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Journal of Clinical Oncology, Vol 25, No 4 (February 1), 2007: pp. 356-361 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.1960 Phase II Trial of Irinotecan in Children With Relapsed or Refractory Rhabdomyosarcoma: A Joint Study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group
From the Department of Pediatrics, Gustave Roussy Institute, Villejuif; Children's Hospital Lenval, Nice; Department of Pediatrics, Curie Institute, Paris; Department of Pediatrics, Oscar Lambret Center, Lille; Department of Pediatrics, La Timone Hospital, Marseille; Department of Pediatrics, Leon Berard Center, Lyon; Sanofi Aventis, Antony, France; Royal Aberdeen Children's Hospital, Aberdeen; Department of Pediatric Oncology, St James's University Hospital, Leeds; Birmingham Children's Hospital NHS Trust, Birmingham, United Kingdom; and Pfizer Inc, New York, NY Address reprint requests to Gilles Vassal, MD, PhD, Department of Pediatrics, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: gvassal{at}igr.fr
Purpose: This phase II study was designed to evaluate the efficacy of irinotecan administered intravenously once every 3 weeks in pediatric patients with recurrent or refractory rhabdomyosarcoma. Patients and Methods: A total of 35 patients younger than age 20 years, with refractory or relapsed rhabdomyosarcoma for which standard treatments have failed, received irinotecan at 600 mg/m2 administered as a 60-minute infusion every 3 weeks. Concomitant treatments included atropine for cholinergic symptoms, loperamide for diarrhea at the first liquid stool, and preventive antiemetic treatment. Tumor response was assessed every two cycles until progression according to WHO criteria. Results: The best overall response rate to irinotecan was 11.4% (95% CI, 3.2 to 26.7%; 2.9% complete responses, 8.5% partial responses) from all patients recruited. The median times to progression and survival were 1.4 and 5.8 months, respectively. A total of 112 cycles were administered, with a median number of two cycles per patient (range, 1 to 16). The most common grade 3/4 toxicities were neutropenia (46%), abdominal pain or cramping (17%), cholinergic syndrome (14%), nausea/vomiting (11%), anemia (11%), thrombocytopenia (9%), and diarrhea (6%). Conclusion: In heavily pretreated children with a high tumor burden who have been treated with multiagent chemotherapy, irinotecan administered intravenously as a single agent, at 600 mg/m2 every 3 weeks, showed an interesting objective response rate and a good tolerance profile in rhabdomyosarcoma.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in patients younger than age 15 years and it accounts for 8% of malignant solid tumors in children.1-2 The prognosis for a child or adolescent with RMS is related to the site of origin, resectability, presence of metastases, number of metastatic sites, and histopathology.3-5 The use of combined-modality therapy comprising chemotherapy, radiation therapy, and surgery has improved the long-term survival rates of these patients from approximately 25% in 1970 to more than 70% currently.5 However, 30% of patients continue to experience relapse after first treatment, and 50% to 95% of these patients die of progressive disease.6 For these patients new active drugs are urgently needed. Camptothecin analogs that target the intranuclear enzyme topoisomerase I represent a promising new class of anticancer agents for the treatment of childhood cancer.7 One of these camptothecin analogs, irinotecan, was shown to be highly active against a variety of experimental tumor models derived from pediatric tumors.8-12 Different pediatric phase I trials of irinotecan have been completed in the United States, Japan, and Europe following different schedules, including daily dosing for 5 days, every 21 days,13 daily dosing for 5 days per week for 2 weeks, every 21 days,14 weekly dosing for 4 weeks, every 6 weeks,15 daily dosing for 3 consecutive days every 25 days,16 or a single infusion every 3 weeks.17 The current open, multicenter phase II study was designed to evaluate the efficacy of irinotecan administered every 3 weeks for three childhood solid tumors with poor prognosis: medulloblastoma/supratentorial primitive neuroectodermal tumor (PNET), RMS, and neuroblastoma. In the French phase I study evaluating irinotecan administered once every 3 weeks in 81 children with refractory or recurrent solid tumors, the dose-limiting toxicities differed according to previous treatments, with neutropenia as dose-limiting toxicity in heavily pretreated patients and delayed diarrhea noted in less heavily pretreated patients.17 The recommended dose was 600 mg/m2 as a 60-minute infusion in both less heavily and heavily pretreated children. In this article, we present the clinical efficacy and safety of irinotecan at 600 mg/m2 in the RMS cohort.
