD6474 150 mg orally every day Eligibility Criteria: • Chemotherapy-naive stage IIIB/IV or recurrent NSCLC • WHO PS 0/1
R A N D O M I Z E
Carboplatin AUC of 6 Paclitaxel 200 mg/m2 every 3 weeks ZD6474 150 mg orally every day Carboplatin AUC of 6 Paclitaxel 200 mg/m2 Placebo every 3 weeks
Abbreviations: PS = performance status; WHO = World Health Organization
Clinical Lung Cancer April 2005
277
research in brief
out ZD6474 (Figure 2). Treatment will be repeated every 3 weeks for a maximum of 6 cycles. The target accrual is 200 patients (100 patients for arm 1 and 50 patients each for arms 2 and 3) for the second part of the study. The primary endpoint is to compare the efficacy, particularly TTP, of ZD6474 alone versus ZD6474 in combination with paclitaxel/carboplatin versus paclitaxel/ carboplatin. The secondary endpoints for all 3 regimens are objective RR, disease control rates, safety, OS, and quality of life. SU11248, another VEGFR tyrosine kinase inhibitor, is being evaluated as a sin-
278
Clinical Lung Cancer April 2005
gle agent. Hopefully, we will see the comparison of the VEGFR monoclonal antibody with small-molecule VEGFR tyrosine kinase inhibitors, both administered simultaneously with chemotherapy.
References _______________________
1. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004; 22:2184-2191. 2. Combination chemotherapy with or without bevacizumab in treating patients with advanced, metastatic, or recurrent non-small cell lung cancer. National Institutes of Health [Web site]. Available at: http://www.clinicaltrials.gov/ct/show/NCT00021060 ?order=1. Accessed March 22, 2005.
3. Bevacizumab combined with chemotherapy prolongs survival for some patients with advanced lung cancer [press release]. National Institutes of Health; March 14, 2005. 4. Kosmidis P, Mylonakis N, Nicolaides C, et al. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol 2002; 20:3578-3585. 5. Gray R, Giantonio BJ, O'Dwyer PJ, et al. The safety of adding angiogenesis inhibition into treatment for colorectal, breast, and lung cancer: The Eastern Cooperative Oncology Group’s (ECOG) experience with bevacizumab (anti-VEGF). Proc Am Soc Clin Oncol 2003; 22:206 (Abstract #825). 6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335-2342. 7. ZD6474, carboplatin, and paclitaxel in treating patients with stage IIIB, stage IV, or recurrent non-small cell lung cancer. National Institutes of Health [Web site]. Available at: http://www.clinicaltrials.gov/ct/show/ NCT00093392?order=2. Accessed March 22, 2005.
rnb Bevacizumab, when Added to Paclitaxel/Carboplatin, Prolongs Survival in Previously Untreated Patients with Advanced Non–Small-Cell Lung Cancer: Preliminary Results from the ECOG 4599 Trial Rationale ________________________ • Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor receptor (VEGFR), has been shown to increase survival in colorectal cancer patients and now appears to increase survival when combined with chemotherapy for non– small-cell lung cancer (NSCLC). The background for this recent success includes the phase II trial by Johnson et al, which compared chemotherapy plus bevacizumab at 2 dose levels with chemotherapy alone.1 Ninety-nine patients with locally advanced or metastatic NSCLC were randomized to 1 of 3 treatment groups as follows: carboplatin to an area under the curve (AUC) of 6, paclitaxel 200 mg/m2, and bevacizumab 7.5 mg/kg; carboplatin to an AUC of 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg; or carboplatin to an AUC of 6 and paclitaxel 200 mg/m2. The primary objectives were time to tumor progression (TTP) and response rate (RR). Chemotherapy plus bevacizumab (15 mg/kg) significantly prolonged TTP to 7.4 months versus 4.2 months with chemotherapy alone (P = 0.023) and produced a higher RR of 31.5% versus 18.8% with chemotherapy alone. In addition, the overall survival (OS) was prolonged with bevacizumab (15 mg/kg) compared with chemotherapy alone, but it did not reach statistical significance (17.7 months vs. 14.9 months; P = 0.63). • Of concern, a bevacizumab-related toxicity is the occurrence of life-threatening hemoptysis, or pulmonary hemorrhaging, in 6 patients (6%) in this study. Curiously, 5 of Prepared by: Preeta Tyagi, PhD
Reviewed by: Chandra P. Belani, MD
these 6 patients had received the lower dose (7.5 mg/kg) of bevacizumab; however, 4 of 6 had squamous cell carcinoma (SCC). It was concluded that the pulmonary hemorrhages were also linked to centrally located tumors, tumors adjacent to major blood vessels, and tumor cavitation, a disease feature more common in SCC than in any other histologic subtype. • The Eastern Cooperative Oncology Group (ECOG) 4599 trial also compared carboplatin/paclitaxel with or without bevacizumab.2 Based on the results from Johnson et al, bevacizumab 15 mg/kg was used, and the trial specifically excluded patients with squamous cell histology or with a previous history of gross hemoptysis. • The Data Safety and Monitoring Committee allowed the preliminary results from the recent interim analysis of ECOG 45993 to be made public on March 14, 2005, because the trial had met its primary endpoint of improving OS with the addition of bevacizumab to chemotherapy.3
