flnru* MtdiaU BulUtin (1992) VoL 48, No. 2, pp. 345-355 © The Britiih Coundl 1992
Hormone replacement and cancer E Barrett-Connor Department of Community and Family Medicine, University of California San Diego, La Jolla, USA
The increasing extended use of noncontraceptive oestrogen by postmenopausal women, intended to prevent other conditions, may at the same time increase their risk of reproductive cancer. The risk of endometrial cancer triples after only a few years of unopposed oestrogen, persists for many years after oestrogen has been discontinued, and appears to be preventable by the addition of a progestin. The effect of replacement hormones on the risk of breast or ovarian cancer is unknown. Most studies suggest a small but significant increased risk of breast cancer after long-term use. Awareness of the known and uncertain cancer risks should be included in decisions to use replacement hormones.
Long term use of oestrogen after the menopause slows postmenopausal bone loss and possibly halves the risk of coronary artery disease.1 In expectation of these benefits, there has been a striking increase in the prescription of non-contraceptive oestrogen in the United States where currently about one-third of postmenopausal women use or have used replacement oestrogen, usually conjugated equine oestrogen, that was until recently taken unopposed (without a progestin).2 In Europe, long term use of replacement oestrogen is increasing, but is still far less common, and the type of treatment is much more varied. In one study from 21 specialist menopause clinics in Britain, unopposed conjugated oestrogen accounted for less than 20% of hormone replacement and a majority of women receiving oestrogen were also treated with a progestin or androgen.3 The decision to continue an asymptomatic woman on oestrogen for prolonged periods is based on a consideration of risks and benefits. For both the patient and the physician, the most worn-
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some risk is cancer. Epidemiologic evidence suggests that endometrial, breast, and ovarian cancer are related to endogenous oestrogen in some way. Morbidity and mortality for these cancers, shown for US women in the Table 1, peak after the menopause. It has been variously stated that postmenopausal hormone replacement increases or decreases the risk of these cancers. The clinical and epidemiologic evidence are reviewed here. ENDOMETRIAL CANCER By the late 1970s it was widely appreciated that postmenopausal oestrogen carried an excess risk of endometrial cancer, and, a few years later, that this excess risk might be ablated by the addition of a progestin. Many conditions that are associated with sustained high levels of endogenous oestrogen, such as obesity and nulliparity, are associated with an increased risk of endometrial cancer. It is not surprising that unopposed exogenous oestrogens given in much higher doses also carry an increased risk. More than 20 case control studies have all confirmed this association, which has also been demonstrated in prospective studies (see review by Henderson*). The increased risk varies from 3 to 25 fold in different studies and appears to apply to all types of unopposed oestrogen. In a prospective study in California, women who had used oestrogen for at least five years had a mean annual incidence of endometrial cancer of 6.7/1000, compared to 0.8/1000 for nonusers.5 The excess risk of uterine cancer increases with dose and duration of unopposed oestrogen use, is apparent within 3 years of beginning treatment, and persists for many years after treatment has stopped.6"8 The risk of oestrogen-associated endometrial cancer is lower in women who have previously used oral contraceptives and higher in overweight women.7 Oestrogen-associated endometrial cancer usually is of early stage Table 1 Average annual age-adjusted (1970 standard) incidence and mortality rates (1982-1986) and 5-year relative survival rates (1980-1985 cases) for selected cancers in women, all races, USA seer areas combined Site
Breast Corpus uteri Ovary
Rates (per 100 000) Indicence
Mortality
97.3 22.3 13.5
27.3 2.1 7.8
Data from National Cancer Inidtutc
5-Year relative survival (%) 75.4 81.9 38.6
HORMONE REPLACEMENT AND CANCER
347
and grade at diagnosis. This is in part because women with occult uterine cancer who are taking oestrogen bleed earlier and are diagnosed earlier than women receiving less regular medical care; oestrogen-associated cancer may also be a less malignant cancer. Whatever the reason, the woman who develops endometrial cancer while taking oestrogen typically has an excellent prognosis. In fact, it has been possible to show overall better survival in oestrogen-treated women with endometrial cancer than in women without cancer who were not taking oestrogen.9 Such an observation could be due to selection bias, meaning that healthy women who would have lived longer even if had they not taken oestrogen are also the women most likely to be prescribed oestrogen. This is not the entire explanation, however, because much of the survival advantage of women with endometrial cancer who use oestrogen is due to lower death rates from endometrial cancer, not other causes.9'10 Not all cancers associated with oestrogen carry a good prognosis. The relative risk of invasive and extrauterine cancer is also increased with long-term high dose oestrogen.6-7 A small percent of oestrogen-treated postmenopausal women have Stage III or IV uterine cancer when first diagnosed and some die of this complication. As early as 1979 Hammond et al.11 reported apparent prevention of oestrogen-associated uterine cancer in a 5-year follow-up study of women treated with oestrogen and cyclic progestin. Many more