Patients Eligible patients were required to have histologically confirmed diagnosis of RMS, with refractory (defined as lack of response to chemotherapy) or relapsed tumors in which standard treatments have failed. Patients were to be between 6 months and 20 years of age, with a WHO performance status of 2 or less, and a life expectancy longer than 8 weeks. Patients were required to have adequate blood cell counts (ie, neutrophils  1.0 x 109/L and platelets 100 x 109/L; or 75 x 109/L in the case of bone marrow disease or post high-dose chemotherapy with stem-cell transplantation), satisfactory hepatic function (ie, bilirubin  1.5 upper normal limit [UNL] in the presence of hepatic metastases or otherwise 1.25 UNL, transaminases 2.5 x UNL), and normal renal function defined as less than or equal to National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grade 1. Prior treatments consisted of no more than one salvage therapy for relapse, no chemotherapy within the last 4 weeks before study entry (6 weeks for nitrosoureas), and no radiotherapy within the last 6 weeks before study entry. Exclusion criteria included a recent history of chronic diarrhea, complete or incomplete bowel obstruction, Crohn's disease, or ulcerative colitis. Before study enrollment a complete medical history including details of any concomitant treatments was obtained and the following tests were carried out: clinical examination, performance status, hematologic and biochemical profiles, cardiac ultrasounds in case of prior treatment with anthracyclines or mediastinal irradiation, chest x-ray, and tumor target assessment. The study was conducted in accordance with good clinical practices and was approved by the local ethics committees. Parents or the legal representatives provided a written informed consent and the patient's assent was obtained, when appropriate.
Treatment Concomitant treatments included atropine (20 µg/kg, subcutaneously) for cholinergic symptoms (preventive treatment was given if severe acute cholinergic symptoms were experienced during a previous cycle) and loperamide as a curative treatment. For children older than age 2 years and younger than age 15 years, a visit to the study physician was mandatory as soon as the first liquid stool occurred and loperamide treatment at the dose of 0.18 mg/kg/d was immediately initiated with drinking solution on a 4-hourly basis. In case of grade 3/4 diarrhea within the first 24 hours, the child was to be hospitalized. Loperamide was then to be given at a dose of 0.06 mg/kg per administration every 4 hours or replaced by another antidiarrheal treatment according to the investigators' judgment. For patients older than age 15 years the treatment of delayed diarrhea was as recommended in adults. Preventive antiemetic treatment according to each center's preferred practice for highly emetogenic antineoplasic drugs was allowed.
Response and Toxicity Evaluation Toxicity, graded according to the NCI-CTC, version 2.0 (1998), was assessed by clinical and biologic examinations before each cycle (weekly within a cycle for hematologic toxicity), and then at the end of treatment.19
Statistical Analysis The primary end point of the study was the objective response rate (ORR; CRs plus PRs) as assessed by the external response review committee, and its exact 95% CI. Complete and partial responses were to be confirmed by two evaluations of the disease, taken at least 4 weeks apart to be considered. The secondary efficacy criteria were the duration of response, TTP, and survival. Censored data were analyzed using the Kaplan-Meier method. The CI on the median was calculated using the Brookmeyer and Crowley method.21 For toxicity analysis, the worst grade for each patient in all cycles of chemotherapy was used. The efficacy analyses were performed on the full analysis population (FAP) defined as all treated patients and the per-protocol population defined as all treated patients without a major protocol violation. The safety analysis was performed in all patients who received at least one dose of study drug.
Patients' Characteristics From November 1999 to June 2002, thirty-five patients were included and treated in the study. Two patients were found to be ineligible at study entry (no bidimensional measurable lesion in progression since last evaluation). Patients' and diseases' characteristics at inclusion are summarized in Table 1. The median time from initial diagnosis to the first irinotecan infusion was 20.3 months. The majority of patients (66%) presented with metastatic disease at study entry; 29% of patients were treated at the second relapse, and 14% had a refractory tumor. All patients had received prior chemotherapy, 60% underwent surgery and 74% had radiotherapy. Most of the patients were treated at diagnosis by the Malignant Mesenchymal Tumors protocols 84 and 89 from the Société Internationale d’Oncologie Pédiatrique ( SIOP) protocols that included courses of ifosfamide, dactinomycin, and vincristin (IVA), and/or carboplatin, epiadriamycin, and vincristin (CEV), and/or ifosfamide, vincristine, and etoposide (IVE). Only one patient received a topoisomerase I inhibitor (topotecan) before study entry. Only one patient received enzyme-inducing anticonvulsant drug during the first cycle of treatment with irinotecan.
