臺灣博碩士論文加值系統

目的:
本研究執行兩個統合分析，其一為針對一新的非類固醇類抗發炎藥物---meloxicam，在隨機分配、有對照組及其適應症為退化性關節炎、類風濕性關節炎或急性腰部疼痛的第三階段臨床試驗中，比較任何不良事件，腸胃道不良事件，因任何或腸胃道不良事件而離開試驗的發生率是否較傳統的非類固醇類抗發炎藥物低。另一研究為針對一類抗癌新藥物topoisomerase I inhibitors中的三個藥物Irinotecan、topotecan 及9-aminocamptothecin，整合目前在各癌症第二階段臨床試驗期間，第三或第四級血液相關毒性--貧血、白血球球減少、嗜中性白血球減少及血小板減少的發生率。
資料來源:
在meloxicam的研究，利用MEDLINE及EMBASE: DRUGS & PHARMACOLOGY兩個資料庫，針對在1990 至1998以英文發表的隨機分配、有對照組的第三階段臨床試驗進行尋索並檢閱相關研究之引用。在topoisomerase I inhibitors的研究，利用MEDLINE及EMBASE: DRUGS & PHARMACOLOGY兩個資料庫，針對在1980至1998以英文發表的第二階段臨床試驗進行尋索並檢閱相關研究之引用。
文章選取與摘錄:
在meloxicam的研究，共十七篇論文中有九篇符合納入條件。在topoisomerase I inhibitors的研究，共五十五篇論文中有三十三篇符合納入條件，所有摘錄的資料遵循標準化的計劃書及資料收集格式。
結果:
在meloxicam的研究，利用Mantel-Haenszel 的方法，meloxicam相較於傳統的非類固醇類抗發炎藥，在任何不良事件(OR:0.80; 95%CI:0.75-0.85)，腸胃道不良事件(OR:0.66; 95%CI:0.61-0.71)，因任何不良事件而離開試驗(OR:0.75; 95%CI: 0.67-0.84)三方面都有較低的對比值，在考慮因腸胃道不良事件而離開試驗方面，各研究間有異質性存在(p=0.04)，利用DerSimonian & Laird 的方法，meloxicam相較於傳統的非類固醇類抗發炎藥，因腸胃道不良事件而離開試驗的對比值為0.59 (95%CI: 0.44-0.78)，另利用隨機效果迴歸(random-effects regression)的方法所得與DerSimonian & Laird方法有一致的結果。在topoisomerase I inhibitors的研究，利用DerSimonian & Laird 的方法，調整零的發生事件後，估計所有病人貧血、白血球減少、嗜中性白血球減少及血小板減少的整體發生率為24.6% (95%CI: 22.4%-26.9%)、32.8% (95%CI: 30.2%-35.5%)、50.4% (95%CI: 47.6%-53.3%)及20.0% (95%CI: 17.9%-22.1%)。利用beta-binomial模式，調整零的發生事件後所得的平均發生率為26.2% (SD: 0.029)、33.1%(SD: 0.043)、50.7%(SD: 0.052)及22.1%(SD: 0.034)，對於之前接受過化療的病人，其貧血及血小板減少的發生率比較高，而在未接受過化療的病人，其白血球球減少及嗜中性白血球減少的發生率較高。
結論:
在meloxicam 的研究中，meloxicam 比傳統非類固醇類抗發炎藥物有較好的耐受性，這個現象可以因meloxicam較選擇性抑制COX-2來解釋；在topoisomerase I inhibitors的研究，本研究提供第二階段臨床試驗期間，關於第三或第四級四個血液相關毒性的發生率。

Objective
Two meta-analyses were performed in our study. One was conducted to compare the incidence rate of any adverse events, gastrointestinal adverse events, dropouts due to adverse events and dropouts due to gastrointestinal adverse events of meloxicam with other standard NSAIDs during phase III clinical trials which indications were osteoarthritis, rheumatoid arthritis or acute lumbago. The other meta-analysis was conducted to integrate the incidence rate of grade 3 or 4 anemia, leukocytopenia, neutropenia and thrombocytopenia of topoisomerase I inhibitors (Irinotecan, topotecan and 9-aminocamptothecin) in cancers during phase II clinical trials.
Data Sources
In meloxicam study, randomized, controlled phase III clinical trials published in the English literature between 1990 and 1998 were identified through a MEDLINE and EMBASE: DRUGS & PHARMACOLOGY computer databases and reviewed citations in relevant articles. In topoisomerase I inhibitors study, phase II clinical trials published in the English literature between 1980 and 1998 were identified through a MEDLINE and EMBASE: DRUGS & PHARMACOLOGY computer databases and reviewed citations in relevant articles.
Study Selection & Data Extraction
In meloxicam study, nine of a totaly of seventeen phase III trials met the inclusion criteria. In topoisomerase I inhibitors study, thirty-three of a totaly fifty-five phase II trials met the inclusion criteria. All the data was abstracted according to a standardized protocol and recorded on the data-collection form.
Results
In meloxicam study, as compared with other standard non-steroidal anti-inflammatory drugs, meloxicam was consistently associated with a reduced odds ratio of any adverse events (OR: 0.80; 95%CI: 0.75-0.85), gastrointestinal (GI) adverse events (OR: 0.66; 95%CI: 0.61-0.71), and dropouts due to any adverse events (OR: 0.75; 95%CI: 0.67-0.84) by Mantel-Haenszel method. When considering the dropping out due to GI adverse events, the heterogeneity exists between the trials (p=0.04). By DerSimonian & Laird method, the overall pooled odds ratio of dropping out the trial due to GI adverse events in meloxicam group was 0.59 (95%CI: 0.44-0.78). The results of random-effects regression were consistent with those of DerSimonian & Laird method.