studies have now shown that the addition of a progestin can prevent endometrial hyperplasia, which is probably a precursor of endometrial cancer. Medroxyprogesterone, in a dose of 10 mg for 12 days, is the least androgenic regimen that has been best documented to prevent hyperplasia.12'13 Some patients are now prescribed oestrogen combined with a continuous lower dose of progestin, because this regimen is much less likely to cause cyclic withdrawal bleeding, which may lead to poor compliance. (About one-third of women who are prescribed oestrogen do not continue to take it, and monthly bleeding associated with cyclic progestin is a major reason for discontinuing drug.13) Long term data on the ability of continuous low dose progestin to protect the uterus over time are sparse but promising.13 Studies suggest that the added progestin not only prevents endometrial cancer, but possibly reduces the risk to below that which would occur in the absence of hormone therapy.14 These observations parallel those in a least 8 case-control studies (see
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review by van Leeuwen and Rookus15) where women who had been treated with combined oral contraceptives also had a reduced risk of endometrial cancer. The efficacy of progestins in preventing endometrial hyperplasia may be less in the clinical setting than in the research setting, however. For example, women in Sweden who had taken unopposed oestrogen for several years before adding progestin were not universally protected from neoplasia.16 In a British study,3 endometrial cancer did occur in some women who were prescribed an oestrogen plus progestin regimen that should have been protective; the authors suggest that this finding may reflect noncompliance with progestin. Endometrial hyperplasia typically has an indolent course, progressing slowly if at all. Kurman et al.17 followed 170 women without hysterectomy an average of 13 years after hyperplasia was found on curettage; endometrial cancer developed in less than 2% (2 of 122) of women with endometrial hyperplasia without atypia, compared to 23% (11 of 48) of women with atypical hyperplasia. The mean duration to progression was nearly 10 years in the first group and an average of 4 years (range 1-11 years) in the second group. Up to 20-25% of women with adenomatous or atypical hyperplasia in curettings will be found to have a well-differentiated carcinoma in the uterus if a hysterectomy is performed within one month, but a much smaller percent ever develop clinically manifest cancer.18'19 This suggests that these cancers usually remain localized and differentiated for a long time, although it is not clear the extent to which the curettage was itself curative in some of these cases. The presence or absence of precancerous adenomatous or atypical hyperplasia is usually readily detected by endometrial sampling. Newer endometrial aspiration techniques make endometrial biopsy an acceptable office procedure to monitor the endometrium in oestrogen-treated women who do not take a progestin. Hyperplasia can also be detected by ultrasound using a vaginal probe; to date, no women with a uterine wall thickness of less than 5 mm has been found to have hyperplasia, whereas a thicker endometrium suggests hyperplasia and requires a tissue diagnosis.20 Overall, there is little doubt that unopposed oestrogen increases the risk of endometrial cancer in proportion to dose and duration of use. On average there is a 3 to 6-fold increase in risk after 3-10 years of use, and a more than 10-fold increment after more than 10 years of use. It seems that an excess risk persists for years after
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349
the oestrogen has been stopped, but can be greatly reduced when a progestin is added to the oestrogen. Although the optimal regimen has yet to be chosen, when primary consideration is given to prevention of endometrial cancer, estrogen plus cyclic progestin is the safest choice. Other options may be considered when adherence or possible sequellae of long term progestins are considered, as described elsewhere in this issue. BREAST CANCER The risk of breast cancer is increased with early menarche, late menopause and late first pregnancy, and is reduced by early oophorectomy, suggesting an aetiologic or promotional role for endogenous oestrogen. Nevertheless, it has been surprisingly difficult to demonstrate an increased risk of breast cancer in women taking oestrogens. The majority of studies, including two prospective studies in Britain, have found no increased risk of breast cancer in women who used oral contraceptives, even after long-term use (see review by Thomas and Chu, 198621). Many case-control studies of non-contraceptive oestrogen also showed no overall increased risk; some studies reported an increased risk in a subgroup (e.g. oophorectomized women), but the subgroup varied from one study to the next.22 An incremental risk with higher dosage or longer duration of use has also been difficult to demonstrate, although most of the women in most of these studies had used oestrogen for less than 10 years. In addition, it is difficult to separate dose from duration, since women who were treated longer also started oestrogen in the era of high dose oestrogens. One recent meta-analysis of 28 studies concluded that there was no increased risk of breast cancer in oestrogen-treated women except possibly in those who had used high dose preparations.23 Another recent meta-analysis of 16 case-control studies concluded that use for more than 10 years carries a 1.3-1.8 fold increased risk of breast cancer.24 In the latter analysis, studies that examined the effect of oestrogen use for an average duration of at least 5 years showed a significant increase in the risk of breast cancer, whereas no significant increase in risk could be shown in women who had taken oestrogen for less than 5 years. In addition, the increase in risk was least equivocal in the studies that were rated as having the best study design (by reviewers who were blinded to the results of the study). In this meta-analysis, the effects of oestrogen were similar in parous and nulliparous women, and in
