Japanese Journal of Clinical Oncology 30:146-152 (2000)
© 2000 Foundation for Promotion of Cancer Research
Alternating Combination Chemotherapy C-MOPP (Cyclophosphamide, Vincristine, Procarbazine, Prednisone) and ABVd (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) in Clinical Stage II–IV Hodgkin’s Disease: a Multicenter Phase II Study (JCOG 8905)
For author affiliations, please see p. 157
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsAffiliations of the AuthorsREFERENCES |
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Background: The main form of cytotoxic treatment for advanced Hodgkin’s disease (HD) is conventional dose multiagents chemotherapy. As HD is not common in Japan, we conducted a phase II study of the commonly used combination chemotherapy (CCT) regimen established in the West for Japanese patients with advanced HD to confirm the efficacy and safety.
Method: Between October 1989 and February 1993, a multicenter phase II study of alternating CCT C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone) and ABVd (adriamycin, vinblastine, bleomycin, dacarbazine) to evaluate its clinical usefulness for clinical stage (cS) II–IV HD was conducted by the Lymphoma Study Group of the Japan Clinical Oncology Group.
Results: Seventy-nine previously untreated patients were enrolled in the study. For 67 eligible patients, the response rate was 92.5% with 83.6% complete response (CR). For 40 cS II and 27 cS III/IV patients the response rate was 95.0% with 90.0% CR and 88.9% with 74.1% CR, respectively. The overall 5-year survival rate was 84.8%. Those of cS II and cS III/IV were 92.5 and 73.1%, respectively. There was no significant difference between cS II and cS III/IV (p = 0.1025). The progression-free 4-year survival rate was 72.8%. Those of cS II and cS III/IV were 77.5 and 65.7%, respectively. There was no significant difference between cS II and cS III/IV (p = 0.2483). Grade 4 toxicity by the criteria of the World Health Organization consisted of leukocytopenia in 28.4% of patients. There was GPT elevation in 4.5%, nausea/vomiting in 11.9% and CNS in 1.5% of patients, but there was no treatment-related death.
Conclusion: The C-MOPP/ABVd regimen for Japanese patients with advanced HD is considered to be one of the effective CCTs according to the results of the present phase II study.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsAffiliations of the AuthorsREFERENCES |
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Radiotherapy (RT) and chemotherapy (CT) are common modalities of treatment for Hodgkin’s disease (HD). Treatment for patients with HD is selected principally on disease stage by the Ann Arbor classification system (1).
In patients with early stage HD, RT is generally considered to be a standard choice. The use of RT for pathological stage IA and IIA HD patients has produced a 68% 20-year survival and 75% 20-year freedom from relapse (2). However, a randomized study compared RT alone with CT alone in patients with stage IAB, IIAB and IIIA disease (3) and overall survival (OS) at 10 years was 76% for RT and 92% for CT of MOPP regimen (p = 0.051). Another randomized study compared CT of CVPP alone with combined modality therapy for cS I or II disease (4), in which patients who received CVPP alone had a 77% 7-year disease-free survival (DFS) and 92% OS. Patients treated with combined modality therapy had a 70% 7-year DFS and 91% OS. There were no significant differences between the CT alone and the combined modality therapy in both DFS and OS in early-stage HD. Although combined therapy with RT and CT is currently advocated for adult patients with bulky mediastinal mass in early stage HD (5,6), there are no convincing data showing that combined modality therapy is superior to RT alone or CT alone in the treatment of early-stage HD (4,7). However, stage III and IV (advanced stage) HD is highly curable by combination CT (CCT) (8–15). It is generally accepted in the West that most patients with advanced stage HD should be treated with one of the standard CCT regimens such as MOPP (mechlorethamine, vincristine, procarbazine, prednisone) (8), ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) (11), MOPP/ABVD (10) or MOPP/ABV (12). In the West, pathological staging by exploratory laparotromy and splenectomy is generally required for strict selection of RT alone in early-stage HD, but not for standard CCT in advanced-stage HD. Consequently, cS II HD is treated by CCT at most institutions.
Under these circumstances, it was considered rational to conduct a phase II study of CCT for cS II–IV HD. Although CCT regimens including mechlorethamine and/or adriamycin are effective for advanced-stage HD, mechlorethamine is not commercially available in Japan.