In topoisomerase I inhibitors study, the overall estimated incidence rates of anemia, leukocytopenia, neutropenia/granulocytopenia and thrombocytopenia in all patients were 24.6% (95%CI: 22.4%-26.9%), 32.8% (95%CI: 30.2%-35.5%), 50.4% (95%CI: 47.6%-53.3%), 20.0% (95%CI: 17.9%-22.1%) by DerSimonian & Laird method. The average estimated incidence rates with adjustment for zero medical event of anemia, leukocytopenia, neutropenia/granulocytopenia, and thrombocytopenia were 26.2%, 33.1%, 50.7%, 22.1%, respectively, with an estimated standard deviation of 0.029, 0.043, 0.052, and 0.034 by beta-binomial model. Anemia and thrombocytopenia was more frequent in patients with prior chemotherapy. Leukocytopenia and neutropenia/granulocytopenia was more frequent in patients without prior chemotherapy.
Conclusions
In meloxicam study, it provided evidence that meloxicam, a preferentially COX-2 inhibitor, exhibits a significantly better safety profile than other standard NSAIDs from published papers by using meta-analysis. It is likely due to its preferential inhibition of inducible COX-2 relative to constitutive COX-1. In topoisomerase I inhibitors study, it provided the incidence rates of four grade 3 or 4 hematologic toxicities of topoisomerase I inhibitors during phase II trials.

Acknowledgment I
English abstract II
Chinese abstract IV
Contents VI
List of tables VIII
List of figures XI
1 Introduction 1
2 Materials & Methods 6
2.1 Meta-analysis 6
2.2 Conduct of meta-analysis 7
2.3 Statistical methods in meta-analysis 10
3 Results 19
3.1 Study 1-Meloxicam 19
3.1.1 Study characteristics 19
3.1.2 Any adverse events 20
3.1.3 GI adverse events 21
3.1.4 Dropping out due to any adverse events 21
3.1.5 Dropping out due to GI adverse events 22
3.1.6 Random -effects regression method 23
3.1.7 Test for publication bias 24
3.2 Study 2-Topoisomerase I inhibitors 25
3.2.1 Patient characteristics 25
3.2.2 DerSimonian & Laird method 27
3.2.3 Beta-binomial model 27
4 Discussion 29
4.1 Meloxicam 29
4.2 Topoisomerase I inhibitors 32
4.2.1 Application from this study 35
4.3 Study limitations 35
4.4 Future development 36
5 Conclusion 38
6 References 39
Appendix I
Protocol I 54
Appendix II
Protocol II 65
Appendix III
SAS programs of Mantel-Haenszel method in meloxicam study 80
Appendix IV
SAS programs of DerSimonian & Laird method in meloxicam study 81
Appendix V
SAS program of random-effects model in meloxicam study 82
Appendix VI
SAS programs of DerSimonian & Laird method in topoisomerase I inhibitors 86
Appendix VII
SAS programs of beta-binomial model in topoisomerase I inhibitors 88

1. Mulrow CD. The Medical review article: state of the science. Ann Intern Med 1987; 106: 485-488.
2. Glass GV. Primary, secondary and meta-analysis of research. Educ Res 1976; 5: 3-8.
3. Freiman JA, Chalmers TC, Smith H, and Kuebler RR. The importance of beta, the type II error and sample size in the design and interpretation of the randomized control trial: survey of 71 "negative" trials. N Engl J Med 1978; 299: 690-694.
4. Chuang-Stein C. An application of the beta-binomial model to combine and monitor medical event rates in clinical trials. Drug Information Journal 1993; 27: 515-523.
5. Chuang-Stein C. Points for consideration in the collection and analysis of safety data. Drug Information Journal 1995; 29: 37-44.
6. Scherer JC and Wiltse CG. Adverse events: after 58 years, do we have it right yet: Biopharmaceutical Report 1996; 4: 1-5.
7. ICH guideline for industry: Clinical safety data management: definitions, and standards for expedited reporting. Quoted in: ICH Expert Working Group. ICH technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline: Structure and content of clinical study reports, Section12. November30, 1995.
8. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature 1971; 231: 232-235.
9. Vane JR. Towards a better aspirin. Nature 1994; 367: 215-216.
10. Engelhardt G. Pharmacology of meloxicam, a new non-steroidal anti-inflammatory drug with an improved safety profile through preferential inhibition of COX-2. British Journal of Rheumatology 1996; 35(suppl, 1): 4-12.
11. Burris HA III, and Fields SM. Topoisomerase I inhibitors. New Drug Therapy 1994; 8: 333-355.
12. Rothenberg ML. Topoisomerase I inhibitors: review and update. Ann Oncol 1997; 8: 837-855.
13. Antman EM, Lau J, Kupelnick B, Mosteller F, and Chalmers TC. A comparison of results of meta-analysis of randomised controlled trials and recommendations of clinical experts. JAMA 1992; 268: 240-248.
14. Egger M, and Smith GD. Meta-analysis: potentials and promise. BMJ 1997; 22: 1371-1374.
15. Wolf F M: Quantitative methods for research synthesis. In: al BRAe, ed. A SAGE university paper: Sara Miller McCune, 1986.
16. Dickersin K, and Berlin JA. Meta-analysis: State-of-the-Science. Epidemiologic Reviews 1992; 14: 154-176.
17. Petitti DB: Meta-analysis decision analysis and cost-effectiveness analysis: Oxford University Press, 1994.
18. Colditz GA, Burdick E, and Mosteller F. Heterogeneity in meta-analysis of data from epidemiologic studies: a commentary. Am J Epidemiol 1995; 142: 371-382.
19. Stenning SP, Freedman LS, and Bleehen NM. An overview of published results from randomized studies of nitrosoureas in primary high grade malignant glioma. Br J Cancer 1987; 56: 89-90.