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women with or without benign breast disease, but were greater in women with a family history of breast cancer. Recently, several prospective studies3>25~28 have found an increased risk of breast cancer after long-term use of postmenopausal oestrogen. The largest study is that reported by Colditz et al.28 who examined the incidence of breast cancer in 121 700 American nurses who were followed from 1976 to 1984. The overall age-adjusted risk was significantly higher in women who had ever used non-contraceptive oestrogen (relative risk = 1.4). Current users who had taken oestrogens for 10-15 years had a similar (1.3) fold increased risk, but past users were not at increased risk. The somewhat lower risk than that reported by others for long-term use may be explained by the fact that the women in this cohort were relatively young, aged 30-55 at baseline, so that most long-term users must have had either oophorectomy or premature menopause, factors that are ordinarily 'protective' against breast cancer. Most studies of long-term non-contraceptive oestrogen use and breast cancer come from the United States, and therefore largely reflect the use of unopposed conjugated oestrogen. Reports from Europe where more potent oestradiols are more commonly used are disconcerting in that they suggest an increased risk after a shorter duration of treatment. In two of these studies,25'26 the highest risk after the shortest duration of treatment was seen in women treated with oestrogen plus a progestin or other androgen. In a Swedish study,26 there was a 4-fold increased risk of breast cancer in women after more than 4 years of oestrogen plus a progestin; the 95% confidence intervals for this association were very wide (0.9-22.4) and the association was found after multiple subgroup comparisons. Nevertheless, the results are compatible with a large population-based case-control study from Denmark,25 where sequential therapy with oestrogen and progestin was associated with a significantly increased risk of breast cancer (RR = 1.36) not observed with oestrogen use overall. These results support the hypothesis of Kay and Pike29 that oestrogen plus progestin could be more carcinogenic than oestrogen alone. In contrast, oestrogen-treated women in Britain had a significantly increased risk ratio of 2.38 associated with 10 or more years of oestrogen, but the risk was not further increased in women who also used a progestin.3 The only randomized long term (10 year) clinical trial reported to date, found a significantly lower risk of breast cancer in 84 institutionalized women assigned to a high dose of oestrogen
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(2.5 mg of Premarin) plus 10 mg of medroxyprogesterine for 7 days, compared to 84 women assigned to placebo.30 Since oestrogen is generally believed to be a risk factor for breast cancer, it is less often prescribed in women who have a family or personal history of breast cancer.31 This would tend to artificially reduce a true association. Similarly, women with early oophorectomy are at low risk for breast cancer but are particularly likely to receive hormone replacement, another bias leading to a spuriously low risk. On the other hand, women taking replacement oestrogen have more physician contact that almost certainly results in their being more often examined and more often recommended for mammography.32 The resultant earlier diagnosis could lead to a spuriously high risk of breast cancer, a better prognosis, and a paradoxically lower risk of fatal breast cancer. This possibility is strongly suggested by a British report3 where the relative risk of fatal breast cancer was only 0.55 in oestrogen treated women. Similarly, Bergkvist et al.33 found a significantly better survival in Swedish women with breast cancer who had been treated with oestrogen, compared to women with breast cancer who had not been so treated. It is not surprising, then, that the results of various observational studies have been heterogenous.34 Whether currently recommended doses of oestrogen significantly increase risk of breast cancer in postmenopausal women remains uncertain. At the present time the safety of less than 5 years of any oestrogen in currently recommended doses, with or without a progestin, seems assured. At the same time, accumulating evidence also suggests that longer use of replacement oestrogen causes a 30-50% increase in the risk of breast cancer in postmenopausal women. This risk appears to be higher in women with a family history of breast cancer and with a higher dose of oestrogen than is required to prevent menopausal bone loss. Whether the addition of a progestin augments this risk is unclear. It is also uncertain how much of the apparent increased risk is due to ascertainment bias, because women taking oestrogens are more likely to have breast examinations and mammography. Obviously, women treated with replacement oestrogen should be particularly careful to have annual breast examination and mammography. Breast cancer is the most common of the reproductive cancers and the one most feared by women; the answer to the oestrogenbreast cancer question is tremendously important in helping women to make a decision about hormone replacement therapy.
