Hormone Replacement Therapy and Cancer

CANADIAN CONSENSUS ON MENOPAUSE AND OSTEOPOROSIS

HORMONE REPLACEMENT THERAPY AND CANCER Serge Bélisle, MSc, MD, FRCSC,1 Christine Derzko, MD, FRCSC2 1

Montreal QC ON

2 Toronto

INTRODUCTION

COMBINED PROGESTIN AND ESTROGEN REPLACEMENT

The fact that several risk factors for breast and endometrial cancer are associated with increased endogenous estrogen exposure1-4 suggests that exogenous estrogen might also increase the incidence of these cancers.4 Repeated gonadotropic stimulation may also be a risk factor for ovarian cancer,5 whereas estrogens are generally accepted as promoters of endometrial and breast epithelial cell proliferation, but their actions within the ovaries are less well known. The association between progesterone, progestins, and cancer remains controversial. In the endometrium, progesterone mostly functions as an anti-estrogen by decreasing the number of nuclear estrogen receptors 6 and introducing 17βhydroxysteroid dehydrogenase.7 Most in vitro studies of cancer cell lines and cultured normal cells show progesterone to have an inhibitory effect on proliferation in the breast, but in vivo experiments with normal breast tissue show a high mitotic index during the luteal phase.8 Similarly, synergistic effects of progestins in combination with estrogen have been found.9

Adding progestins or progesterone to an ERT regimen markedly reduces the risk of developing both endometrial hyperplasia11 and cancer,10 although no hormone replacement therapy (HRT) regimen has proven completely protective. Various regimens using different dosages of progestins for a minimum of 12 to 14 days per month13 have been proposed. While the dose of progestin should be individualized, as a general rule higher progestin doses should accompany higher-dose estrogen administration. In keeping with the observation that the duration of progestin therapy is more important than the actual dose,14 continuous therapy with low-dose progestin may offer endometrial protection equivalent or superior to that of cyclical therapy. Limited experience suggests that 14 days of progestin therapy every three months may not be completely protective against atypical endometrial hyperplasia.15 Limited data also suggest that daily micronized progesterone for 25 to 30 days may be protective against hyperplasia.16 Long-term follow-up data on endometrial cancer are not yet available with these regimens.

ENDOMETRIAL CANCER HRT FOR WOMEN PREVIOUSLY TREATED FOR ENDOMETRIAL CANCER

UNOPPOSED ESTROGEN

Several lines of evidence indicate that unopposed estrogen replacement therapy (ERT) increases the risk of endometrial cancer.1,2 Epidemiological studies have shown a five to 10fold increased risk of endometrial cancer in women taking ERT;9 this risk is related to estrogen dose and duration of therapy.10 Furthermore, this increased risk of developing endometrial carcinoma persists for at least five years after unopposed ERT has ceased.10 In the PEPI trial, unopposed ERT has also been shown to cause atypical endometrial hyperplasia in up to 30 percent of study subjects.11 Whereas the risk of developing endometrial cancer is significantly elevated after at least five years of therapy,10 the risk of developing invasive cancer or of dying from endometrial cancer while taking ERT remains uncertain. Although most studies report no excess deaths due to endometrial cancer among ERT users,10 one meta-analysis has shown an increased risk for late-stage, high grade invasive tumours.12

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HRT has traditionally been withheld from women after treatment for endometrial cancer, based on the belief that HRT might increase the risk of recurrence. This belief has never been substantiated, and two recent retrospective studies have questioned it.17,18 Based on these limited studies, a committee opinion of the American College of Obstetricians and Gynecologists concluded that HRT may be used by women who have been treated for endometrial cancer and who fall into a low-risk group, defined as women with stage I disease, grade 1 or 2 histiology, and less than 50 percent depth of myometrial invasion.19 Estrogen administration is commonly begun postoperatively when the patient is ambulatory. It remains undetermined whether progestin should be added to the regimen in these patients. The use of androgens in these patients is controversial, because androgens may undergo aromatization to estrogen.20