20. Mantel N, and Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 718-748.
21. Miettinen OS. Estimability and estimation in case-referent studies. Am J Epidemiol 1976; 103: 226-235.
22. Breslow NE, and Day NE. Statistical methods in cancer research, Volume 1: the analysis of case-control studies, Lyon: international agency for research on cancer, 1980.
23. Yusuf S, Peto R, Lewis J, Collins R, and Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985: 27: 335-371.
24. Greenland S and Salvan A. Bias in the one-step method for pooling study results. Stat Med 1990; 9: 247-252.
25. DerSimonian R and Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986; 7: 177-188.
26. Thompson SG, and Pocock SJ. Can meta-analysis be trusted? Lancet 1991; 338: 1127-1130.
27. Fleiss RA, and Gloss AJ. Meta-analysis in epidemiology, with special reference to studies of the association between exposure to environmental tobacco smoke and lung cancer: a critique. J Clin Epidemiol 1991; 44: 127-139.
28. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 1987; 9: 1-30.
29. Berlin JA, Longnecker MP, and Greenland S. Meta-analysis of epidemiologic dose-response data. Epidemiology 1993; 4: 218-228.
30. Berkey CS, Hoaglin DC, Mosteller F, and Colditz GA. A random-effects regression model for meta-analysis. Statistics in Medicine 1995; 14: 395-411.
31. Morris CN. Parametric empirical Bayes inference: theory and applications. J Am Stat Assoc 1983; 78: 47-55.
32. Louis TA. Using empirical bayes methods in biopharmaceutical research. Stat Med 1991; 10: 811-829.
33. Kleinman JC. Proportions with extraneous variance: single and independent samples. J Am Stat Assoc 1973; 68: 46-54.
34. Wojtulewski JA, Schattenkirchner M, Barcelo P, Leloet X, Bevis PJR, Bluhmki E, et al. A six-month double-blind trial to compare the efficacy and safety of meloxicam 7.5mg daily and naproxen 750mg daily in patients with rheumatoid arthritis. Br J Rheumatol 1996; 35(suppl. 1): 22-28.
35. Turck D, Busch U, Heinzel G, and Narjes H: Rheumatol Eur 1995; 24 (suppl. 3) Abstract D16.
36. Cappelleri JC, Ioannidis JPA, Schmid CH, De Ferranti SD, Aubert M, Chalmer TC, and Lau J. Large trials vs. meta-analysis of smaller trials. JAMA 1996; 276: 1332-1338.
37. Lelorier J, Gregoire G, Benhaddad A, Lapieree J, and Derderian F. Discrepancies between meta-analyses and subsequent large randomized, contrilled trials. N Engl J Med 1997; 337: 536-542.
38. Distel M, Mueller C, Bluhmki E, and Fries J. Safety of meloxicam: a global analysis of clinical trials. Br J Rheumatol 1996; 35(suppl. 1): 68-77.
39. Easterbrook PJ, Berlin JA, Gopalan R, and Matthews DR. Publication bias in clinical research. Lancet 1991; 337: 867-872.
40. Light RJ, and Pillemer DB. Summing up: the science of reviewing research. Cambridge, MA: Harvard University Press, 1984.
41. Burris HA III, Rothenberg ML, Kuhn JG, Von Hoff DD. Clinical trials with the topoisomerase I inhibitors. Seminars in Oncology 1992; 19: 663-669.
42. Chalmers TC, Smith H Jr, Blackburn B, Silverman B, Schroeder B, Reitman D, and Ambroz A. A method for assessing the quality of a randomized control trial. Controlled Clin Trials 1981; 2: 31-49.
43. Stewart LA, and Parmar MK. Meta-analysis of the literature or of individual patient data: is there a difference? Lancet 1993; 341: 418-422.
44. Bero L, and Rennie D. The Cochrane Collaboration Preparing, maintaining and disseminating systematic reviews of the effects of health care. JAMA 1995; 274: 1935-1938.
45. Chalmers I, Dickersin K, and Chalmers TC. Getting to grips with Arche Cochrane''s agenda. BMJ 1992; 305: 786-788.
The references used in the meloxicam study were listed as follows:
1. Bevis PJR, Bird HA, and Lapham G. An open study to assess the safety and tolerability of meloxicam 15mg in subjects with rheumatic disease and mild renal impairment. Br J Rheumatol 1996; 35(suppl. 1): 56-60.
2. Bosch H, Sigmund R, and Hettich M. Efficacy and tolerability of intramuscular and oral meloxicam in patients with acute lumbago: a comparison with intramuscular and oral piroxicam. Curr Med Res Opin 1997; 14: 29-38.
3. Carrabba M, Paresce E, Angelini M, Galanti A, Marini MG, and Cigarini P. A comparison of the local tolerability, safety and efficacy of meloxicam and piroxicam suppositories in patients with osteoarthritis in patients with osteoarthritis: a single-blind, randomized, multicentre study. Curr Med Res Opin 1995; 13: 343-355.
4. Colerg K, Marceline H, Sigmund R, and Degner FL. The efficacy and tolerability of an 8-day administration of intravenous and oral meloxicam: a comparison with intramuscular and oral diclofenac in patients with acute lumbago. Curr Med Res Opin 1996; 13: 363-377.
5. Dequeker J, Hawkey C, Kahan A, Steinbruck K, Alegre C, Baumelou E, Begaud B, Isomaki H, Littlejohn G, Mau J, and Papazoglou S. Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the safety and efficacy large-scale evaluation of cox-inhibiting therapies (SELECT) trial in osteoarthritis. Br J Rheumatol 1998; 37: 946-951.
