Cánceres del tracto digestivo superior 

Cáncer hepatocelular 

El carcinoma hepatocelular (CHC) es una enfermedad maligna poco común y hay pocos estudios analizando asociaciones con la THM. El análisis de los resultados de estudios casoscontroles de Italia comunicó un OR de 0,2 (IC del 95%: 0,1-0,8) para mujeres que fueron alguna vez usuarias (n = 3) en comparación con nunca usuarias (controles basados en el hospital, n = 102)1. <2+> Sin embargo, un estudio reciente con datos agrupados de 11 cohortes de los EE.UU. que evaluaban 800.000 mujeres no encontró efecto de la THM de manera global o cuando se analiza por la edad de la menopausia natural, uso actual o pasado, el tipo de hormona y la duración de exposición2. <2+> Sin embargo, los investigadores descubrieron que la ooforectomía bilateral se asoció con un aumento significativo del riesgo de CHC (HR 2,67; IC del 95%: 1,22-5,85). Además, las asociaciones positivas previas desaparecerían si se ajustaba el análisis adecuadamente para la ooforectomía.

Mensajes clave 

• No existe una asociación clara entre el uso de THM y CHC. [C]
• La ooforectomía bilateral podría estar asociada a riesgo aumentado de CHC. [C].

Cáncer gástrico, esofágico y de la vesícula biliar 

En un estudio prospectivo observacional de Shangai, China, con solo 2,1% de personas-año siendo mujeres posmenopáusicas expuestas a THM, se comunicó que la incidencia de cáncer gástrico en este subgrupo fue similar a la de las no usuarias3. <2+> Curiosamente, el estudio también encontró que a mayor tiempo desde el inicio de la menopausia y menos años de fertilidad se asociaron a un mayor riesgo de cáncer gástrico, aspecto que estaría en concordancia con estudios previos demostrando un efecto protector de la THM en poblaciones con tasas mayores de uso de hormonas. Un estudio anidado de casos y controles del Reino Unido demostró que el uso de THM (OR 0,56; IC del 95%: 0,33-0,96), así como el uso previo (OR 0,25; IC del 95%: 0,09-0,70), se asocian a menor riesgo de cáncer gástrico4. <2-> Además un metaanálisis de siete estudios observacionales (cohortes y de casos y controles) señaló la misma asociación5: al comparar alguna vez usuarias con las que nunca usaron THM se demostró una reducción significativa en el riesgo de cáncer gástrico (RR 0,77; IC del 95%: 0,64-0,92). <2++>

Aunque las diferencias de género en cuanto a la susceptibilidad para desarrollar cáncer de esófago sugieren un papel de los estrógenos, hay pocos estudios que evalúen los posibles vínculos con la THM. La base de datos de Lindblad y colaboradores incluyó 299 pacientes con cáncer de esófago, en las que no se detectó asociación entre el riesgo tumoral y THM (OR 1,17; IC del 95%: 0,41-3,32)4. <2-> Sin embargo, un meta-análisis de ocho estudios de cohorte de varios tipos mostró un efecto beneficioso de la THM, con una reducción del 28% en el riesgo grupal en las usuarias de hormonas (RR 0,72; IC del 95%: 0,60-0,86)6. <2++>

Aunque se sabe que la tasa de enfermedad de la vesícula biliar puede ser incluso un 50% mayor en mujeres usuarias de THM oral, hay pocos estudios que informen sobre una asociación con el cáncer de vesícula biliar. Solo un estudio de Italia señaló un mayor riesgo para aquellas que alguna vez habían utilizado THM (OR 3,2; IC del 95%: 1,1-9,3) y la tasa mostró una tendencia al alza a mayor duración del uso7. <2->

Mensajes clave 

• Existen pocos estudios buenos que examinen el vínculo entre los cánceres del tracto gastrointestinal superior, la menopausia y la THM.
• La THM podría asociarse a un riesgo reducido de cáncer gástrico. [C ]