Study Design The ECOG 4599 trial enrolled 878 previously untreated patients with advanced nonsquamous cell NSCLC with histologically or cytologically confirmed stage IIIB (with malignant pleural effusion), stage IV, or recurrent NSCLC with an ECOG performance status of 0/1. No previous systemic chemotherapy was allowed, but other therapies—surgery or biologic, endocrine, or radiation therapy—were allowed if completed ≥ 3 weeks before enrollment. Concurrent use of therapeutic anticoagulators or chronic use of aspirin
(> 325 mg per day), dipyridamole, ticlopidine, clopidogrel, or cilostazol was not permitted. The treatment group receiving bevacizumab could not use concurrent nonsteroidal antiinflammatory agents. Patients with concurrent hypertension were eligible, provided the hypertension was well controlled on a stable regimen of antihypertensive therapy. Preexisting cardiovascular conditions such as symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia were the reasons for ineligibility. Patients must have had no history of gross hemoptysis (defined in the protocol as at least one-half teaspoon of bright red blood). Patients were required to have no known central nervous system metastases as determined by computed tomography scan of the head or magnetic resonance imaging within the 4 weeks before enrollment. Patients were stratified on the basis of measurable disease (presence vs. absence), previous radiation therapy (yes vs. no), weight loss (< 5% vs. ≥ 5%), and disease stage (IIIB vs. IV vs. recurrent; Figure 1) Patients were randomized to paclitaxel 200 mg/m2 administered intravenously (I.V.) over 3 hours followed by I.V. carboplatin to an AUC of 6 over 15-30 minutes on day 1 alone (arm 1) or in combination with I.V. bevacizumab 15 mg/kg (arm 2) over 30-90 minutes on day 1. Treatment was repeated every 3 weeks for a maximum of 6 cycles until disease progression or unacceptable toxicity. After 6 cycles, patients with stable disease or a response to bevacizumab continued to receive bevacizumab on an every-3-week schedule until disease progression or unacceptable toxicity occurred.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
276
Clinical Lung Cancer April 2005
Eligibility criteria: • Previously untreated stage IIIB/IV • Nonsquamous histology • ECOG PS 0/1 Stratification: • Measurable disease (yes vs. no) • Prior radiation therapy (yes vs. no) • Weight loss (< 5% vs. ≥ 5%) • Disease stage (IIIB vs. IV vs. recurrent)
R A N D O M I Z E
Paclitaxel 200 mg/m2 Carboplatin AUC of 6 Placebo every 3 weeks Paclitaxel 200 mg/m2 Carboplatin AUC of 6 Bevacizumab 15 mg/kg every 3 weeks
Abbreviation: PS = performance status
All patients were to be followed up every 3 months for 2 years, and then every 6 months for 3 years. The objectives of ECOG 4599 were to compare the OS, RR, TTP, and toxicity for the paclitaxel/carboplatin regimen with or without bevacizumab. A 25% improvement in OS was required for the success of the trial.
Results From July 2001 to April 2004, a total of 878 previously untreated patients with advanced nonsquamous cell NSCLC were enrolled in this study. Patients receiving carboplatin/paclitaxel/ bevacizumab had a statistically prolonged median OS of 12.5 months compared with patients treated with carboplatin/paclitaxel alone, who had a median OS of 10.2 months. Of note, even after strict patient selection, the median OS of 10.2 months for the control arm in the ECOG 4599 trial was similar to the historic OS of 10.4 months in a previous trial that included 31% of patients with squamous cell histology.4 Although infrequent, the most significant adverse event was life-threatening/ fatal bleeding, primarily from the lungs, which was reported in more patients treated with the bevacizumab-containing regimen than those treated with chemotherapy alone.5 Three patients experienced grade 3 hemorrhages on either arm, but fatal grade 5 hemorrhages were reported in 3 patients on the bevacizumab-only arm. A single incident of grade 3 thrombosis was reported in the bevacizumab group compared with none in the chemotherapy-only arm. Grade 4 neutropenia was reported by 24%
of patients treated with bevacizumab in combination with paclitaxel/carboplatin, compared with 17% of patients treated with carboplatin/paclitaxel alone. The detailed results from ECOG 4599 will be presented at the 41st Annual Meeting of the American Society of Clinical Oncology in May 2005 in Orlando, FL.