6. Ghozlan PR, Bernhardt M, Velicitat P, and Bluhmki E. Tolerability of multiple administration of intramuscular meloxicam: a comparison with intramuscular piroxicam in patients with rheumatoid arthritis or osteoarthritis. Br J Rheumatol 1996; 35(suppl. 1): 51-55.
7. Goei The HS, Lund B, Distel MR, and Bluhmki E. A double-blind, randomized trial to compare meloxicam 15mg with diclofenac 100mg in the treatment of osteoarthritis of the knee. Osteoarthritis and Cartilage 1997; 5: 283-288.
8. Hawkey C, Kahan A, Steinbruck K, Alegre C, Baumelou E, Begaud B, Dequeker J., Isomaki H, Littlejohn G, Mau J, Papazoglou S, and The international MELISSA group. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. Br J Rheumatol 1998; 37: 937-945.
9. Hosie J, Distel M, and Bluhmki E. Meloxicam in osteoarthritis: a 6-month, double-blind comparison with diclofenac sodium. Br J Rheumatol 1996; 35(suppl. 1): 39-43.
10.Huskisson EC, Ghozlan R, Kurthen R, Degner FL, and Bluhmki E. A long-term study to evaluate the safety and efficacy of meloxicam therapy in patients with rheumatoid arthritis. Br J Rheumatol 1996; 35(suppl. 1): 29-34.
11.Lemmel E, Bolten W, Burgos-Vargas R, Platt P, Nissila M, Sahlberg D, Bjorneboe O, Baumgartner H, Valat J, Franchimont P, Bluhmki E, Hanft G, and Distel M. Efficacy and safety of meloxicam in patients with rheumatoid arthritis. J Rheumatol 1997; 24: 282-290.
12.Linden B, Distel M, Bluhmki E. A double-blind study to compare the efficacy and safety of meloxicam 15mg with piroxicam 20mg in patients with osteoarthritis of the hip. Br J Rheumatol 1996; 35(suppl. 1): 35-38.
13.Lipscomb GR, Wallis N, Armstrong G, Rees WDW. Gastrointestinal tolerability of meloxicam and piroxicam: a double-blind placebo-controlled study. Br J Clin Pharmacol 1998; 46: 133-137.
14.Lund B, Distel M, and Bluhmki E. A double-blind, randomized, placebo-controlled study of efficacy and tolerance of meloxicam treatment in patients with osteoarthritis of the knee. Scand J Rheumatol 1998; 27: 32-37.
15.Patoia L, Santucci L, Furno P, Dionisi MS, Dell''orso S, Romagnoli M, Sattarinia A, and Marini MG. A 4-week, double-blind, parallel-group study to compare the gastrointestinal effects of meloxicam 7.5mg, meloxicam 15mg, piroxicam 20mg and placebo by means of fecal blood loss, endoscopy and symptom evaluation in healthy volunteers. Br J Rheumatol 1996; 35(suppl. 1): 61-67.
16.Reginster JY, Distel M, and Bluhmki E. A double-blind, three-week study to compare the efficacy and safety of meloxicam 7.5mg and meloxicam 15mg in patients with rheumatoid arthritis. Br J Rheumatol 1996; 35(suppl. 1): 17-21.
17.Wojtulewski JA, Schattenkirchner M, Barcelo P, Leloet X, Bevis PJR, Bluhmki E, and Distel M. A six-month double-blind trial to compare the efficacy and safety of meloxicam 7.5mg daily and naproxen 750mg daily in patients with rheumatoid arthritis. Br J Rheumatol 1996; 35(suppl. 1): 22-28.
The references used in topoisomerase I inhibitors study were listed as follows: (T: topotecan, I: irinotecan and A: 9-aminocamptothecin)
T1. Creemers GJ, Bolis G, Gore M, Scarfone G, Lacave AJ, Guastalla JP, Despax R, Favalli G, Kreinberg R, Van Belle S, Hudson I, Verweij J, and Ten Bokkel Huinink WW. Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 1996; 14: 3056-3061.
T2. Kraut EH, Walker MJ, Staubus A, Gochnour D, and Balcerzak SP. Phase II trial of topotecan in malignant melanoma. Cancer Investigation 1997; 15: 318-320.
T3. Mainwaring PN, Nicolson MC, Hickish T, Penson R, Joel S, Slevin M, and Smith IE. Continuous infusional topotecan in advanced breast and non-small-cell lung cancer: no evidence of increased efficacy. Br J Cancer 1997; 76: 1636-1639.
T4. Saltz LB, Schwartz GK, Ilson DH, Quan V, and Kelsen DP. A phase II study of topotecan administered five times daily in patients with advanced gastric cancer. Am J Clin Oncol 1997; 20: 621-625.
T5. Lynch TJ, Kalish L, Strauss G, Elias A, Skarin A, Shulman LN, Posner M, and Frei III E. Phase II study of topotecan in metastatic non-small-cell lung cancer. J Clin Oncol 1994; 12: 247-352.
T6. Beran M, Kantarjian H, O''Brien S, Koller C, Al-Bitar M, Arbuck S, Pierce S, Moore M, Abbruzzese JL, Andreeff M, Keating M and Estey E. Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 1996; 88: 2473-2479.
T7. Kudelka AP, Tresukosol D, Edwards CL, Freedman RS, Levenback C, Chantarawiroj P, De Leon CG, Edmund Kim E, Madden T, Wallin B, Hord M, Verschraegen C, Raber M, and Kavanagh JJ. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 1996; 14: 1552-1557.
T8. Macdonald JS, Benedetti JK, Modiano M, and Alberts DS. Phase II evaluation of topotecan in patients with advanced colorectal cancer. Invertigational New Drugs 1997; 15: 357-359.
T9. Swisher EM, Mutch DG, Rader JS, Elbendary A, and Herzog Tj. Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecologic Oncology 1997; 66: 480-486.