Based on these observations, the Lymphoma Study Group (LSG) of the Japan Clinical Oncology Group (JCOG) began a multicenter phase II study (JCOG 8905) of alternating combination chemotherapy C-MOPP, substituting cyclophosphamide for mechlorethamine, and ABVd for clinical stage (cS) II–IV patients in October 1989. We report here the results of the final analysis of response, survival and toxicity with a median follow-up of 6.3 years for surviving patients.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsAffiliations of the AuthorsREFERENCES |
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Patient entry began in October 1989 and continued through February 1993. Verbal or written informed consent was obtained before entry to the study in keeping with the guidelines of JCOG (16) and the Institutional Review Boards of all participating institutions.
Patients
HD was pathologically diagnosed according to the Rye classification (17). Patients were classified by cS using the Ann Arbor method (1). To be eligible, patients had to have newly diagnosed, previously untreated HD with cS II, III or IV. All patients in each participating institution had biopsy-proven HD at entry. However, as defined in advance, patients with HD verified by three hematopathologists (Dr Kiyoshi Mukai at the National Cancer Center, Dr Masafumi Abe at Fukushima Medical College and Dr Kohichi Ohshima at Fukuoka University) for central review, were evaluated in the final analysis. Furthermore, patients had to be under 65 years old, performance status (PS) (18) 0–3 and without severe organ dysfunction (hematopoietic, granulocytes 
1500/µl and platelets 10 x 104/µl; hepatic, GOT/GPT 
2 times normal upper limit; renal, BUN 25 mg/dl and creatinine 1.2 mg/dl; pulmonary, PaO2 70 mmHg). Patients were not registered as ineligible due to complications such as severe infection, cardiac disease requiring intensive treatment, diabetes mellitus requiring insulin therapy, active gastroduodenal ulcer or other active malignancies.
Treatment
The alternating chemotherapy consisted of a C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone) regimen and ABVd (adriamycin, bleomycin, vinblastine, dacarbazine) regimen with dose schedules as shown in Table 1. According to our experience in a pilot study (data not shown), a full dose (375 mg/m2) of dacarbazine in the ABVD regimen was intolerable owing to severe emesis. Therefore, a two-thirds dose (250 mg/m2) of dacarbazine was used in the present trial. The cycle was repeated every 4 or 5 weeks depending on the hematological and hepatic parameters.
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If the pretreatment granulocyte count was <1500/µl or platelet count <10 x 104/µl and/or GOT >100 IU/l or total bilirubin >2 mg/dl, treatment was postponed for at least 1 week or until recovery. Vincristine or vinblastine was temporarily discontinued if signs of grade 2 or more neurotoxicity such as motor weakness, paresthesia or constipation appeared. Adriamycin was discontinued if cardiac hypofunction (ejection fraction <50%) appeared. Bleomycin was stopped if the PaO2 level decreased under 70 mmHg or by more than 10 mmHg from the prior level. The full chemotherapy schedule for both regimens in this trial was five courses each. When a complete response (CR) was achieved within five courses of treatment, the patient was observed without further treatment until relapse. Patients with bulky (maximum diameter
10 cm) disease were given involved field irradiation (30 Gy) after completion of chemotherapy as a rule. Non-responders with progressive disease were taken off treatment immediately, but those with stable disease with an increment <25% from the pretreatment abnormalities were continued for five courses of treatment.
Evaluation of Response, PFS, OS and Toxicity
Response was principally evaluated according to World Health Organization (WHO) criteria (1979) (19).
CR was defined as complete resolution of all disease-related symptoms and normalization of initial physical examination, laboratory and imaging abnormalities for a minimum of 4 weeks. Partial response (PR) was defined as a reduction of >50% of all disease-related abnormalities for a minimum of 4 weeks. No response (NR) was defined as definite clinical improvement, but with <50% reduction of the abnormalities. Progressive disease (PD) was defined as >25% progression from the pretreatment level of each factor and/or development of new lesions.
Relapse-free survival (RFS) was dated from initiation of response to relapse. Progression-free survival (PFS) and overall survival (OS) were dated from initiation of the first course of C-MOPP. Events of PFS included disease progression or death from HD. Events of OS included death from any cause.
