Effects of different chemotherapy regimens on survival for advanced cervical cancer: Systematic review and meta-analysis

Cancer Treatment Reviews

Volumn 33, Issue 1, 2007, Pages 24-38

  Tzioras, Spyridon ^a   Pavlidis, Nicholas ^a   Paraskevaidis, Evangelos ^a   Ioannidis, John P A ^a,b,c  

^a UNIVERSITY OF IOANNINA   (Greece)

^b INSTITUTE OF COMPUTER SCIENCE   (Greece)

^c TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Advanced stage; Cervical cancer; Chemotherapy; Meta analysis; Randomized controlled trials; Survival

Indexed keywords

ALTRETAMINE; AMIFOSTINE; BLEOMYCIN; CARBOPLATIN; CHLORAMBUCIL; CISPLATIN; CYCLOPHOSPHAMIDE; DOXIFLURIDINE; DOXORUBICIN; EPIRUBICIN; FLUOROURACIL; GEMCITABINE; HYDROXYUREA; IFOSFAMIDE; IPROPLATIN; LOMUSTINE; METHOTREXATE; MITOLACTOL; MITOMYCIN; MITOMYCIN C; PACLITAXEL; PLACEBO; PLATINUM COMPLEX; TENIPOSIDE; TOPOTECAN; VINBLASTINE; VINCRISTINE; VINDESINE;

ADVANCED CANCER; CANCER ADJUVANT THERAPY; CANCER SURVIVAL; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; CONTROLLED CLINICAL TRIAL; HUMAN; META ANALYSIS; METASTASIS; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; RANDOMIZED CONTROLLED TRIAL; REVIEW; SURVIVAL TIME; SYSTEMATIC REVIEW; UTERINE CERVIX CANCER;

ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CISPLATIN; COMBINED MODALITY THERAPY; FEMALE; HUMANS; PLATINUM COMPOUNDS; RANDOMIZED CONTROLLED TRIALS; SURVIVAL ANALYSIS; UTERINE CERVICAL NEOPLASMS;

EID: 33846372687     PISSN: 03057372     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ctrv.2006.09.007     Document Type: Review

References (92)