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between HRT and breast cancer is real or merely the result of surveillance bias.27 The magnitude of this putative risk can be appreciated better by comparing it with other known risk factors for breast cancer. As illustrated in Table 1,25 there appears to be a greater risk of breast cancer associated with excessive alcohol consumption28 or with failure to exercise regularly29 than is associated with HRT. Data from the Nurses’ Health Study suggest that the following variables increase a woman’s risk for breast cancer: elevated serum testosterone levels, high BMI or waist-to-hip ratio, high alcohol consumption, increased breast tissue density on mammography, previous benign breast disease, and a positive family history of breast cancer.30 Studies have specifically examined the effect of long-term HRT with or without progestin on breast cancer risk; of these, two case-control studies reported conflicting results,31,32 while all three prospective cohort studies reported that progestins did not alter the estrogen-related risk of breast cancer.33-35 Furthermore, most recent studies suggested that an estrogen-progestin regimen might increase the risk of breast cancer to a greater extent than estrogen alone.34,35 In one of these studies34 the effect was largely confined to lean women, while another35 suggested that a combination of estrogen and cyclical progestin was associated with a greater risk of breast cancer than that associated with a continuous-combined regimen. However, these conclusions were based on very small numbers. According to the WHI Study 36 the use of estrogenprogestin treatment increases the risk of breast cancer after 5 years of use, but not in a statistically significant way. The risk returns to baseline 5 years after stopping therapy.

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS)

Long-term tamoxifen users have an increased risk of endometrial cancer,21 and a subgroup of high-risk patients may develop cancers with a worse prognosis.21 However, newer SERMs such as raloxifene have no stimulatory effects on the endometrium.22 There is insufficient evidence regarding the value of routine transvaginal ultrasonography or endometrial sampling for the early detection of endometrial cancer in women using tamoxifen.23 The American College of Obstetricians and Gynecologists has issued the recommendation that women taking tamoxifen should have annual gynaecological examinations, and that the indication for endometrial biopsy should be based on the presence of bleeding.24 BREAST CANCER

Factors that influence breast cancer are listed in Table 1.25 Based on a recent reanalysis of over 90 percent of the epidemiological studies published on this subject, current users of HRT and those who ceased HRT one to four years prior to the study had a small increase in relative risk of breast cancer, comparable to the effect of a delayed menopause.26 The combined analysis reported no increased risk for HRT use of less than five years.26 For women who had used HRT for five years or longer, the average relative risk of breast cancer increased by approximately two percent per year of use.26 Translated into real estimates, this relative risk for breast cancer with HRT would account after five, 10, or 15 years of use for an excess of two, six or 12 cases per 1000 HRT users respectively. Within five years of discontinuation of HRT use, the increased relative risk virtually disappeared.26 Some authorities have questioned whether the association

HRT AND WOMEN WITH BENIGN BREAST DISEASE

HRT can be prescribed to women with benign breast disease.

TABLE 1 RISK FACTORS FOR BREAST CANCER25 Baseline breast cancers* per 1000 women

Additional cancers per 1000 women

Total cancers per 1000 women

45

0

45

5 years HRT use

2

47

10 years HRT use

6

51

15 years HRT use

12

57

Alcohol consumption (2 drinks/day)

27

72

Lack of regular exercise (< 4 hrs/week)

27

72

Late menopause (10 yr delay)

13

58

14

59

45

90

Factor No HRT use (baseline)*

Body mass index (10

kg/m2

increase)

Weight gain after menopause (≥ 20 kg) *

Baseline or basic risk applies to all women and is due to factors that cannot be controlled (such as aging and gender). From Reid RL. Progestins in hormone replacement therapy: impact on endometrial and breast cancer. J Soc Obstet Gynaecol Can 2000;22:679. With permission.