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CANCER OF THE OVARY Ovarian cancer is less common than either breast or uterine cancer, but nevertheless of considerable concern because of the late stage at diagnosis and poor prognosis. The risk of ovarian cancer is reduced by factors related to ovulation, such as multiparity35 and the use of combined oral contraceptives; the latter reduces the risk of epithelial ovarian cancer for years after use.36 A role for non-contraceptive oestrogen is less clear. At least 10 case-control studies conducted in the United States and Europe found no significant association of ovarian cancer with postmenopausal oestrogen.21 Hartge et al,37 reported a significantly reduced risk of serous cancer in oestrogen-using women. Other observations, however, suggest that it would be premature to exclude an increased risk. Time trends show that the incidence of carcinoma of the ovary between 1969 and 1977 in 4 different geographic areas of the United States paralleled the incidence of endometrial cancer, and the prescription of replacement oestrogen.38 Hoover et al.39 found a 2.5 fold increased risk in ovarian cancer in postmenopausal women treated with oestrogen; the risk ratio of observed to expected cases was almost identical in users of diethylstilbesterol and conjugated equine oestrogen, although only the former was statistically significant. When all types of oestrogen were considered, the risk increased with increasing dose but not duration of use. Weiss et al.40 reported an increased risk of endometroid cancers, but no trend with dose or duration of oestrogen use. In Britain, using cancer registry data for comparison, a modest but not statistically significant 1.4 fold increased risk of fatal ovarian cancer was seen in women who had used replacement oestrogen.3 In this study, cancer incidence by years since first use of oestrogen showed a stepwise trend (estimated risk 0.41 for 0-4 years; 1.70 for 5-9 years and 2.38 for 10+ years); this trend was based on only 6 cases, and was not statistically significant. Small numbers of cases of different histological types in women exposed to different hormone replacement regimens characterize many published studies. It is not possible to preclude an effect of long-term replacement oestrogen on ovarian cancer risk. CONCLUSIONS Essentially all of the data on oestrogen therapy and cancer in postmenopausal women are based on observational studies, subject
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to the usual caveats of interpretation. Factors related to who receives replacement oestrogen, who remains on it, and consequent differences in symptoms and health care all confound the associations. The only unequivocal association is the increased risk of endometrial cancer with and after the use of unopposed oestrogen. The risk, especially with long-term use, is too large and the results are too consistent to be explained by chance, confounding or bias. Because endometnal hyperplasia precedes cancer in most cases, randomized trials have been able to study the (relatively short term) effect of different oestrogens with and without different progestins. In this instance, two major questions remain: what is the optimal progestin regimen; and is a program of unopposed estrogen either necessary or feasible? Whether replacement oestrogen alone or with a progestin increases the risk of breast or ovarian cancer remains an unanswered question, one that is not likely to be resolved by clinical trials with cancer as an outcome. Because widespread oestrogen replacement is a recent addition to medical practice, relatively few studies have included many long-term oestrogen users. All these reports are compatible with the possibility that non-contraceptive oestrogen increases the risk of breast cancer by 30-50%. These studies do not exclude other explanations for the observed oestrogen-breast cancer association, however. In the meantime, physicians need to help their patients make informed choices about when, whether and how to use oestrogen replacement. These choices must consider more than the possible prevention of one specific disease, but also issues of the individual woman's risk pattern, fears and quality of life. REFERENCES 1 Barrett-Connor EL. Postmenopausal estrogen, cancer and other considerations. Women Health 1986; 11(3-4): 179-195 2 Hemminki E, Kennedy DL, Baum C, McKinlay SM. Precursing of noncontraceptive estrogen and progestins in the United States, 1974-1986. Am J Public Health 1988; 78:1479-1481 3 Hunt K, Vessey MP, MacPherson K, Colcman M. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Gynecol 1987; 94: 620-635 4 Henderson BE. The cancer question: An overview of recent epidemiologic and retrospective data. Am J Obstet Gynecol 1989; 161:1859-1864 5 Etringer B, Golditch IM, Friedman G. Gynecologic consequences of longterm, unopposed estrogen replacement therapy. Mflturitis 1988; 10: 271-282 6 Shapiro S, Kelly JP, Rosenberg L, et al. Risk of localized and widespread