1. American Cancer Society. Cancer facts and figures 2006 (2006), American Cancer Society, Atlanta (GA)
2. Haie-Meder C., Fervers B., Fondrinier E., Haugh M., Lhomme C., and Guastalla J.P. SOR guidelines for concomitant chemoradiotherapy for patients with uterine cervical cancers : evidence update bulletin 2004. Ann Oncol 16 (2005) 1100-1108
3. American College of Obstetricians and Gynecologists. ACOG practice bulletin. Diagnosis and treatment of cervical carcinomas. Number 35, May 2002. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002; 78:79-91.
4. Friedlander M., and Grogan M. U.S. preventative services task force. guidelines for the treatment of recurrent and metastatic cervical cancer. Oncologist 7 (2002) 342-347
5. Lukka H., Hirte H., Fyles A., et al. Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer-a meta-analysis. Clin Oncol (R Coll Radiol) 14 (2002) 203-212
6. Green J.A., Kirwan J.M., Tierney J.F., et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 358 (2001) 781-786
7. Whitney C.W., Sause W., Bundy B.N., et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17 (1999) 1339-1348
8. Rose P.G., Bundy B.N., Watkins E.B., et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340 (1999) 1144-1153
9. Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy for locally advanced cervical cancer: a systematic review and meta-analysis of individual patient data from 21 randomised trials. Eur J Cancer 39 (2003) 2470-2486
10. Vale C., Tierney J., and Stewart L. Concomitant chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data. Gynecol Oncol 100 (2006) 442-443
11. Green J., Kirwan J., Tierney J., et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 3 (2005) CD002225
12. Ioannidis J.P., Polycarpou A., Ntais C., and Pavlidis N. Randomized trials comparing chemotherapy regimens for advanced non-small cell lung cancer: biases and evolution over time. Eur J Cancer 39 (2003) 2278-2287
13. Polyzos N.P., Pavlidis N., Paraskevaidis E., and Ioannidis J.P. Randomized evidence on chemotherapy and hormonal therapy regimens for advanced endometrial cancer: an overview of survival data. Eur J Cancer 42 (2006) 319-326
14. Parmar M.K., Torri V., and Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17 (1998) 2815-2834
15. Lau J., Ioannidis J.P., and Schmid C.H. Quantitative synthesis in systematic reviews. Ann Intern Med 127 (1997) 820-826
16. Higgins J.P., Thompson S.G., Deeks J.J., and Altman D.G. Measuring inconsistency in meta-analyses. BMJ 327 (2003) 557-560
17. DerSimonian R., and Laird N. Meta-analysis in clinical trials. Control Clin Trials 7 (1986) 177-188
18. Begg C.B., and Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 50 (1994) 1088-1101
19. Ikeda O., Mizukami N., Murata Y., et al. Randomized comparison of intra-arterial chemotherapy versus intra-arterial chemotherapy and gelfoam embolization for treatment of advanced cervical carcinoma. Cardiovasc Intervent Radiol 28 (2005) 736-743
20. Duenas-Gonzalez A., Cetina-Perez L., Lopez-Graniel C., et al. Pathologic response and toxicity assessment of chemoradiotherapy with cisplatin versus cisplatin plus gemcitabine in cervical cancer: a randomized Phase II study. Int J Radiat Oncol Biol Phys 61 (2005) 817-823
21. Buda A., Fossati R., Colombo N., et al. Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study. J Clin Oncol 23 (2005) 4137-4145
22. Long III H.J., Bundy B.N., Grendys Jr. E.C., et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol 23 (2005) 4626-4633
23. Lanciano R., Calkins A., Bundy B.N., et al. Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: a gynecologic oncology group study. J Clin Oncol 23 (2005) 8289-8295
24. Cadron I., Jakobsen A., and Vergote I. Report of an early stopped randomized trial comparing cisplatin versus cisplatin/ifosfamide/ 5-fluorouracil in recurrent cervical cancer. Gynecol Obstet Invest 59 (2005) 126-129
25. Moore D.H., Blessing J.A., McQuellon R.P., et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 22 (2004) 3113-3119
26. Garipagaoglu M., Kayikcioglu F., Kose M.F., et al. Adding concurrent low dose continuous infusion of cisplatin to radiotherapy in locally advanced cervical carcinoma: a prospective randomized pilot study. Br J Radiol 77 (2004) 581-587