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for future osteoporotic fractures, and other options for control of symptoms and disease prevention. At present, the risks and benefits of HRT in breast cancer survivors are poorly defined.44,45 Recruitment bias is a major factor in interpreting outcome reports, and most study subjects to date had favourable prognostic factors. A mean of 7.4 percent (range 0–9%) of women with localized breast cancer showed recurrence of disease equivalent to the predicted rate of recurrence.46 The National Cancer Institute of the United States has initiated a randomized prospective trial of HRT following treatment of breast cancer in women with stage I and II disease to clarify some of these issues. There is no reliable information about the influence of HRT on cancer progression in a woman found to have breast cancer while taking HRT. In general, the current practice is to stop HRT until proper staging and therapy are completed. Breast cancer survivors frequently report such symptoms as hot flashes, vaginal dryness, and decreased libido, especially if the cancer occurred premenopausally and was followed by chemotherapy. For such patients, non-hormonal medications have been proven more effective than placebo in reducing hot flashes.47* Similarly, high doses of progestins are effective in alleviating vasomotor symptoms, although their safety has not been established in women previously treated for breast cancer.† Certain forms of topical estrogen therapy, such as sustained-release estradiol vaginal rings or low-dose vaginal cream (equivalent to 0.5 g or one-eighth applicator of CEE cream daily) will control hypo-estrogenic vaginal symptoms with minimal systemic absorption. The vaginal mucosa will readily absorb higher dosages of estrogenic vaginal cream.‡ Other approaches may also be considered, including the use of lubricants or gels. In women with reduced libido, androgen therapy may be considered, although the same concerns exist as for HRT because androgens may be aromatized into estrogens.20 There is presently no evidence to support or refute the usefulness of adding androgens to an HRT regimen in breast cancer survivors.

Women with a personal history of premalignant disease of the breast are at increased risk for breast cancer.37 The relative risk of developing breast cancer is 1.8 in women with a history of proliferative breast disease without atypical hyperplasia, and 3.6 in those with atypical hyperplasia,38 compared to women with non-proliferative benign histology. These risks are not affected by the use of HRT.39 RISK OF BREAST CANCER IN WOMEN CONSIDERING HRT WITH A HISTORY OF ORAL CONTRACEPTIVE USE

Previous use of oral contraceptives (OCs) does not further increase the HRT-related risk for breast cancer. Neither longterm past use nor use prior to menopause confers any appreciable increase in the risk of HRT-related breast carcinoma.40 HRT AND WOMEN WITH RISK FACTORS FOR BREAST CANCER

HRT can be prescribed for women with a history of breast cancer after proper counselling. Women with a history of breast cancer in a first-degree relative carry a two to four times increased risk of developing breast cancer.41 This risk increases even further if two first-degree relatives are affected or if the cancer occurs premenopausally.41 The available data suggest that the addition of HRT does not further increase this risk.41 HRT can also be prescribed to women with a genetic predisposition to breast or ovarian cancer, after bilateral prophylactic oophorectomy (BPO) and after proper counselling. Three to five percent of these women carry a specific genetic mutation (BRCA1 or 2) that confers a 60 to 80 percent lifetime risk of developing breast cancer.42 Some of the women may elect to undergo BPO, which raises concerns about use of HRT after surgical menopause. The effects of HRT on women carrying BRCA1 or 2 genes have not been well studied. Rebbeck et al.43 reported that ever-use or never-use of HRT was not a significant independent predictor of breast cancer outcome, in a model that included BPO. Exclusion of women who had HRT exposure after BPO43 did not significantly affect the risk reduction conferred by BPO. The use of newer synthetic antiestrogens such as raloxifene is an option that may also be considered for prevention of osteoporosis.