Bibliografia 

Sistema nervioso central 

1. Weber MT, Maki PM, McDermott MP. Cognition and mood in perimenopause: a systematic review and meta-analysis. J Steroid Biochem Mol Biol 2014;142:90-8.
2. Henderson VW. Gonadal hormones and cognitive aging: a midlife perspective. Womens Health 2011;7:81-93.
3. Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS-Cognitive and Affective Study. PLoS Med 2015;12:e1001833.
4. Espeland MA, Shumaker SA, Leng I, et al. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med 2013;173:1429-36 68.
5. Henderson VW, Sherwin BB. Surgical versus natural menopause: cognitive issues. Menopause 2007;14:572-9.
6. Resnick SM, Maki PM, Rapp SR, et al. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab 2006;91:1802-10.
7. Resnick SM, Espeland MA, An Y, et al. Effects of conjugated equine estrogens on cognition and affect in postmenopausal women with prior hysterectomy. J Clin Endocrinol Metab 2009;94:4152-61.
8. Yaffe K, Vittinghoff E, Ensrud KE, et al. Effects of ultra-low-dose transdermal estradiol on cognition and health-related quality of life. Arch Neurol 2006;63:945-50.
9. Greenspan SL, Resnick NM, Parker RA. The effect of hormone replacement on physical performance in community-dwelling elderly women. Am J Med 2005;118:1232-9.
10. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA 2000;283: 1007-15.
11. Henderson VW. Alzheimer’s disease: review of hormone therapy trials and implications for treatment and prevention after menopause. J Steroid Biochem Mol Biol 2014;142:99-106.
12. Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience 2000; 101:485-512.
13. LeBlanc ES, Janowsky J, Chan BKS, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 2001;285:1489-99.
14. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;291:2947-58.
15. Henderson VW. Estrogen-containing hormone therapy and Alzheimer’s disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience 2006;138:1031-9.
16. Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA. Postmenopausal hormone therapy and Alzheimer’s disease risk: interaction with age. J Neurol Neurosurg Psychiatry 2005;76:103-5.
17. Whitmer RA, Quesenberry CP, Zhou J, Yaffe K. Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol 2011;69:163-9 .
18. Shao H, Breitner JCS, Whitmer RA, et al. Hormone therapy and AD dementia: new findings from the Cache County study. Neurology 2012;79:1846-52.
19. Yaffe K, Krueger K, Sarkar S, et al. Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med 2001;344:1207-13.
20. Yaffe K, Krueger K, Cummings SR, et al. Effect of raloxifene on the prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry 2005;162:683-90.
21. Henderson VW, Ala T, Sainani KL, et al. Raloxifene for women with Alzheimer disease: A randomized controlled pilot trial. Neurology 2015;85:1937-44.
22. Kreijkamp-Kaspers S, Kok L, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA 2004;292: 65-74 69.
23. Henderson VW, St John JA, Hodis HN, et al. Long-term soy isoflavone supplementation and cognition in women: A randomized, controlled trial. Neurology 2012;78:1841-8.
24. Büchtemann D, Luppa M, Bramesfeld A, Riedel-Heller S. Incidence of late-life depression: a systematic review. J Affect Disord 2012;142:172-9.
25. Maki PM, Gast MJ, Vieweg A, Burriss SW, Yaffe K. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology 2007;69:1322-30.26. Schmidt PJ, Nieman L, Danace au MA, et al. Estrogen replacement in perimenopauserelated depression: a preliminary report. Am J Obstet Gynecol 2000;183:414-20.
27. Soares CD, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebocontrolled trial. Arch Gen Psychiatry 2001;58: 529-34.
28. Brandes JL. The influence of estrogen on migraine: a systematic review. JAMA 2006;295:1824-30.
29. Wang SJ, Fuh JL, Lu SR, Juang KD, Wang PH. Migraine prevalence during menopausal transition. Headache 2003;43:470-8
30. Christianson MS, Mensah VA, Shen W. Multiple sclerosis at menopause: Potential neuroprotective effects of estrogen. Maturitas 2015;80:133-9.
31. Wang P, Li J, Qiu S, Wen H, Du J. Hormone replacement therapy and Parkinson’s disease risk in women: a meta-analysis of 14 observational studies. Neuropsychiatric Dis Treat 2015;11:59-66.
32. Parkinson Study Group POETRY Investigators. A randomized pilot trial of estrogen replacement therapy in postmenopausal women with Parkinson’s disease. Parkinsonism Relat Disord 2011;17:757-60.
33. Harden CL, Herzog AG, Nikolov BG, et al. Hormone replacement therapy in women with epilepsy: a randomized, double-blind, placebocontrolled study. Epilepsia 2006;47:1447-51.