Patients were closely monitored for adverse drug reactions with adjustment if necessary. Toxic grade was evaluated according to the toxicity criteria of WHO (19).
Statistical Analysis
Data were analyzed as of March 1998. RFS, PFS or OS distributions were estimated by the product-limit method (20). In subgroup analyses, Fisher’s exact test was used to test the association of categorical variables and the log-rank test was used in comparing survival distribution. Each p-value was two-sided and not adjusted for multiplicity. The confidence interval was calculated based on a binomial distribution in categorical variables and on Greenwood’s formula in time-to-event variables. All tests were performed with SAS statistical software version 6.12.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsAffiliations of the AuthorsREFERENCES |
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Patient Population
Seventy-nine patients were registered at 29 participating institutions. Twelve of 79 patients were declared ineligible after registration for various reasons [cS I in one patient, high age in two, granulocytopenia in two, low PaO2 in one, high GOT/GPT in one, change of pathological diagnosis in five (three non-Hodgkin’s B-cell lymphomas, one anaplastic large cell lymphoma, two reactive hyperplasias].
The characteristics of 67 eligible and evaluable patients (37 males and 30 females) are summarized in Table 2. Patient ages ranged from 15 to 65 (median 33) years. Forty-six patients (68.7%) had nodular sclerosis type HD, 32 (47.8%) had cS II A, 48 (71.6%) had PS 0 and 16 (23.9%) had bulky disease.
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Treatment Response and Survival
Fifty-five of 67 eligible patients were treated with five courses of C-MOPP/ABVd, seven patients received three or four courses and five patients received two courses or less. The reasons for early discontinuation of treatment in 12 patients were PD or early relapse in five, adverse drug reactions in two, treatment refusal in four and accidental bone fracture in one.
Sixty-seven eligible patients were analyzed for response. There were 62 responders (92.5%, 95% CI = 83.4–97.5%) with 56 CRs and six PRs as shown in Table 3. The overall response rate was 95.0% (95% CI = 83.1–99.4%) in 40 cS II patients and 88.9% (95% CI = 70.8–97.6%) in 27 cS III/IV patients, respectively. There was no significant difference between cS II and cS III/IV (p = 0.385).
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Thirteen of 16 patients with bulky tumor achieved CR with C-MOPP/ABVd. Seven of 13 patients received post-chemotherapeutic RT after complete remission according to the protocol, but the remaining six patients did not receive RT for protocol violation. There were no significant differences between two groups in either OS (p = 0.7919) or PFS (p = 0.7498).
At the time of analysis (March 31, 1998), there had been 12 deaths, of which 11 were attributed to progressive disease. The remaining one was lost to follow-up and the cause of death was unknown.
RFS curves of overall, cS II and cS III/IV are shown in Fig. 1A and B. The 2-year RFS rates of overall, cS II and cS III/IV were 83.6% (95% CI = 73.9–93.4%), 86.1% (95% CI = 74.8–97.4%) and 78.9% (95% CI = 60.6–97.3%), respectively, while the projected 5-year RFS rates of overall, cS II and cS III/IV were 81.8%, 83.3% and 78.9%, respectively. There was no significant difference observed between cS II and cS III/IV (p = 0.671).
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OS curves of all eligibles, cS II and cS III/IV are shown in Fig. 2A and B. The 5-year OS rates of all eligibles, cS II and cS III/IV were 84.4% (95% CI = 76.2–93.5%), 92.5% (95% CI = 84.4–100.0%) and 73.1% (95% CI = 56.0–90.1%), respectively. There was no significant difference observed between cS II and cS III (p = 0.1025).
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PFS curves of all eligibles, cS II and cS III/IV are shown in Fig. 3A and B. The 4-year PFS rate of all eligibles, cS II and cS III/IV were 72.8% (95% CI = 62.0–83.5%), 77.5% (95% CI = 64.6–90.4%) and 65.7% (95% CI = 47.5–83.9%), respectively. There was no significant difference observed between cS II and cS III/IV (p = 0.2483).