OTHER CANCERS HRT AND COLO-RECTAL CANCER

Most case-control and cohort studies in current HRT users have shown a decrease in the incidence of colo-rectal cancers.48,49 Moreover, two recent meta-analyses summarizing the results of these studies show that the risk is reduced by one-third in current and recent (within one year of assessment) users of HRT.48,49 According to the WHI Study36 continuous-combined treatment with HRT was associated with a reduction in the risk of colorectal cancer, which failed to reach statistical significance (6 fewer cases/10,000 women/year). The benefit did not appear until after three years of use.

HRT AND WOMEN WITH BREAST CANCER

It remains unclear whether HRT can be prescribed to women previously treated for breast cancer. All women should receive expert individualized counselling which takes into account prognostic factors for breast cancer (stage of disease, estrogen receptor status of the tumour, and time since diagnosis of breast cancer), immediate quality of life issues related to estrogen deficiency, risk factors

* Complementary approaches, J Obstet Gynaecol Can 2001;23(12):1204-13. † Pharmacotherapy, J Obstet Gynaecol Can 2001;23(11):1105-14. ‡ Urogenital health, J Obstet Gynaecol Can 2001;23(10):973-7. JOGC

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and endometrial carcinoma (II-2). The appropriate dose and duration of progestin therapy will reduce these estrogen-associated risks. J8. Continuous combined HRT was associated with a reduction in the risk of colorectal cancer, which failed to reach statistical significance (6 fewer cases per 10,000 women per year). (I)

HRT AND OTHER CANCERS OF THE REPRODUCTIVE TRACT

There is too little information to comment on any relationship between HRT use and cancers of the cervix, vagina or vulva.50 A recent epidemiological study reported that long-term use of unopposed estrogens was associated with an increased risk of ovarian cancer, but data were not available on the hormone regimens used.51

J Obstet Gynaecol Can 2001;23(12):1198-1203.

OTHER CANCERS PRECLUDING THE USE OF HRT

Melanoma, especially the cutaneous form, is considered to be potentially hormone-sensitive, but it is not possible to comment on any relationship between melanoma and HRT because of insufficient data, and the confounding factor of quantity of exposure to ultraviolet light.50 Although OCs are associated with an increased risk of hepatocellular cancer, no data supports an association. Thyroid carcinoma is quite prevalent in postmenopausal women, but available data again shows no association between ever-use of HRT and this malignancy.52

REFERENCES 1. 2.

3. 4. 5.

RECOMMENDATIONS:

6.

J1. No estrogen-progestin regimen is completely protective against endometrial carcinoma, and all unscheduled uterine bleeding should be investigated. (II-2) J2. Estrogen-progestin therapy should not be withheld from women with treated stage 1 and 2, grade 1 or 2 adenocarcinoma of the endometrium who have moderate to severe menopausal symptoms. (II-3) J3. According to the WHI study, physicians should inform their patients that the use of estrogen-progestin treatment increases the risk of breast cancer after 5 years of use but not in a statistically significant way. The risk returns to baseline after 5 years of stopping therapy.(I) J4. There should be increased breast surveillance for women who are at high risk of developing breast cancer when using estrogen-progestin therapy. (III) J5. In very special circumstances, women at increased risk of developing breast cancer or who have been treated for breast cancer may be prescribed low dose estrogen-progestin therapy for severe symptoms unrelieved by effective alternative therapies, after risks and benefits have been extensively discussed. The duration of therapy should be regularly reviewed; there is no preventative role for estrogen therapy in this population. (III) J6. Physicians should be aware that the reported effects of estrogen-progestin therapy on ovarian cancer have been inconsistent. A possible increased risk may occur in women on long-term estrogen-only therapy (10 or more years). (I)

7. 8. 9.

10.

11.

12.

13.

14.

15.

16. 17.

18.

19.

SUMMARY OF KEY POINTS:

J7. Unopposed estrogen therapy substantially increases the risk of developing atypical endometrial hyperplasia (I) JOGC

20.