Efficacy Results In the FAP (n = 35), the ORR to irinotecan was 11.4% (95% CI, 3.2% to 26.7%) with one CR (2.9%) and three PRs (8.5%; Table 2). The response durations were 7.8 months for the CR, 2.8, 3.7, and 6.4 months for the three PRs. Stable disease was observed in 17% of patients. The patient with CR had a stage IV alveolar RMS of the anterior chest wall and patients with PRs had stage IV alveolar (n = 1) or embryonal (n = 2) RMS. One additional patient experienced a PR after two cycles that was not confirmed on the computed tomography scan performed 8 weeks apart. In the per-protocol population (n = 32), the ORR was 12.5% (95% CI, 3.5% to 29.0%) with one CR (3.1%) and three PRs (9.4%). In the FAP, the median TTP was 1.4 months (95% CI, 1.2 to 1.6 months) and the median survival time was 5.8 months (95% CI, 4.3 to 9.4 months).
Treatment Exposure Overall, 112 cycles were administered to 35 patients, with a median number of two cycles per patient (range, 1 to 16 cycles). The median dose intensity (195.4 mg/m2/wk) corresponded to 98% of the scheduled dose. The dose was reduced in 14% of patients and 5% of cycles, mainly due to hematologic toxicity. Treatment was delayed in 14% of patients and 14% of cycles, mainly due to reasons other than toxicity. The reasons for treatment discontinuation were progressive disease (n = 26), no further benefit expected (n = 3), death due to malignant disease (n = 2), occurrence of an adverse event related to irinotecan (n = 1), patient who required radiotherapy (n = 1), consent withdrawn (n = 1), and investigator's decision (n = 1).
Safety Results
Grade 3/4 nonhematologic toxicity consisted mainly of abdominal pain or cramping (17% of patients; 5% of cycles), cholinergic syndrome (14% of patients; 5% of cycles), nausea (11% patients; 4% of cycles), vomiting (11% patients; 5% of cycles), and diarrhea (6% patients; 2% of cycles). All patients but one had received at least one administration of atropine during study participation. Indeed, most of patients received atropine as a preventive treatment without prior occurrence of cholinergic syndrome. Sixty-nine percent of patients received antidiarrheal treatment and 20% were hospitalized due to occurrence of diarrhea. No treatment-related deaths occurred during the study.
This study showed that irinotecan as a single agent, at 600 mg/m2 administered intravenously every 3 weeks, exhibits antitumor activity in children with relapsed or refractory RMS with a good tolerance profile. In this heavily pretreated pediatric population with a high tumor burden, most of whom had received multiagent chemotherapy, irinotecan induced an ORR of 11.4%. Up to now, few phase II trials have been performed in pediatric tumors. The protracted administration schedule, daily for 5 days for 2 consecutive weeks, was evaluated in a phase II window trial in 20 children with newly diagnosed metastatic RMS.22 Patients received two cycles of irinotecan 20 mg/m2/d, and then patients who responded received vincristine and irinotecan alternating with vincristine, actinomycin D, and cyclophosphamide (VAC); patients who did not respond received VAC alone. The PR rate after two irinotecan cycles was 45% (9/20 patients; 95% CI, 23% to 67%). However, the high progressive disease rate (30%) and two early deaths prompted early termination of the protocol. Recently a randomized phase II trial of carboplatin plus irinotecan (n = 74) versus irinotecan alone (n = 74) was performed in miscellaneous pediatric refractory tumors.23 Irinotecan as monotherapy administered at 20 mg/m2/d for 10 consecutive days every 21 days induced one CR and three PRs of 74 patients including two PRs in 16 RMS (ie,12.5% with a 95% CI of 3.5 to 36%). Retrospective data were published concerning 22 heavily pretreated children with relapsed tumors treated with the daily for 5 days (for 2 weeks) regimen at the Memorial Sloan-Kettering Cancer Center (New York, NY).24 Of the 19 patients assessable for response, two CRs and one PR were observed among the four patients with RMS (75%; 95% CI, 30% to 95%) and one PR was noted in a patient with undifferentiated sarcoma. Even though the sample of patients was low, the number of responding patients in relapsed RMS in this retrospective study was higher than in this study. Experience with the same protracted schedule of irinotecan was recently reported by the Italian Soft Tissue Sarcoma Group. Of 30 patients, 12 had a RMS and two experienced PR25 (17%; 95% CI, 5% to 45%). Altogether, these results show that RMS is sensitive to