T10. Schiller JH, Kim K, Hutson P, DeVore R, Glick J, Stewart J, and Johnson D. Phase II study of topotecan in patients with extensive stage small-cell carcinoma of the lung: an eastern cooperative oncology group trial. J Clin Oncol 1996; 14: 2345-2352.
T11. Benedetti JK, Burris III HA, Balcerzak SP, and Macdonald JS. Phase II trial of topotecan in advanced gastric cancer: a southwest oncology group study. Investigational New Drugs 1997; 15: 261-264.
T12. Perez-Soler R, Fossella FV, Glisson BS, Lee JS, Murphy WK, Shin DM, Kemp BL, Lee JJ, Kane J, Robinson RA, Lippman SM, Kurie JM, Huber MH, Raber MN, and Hong WK. Phase II study of topotecan in patients with advanced non-small-cell lung cancer previously untreated with chemotherapy. J Clin Oncol 1996; 14: 503-513.
T13. Ardizzoni A, Hansen H, Dombernowsky P, Gamucci T, Kaplan S, Postmus P, Giaccone G, Schaefer B, Wanders J, and Verweij J for the European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. J Clin Oncol 1997; 15: 2090-2096.
T14. Creemers GJ, Gerrits CJH, Schellens JHM, Planting AST, Van der Burg MEL, Van Beurden VM, De Boer-Dennert M, Harteveld M, Loos W, Hudson I, Stoter G, and Verweij J. Phase II study and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer. J Clin Oncol 1996; 14: 2540-2545.
T15. Perez-Soler R, Glisson BS, Lee JS, Fossella FV, Murphy WK, Shin DM, and Hong WK. Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 1996; 14: 2785-2790.
T16. Van Warmerdam LJC, Creemers GJ, Rodenhuis S, Rosing H, De Boer-Dennert M, Schellens JHM, Ten Bokkel Huinink WW, Davies BE, Maes RAA, Verweij J, and Beijnen JH. Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure. Cancer Chemother Pharmacol 1996; 38: 254-260.
T17. Robert F, Soong S, and Wheeler RH. A phase II study of topotecan in patients with recurrent head and neck cancer. Am J Clin Oncol 1997; 20: 298-302.
T18. Blaney SM, Needle MN, Gillespoe A, Sato JK, Reaman GH, Berg SL, Adamson PC, Krailo MD, Bleyer WA, Poplack DG, and Balis FM. Phase II trial of topotecan administered as a 72-hour continuous infusion in children with refractory solid tumors: a collaborative pediatric branch, national cancer institute, and children''s cancer group study. Clinical Cancer Research 1998; 4: 357-360.
T19. Blaney SM, Phillips PC, Packer RJ, Heideman RL, Berg SL, Adamson PC, Allen JC, Sallan SE, Jakacki RI, Lange BJ, Reaman GH, Horowitz ME, Poplack DG, and Balis FM. Phase II evaluation of topotecan for pediatric central nervous sustem tumors. Cancer 1996; 78: 527-531.
T20. Hoskins P, Eisenhauer E, Beare S, Roy M, Drouin P, Stuart G, Bryson P, Grimshaw R, Capstick V, and Zee B. Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a national cancer institute of Canada clinical trials group study. J Clin Oncol 1998; 16: 2233-2237.
T21. Fleming GF, Kugller JW, Hoffman PC, Ansari R, Bitran JD, Klepsch A, Malone D, Fasanmade AA, Ratain M, and Vokes EE. Phase II trial of paclitaxel and topotecan with granulocyte colony-stimulating factor support in stage IV breast cancer. J Clin Oncol 1998; 16: 2032-2037.
T22. Bramwell VHC, Eisenhauer EA, Blackstein M, Boos G, Knowling M, Jolivet J, and Bogues W. Phase II study of topotecan (NSC 609 699) in patients with recurrent or metastatic soft tissue sarcoma. Annals of Oncology 1995; 6: 847-849.
T23. Macdonald D, Cairncross G, Stewart D, Forsyth P, Sawka C, Wainman N, and Eisenhauer E for the National Clinical Institute of Canada Clinical Trials Group. Phase II study of topotecan in patients with recurrent malignant glioma. Annals of Oncology 1996; 7: 205-207.
T24. Rowinsky EK, Baker SD, Burks K, O''Reilly S, Donehower RC, and Grochow LB. High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer: A phase II study and pharmacodynamic study. Annals of Oncology 1998; 9: 173-180.
T25. Creemers GJ, Wanders J, Gamucci T, Vallentin S, Dirix LY, Schoffski P, Hudson I, and Verweij J. Topotecan in colorectal cancer: A phase II study of the ECORT early clinical trials group. Annals of Oncology 1995; 6: 844-846.
T26. Law TM, Ilson DH, and Motzer RJ. Phase II trial of topotecan in patients with advanced renal cell carcinoma. Investigational New Drugs 1994; 12: 143-145.
T27. Puc HS, Bajorin DF, Bosl GJ, Amsterdam A, and Motzer RJ. Phase II trial of topotecan in patients with cisplatin-refractory germ cell tumors. Investigational New Drugs 1995; 13: 163-165.
T28. Hudes GR, Kosierowski R, Greenberg R, Ramsey HE, Fox SC, Ozols RF, McAleer CA, and Giantonio BJ. Phase II study of topotecan in metstatic hormone-refractory prostate cancer. Investigational New Drugs 1995; 13: 235-240.
T29. Smith RE, Lew Danika, Rodriguez GI, Taylor SA, Schuller D, and Ensley JF. Evaluation of topotecan in patients with recurrent for metastatic squamous cell carcinoma of the head and neck. Investigational New Drugs 1996; 14: 403-407.