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Beral V, Banks E, Reeves G,Appleby P. Use of HRT and the subsequent risk of cancer. J Epidemiol Biost 1999;4(3):191-215. Burger CW, Koomen I, Peters NJAB,Van Leeuwen FE, Kenemans P. Postmenopausal hormone replacement therapy and cancer of the female genital tract and the breast. Eur Menopause J 1997;4:23-36. Brinton LA, Schairer C. ERT and breast cancer risk. Epidemiol Rev 1995;15:66-79. King RJB.A discussion of the roles of estrogen and progestin in human mammary carcinogensis. J Steroid Biochem Mol Biol 1991;39:811-8. Rao BR, Slotman BJ. Endocrine factors in common epithelial ovarian cancer. Endocr Rev 1991;12:14-26. Hsueh AJW, Peck EJ, Clark JH. Control of uterine estrogen receptor levels by progesterone. Endocrinology 1976;98:438-44. Tseng L, Gurpide E. Induction of human estradiol dehydrogenase by progestins. Endocrinology 1975;97:825-33. Speroff L. Role of progesterone in normal breast physiology. J Reprod Med 1999;44(2 Suppl):172-9. Campagnoli C, Biglia N, Cantamessa C, Lesca L, Sismondi P. HRT and breast cancer risk: a clue for interpreting the available data. Maturitas 1999;33:185-90. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304-13. Writing Group for the PEPI trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. J Am Med Assoc 1995;273:199-208. Ettinger B, Golditch IM, Friedman G. Gynecologic consequences of long-term unopposed estrogen replacement therapy. Maturitas 1998;10:271-82. Gibbons WE,Thorneycroft IH. Protecting the endometrium. Opposing the hyperplasia/malignancy potential of ERT. J Reprod Med 1999;44(2 Suppl):203-8. Weiderpass E,Adami HO, Baron JA, Magnusson C, Bergström R, Lindgren A, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999;91(13):1331-7. Guerin A, Heldass K, Moeller B.Adverse endometrial effects of long cycle estrogen and progestogen replacement therapy. N Engl J Med 1996;334:668-9. Fitzpatrick LA, Good A. Micronized progesterone: clinical indications and comparison with current treatments. Fertil Steril 1999;72:389-97. Creasman WT, Henderson D, Hinshaw W, Clarke-Pearson D. Estrogen replacement therapy in the patient treated for endometrial cancer. Obstet Gynecol 1986;67:326-30. Lee RB, Burke TW, Park RC. Estrogen replacement therapy following treatment for stage I endometrial carcinoma. Gynecol Oncol 1990;36(2):189-91. ACOG Committee Opinion (no. 126). Estrogen Replacement Therapy and Endometrial Cancer.Washington DC:American College of Obstetricians and Gynecologists, 1993. Siiteri PK, MacDonald PC. In: Greep RO,Astwood E, editors. Handbook of physiology and endocrinology.Vol 2, pt. 1. 1973.Washington:Ameri-

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44. Vassilopoulou-Sellin R,Theriault R, Klein MJ. Estrogen replacement therapy in women with prior diagnosis and treatment for breast cancer. Gynecol Oncol 1997;65:89-93. 45. Disaia PJ, Grosen EA, Kurosaki T, Gildea M, Cohen B, Culver HA. Hormone replacement therapy in breast cancer survivors: a cohort study. Am J Obstet Gynecol 1996;174:1494-8. 46. Vassilopoulou-Sellin R,Asmar L, Hortobagyi GN, Klein MJ, McNeese M, Singletary SE, et al. Estrogen replacement therapy after localized breast cancer. J Clin Oncol 1999;17:1482-7. 47. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al.Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet 2000;356(9247):2059-63. 48. Nanda K, Bastian LA, Hasselblad V, Simel DL. Hormone replacement therapy and the risk of colorectal cancer: a meta-analysis. Obstet Gynecol 1999;93(5 Pt 2):880-8. 49. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colo-rectal cancer: a review and meta-analysis. Am J Med 1999;106:574-82. 50. Beral V, Banks E, Reeves G,Appleby P. Use of HRT and the subsequent risk of cancer. J Epidemiol 1999;4(3):191-215. 51. Rodriguez C, Patel AV, Calle EE, Jacob EJ,Thun MJ. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. J Am Med Assoc 2001;285(11):1460-5. 52. Persson T,Yuen J, Bergkvist L, Schaimer C. Cancer incidence and mortality in women receiving HRT: long-term follow-up. Intl J Cancer 1996;67:327-33.