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endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med 1985; 313:969-972 7 Rubin GL, Peterson HB, Lee NC, Maes EF, Wingo PA, Becker S. Estrogen replacement therapy and the risk of endometrial cancer: remaining controversies. Am J Obstet Gynecol 1990; 162: 148-154 8 Paganini-Hill A, Ross RK, Henderson BE. Endometrial cancer and patterns of use of estrogen replacement therapy: a cohort study. Br J Cancer 1989; 59: 445-447 9 Collins J, Allen LH, Dormer A, Adams O. Oestrogen use and survival in endometrial cancer. Lancet 1980: ii 961-963 10 Schwartzbaum JA, Hulka BS, Fowler WC, et al. The influence of exogenous estrogen use on survival after diagnosis of endometrial cancer. Am J Epidemiol 1987; 126(5): 851-860 11 Hammond CB, Jelovsek FR, Lee KL, et al. Effects of long-term estrogen replacement therapy. Am J Obstet Gynecol 1979; 133: 537 12 Paterson MEL, Wade-Evans T, Sturdee DW, Thorn MH, Studd JWW. Endometrial disease after treatment with oestrogens and progestogens in the climacteric. Br Med J 1980; 22 March: 822-824 13 Whitehead MI, Hillard TC, Crook D. The role and use of progestogens. Obstet Gynecol 1990; 75: 59S-80S 14 Endometrial cancer and combined oral contraceptives. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Epidemiol 1988; 17: 263-269 15 Van Leeuwen FE, Rookus MA. The role of exogenous hormones in the epidemiology of breast, ovarian and endometrial cancer. Eur J Cancer Clin Oncol 1989; 25: 1961-1972 16 Persson IR, Adami HO, Bergkvist L, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: Results of a prospective study. Br Med J 1989; 278: 147-151 17 Kurman RJ, Karainski PF, Norris HJ. The behavior of endometrial hyperplasia: a long-study of 'untreated' hyperplasia in 170 patients. Cancer 1985; 56: 403-412 18 Gusberg SB, Kaplan AL. Precursor of corpus cancer IV adenomatous hyperplasia as stage O carcinoma of the endometrium. Am J Obstet Gynecol 1963; 87: 662-678 19 King A, Seraj IM, Wagner RJ. Stomal invasion in endometrial carcinoma. Am J Obstet Gynecol 1984; 149: 10-14 20 Granberg S, Wikland M, Karlsson B, et al. Endometrial thickness as measured by endovaginal ultrasonography for identifying endometrial abnormality. Am J Obstet Gynecol 1991; 164(1): 47-52 21 Thomas DB, Chu J. Nutritional and endocrine factors in reproductive organ cancers: Opportunities for primary prevention. J Chron Dis, 1986; 39(12): 1031-1050 22 Hulka BS. Hormone-replacement therapy and the risk of breast cancer. CA 1990; 40: 289-296 23 Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer, Arch Intern Med 1991; 151: 67-72 24 Steinberg KK, Thacker SB, Smith SJ, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. J Am Med Assoc 1991; 265(15): 1985-1990 25 Ewertz M. Influence of non-contraceptive oxogenous and endogenous sex hormones on breast cancer risk in Denmark. Int J Cancer 1988; 42: 832-838 26 Bergkvist L, Adami H-O, Persson I, Hoover R, Schairer C. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 1989; 321: 293-297 27 Mills PK, Beeson WL, Phillips RL, Fraser GE. Prospective study of exogenous
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28 29 30 31 32 33 34 35 36 37 38 39 40
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hormone use and breast cancer in Seventh-Day Adventists. Cancer 1989; 64: 591-597 Colditz GA, Stampfer MJ, Willctt WC, Hennekens CH, Rosner B, Speizer FE. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. J Am Med Assoc 1991; 264(20): 2648-2653 Kay TJ, Pike M. The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 1988; 24: 29-43 Nachtigall LE, Nachtigall RH, NachtigaU RD, Beckman EM. Estrogen replacement therapy. II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979; 54: 74-79 Bergkvist L, Persson I, Adami HO, Schairer C. Risk factors for breast and endometria] cancer in a cohort of women treated with menopausal oestrogens. Int J Epi 1988; 17 (4): 732-737 Barrett-Connor, EL. Postmenopausal estrogen and prevention bias. Ann Intern Med 1991; 115: 455-456 Bergkvist L, Adami HO, Persson I, Bergstrom R, Krusemo UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogenprogestogen replacement therapy. Am J Epidemiol 1989; 130: 221-8 Armstrong BK. Estrogen therapy after the menopause—boom or bane? Med J Aust 1988; 148: 213-214 Henderson BH, Ross RK, Pike MC, Casagrande JT. Endogenous hormones as a major factor in human cancer, Cancer Res 1982; 42: 3232-3239 Ory HW. The reduction in risk of ovarian cancer associated with oralcontraceptive use. N Engl J Med 1987; 316: 650-655 Hartge P, Hoover R, McGowan L, Lcsher L, Norris HJ. Menopause and ovarian cancer. Am J Epidemiol 1988; 127(5): 990-998 Cramer DW, Devesa SS, Welch WR. Trends in the incidence of endometroid and clear cell cancers of the ovary in the United States. Am J Epidemiol 1981; 114: 201-208 Hoover R, Gray LA, Fraumeni JF Jr. Stilbestrol and the risk of ovarian cancer. Lancet 1977; 2: 533-534 Weiss NS, Lyon JL, Krishnamurthy S, Dietert SE, Liff JM, Daling JR. Noncontraceptive estrogen use and the occurrence of ovarian cancer. J Nad Cancer Instit 1982; 68(1): 95-98