irinotecan in relapse and in newly diagnosed patients. These results suggest that a prolonged schedule of administration may be preferable to a single administration every 21 days. However, the heterogeneity of prior and concomitant therapies received in these different studies does not allow drawing definite conclusions. Concurrent administration of anticonvulsants and/or corticosteroids has been reported to alter irinotecan disposition in adults26 and children.27 In addition, we showed that corticosteroids significantly enhanced irinotecan clearance in children.17 Therefore, concomitant medication could influence the effect of irinotecan and could in part explain the differences in response rates observed from one study to another. The tolerance profile of irinotecan as a 3-week schedule was acceptable in these heavily pretreated patients and was consistent with that obtained in the previous phase I trial.17 At a dose higher (600 mg/m2 every 3 weeks) than that used in adult patients (350 mg/m2 every 3 weeks), irinotecan was well tolerated in children (even in adolescents) with manageable and reversible toxicities. Nonhematologic adverse events related to irinotecan were similar to those observed in adults (ie, mainly gastrointestinal disorders—nausea/vomiting, diarrhea with abdominal pain and cramping). Grade 3/4 toxicities remained infrequent. As already observed in the phase I study,17 the rate of severe delayed diarrhea was lower than that observed in adults (21% to 42% of grade 3/4 diarrhea in patients with colorectal cancer).28 Irinotecan-induced delayed diarrhea was well managed with the antidiarrheal guidelines including intensive and early use of loperamide (even in the youngest patients). Cholinergic syndrome was well controlled by the atropine treatment and we would recommend routine use of atropine as a preventive measure. As expected, myelosuppression was among the main toxicities occurring during treatment, with a relatively high incidence of grade 3/4 neutropenia (46% of patients), which is comparable with that observed in adult patients treated with irinotecan in monotherapy (41% to 45% in phase II studies). Few children experienced complicated neutropenia. In children with RMS treated with protracted administration of irinotecan (daily for 5 day for 2 weeks), the most common grade 3/4 toxicities experienced during the two cycles of irinotecan included dehydration (19%), anemia with RBC transfusion (19%), hypokalemia (14%), and vomiting (14%).22 The once every 3 weeks schedule was well tolerated in children. In conclusion, in children with relapsed or refractory RMS who have been heavily pretreated, often with multiagent chemotherapy, and who have a high tumor burden, irinotecan at 600 mg/m2 administered intravenously every 3 weeks, showed an ORR of 11.4%. The good tolerance profile of irinotecan in children was confirmed. Those results, along with those obtained with the protracted administration in newly diagnosed or relapsed tumors indicate that irinotecan deserves further evaluation in combination with other anticancer compounds in RMS.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Laura Cisar, Pfizer; Sylvie Assadourian, sanofi aventis Leadership: N/A Consultant: N/A Stock: Laura Cisar, Pfizer; Sylvie Assadourian, sanofi aventis Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Gilles Vassal, Sylvie Assadourian, Bruce Morland Financial support: Laura Cisar, Sylvie Assadourian Administrative support: Laura Cisar, Sylvie Assadourian Provision of study materials or patients: Gilles Vassal, Birgit Geoerger, Daniel Orbach, Fabienne Pichon, Jean Claude Gentet, Susan Picton, Christophe Bergeron, Bruce Morland Collection and assembly of data: Sylvie Assadourian Data analysis and interpretation: Gilles Vassal, Dominique Couanet, Elizabeth Stockdale, Anne Geoffray, Sylvie Assadourian, Bruce Morland Manuscript writing: Gilles Vassal Final approval of manuscript: Gilles Vassal, Laura Cisar, Sylvie Assadourian, Bruce Morland
We thank Hamish Wallace, Royal Hospital for Sick Children, Edinburgh; Heather McDowell, Royal Liverpool Children NHS Trust, Liverpool; Bernadette Brennan, Royal Manchester Children’s Hospital, Manchester; Ross Pinkerton, Royal Marsden Hospital NHS Trust, London; Andrew Pearson, University of Newcastle, Newcastle Upon Tyne, United Kingdom, for their participation in the trial. We also thank Maryse Berlion for assistance with preparation and editing of the manuscript. For a list of participating centers please see Appendix Table A1 (online only).