T30. Scher RM, Kosierowski R, Lusch C, Alexander R, Fox S, Redei I, Green F, Raskay B, Amfoh K, Engstrom PF, and O''Dwyer PJ. Phase II trial of topotecan in advanced or metastatic adenocarcinoma of the pancreas. Investigational New Drugs 1996; 13: 347-354.
I1. Ohno R, Okada K, Masaoka T, Kuramoto A, Arima T, Yoshida Y, Ariyoshi H, Ichimaru M, Sakai Y, Oguro M, Ito Y, Morishima Y, Yokomaku S, and Ota K. An early phase II study of CPT-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma. J Clin Oncol 1990; 8: 1907-1912.
I2. Fukuoka M, Niitani H, Suzuki A, Motomiya M, Hasegawa K, Nishiwaki Y, Kuriyama T, Ariyoshi Y, Negoro S, Masuda N, Nakajima S, and Taguchi T for the CPT-11 Lung Cancer Group. A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small-cell lung cancer. J Clin Oncol 1992; 10: 16-20.
I3. Masuda N, Fukuoka M, Kusunoki Y, Matsui K, Takifuji N, Kudoh S, Negoro S, Nishioka M, Nakagawa K, and Takada M. CPT-11: a new derivative of camptothcin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1992; 10: 1225-1229.
I4. Masuda N, Fukuoka M, Takada M, Kusunoki Y, Negoro S, Matsui K, Matsui K, Kudoh S, Takifuji N, Nakagawa K, and Kishimoto S. CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer. J Clin Oncol 1992; 10: 1775-1780.
I5. Shimada Y, Yoshino M, Wakui A, Nakao I, Futatsuki K, Sakata Y, Kambe M, Taguchi T, Ogawa N, and the CPT-11 Gastrointestinal Cancer Study Group. Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. J Clin Oncol 1993; 11: 909-913.
I6. Tsuda H, Takatsuki K, Ohno R, Masaoka T, Okada K, Shirakawa S, Ohashi Y, Ota K, and the CPT-11 Study Group On Hematological Malignancy, Tokyo, Japan. Treatment of adult T-cell leukaemia-lymphoma with irinotecan hydrochloride (CPT-11). Br. J. Cancer 1994; 70: 771-774.
I7. Conti JA, Kemeny NE, Saltz LB, Huang Y, Tong WP, Chou T, Sun M, Pulliam S, and Gonzalez C. Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 1996; 14: 709-715.
I8. Rothenberg ML, Eckardt JR, Kuhn JG, Burris III HA, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, and Von Hoff DD. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996; 14: 1128-1135.
I9. Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P, Becouarn Y, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer M, Conroy T, Negrier S, Merrouche Y, Burki F, Mousseau M, Herait P, and Mahjoubi M. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997; 15: 251-260.
I10. Oshita F, Noda K, Nishiwaki Y, Fujita A, Kurita Y, Nakabayashi T, Tobise K, Abe S, Suzuki S, Hayashi I, Kawakami Y, Matsuda T, Tsuchiya S, Takahashi S, Tamura T, and Saijo N. Phase II study of irinotecan and etoposide in patients with metastatic non-small -cell lung cancer. J Clin Oncol 1997; 15: 304-309.
I11. Verschraegen CF, Levy T, Kudelka AP, Llerena E, Ende K, Freedman RS, Edwards CL, Hord M, Steger M, Kaplan AL, Kieback D, Fishman A, and Kavanagh JJ. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol 1997; 15: 625-631.
I12. Shirao K, Shimada Y, Kondo H, Saito D, Yamao T, Ono H, Yokoyama T, Fukuda H, Oka M, Watanabe Y, Ohtsu A, Boku N, Fujii T, Oda Y, Muro K, and Yoshida S. Phase I-II study of irinotecan hydrochloride combined with cisplatin in patients with advanced gastric cancer. J Clin Oncol 1997; 15: 921-927.
I13. Pitot HC, Wender DB, O''Connell MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, and Windsxhitl HE. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 1997; 15: 2910-2919.
I14. Kudoh S, Fujiwara Y, Talada Y, Yamamoto H, Kinoshita A, Ariyoshi Y, Furuse K, and Fukuoka M for the West Japan Lung Cancer Group. Phase II study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer. J Clin Oncol 1998; 16: 1068-1074.
I15. Irvin WP, Price FV, Bailey H, Gelder M, Rosenbluth R, Durivage HJ, and Potkul RK. A phase II study of irinotecan (CPT-11) in patients with advanced squamous cell carcinoma of cervix. Cancer 1998; 82: 328-333.
I16. Sugiyama T, Yakushiji M, Nishida T, Ushijima K, Okura N, Kigawa J, and Terakawa N. Irinotecan (CPT-11) combined with cisplatin in patients with refractory or recurrent ovarian cancer. Cancer Letters 1998; 128: 211-218.
I17. Masuda N, Fukuoka M, Fujita A, Kurita Y, Tsuchiya S, Nagao K, Negoro S, Nishikawa H, Katakami N, Nakagawa K and Niitani H for the CPT-11 Lung Cancer Study Group. A phase II trial of combination of CPT-11 and cisplatin for advanced non-small-cell lung cancer. Br J Cancer 1998; 78: 251-256.
I18. Cunningham D, Pyrhonen S, James RD, Punt CJA, Hixkish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Award L, Jacques C, and Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998; 352: 1413-1418.
I19. Wagener DJT, Verdonk HER, Dirix LY, Catimel G, Siegenthaler P, Buitenhuis M, Mathieu-Boue A, and Verweij J. Phase II trial of CPT-11 in patients with advanced pancreatic cancer, and EORTC early clinical trials group study. Annals of Oncology 1995; 6: 129-132.