27. Yamamoto K., Izumi R., Hasegawa K., et al. Adjuvant oral 5-fluorouracil for cervical cancer: Japanese Gynecologic Oncology Group report. Int J Oncol 24 (2004) 1175-1179
28. Lorvidhaya V., Chitapanarux I., Sangruchi S., et al. Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys 55 (2003) 1226-1232
29. Tabata T., Takeshima N., Nishida H., Hirai Y., and Hasumi K. A randomized study of primary bleomycin, vincristine, mitomycin and cisplatin (BOMP) chemotherapy followed by radiotherapy versus radiotherapy alone in stage IIIB and IVA squamous cell carcinoma of the cervix. Anticancer Res 23 (2003) 2885-2890
30. Bloss J.D., Blessing J.A., Behrens B.C., et al. Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 20 (2002) 1832-1837
31. Pearcey R., Brundage M., Drouin P., et al. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20 (2002) 966-972
32. Yamamoto K., Noda K., Hatae M., et al. Effects of concomitant use of doxifluridine, radiotherapy and immunotherapy in patients with advanced cervical cancer. Oncol Rep 8 (2001) 273-277
33. Nagai N., Oshita T., Murakami J., Shigemasa K., Hirokawa Y., and Ohama K. Radiotherapy combined with transcatheter arterial infusion of cisplatin versus oral fluoropyrimidine anticancer agent for locally advanced carcinoma of the uterine cervix: a prospective follow-up study. Oncol Rep 8 (2001) 119-125
34. Vermorken J.B., Zanetta G., De Oliveira C.F., et al. Randomized phase III trial of bleomycin, vindesine, mitomycin-C, and cisplatin (BEMP) versus cisplatin (P) in disseminated squamous-cell carcinoma of the uterine cervix: an EORTC Gynecological Cancer Cooperative Group study. Ann Oncol 12 (2001) 967-974
35. Herod J., Burton A., Buxton J., et al. A randomised, prospective, phase III clinical trial of primary bleomycin, ifosfamide and cisplatin (BIP) chemotherapy followed by radiotherapy versus radiotherapy alone in inoperable cancer of the cervix. Ann Oncol 11 (2000) 1175-1181
36. Symonds R.P., Habeshaw T., Reed N.S., et al. The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer. Eur J Cancer 36 (2000) 994-1001
37. Roberts K.B., Urdaneta N., Vera R., et al. Interim results of a randomized trial of mitomycin C as an adjunct to radical radiotherapy in the treatment of locally advanced squamous-cell carcinoma of the cervix. Int J Cancer 90 (2000) 206-223
38. Gallardo D., Mohar A., Calderillo G., et al. Cisplatin, radiation, and amifostine in carcinoma of the uterine cervix. International Journal of Gynecological Cancer 9 (1999) 225-230
39. Wong L.C., Ngan H.Y., Cheung A.N., et al. Chemoradiation and adjuvant chemotherapy in cervical cancer. J Clin Oncol 17 (1999) 2055-2060
40. Thomsen T.K., Pfeiffer P., and Bertelsen K. Teniposide or carboplatin in patients with recurrent or advanced cervical carcinoma: A randomized phase II trial. International Journal of Gynecological Cancer 8 (1998) 310-314
41. Thomas G., Dembo A., Ackerman I., et al. A randomized trial of standard versus partially hyperfractionated radiation with or without concurrent 5-fluorouracil in locally advanced cervical cancer. Gynecol Oncol 69 (1998) 137-145
42. Sardi J.E., Sananes E., Giaroli A., et al. Neoadjuvant chemotherapy in cervical carcinoma stage IIB: a randomized trial. Internat J Gynecol Oncol 8 (1998) 441-450
43. Omura G.A., Blessing J.A., Vaccarello L., et al. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 15 (1997) 165-171
44. Leborgne F., Leborgne J.H., Doldan R., et al. Induction chemotherapy and radiotherapy of advanced cancer of the cervix: a pilot study and phase III randomized trial. Int J Radiat Oncol Biol Phys 37 (1997) 343-350
45. Tseng C.J., Chang C.T., Lai C.H., et al. A randomized trial of concurrent chemoradiotherapy versus radiotherapy in advanced carcinoma of the uterine cervix. Gynecol Oncol 66 (1997) 52-58
46. Sundfor K., Trope C.G., Hogberg T., et al. Radiotherapy and neoadjuvant chemotherapy for cervical carcinoma. A randomized multicenter study of sequential cisplatin and 5-fluorouracil and radiotherapy in advanced cervical carcinoma stage 3B and 4A. Cancer 77 (1996) 2371-2378