Cáncer de mama 

1. Chlebowski RT, Hendrix SL, Langer RD, et al.; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA 2003;289:3243-53.
2. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas 2006;55:103-15.
3. Colditz GA, Hankinson SE, Hunter DJ, et al.The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332:1589-93.
4. Bakken K, Fournier A, Lund E, et al. Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2011;128: 144-56.
5. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-27.
6. Fournier A, Berrino F, Clavell-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103-11.
7. Chlebowski RT, Anderson GL, Gass M, et al.; WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304: 1684-92 70.
8. Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012;13:476-86.
9. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006;166:1027-32.
10. Lundström E, Christow A, Kersemaekers W, et al. Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density. Am J Obstet Gynecol 2002;186:717-22.
11. Kenemans P, Bundred NJ, Foidart JM, et al.; LIBERATE Study Group. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol2009;10:135-46.
12. Cordina-Duverger E, Truong T, Anger A, et al. Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France. PLoS One 2013;8:e78016.
13. Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstet Gynecol2009;113:65-73.

Seguridad endometrial y hemorragia genital 

1. Gupta JK, Chien PF, Voit D, Clark TJ, Khan KS. Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand 2002;81:799-816.
2. American College of Obstetricians and Gynecologists. Diagnosis of abnormal uterine bleeding in reproductive-aged women. Practice Bulletin no. 128. Obstet Gynecol 2012;120:197-206.
3. Guido RS, Kanbour-Shakir A, Rulin MC, Christopherson WA. Pipelle endometrial sampling. Sensitivity in the detection of endometrial cancer. J Reprod Med 1995;40:553-5.
4. Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol 1994;170: 1213-23.
5. Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999;91:1131-7.
6. Lethaby A, Suckling J, Barlow D, Farquhar CM, Jepson RG, Roberts H. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2004;CD000402.
7. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996;275:370-5.
8. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA 2003;290:1739-48.
9. Allen N, Tsilidis K, Key T, et al. Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol 2010;172:1394-403 71.
10. Somboonporn W, Panna S, Temtanakitpaisan T, Kaewrudee S, Soontrapa S. Effects of the levonorgestrel-releasing intrauterine system plus estrogen therapy in perimenopausal and postmenopausal women: systematic review and meta-analysis. Menopause 2011;18:1060-6.
11. Pickar JH, Yeh IT, Bachmann G, Speroff L. Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril 2009;92:1018-24.
12. Stovall DW, Utian WH, Gass ML, et al. The effects of combined raloxifene and oral estrogen on vasomotor symptoms and endometrial safety. Menopause 2007;14:510-17.
13. Bjarnason K, Cerin A, Lindgren R, Weber T. Adverse endometrial effects during long cycle hormone replacement therapy. Scandinavian Long Cycle Study Group. Maturitas 1999;32: 161-70.
14. Erkkola R, Kumento U, Lehmuskoski S, Mattila L, Mustonen M. No increased risk of endometrial hyperplasia with fixed long-cycle estrogen-progestogen therapy after five years. J Br Menopause Soc 2004;10:9-13.
15. Allen NE, Tsilidis KK, Key TJ, et al.
Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition. Am J Epidemiol 2010;172:1394-403.
16. Archer DF, Hendrix S, Gallagher JC, et al. Endometrial effects of tibolone. J Clin Endocrinol Metab 2007;92:911-18.
17. Clarke MJ. Tamoxifen for early breast cancer. Cochrane Database Syst Rev 2008;CD000486.
18. Goldstein SR, Scheele WH, Rajagopalan SK, Wilkie JL, Walsh BW, Parsons AK. A 12- month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet Gynecol 2000;95:95-103.
19. Ronkin S, Northington R, Baracat E, et al. Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women. Obstet Gynecol 2005;105:1397-404.
20. Constantine GD, Goldstein SR, Archer DF. Endometrial safety of ospemifene: results of the phase 2/3 clinical development program. Menopause 2015;22:36-43.
21. Goldstein SR, Bachmann GA, Koninckx PR, Lin VH, Portman DJ, Ylikorkala O; Ospemifene Study Group. Ospemifene 12- month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy. Climacteric 2014;17:173-82.
22. Goldstein SR, Neven P, Cummings S, et al. Postmenopausal evaluation and risk reduction with lasofoxifene (PEARL) trial: 5-year gynecologic outcomes. Menopause 2011;18:17-22.

Cáncer de ovario 

1. de Villiers TJ, Pines A, Panay N, et al.; International Menopause Society. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric 2013;16:316-72.
2. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet 2015;385:1835-42.
3. Gompel A, Burger H. A Commentary on a recent update of the ovarian cancer risk attributable to menopausal hormone therapy. Climacteric 2015;18:376-8 72.