can Physiological Society. p. 615-29. 21. Bergman L. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000;356:881-7. 22. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-7. 23. Smedira HJ. Practical issues in counseling healthy women about their breast cancer risk and use of tamoxifen citrate. Arch Intern Med 2000;160:3034-42. 24. ACOG Committee Opinion.Tamoxifen and Endometrial Cancer.Washington DC:American College of Obstetricians and Gynecologists, 1996. 25. Reid RL. Progestins in hormone replacement therapy: impact on endometrial and breast cancer. J Soc Obstet Gynaecol Can 2000;22:679. 26. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,401 women without breast cancer. Lancet 1997;350:1047-59. 27. MacLennan AH, Smith M. Hormone replacement therapy and breast cancer: what are the facts? Med J Aust 1995 6;163(9):483-5. 28. Fuchs CS, Stampfer MJ, Colditz GA, et al.Alcohol consumption and mortality among women. N Engl J Med 1995;332(19):1245-50. 29. Thune I, Brenn T, Lund E, Gaard M. Physical activity and the risk of breast cancer. N Engl J Med 1997;336(18):1269-75. 30. Colditz GA. Hormones and breast cancer: evidence and implications for consideration of risks and benefits of HRT. J Women Health 1999;8(3):349-57. 31. Schairer C, Byrne C, Keyl PM, Brinton LA, Sturgeon SR, Hoover RN. Menopausal estrogen and estrogen-progestin replacement therapy and the risk of breast cancer (United States). Cancer Causes Control 1994;5(6):491-500. 32. Stanford J,Weiss N,Voigt L, Daling L, Habel L, Rossing M. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. J Am Med Assoc 1995;274:137-42. 33. Grodstein F, Stampfer MJ, Colditz GA,Walter C,Willett MD. Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336:1769-75. 34. Schairer G, Lubin J,Troisi R, et al. Menopausal estrogen and estrogenprogestin replacement therapy and breast cancer risk. J Am Med Assoc 2000;283:485-91. 35. Ross RK, Paganini-Hill A,Wan PC, Pike MC. Effect of hormonal replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328-32. 36. Writing Group for the Women’s Health Initiative Investigators. JAMA, 2002;288:321-33. 37. Colditz GA, Rosner B. HRT use increases cumulative risk of breast cancer at age 70.Am J Epidemiol 2000;92:328-32. 38. Byrne C, Connolly JL, Colditz GA, Schnitt SJ. Biopsy confirmed benign breast disease, postmenopausal use of exogenous female hormones, and breast carcinoma risk. Cancer 2000;89:2046-52. 39. Dupont WD, Page DL, Parl FF, Plummer WD Jr., Schuyler PA, Kasami M, et al. Estrogen replacement therapy in women with a history of proliferative breast disease. Cancer 1999;85:1279-83. 40. Clemons M, Gauss P. Estrogen and the risk of breast cancer. N Engl J Med 2001;344(4):276-85. 41. Hoskins KF, Stopfer JE, Calzone KA, et al.Assessment and counseling for women with a family history of breast cancer.A guide for clinicians. J Am Med Assoc 1995;273(7):577-85. 42. Whittemore AS, Gong G, Itnyre J. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U.S. population-based case-control studies of ovarian cancer.Am J Hum Genet 1997;60(3):496-504. 43. Rebbeck TR, Levin AM, Eisen A, et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA-1 mutation carriers. J Natl Cancer Inst 1999;91(17):1475-9.

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