Hormone replacement and cancer E Barrett-Connor Department of Community and Family Medicine, University of California San Diego, La Jolla, USA
The increasing extended use of noncontraceptive oestrogen by postmenopausal women, intended to prevent other conditions, may at the same time increase their risk of reproductive cancer. The risk of endometrial cancer triples after only a few years of unopposed oestrogen, persists for many years after oestrogen has been discontinued, and appears to be preventable by the addition of a progestin. The effect of replacement hormones on the risk of breast or ovarian cancer is unknown. Most studies suggest a small but significant increased risk of breast cancer after long-term use. Awareness of the known and uncertain cancer risks should be included in decisions to use replacement hormones.
Long term use of oestrogen after the menopause slows postmenopausal bone loss and possibly halves the risk of coronary artery disease.1 In expectation of these benefits, there has been a striking increase in the prescription of non-contraceptive oestrogen in the United States where currently about one-third of postmenopausal women use or have used replacement oestrogen, usually conjugated equine oestrogen, that was until recently taken unopposed (without a progestin).2 In Europe, long term use of replacement oestrogen is increasing, but is still far less common, and the type of treatment is much more varied. In one study from 21 specialist menopause clinics in Britain, unopposed conjugated oestrogen accounted for less than 20% of hormone replacement and a majority of women receiving oestrogen were also treated with a progestin or androgen.3 The decision to continue an asymptomatic woman on oestrogen for prolonged periods is based on a consideration of risks and benefits. For both the patient and the physician, the most worn-
346
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some risk is cancer. Epidemiologic evidence suggests that endometrial, breast, and ovarian cancer are related to endogenous oestrogen in some way. Morbidity and mortality for these cancers, shown for US women in the Table 1, peak after the menopause. It has been variously stated that postmenopausal hormone replacement increases or decreases the risk of these cancers. The clinical and epidemiologic evidence are reviewed here. ENDOMETRIAL CANCER By the late 1970s it was widely appreciated that postmenopausal oestrogen carried an excess risk of endometrial cancer, and, a few years later, that this excess risk might be ablated by the addition of a progestin. Many conditions that are associated with sustained high levels of endogenous oestrogen, such as obesity and nulliparity, are associated with an increased risk of endometrial cancer. It is not surprising that unopposed exogenous oestrogens given in much higher doses also carry an increased risk. More than 20 case control studies have all confirmed this association, which has also been demonstrated in prospective studies (see review by Henderson*). The increased risk varies from 3 to 25 fold in different studies and appears to apply to all types of unopposed oestrogen. In a prospective study in California, women who had used oestrogen for at least five years had a mean annual incidence of endometrial cancer of 6.7/1000, compared to 0.8/1000 for nonusers.5 The excess risk of uterine cancer increases with dose and duration of unopposed oestrogen use, is apparent within 3 years of beginning treatment, and persists for many years after treatment has stopped.6"8 The risk of oestrogen-associated endometrial cancer is lower in women who have previously used oral contraceptives and higher in overweight women.7 Oestrogen-associated endometrial cancer usually is of early stage Table 1 Average annual age-adjusted (1970 standard) incidence and mortality rates (1982-1986) and 5-year relative survival rates (1980-1985 cases) for selected cancers in women, all races, USA seer areas combined Site
Breast Corpus uteri Ovary
Rates (per 100 000) Indicence
Mortality
97.3 22.3 13.5
27.3 2.1 7.8
Data from National Cancer Inidtutc
5-Year relative survival (%) 75.4 81.9 38.6
HORMONE REPLACEMENT AND CANCER
347