Supported by Pfizer Inc. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Gurney JG, Young JL, Roffers SD, et al: Soft tissue sarcomas, in Ries LAG, Smith MA, Gurney JG, et al (eds): Cancer Incidence and Survival Among Children and Adolescents: United States Surveillance, Epidemiology, and End-Results (SEER) Program 1975-1995. Bethesda, MD, National Cancer Institute, 1999 2. Dagher R, Helman L: Rhabdomyosarcoma: An overview. Oncologist 4:34-44, 1999 3. Breneman JC, Lyden E, Pappo AS, et al: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21:78-84, 2003 4. Carli M, Colombatti R, Oberlin O, et al: European intergroup studies (MMT4-89 and MMT4-91) on childhood metastatic rhabdomyosarcoma: Final results and analysis of prognostic factors. J Clin Oncol 22:4787-4794, 2004 5. Stevens MC, Rey A, Bouvet N, et al: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: Third study of the International Society of Paediatric Oncology-SIOP Malignant Mesenchymal Tumor. J Clin Oncol 23:2618-2628, 2005 6. Raney BT, Crist WM, Maurer HM, et al: Prognosis of children with soft tissue sarcoma who relapse after achieving a complete response: A report for the Intergroup Rhabdomyosarcoma study I. Cancer 52:44-50, 1983[CrossRef][Medline] 7. Bomgaars L, Berg SL, Blaney SM: The development of Camptothecin analogs in childhood cancers. Oncologist 6:506-516, 2001 8. Hare CB, Elion GB, Houghton PJ, et al: Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 39:187-191, 1997[CrossRef][Medline] 9. Houghton PT, Cheshire PJ, Hallman JDN, et al: Therapeutic activity of the topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin against human tumor xenografts: Lack of cross resistance in vivo in tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxy camptothecin. Cancer Res 53:2823-2829, 1993 10. Vassal G, Boland I, Santos A, et al: Potent therapeutic activity of irinotecan (CPT-11) and its schedule dependency in medulloblastoma xenografts in nude mice. Int J Cancer 73:156-163, 1997[CrossRef][Medline] 11. Vassal G, Terrier-Lacombe M, Bissery MC, et al: Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts. Br J Cancer 74:737-745, 1996 12. Vassal G, Pondarre C, Boland I, et al: Preclinical development of camptothecin derivatives and clinical trials in pediatric oncology. Biochimie 80:271-280, 1998[Medline] 13. Blaney S, Berg SL, Pratt C, et al: A phase I study of irinotecan in pediatric patients: A pediatric oncology group study. Clin Cancer Res 7:32-37, 2001 14. Furman WL, Stewart CF, Poquette CA, et al: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17:1815-1824, 1999 15. Bomgass L, Kerr J, Berg S, et al: A phase I study of irinotecan administered on a weekly schedule in pediatric patients. Pediatric Blood Cancer 46:50-55, 2006[CrossRef][Medline] 16. Mugishima H, Matsunaga T, Yagi K, et al: Phase I study of irinotecan in pediatric patients with malignant solid tumors. J Pediatr Hematol/Oncol 24:94-100, 2002[CrossRef][Medline] 17. Vassal G, Doz F, Frappaz D, et al: A phase I study of irinotecan as a 3-week schedule in children with refractory or recurrent solid tumors. J Clin Oncol 21:3844-3852, 2003 18. World Health Organization: Handbook for reporting results of cancer treatment. Geneva, Switzerland, World Health Organization, 1979 19. National Cancer Institute: Investigator's Handbook: A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by DCTD, NCI. Bethesda, MD, National Cancer Institute, 1993 20. Fleming TR: One sample multiple testing procedure for phase II clinical trials. Biometrics 38:143-151, 1982[CrossRef][Medline] 21. Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 38:29-41, 1982[CrossRef] 22. Pappo AS, Lyden E, Breitfeld PP, et al: Irinotecan is active against pediatric rhabdomyosarcoma: A phase II window trial from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Proc Am Soc Clin Oncol 21:393a, 2002 (abstr 1570) 23. Petrilli AS, Jakacki RI, Perek D, et al: Randomized phase II study of carboplatin and irinotecan or irinotecan in 1-21 year old patients with refractory solid tumors. J Clin Oncol 22:14S, 2004 (abstr 8559) 24. Cosetti M, Wexler LH, Calleja E, et al: Irinotecan for pediatric solid tumors: The Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol 24:101-105, 2002[CrossRef][Medline] 25. Bisogno G, Riccardi R, Ruggiero A, et al: Phase II study of a protracted irinotecan schedule in children with refractory or recurrent soft tissue sarcoma. Cancer 106:703-707, 2006[CrossRef][Medline] 26. Friedman HS, Petros WP, Friedman AH, et al: Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17:1515-1525, 1999 27. Crews KR, Stewart CF, Jones-Wallace D, et al: Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy. Clin Cancer Res 8:2202-2209, 2002 28. Vanhoefer U, Harstrick A, Achterrath W, et al: Irinotecan in the treatment of colorectal cancer: Clinical overview. J Clin Oncol 19:1501-1518, 2001 Submitted March 22, 2006; accepted November 14, 2006. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