Cáncer de pulmón 

1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
2. Weir HK, Thompson TD, Soman A, Møller B, Leadbetter S. The past, present, and future of cancer incidence in the United States: 1975 through 2020. Cancer 2015;121:1827-37.
3. Gallagher LG, Rosenblatt KA, Ray RM, et al. Reproductive factors and risk of lung cancer in female textile workers in Shanghai, China. Cancer Causes Control 2013;24:1305-14.
4. Pesatori AC, Carugno M, Consonni D, et al. Reproductive and hormonal factors and the risk of lung cancer: the EAGLE study. Int J Cancer 2013;132:2630-9.
5. Greiser CM, Greiser EM, Dören M. Menopausal hormone therapy and risk of lung cancer – systematic review and metaanalysis. Maturitas 2010;65:198-204.
6. Clague J, Reynolds P, Sullivan-Halley J, et al. Menopausal hormone therapy does not influence lung cancer risk: results from the California Teachers Study. Cancer Epidemiol Biomarkers Prev 2011;20:560-4.
7. Chlebowski RT, Anderson GL, Manson JE, et al. Lung cancer among postmenopausal women treated with estrogen alone in the Women’s Health Initiative randomized trial. J Natl Cancer Inst 2010;102:1413-21.
8. Chlebowski RT, Schwartz AG, Wakelee H, et al. Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet 2009;374: 1243-51.
9. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310:1353-68.
10. Schwartz AG, Ray RM, Cote ML, et al. Hormone use, reproductive history and risk of lung cancer: the Women’s Health Initiative studies. J Thorac Oncol 2015;10:1004-13.

Cáncer colorectal 

1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet 2014;383:1490-502.
2. Grodstein F, Martinez ME, Platz EA, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med 1998;128:705-12.
3. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and metaanalysis. Am J Med 1999;106:574-82.
4. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321-33.
5. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701-12.
6. Prentice RL, Pettinger M, Beresford SA. Colorectal cancer in relation to postmenopausal estrogen and estrogen plus progestin in the Women’s Health Initiative clinical trial and observational study. Cancer Epidemiol Biomarkers Prev 2009;18:1531-7.
7. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310:1353-68, 73.
8. Morois S, Fournier A, Clavel-Chapelon F, et al. Menopausal hormone therapy and risks of colorectal adenomas and cancers in the French E3N prospective cohort: true associations or bias? Eur J Epidemiol 2012;27:439-52.
9. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697-708.

Cáncer cervical 

1. http://www.cancerresearchuk.org/cancerinfo/cancerstats/types/cervix/incidence/ukcervical-cancer-incidence-statistics (section reviewed 11(06/2014).
2. Marsden J, Sturdee D. Cancer issues. Best Pract Res Clin Obstet Gynaecol 2009;23:87-107.
3. Yasmeen S, Romano PS, Pettinger M, et al. Incidence of cervical cytological abnormalities with aging in the Women’s Health Initiative: a randomized controlled trial. Obstet Gynecol 2006;108:410-19.
4. Sawaya GF, Grady D, Kerlikowske K, et al. The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/progestin Replacement Study (HERS). Ann Intern Med 2000;133:942-50.
5. Jaakkola S, Pukkala E, Lyytinen HK, Ylikorkala O. Postmenopausal estradiol-progestagen therapy and risk for uterine cervical cancer. Int J Cancer 2012;131:E537-43.

Cánceres del tracto digestivo superior 

1. Fernandez E, Gallus S, Bosetti C, Franceschi S, Negri E, La Vecchia C. Hormone replacement therapy and cancer risk: a systematic analysis from a network of casecontrol studies. Int J Cancer 2003;105:408-12.
2. McGlynn KA, Sahasrabuddhe VV, Campbell PT, et al. Reproductive factors, exogenous hormone use and risk of hepatocellular carcinoma among US women: results from the Liver Cancer Pooling Project. Br J Cancer 2015;112(Suppl):1266-72.
3. Freedman ND, Chow WH, Gao YT, et al. Menstrual and reproductive factors and gastric cancer risk in a large prospective study of women. Gut 2007;56:1671-7.
4. Lindblad M, García Rodríguez LA, Chandanos E, Lagergren J. Hormone replacement therapy and risks of oesophageal and gastric adenocarcinomas. Br J Cancer 2006;94:136-41.
5. Camargo MC, Goto Y, Zabaleta J, Morgan DR, Correa P, Rabkin CS. Sex hormones, hormonal interventions, and gastric cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2012;21:20-38.
6. Wang BJ, Zhang B, Yan SS, et al. Hormonal and reproductive factors and risk of esophageal cancer in women: a meta-analysis. Dis Esophagus 2015 Mar 23. Epub ahead of print .
7. Gallus S, Negri E, Chatenoud L, Bosetti C, Franceschi S, La Vecchia C. Post-menopausal hormonal therapy and gallbladder cancer risk. Int J Cancer 2002;99:762-3.