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Toxicity
The frequency of adverse drug reactions and the highest grade observed during a total of 300 treatment courses in 67 eligible patients are summarized in Table 4. There were no deaths that were considered treatment related. As for grade 4 hematological toxicity, leucocytopenia was observed in 19 (28.4%) patients. The toxic grade of anemia and thrombocytopenia was <3. There were no patients with documented systemic bacterial and/or fungal infections. Three patients developed localized herpes zoster. Two patients had interstitial pneumonia controlled with corticosteroid hormone therapy. Nausea and vomiting accounted for most of the gastrointestinal toxicity and severe (>grade 3) in 25 (37.3%) patients. GPT elevation of >grade 3 was observed in 25 (37.3%) patients but they recovered after completion of C-MOPP/ABVd. Eight of 31 patients developed fever (>grade 1) as a toxic effect of bleomycin. Drug eruption due to procarbazine was seen in five patients but the toxic grade was mild (grade 1).
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As an adverse event, grade 4 CNS toxicity with convulsion was observed in a 25-year-old male patient on the second day after ABVd administration during the first treatment course. Within 30 min after injection of diazepam, the convulsion disappeared. There were no abnormal findings recognized on electroencephalogram, cerebral computed tomography and cerebrospinal fluid.
Second malignancies as a late onset toxicity has not been encountered to date.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsAffiliations of the AuthorsREFERENCES |
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Some differences exist between MOPP/ABVD regimen and C-MOPP/ABVd regimen. The most prominent difference is substituting cyclophosphamide for mechlorethamine in ABVd regimen. Nextly, the dose of DTIC in ABVd regimen is reduced to two thirds the dose of DTIC in ABVD regimen. Furthermore, the present phase II study included about one half of cS IIA HD patients.
The median age of 33 years in the present study seems not to be different compared with HD patients in the Western study. According to data from the SEER program 1987–91, there is a unimodal age distribution with a peak at young adult (20–34 years) with a median age of 33 years (21). Also, according to a study conducted by Canellos et al. (11), the median age was 34 years (range 16–72 years).
As expected, the efficacy of C-MOPP/ABVd for Japanese patients with advanced HD is excellent and is considered almost equivalent to that of MOPP/ABVD reported in the West. During the present study, however, the Cancer and Leukemia Group B reported the results of a randomized study for stage IIIA2–IVAB HD, comparing MOPP with ABVD and with MOPP/ABVD (11). The CR rate and 5-year survival were 67 and 66% with MOPP, 73 and 82% with ABVD and 83 and 75% with MOPP/ABVD, respectively. ABVD and MOPP/ABVD were superior in efficacy to MOPP alone in the treatment of advanced HD. As ABVD is less toxic than MOPP/ABVD, ABVD has been considered to be a superior CCT for advanced HD. In this context, we started a phase II study of ABVd regimen for advanced HD in 1995. It is necessary to perform prospective randomized trials to determine whether there are significant differences in efficacy and toxicity between C-MOPP/ABVd and ABVd in treating advanced HD. However the incidence of HD in Japan is as low as 0.8 per 100 000 population (only about 900 patients per year in Japan), so it seems to be difficult to conduct a randomized controlled trial for advanced HD in Japan.
In the ABVD regimen, dacarbazine is used as an effective drug for HD in the West, but the Japanese regulations do not permit the use of dacarbazine under the National Health Insurance system.
Under these conditions, the present trial of C-MOPP/ABVd was planned and conducted as the first prospective multicenter phase II study for Japanese HD patients. The results have shown a high response rate and high survival rate comparable to those previously reported in the West (11). Consequently, we hope to be able to administer the C-MOPP/ABVd regimen for HD freely under the National Health Insurance system as early as possible.
The toxicity of the C-MOPP/ABVd regimen is moderate and tolerable. Although myelotoxicity was the most frequent toxicity observed, there was no treatment-related death due to infection. There was no ileus or grade 3/4 neurotoxicity. The peripheral neuropathy was moderate and acceptable. Grade 3/4 GOT elevation was transient and all patients recovered before the next course of treatment. Nausea/vomiting due to dacarbazine was the main reason for early discontinuation of treatment (33.3%) because effective antiemetics (ondansetron, granisetron, etc.) were not commercially available at that time.
Promethazine hydrochloride (22) and/or haloperidol (23) used for antiemetic effects may have induced grade 4 CNS toxicity with convulsion. This convulsion was transient and the patient concerned recovered soon after administration of diazepam. Although such toxicity is rare, attention is needed during the ABVd regimen.