Conclusion Significantly prolonged median OS in favor of chemotherapy/bevacizumab compared with chemotherapy alone is a tremendous step forward in lung cancer treatment. To date, ECOG 4599 is the first trial in lung cancer to show a survival advantage for a triplet (third agent not being a traditional chemotherapeutic agent) over a doublet regimen in first-line treatment of NSCLC. These results are similar to the first-line efficacy data of bevacizumab in combination with
chemotherapy for colorectal cancer, in which the median OS was significantly improved by almost 5 months with the addition of bevacizumab (P < 0.001).6 These data from 2 different tumor types validate the previously unsupported hypothesis that adding a targeted agent to chemotherapy would result in improved survival. Further efficacy and safety data from this trial are awaited. It is hoped that ECOG 4599 will mark the start of a new paradigm in lung cancer treatment that results in significantly improved survival for patients. Additional small-molecule VEGFR tyrosine kinase inhibitors, such as ZD6474 and SU11248, and targeted approaches will be added to chemotherapy for evaluation in advanced NSCLC. A phase II trial is currently evaluating ZD6474 in combination with carboplatin/paclitaxel for first-line treatment of advanced NSCLC.7 Eligible patients are required to have histologically or cytologically confirmed stage IIIB (with pleural effusion), stage IV, or previously resected stage I-III disease that relapsed in a nonresected metastatic site. This is a 2-part, randomized study, the first part of which recommended a safe ZD6474 dose of 150 mg orally every day to be used with the chemotherapy regimen. In the second part, patients will be randomized to 1 of 3 treatment arms: ZD6474 150 mg alone orally once daily, ZD6474 150 mg in combination with paclitaxel 200 mg/m2 and carboplatin to an AUC of 6, or paclitaxel/carboplatin at the same dosages with-
research in brief
Figure 1: Treatment Schema of the ECOG 4599 Trial: Bevacizumab in First-Line Treatment of NSCLC
Figure 2: Treatment Schema of ZD6474 in First-Line Treatment of NSCLC ZD6474 150 mg orally every day Eligibility Criteria: • Chemotherapy-naive stage IIIB/IV or recurrent NSCLC • WHO PS 0/1
R A N D O M I Z E
Carboplatin AUC of 6 Paclitaxel 200 mg/m2 every 3 weeks ZD6474 150 mg orally every day Carboplatin AUC of 6 Paclitaxel 200 mg/m2 Placebo every 3 weeks
Abbreviations: PS = performance status; WHO = World Health Organization
Clinical Lung Cancer April 2005
277
research in brief
out ZD6474 (Figure 2). Treatment will be repeated every 3 weeks for a maximum of 6 cycles. The target accrual is 200 patients (100 patients for arm 1 and 50 patients each for arms 2 and 3) for the second part of the study. The primary endpoint is to compare the efficacy, particularly TTP, of ZD6474 alone versus ZD6474 in combination with paclitaxel/carboplatin versus paclitaxel/ carboplatin. The secondary endpoints for all 3 regimens are objective RR, disease control rates, safety, OS, and quality of life. SU11248, another VEGFR tyrosine kinase inhibitor, is being evaluated as a sin-
278
Clinical Lung Cancer April 2005
gle agent. Hopefully, we will see the comparison of the VEGFR monoclonal antibody with small-molecule VEGFR tyrosine kinase inhibitors, both administered simultaneously with chemotherapy.
References _______________________
1. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004; 22:2184-2191. 2. Combination chemotherapy with or without bevacizumab in treating patients with advanced, metastatic, or recurrent non-small cell lung cancer. National Institutes of Health [Web site]. Available at: http://www.clinicaltrials.gov/ct/show/NCT00021060 ?order=1. Accessed March 22, 2005.
3. Bevacizumab combined with chemotherapy prolongs survival for some patients with advanced lung cancer [press release]. National Institutes of Health; March 14, 2005. 4. Kosmidis P, Mylonakis N, Nicolaides C, et al. Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol 2002; 20:3578-3585. 5. Gray R, Giantonio BJ, O'Dwyer PJ, et al. The safety of adding angiogenesis inhibition into treatment for colorectal, breast, and lung cancer: The Eastern Cooperative Oncology Group’s (ECOG) experience with bevacizumab (anti-VEGF). Proc Am Soc Clin Oncol 2003; 22:206 (Abstract #825). 6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335-2342. 7. ZD6474, carboplatin, and paclitaxel in treating patients with stage IIIB, stage IV, or recurrent non-small cell lung cancer. National Institutes of Health [Web site]. Available at: http://www.clinicaltrials.gov/ct/show/ NCT00093392?order=2. Accessed March 22, 2005.