I20. Tobinai K, Hotta T, Saito H, Ohnishi K, Ohno R, Ogura M, Ariyoshi Y, Takeyama K, Kobayashi T, Ohashi Y, Shirakawa S and members of the CPT-11/Lymphoma Study Group. Combination phase I/II study of irinotecan hydrochloride (CPT-11) and carboplatin in relapsed or refractory non-Hodgkin''s lymphoma. Jpn J Clin Oncol 1996; 26: 455-460.
I21. Yokoyama A, Kurita Y, Saijo N, Tamura T, Noda K, Shimokata K, and Matsuda T. Dose-finding study of irinotecan and cisplantin plus concurrent radiotherapy for unresectable stage III non-small-cell lung cancer. Br J Cancer 1998; 78: 257-262.
I22. Masuda N, Matsui K, Negoro S, Takifuji N, Takeda K, Yana T, Kobayashi M, Hirashima T, Kusunoki Y, Ushijima S, Kawase I, Tada T, Sawaguchi H, and Fukuoka M. Combination of irinotecan and etoposide for treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1998; 16: 3329-3334.
A1. Pazdur R, Diaz-Canton E, Ballard PW, Bardof Je, Graham S, Arbuck SG, Abbruzzese JL, and Winn R. Phase II trial of 9-aminocamptothecin administered as a 72-hour continuous infusion in metastatic colorectal carcinoma. J Clin Oncol 1997; 15: 2905-2909.
A2. Saltz LB, Kemeny NE, Tong W, Harrison J, Berkery T, and Kelsen DP. 9-aminocamptothecin by 72-hour continuous intravenous infusion is inactive in the treatment of patients with 5-fluorouracil-refractory colorectal carcinoma. Cancer 1997; 80: 1727-1732.
A3. Wilson WH, Little R, Pearson D, Jaffe ES, Steinberg SM, Cheson BD, Humphrey R, Kohler DR, and Elwood P. Phase II and dose-escalation with or without granulocyte colony-stimulating factor study of 9-aminocamptothecin in relapsed and refractory lymphomas. J Clin Oncol 1998; 16: 2345-2351.
References of protocol I
1. Giercksky KE, Huseby G, and Rugstad HE. Epidemiology of NDAID-related gastrointestinal side effects. Scand J Gastroenterol 1989; 24: 3-8.
2. Lanza FL. Gastrointestinal toxicity of newer NSAIDs. Clinical Reviews 1993; 88: 1318-1323.
3. Fries JF. NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal. J Rheumatol 1991; 18(suppl. 28): 6-10.
4. Fries J. Toward an understanding of NSAID-related adverse events: the contribution of longitudinal data. Scand J Rheumatol 1996; 25(suppl 102): 3-8.
5. Fries JF. Postmarketing drug surveillance: are our priorities right? J Rheumatol 1988; 15: 389-390.
6. Fries JF, Miller SR, Spitz PW, Williams CA, Hubert HB, and Bloch DA. Toward an epidemiology of gastropathy associated with nonsteroidal antiinflammatory drug use. Gastroenterology 1989; 96: 647-655.
7. Fries JF. The relative toxicity of non-steroidal anti-inflammatory drugs. Arthritis Rheum 1991; 34: 1353-1360.
8. Fries JF, Williams CA, Bloch DA, and Michel BA. Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence rate and risk factor models. The American Journal of Medicine 1991; 91: 213-222.
9. Garcia-Rodriguez LA, and Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steridal anti-inflammatory drugs. The Lancet 1994; 343: 769-772.
10. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115: 787-796.
11. Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic ulcers. BMJ 1990; 300: 278-284.
12. MacDonald TM, Morant SV, Robinson GC, Shield MJ, Mcgilchrist MM, Murray FE, and Mcdevitt DG. Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. BMJ 1997; 315: 1333-1337.
13. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature 1971; 231: 232-235.
14. Vane JR: Towards a better aspirin. Nature 1994; 367: 215-216.
15. Engelhardt G. Pharmacology of meloxicam, a new non-steroidal anti-inflammatory drug with an improved safety profile through preferential inhibiton of COX-2. British Journal of Rheumatology 1996; 35(suppl, 1): 4-12.
16. Meade EA, Smith WL, and DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthease (cytooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1993; 268: 6610-6614.
17. Turck D, Busch U, Heinzel G, and Narjes H. Clinical pharmacokinetics of meloxicam. Eur J Rheumatol Inflamm 1995; 15: 23-30.
18. Barner A. Review of clinical trials and benefit/risk ratio of meloxicam. Scan J Rheumatol 1996; 25(suppl. 1): 29-37.
19. Engelhardt G, Homma D, Schlegel K, Utzmann R, and Schnitzler C. Anti-inflammatory, analgesic, antipyret
References of protocol II
1. Wang JC. DNA topoisomerases. Ann Rev Biochem 1985; 54: 665-697.
2. Zijlstra JG, De Jong S, De Vries EGE, and Mulder NH. Topoisomerase, new targets in cancer chemotherapy. Med Oncol Tumor Pharmacother 1990; 7: 11-18.
3. Pommier Y. DNA topoisomerase I and II in cancer chemotherapy: update and perspectives. Cancer Chem Pharmacol 1993; 32: 103-108.
4. Burris HA III, and Fields SM. Topoisomerase I inhibitors. New Drug Therapy 1994; 8: 333-355.
5. Giovanella BC, Stehlin JS, Wall ME, Wani MC, Nixholas AW, Liu LF, Silber R, and Potmesil M. DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenogragts. Science 1989; 246: 1046-1048.
6. Horwitz SP, and Horwitz HS. Effects of camptothecin on the breakage and repair of DNA during the cell cycle. Cancer Res 1973; 33: 2834-2836.
7. Tewey KM, Chen GL, Nelson EM, and Liu LF. Intercalative antitumour drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem 1984; 259: 9182-9187.