47. Sardi J., Gairoli A., Snanes C., et al. Randomized trial with neoadjuvant chemotherapy in stage IIIB squamous carcinoma cervix uteri: an unexpected therapeutic management. International Journal of Gynecologic Oncology 6 (1996) 85-93
48. Tattersall M.H., Lorvidhaya V., Vootiprux V., et al. Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer. Cervical Cancer Study Group of the Asian Oceanian Clinical Oncology Association. J Clin Oncol 13 (1995) 444-451
49. Husseinzadeh N., Shrake P., DeEulis T., Rowley K., and Aron B. Chemotherapy and extended-field radiation therapy to para-aortic area in patients with histologically proven metastatic cervical cancer to para-aortic nodes: a phase II pilot study. Gynecol Oncol 52 (1994) 326-331
50. Kumar L., Kaushal R., Nandy M., et al. Chemotherapy followed by radiotherapy versus radiotherapy alone in locally advanced cervical cancer: a randomized study. Gynecol Oncol 54 (1994) 307-315
51. Chiara S., Bruzzone M., Merlini L., et al. Randomized study comparing chemotherapy plus radiotherapy versus radiotherapy alone in FIGO stage IIB-III cervical carcinoma. GONO (North-West Oncologic Cooperative Group). Am J Clin Oncol 17 (1994) 294-297
52. Chauvergne J., Lhomme C., Rohart J., et al. Chimiotherapie neoadjuvante des cancer du col uterin aux stades IIb et III. Bull Cancer 80 (1993) 1069-1079
53. Tatterall M.H.N., Ramirez C., and Coppleson M. A randomized trial comparing platimum-based chemotherapy vs. radiotherapy alone in patients with locally advanced cervical cancer. International Journal of Gynecological Cancer 2 (1992) 244-251
54. Lira-Puerto V., Silva A., Morris M., et al. Phase II trial of carboplatin or iproplatin in cervical cancer. Cancer Chemother Pharmacol 28 (1991) 391-396
55. Souhami L., Gil R.A., Allan S.E., et al. A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix. J Clin Oncol 9 (1991) 970-977
56. Tobias J., Buxton E.J., Blackledge G., et al. Neoadjuvant bleomycin, ifosfamide and cisplatin in cervical cancer. Cancer Chemother Pharmacol 26 Suppl. (1990) S59-S62
57. McGuire III W.P., Arseneau J., Blessing J.A., et al. A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol 7 (1989) 1462-1468
58. Wong L.C., Choo Y.C., Choy D., Sham J.S., and Ma H.K. Long-term follow-up of potentiation of radiotherapy by cis-platinum in advanced cervical cancer. Gynecol Oncol 35 (1989) 159-163
59. Piver M., Khalil M., and Emrich L.J. Hydroxyurea plus pelvic irradiation versus placebo plus pelvic irradiation in nonsurgically staged stage IIIB cervical cancer. J Surg Oncol 42 (1989) 120-125
60. Thigpen J.T., Blessing J.A., DiSaia P.J., Yordan E., Carson L.F., and Evers C. A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 12 (1994) 1408-1414
61. Edmonson J.H., Johnson P.S., Wieand H.S., et al. Phase II studies of bleomycin, cyclophosphamide, doxorubicin and cisplatin, and bleomycin and cisplatin in advanced cervical carcinoma. Am J Clin Oncol 11 (1988) 149-151
62. Alberts D.S., Kronmal R., Baker L.H., et al. Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study. J Clin Oncol 5 (1987) 1791-1795
63. Bezwoda W.R., Nissenbaum M., and Derman D.P. Treatment of metastatic and recurrent cervix cancer with chemotherapy: a randomised trial comparing hydroxyurea with cis-diamminedichloro-platinum plus methotrexate. Med Pediatr Oncol 14 (1986) 17-19
64. Choo Y.C., Choy T.K., Wong L.C., and Ma H.K. Potentiation of radiotherapy by cis-dichlorodiammine platinum (II) in advanced cervical carcinoma. Gynecol Oncol 23 (1986) 94-100
65. Bonomi P., Blessing J.A., Stehman F.B., et al. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 3 (1985) 1079-1085
66. Singh P., Dharmalingam S.K., Tan M.K., and Tan C.K. Chemotherapy-radiotherapy combination in the treatment of carcinoma of the cervix. Southeast Asian J Trop Med Public Health 16 (1985) 665-668
67. Piver M.S., Barlow J.J., Vongtama V., and Blumenson L. Hydroxyurea: a radiation potentiator in carcinoma of the uterine cervix. A randomized double-blind study. Am J Obstet Gynecol 147 (1983) 803-808
68. Omura G.A., Velez-Garcia E., and Birch R. Phase II randomized study of doxorubicin, vincristine, and 5-FU versus cyclophosphamide in advanced squamous cell carcinoma of the cervix. Cancer Treat Rep 65 (1981) 901-903