In summary, based on the present phase II trial, the alternating C-MOPP and ABVd regimen for cS II–IV HD was considered an effective chemotherapeutic regimen for advanced-stage HD.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsAffiliations of the AuthorsREFERENCES |
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This work was supported in part by Grants-in-Aid for Cancer Research (62S-1, 2S-1, 5S-1 8S-1, HS-4, 1–1 and 4–5) and for a New 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare. The authors are grateful to Drs T. Sai (Iwaki-Kyoritsu Hospital, Iwaki), I. Aoki (Kyorin University, Mitaka), A. Togawa (International Medical Center of Japan, Tokyo), S. Konda (Kanazawa Medical University, Kahoku), K. Deura (Saku Central Hospital, Saku), S. Minami (Nagoya First Red Cross Hospital, Nagoya), S. Sirakawa (Mie University Faculty of Medicine, Tsu), T. Suzuki (Shiga Medical Center For Adults, Moriyama), T. Abe (Kyoto Prefectural University of Medicine, Kyoto), E. Tatsumi (Kobe University School of Medicine, Kobe), Y. Ohno (Tenri Yorozu-Sodan-Sho Hospital, Tenri), M. Nagai (Kagawa Medical University, Kida), H. Toki (National Shikoku Cancer Center Hospital, Matsuyama), Y. Shimamoto (Saga Medical School, Saga), K. Takatsuki (Kumamoto University School of Medicine, Kumamoto) and K. Araki (Ryukyu University School of Medicine, Nakagusuku) and other participating doctors from the 29 institutions in the Lymphoma Study Group of the Japan Clinical Oncology Group for their cooperation.
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Affiliations of the Authors |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsAffiliations of the AuthorsREFERENCES |
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1Hematology Division, National Cancer Center Hospital, Tokyo, 2Department of Internal Medicine, Sapporo National Hospital, Sapporo, 3Third Department of Internal Medicine, Akita University School of Medicine, Akita, 4Department of Chemotherapy, Metropolitan Komagome Hospital, Tokyo, 5Department of Hematology–Oncology, Aichi Cancer Center Hospital, Nagoya, 6First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, 7Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, 8Department of Internal Medicine, Kyoto University School of Medicine, Kyoto, 9Department of Internal Medicine, Osaka University School of Medicine, Osaka, 10Department of Internal Medicine, Osaka Red Cross Hospital, Osaka, 11Department of Internal Medicine, Hiroshima Red Cross and Atomic Disease Hospital, Hiroshima, 12Department of Internal Medicine, Kyusyu National Hospital, Fukuoka, 13Department of Internal Medicine, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki, 14Department of Medical Oncology, National Cancer Center Hospital, Tokyo, 15Cancer Information and Epidemiology Division, National Cancer Research Institute, Tokyo, 16Pathology Division, National Cancer Research Institute, Tokyo, 17Department of Pathology, Tokyo Medical University, Tokyo and 18Department of Internal Medicine, Nagoya National Hospital, Nagoya, Japan
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FOOTNOTES |
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+ For reprints and all correspondence: Takeaki Takenaka, Hematology Division, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, JapanAbbreviations: CCT, combination chemotherapy; cS, clinical stage; CI, confidence interval; GPT, glutamic–pyruvic transaminase; CNS, central nervous system; MOPP, mechlorethamine, vincristine (Oncovin), procarbazine, prednisone; C-MOPP, cyclophosphamide, vincristine (Oncovin), procarabazine, prednisone; ABVD/d, adriamycin, bleomycin, vinblastine, dacarbazine; RT, radiotherapy; CT, chemotherapy; HD, Hodgkin’s disease; LSG, Lymphomas Study Group; JCOG, Japan Clinical Oncology Group; PS, performance status; GOT, glutamic–oxaloacetic transaminase; CR, complete response; PR, partial response; NR, no response; PD, progressive disease; RFS, relapse-free survival; PFS, progression-free survival; OS, overall survival; CVPP, cyclophosphamide, vinblastine, procarbazine, prednisone
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsAffiliations of the AuthorsREFERENCES |
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Received November 15, 1999; accepted December 28, 1999.
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