8. Rothenberg ML. Topoisomerase I inhibitors: review and update. Ann Oncol 1997; 8: 837-855.
9. Wall ME, Wani MC, Cooke CE, Palmer KH, McPhail AT, and Slim GA. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc 1966; 88: 3888-3890.
10. Gottlieb JA, Guarino AM, Call JB, Oliverio VT, and Block JB. Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC 100880). Cancer Chemother Rep 1970; 54: 461-470.
11. Moertel CG, Schutt AJ, Reitemeier RJ, and Hahn RG. Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother. Rep. 1972; 56: 95-101.
12. Wani MC, Ronman PE, Lindley JT, and Wall ME. Plant antitumor agents. 18. Synthesis and biological activity of camptothecin analogues. J Med Chem 1980; 23: 554-560.
13. Wani MC, Nicholas AW, ME. W: Plant antitumor agents. 23. Synthesis and biological activity of camptothecin analogues. J Med Chem 1986; 29: 2358-2363.
14. Creemers GJ, Lund B, and Verweij J. Topoisomerase I inhibitors: Topotecan and irinotecan. Cancer Treat Rev 1994; 20: 73-96.
15. Shimada Y, Rothenberg M, Hilsenbeck SG et al. Activity of CPT-11 (irinotecan hydrochloride), a topoisomerase I inhibitor, against human tumour colony-forming units. Anti-cancer drugs 1994; 5: 202-206.
16. Burris HA III, Rothenberg ML, Kuhn JG, Von Hoff DD. Clinical trials with the topoisomerase I inhibitors. Seminars in Oncology 1992; 19: 663-669.
17. Johnson RK, McCabe FL, Gallagher G et al. Comparative efficacy of topotecan irinotecan and 9-aminocamptothecin in preclinical tumour models. Ann Oncol 1992; 3(suppl. 1): 85(Abstr).
18. Tsuji T, Kaneda N, Kado K, Yokokura T, Yoshimoto T, and Tsuru D. CPT-11 converting enzyme from rat serum: Purification and some properties. J pharmacobiodyn 1991; 14: 341-349.
19. Abigerges D, Chabot GG, Armand JP et al. Phase I and pharmacologic studies of the camptothecin analogue irinotecan administered every three weeks in cancer patients. J Clin Oncol 1995; 13: 210-221.
20. Rothenberg ML, Kuhn JG, Burris HA et al. Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 1993; 11: 2194-2204.
21. Kingsbury WD, Boehm JC, Jakas DR, Holden KG, Hecht SM, Gallagher G, Caranfa MJ, Garenfa DR, McCabe FL, Faucette LF, Johnson RK, and Hertzberg RP. Synthesis of watersoluble (aminoalkyl) camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J Med Chem 1991; 34: 98-107.
22. Sirott MN, Saltz L, Young C, and Tong W. Phase I trial and pharmacologic study of intravenous topotecan. Proc Am Soc Clin Oncoll 1991; 10: 104(Abstr).
23. Rowinsky EK, Grochow LB, Hendrick CB, et al. Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 1992; 10: 647-656.
24. Barnett AA. FDA approve bark-derived drug. Lancet 1996; 347: 1613.
25. Hochster H, Liebes L, Speyer J et al. Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well tolerated regimen. J Clin Oncol 1994; 12: 553-559.
26. Verweij J, Lund B, Beignen J et al. Phase I and pharmacokinetic study of topotecan: A new topoisomerase I inhibitor. Ann Oncol 1993; 4: 673-678.
27. Haas NB, LaCreta FP, Walczak J, Hezdis GR, Brennan J, Ozols RF, and O''Dwyer PJ. Phase I / pharmacokinetic study of topotecan by 24-hour continuous infusion. Cancer Res 1994; 54: 1220-1226.
28. Abbruzzese JL, Madden T, Sugarman SM et al. Phase I clinical and plasma and cellular pharmacological study of topotecan without and with granulocyte colony-stimulating factor. Clin Cancer Res 1996; 2: 1489-1497.
29. Pratt CB, Stewart C, Santana VW et al. Phase I study of topotecan for pediatric patients with malignant solid tumours. J Clin Oncol 1994; 12: 539-543.
30. Rowinsky EK, Adjei A, Ross C et al. Phase I and pharmacodynamic study of the topoisomerase I inhibitor topotecan in patients with refractory acute leukemia. J Clin Oncol 1994; 12: 2193-2203.
31. Hsiang YH, Liu LF, Wall MW, et al. DNA topoisomerase I mediated DNA cleavage and cytotoxicity of camptothecin analogs. Cancer Res 1989; 49: 4385-4389.
32. Tanizawa A, and Pommier Y. Topoisomerase I inhibition, DNA damage and cytotoxicity induced by camptothecin derivatives in clinical trials. Proc Am Assoc Cancer Res 1993; 34: 329(Abstr).
33. Broom C. Clinical studies of topotecan. Ann NY Acad Sci 1996; 803: 264-271.
34. Tobinai K, Kohni A, Shimada Y, Watanabe T, Tamura T, et. al. Toxicity grading criteria of the Japan Clinical Oncology Group. Jpn J Clin Oncol 1993; 23: 250-257.
35. Guidelines for the reporting of adverse drug reactions. Besthesda: division of cancer treatment. National Cancer Institute, 1988.
36. Miller AB, Hoogastraten B, Staquet M, and Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-214.
37. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
38. DerSimonian R, and Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986; 7: 177-188.
39. Chuang-Stein C. An application of the beta-binomial model to combine and monitor medical event rates in clinical trials. Drug Information Journal 1993; 27: 515-523.
40. Jennison C, and Turnbull BW. Sequential equivalence testing and repeated confidence intervals, with applications to normal and binary responses. Biometrics 1993; 49: 31-43.