and grade at diagnosis. This is in part because women with occult uterine cancer who are taking oestrogen bleed earlier and are diagnosed earlier than women receiving less regular medical care; oestrogen-associated cancer may also be a less malignant cancer. Whatever the reason, the woman who develops endometrial cancer while taking oestrogen typically has an excellent prognosis. In fact, it has been possible to show overall better survival in oestrogen-treated women with endometrial cancer than in women without cancer who were not taking oestrogen.9 Such an observation could be due to selection bias, meaning that healthy women who would have lived longer even if had they not taken oestrogen are also the women most likely to be prescribed oestrogen. This is not the entire explanation, however, because much of the survival advantage of women with endometrial cancer who use oestrogen is due to lower death rates from endometrial cancer, not other causes.9'10 Not all cancers associated with oestrogen carry a good prognosis. The relative risk of invasive and extrauterine cancer is also increased with long-term high dose oestrogen.6-7 A small percent of oestrogen-treated postmenopausal women have Stage III or IV uterine cancer when first diagnosed and some die of this complication. As early as 1979 Hammond et al.11 reported apparent prevention of oestrogen-associated uterine cancer in a 5-year follow-up study of women treated with oestrogen and cyclic progestin. Many more studies have now shown that the addition of a progestin can prevent endometrial hyperplasia, which is probably a precursor of endometrial cancer. Medroxyprogesterone, in a dose of 10 mg for 12 days, is the least androgenic regimen that has been best documented to prevent hyperplasia.12'13 Some patients are now prescribed oestrogen combined with a continuous lower dose of progestin, because this regimen is much less likely to cause cyclic withdrawal bleeding, which may lead to poor compliance. (About one-third of women who are prescribed oestrogen do not continue to take it, and monthly bleeding associated with cyclic progestin is a major reason for discontinuing drug.13) Long term data on the ability of continuous low dose progestin to protect the uterus over time are sparse but promising.13 Studies suggest that the added progestin not only prevents endometrial cancer, but possibly reduces the risk to below that which would occur in the absence of hormone therapy.14 These observations parallel those in a least 8 case-control studies (see
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review by van Leeuwen and Rookus15) where women who had been treated with combined oral contraceptives also had a reduced risk of endometrial cancer. The efficacy of progestins in preventing endometrial hyperplasia may be less in the clinical setting than in the research setting, however. For example, women in Sweden who had taken unopposed oestrogen for several years before adding progestin were not universally protected from neoplasia.16 In a British study,3 endometrial cancer did occur in some women who were prescribed an oestrogen plus progestin regimen that should have been protective; the authors suggest that this finding may reflect noncompliance with progestin. Endometrial hyperplasia typically has an indolent course, progressing slowly if at all. Kurman et al.17 followed 170 women without hysterectomy an average of 13 years after hyperplasia was found on curettage; endometrial cancer developed in less than 2% (2 of 122) of women with endometrial hyperplasia without atypia, compared to 23% (11 of 48) of women with atypical hyperplasia. The mean duration to progression was nearly 10 years in the first group and an average of 4 years (range 1-11 years) in the second group. Up to 20-25% of women with adenomatous or atypical hyperplasia in curettings will be found to have a well-differentiated carcinoma in the uterus if a hysterectomy is performed within one month, but a much smaller percent ever develop clinically manifest cancer.18'19 This suggests that these cancers usually remain localized and differentiated for a long time, although it is not clear the extent to which the curettage was itself curative in some of these cases. The presence or absence of precancerous adenomatous or atypical hyperplasia is usually readily detected by endometrial sampling. Newer endometrial aspiration techniques make endometrial biopsy an acceptable office procedure to monitor the endometrium in oestrogen-treated women who do not take a progestin. Hyperplasia can also be detected by ultrasound using a vaginal probe; to date, no women with a uterine wall thickness of less than 5 mm has been found to have hyperplasia, whereas a thicker endometrium suggests hyperplasia and requires a tissue diagnosis.20 Overall, there is little doubt that unopposed oestrogen increases the risk of endometrial cancer in proportion to dose and duration of use. On average there is a 3 to 6-fold increase in risk after 3-10 years of use, and a more than 10-fold increment after more than 10 years of use. It seems that an excess risk persists for years after