69. Malkasian Jr. G.D., Decker D.G., Green S.J., Edmonson J.H., Jefferies J.A., and Webb M.J. Treatment of recurrent and metastatic carcinoma of the cervix: comparison of doxorubicin with a combination of vincristine and 5-fluorouracil. Gynecol Oncol 11 (1981) 235-239
70. Freedman R.S., Herson J., Wharton J.T., and Rutledge F.N. Single-agent chemotherapy for recurrent carcinoma of the cervix. Cancer Clin Trials 3 (1980) 345-350
71. Hreshchyshyn M.M., Aron B.S., Boronow R.C., Franklin III E.W., Shingleton H.M., and Blessing J.A. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys 5 (1979) 317-322
72. Omura G.A., Shingleton H.M., Creasman W.T., Blessing J.A., and Boronow R.C. Chemotherapy of gynecologic cancer with nitrosoureas: a randomized trial of CCNU and methyl-CCNU in cancers of the cervix, corpus, vagina, and vulva. Cancer Treat Rep 62 (1978) 833-835
73. Wallace Jr. H.J., Hreshchyshyn M.M., Wilbanks G.D., Boronow R.C., Fowler Jr. W.C., and Blessing J.A. Comparison of the therapeutic effects of adriamycin alone versus adriamycin plus vincristine versus adriamycin plus cyclophosphamide in the treatment of advanced carcinoma of the cervix. Cancer Treat Rep 62 (1978) 1435-1441
74. Baker L.H., Opipari M.I., and Izbicki R.M. Mitomycin C, vincristine, and bleomycin therapy for advanced cervical cancer. Obstet Gynecol 52 (1978) 146-150
75. Greenberg B.R., Kardinal C.G., Pajak T.F., and Bateman J.R. Adriamycin versus adriamycin and bleomycin in advanced epidermoid carcinoma of the cervix. Cancer Treat Rep 61 (1977) 1383-1384
76. Moseley H.S., Sasaki T., McConnell D.B., et al. A randomized pilot study comparing two regimens in the treatment of squamous cell carcinoma. J Surg Oncol 8 (1976) 35-42
77. Bond W.H., Arthur K., Banks A.J., et al. Combination chemotherapy in the treatment of advanced squamous cell carcinoma of the cervix. Clin Oncol 2 (1976) 173-178
78. de Palo G.M., Bajetta E., Luciani L., Musumeci R., Di Re F., and Bonadonna G. Methotrexate (NSC-740) and bleomycin (NSC-125066) in the treatment of advanced epidermoid carcinoma of the uterine cervix. Tumori 62 (1976) 113-122
79. de Palo G.M., Bajetta E., Beretta G., and Bonadonna G. Adriamycin plus bleomycin versus cyclophosphamide plus vincristine in advanced carcinoma of the uterine cervix. Cancer Chemother Rep 57 (1973) 429-435
80. Barlow J.J., Piver M.S., Chuang J.T., Cortes E.P., Onuma T., and Holland J.F. Adriamycin and bleomycin, alone and in combination, in gynecologic cancers. Cancer 32 (1973) 735-743
81. Ioannidis J.P., and Pavlidis N. Levels of absolute survival benefit for systemic therapies of advanced cancer. A call for standards. Eur J Cancer 39 (2003) 1194-1198
82. Eifel P.J., Winter K., Morris M., et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 22 (2004) 872-880
83. Ioannidis J.P. Indirect comparisons: the mesh and mess of clinical trials. Lancet 368 (2006) 1470-1472
84. Glenny A.M., Altman D.G., Song F., et al. Indirect comparisons of competing interventions. Health Technol Assess 9 (2005) 1-134 iii-iv
85. Chan A.W., Hrobjartsson A., Haahr M.T., Gotzsche P.C., and Altman D.G. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA 291 (2004) 2457-2465
86. Ioannidis J.P., Cappelleri J.C., and Lau J. Issues in comparisons between meta-analyses and large trials. JAMA 279 (1998) 1089-1093
87. Oxman A.D., and Guyatt G.H. A consumer's guide to subgroup analyses. Ann Intern Med 116 (1992) 78-84
88. Montori V.M., Devereaux P.J., Adhikari N.K., et al. Randomized trials stopped early for benefit: a systematic review. JAMA 294 (2005) 2203-2209
89. Keys H.M., Bundy B.N., Stehman F.B., Muderspach L.I., Chafe W.E., Suggs III C.L., et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340 (1999) 1154-1161
90. Peters III W.A., Liu P.Y., Barrett II R.J., Stock R.J., Monk B.J., Berek J.S., Souhami L., et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18 (2000) 1606-1613
91. Ioannidis J.P. Effect of the statistical significance of results on the time to completion and publication of randomized efficacy trials. JAMA 279 (1998) 281-286
92. Easterbrook P.J., Berlin J.A., Gopalan R., and Matthews D.R. Publication bias in clinical research. Lancet 337 (1991) 867-872