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the oestrogen has been stopped, but can be greatly reduced when a progestin is added to the oestrogen. Although the optimal regimen has yet to be chosen, when primary consideration is given to prevention of endometrial cancer, estrogen plus cyclic progestin is the safest choice. Other options may be considered when adherence or possible sequellae of long term progestins are considered, as described elsewhere in this issue. BREAST CANCER The risk of breast cancer is increased with early menarche, late menopause and late first pregnancy, and is reduced by early oophorectomy, suggesting an aetiologic or promotional role for endogenous oestrogen. Nevertheless, it has been surprisingly difficult to demonstrate an increased risk of breast cancer in women taking oestrogens. The majority of studies, including two prospective studies in Britain, have found no increased risk of breast cancer in women who used oral contraceptives, even after long-term use (see review by Thomas and Chu, 198621). Many case-control studies of non-contraceptive oestrogen also showed no overall increased risk; some studies reported an increased risk in a subgroup (e.g. oophorectomized women), but the subgroup varied from one study to the next.22 An incremental risk with higher dosage or longer duration of use has also been difficult to demonstrate, although most of the women in most of these studies had used oestrogen for less than 10 years. In addition, it is difficult to separate dose from duration, since women who were treated longer also started oestrogen in the era of high dose oestrogens. One recent meta-analysis of 28 studies concluded that there was no increased risk of breast cancer in oestrogen-treated women except possibly in those who had used high dose preparations.23 Another recent meta-analysis of 16 case-control studies concluded that use for more than 10 years carries a 1.3-1.8 fold increased risk of breast cancer.24 In the latter analysis, studies that examined the effect of oestrogen use for an average duration of at least 5 years showed a significant increase in the risk of breast cancer, whereas no significant increase in risk could be shown in women who had taken oestrogen for less than 5 years. In addition, the increase in risk was least equivocal in the studies that were rated as having the best study design (by reviewers who were blinded to the results of the study). In this meta-analysis, the effects of oestrogen were similar in parous and nulliparous women, and in
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women with or without benign breast disease, but were greater in women with a family history of breast cancer. Recently, several prospective studies3>25~28 have found an increased risk of breast cancer after long-term use of postmenopausal oestrogen. The largest study is that reported by Colditz et al.28 who examined the incidence of breast cancer in 121 700 American nurses who were followed from 1976 to 1984. The overall age-adjusted risk was significantly higher in women who had ever used non-contraceptive oestrogen (relative risk = 1.4). Current users who had taken oestrogens for 10-15 years had a similar (1.3) fold increased risk, but past users were not at increased risk. The somewhat lower risk than that reported by others for long-term use may be explained by the fact that the women in this cohort were relatively young, aged 30-55 at baseline, so that most long-term users must have had either oophorectomy or premature menopause, factors that are ordinarily 'protective' against breast cancer. Most studies of long-term non-contraceptive oestrogen use and breast cancer come from the United States, and therefore largely reflect the use of unopposed conjugated oestrogen. Reports from Europe where more potent oestradiols are more commonly used are disconcerting in that they suggest an increased risk after a shorter duration of treatment. In two of these studies,25'26 the highest risk after the shortest duration of treatment was seen in women treated with oestrogen plus a progestin or other androgen. In a Swedish study,26 there was a 4-fold increased risk of breast cancer in women after more than 4 years of oestrogen plus a progestin; the 95% confidence intervals for this association were very wide (0.9-22.4) and the association was found after multiple subgroup comparisons. Nevertheless, the results are compatible with a large population-based case-control study from Denmark,25 where sequential therapy with oestrogen and progestin was associated with a significantly increased risk of breast cancer (RR = 1.36) not observed with oestrogen use overall. These results support the hypothesis of Kay and Pike29 that oestrogen plus progestin could be more carcinogenic than oestrogen alone. In contrast, oestrogen-treated women in Britain had a significantly increased risk ratio of 2.38 associated with 10 or more years of oestrogen, but the risk was not further increased in women who also used a progestin.3 The only randomized long term (10 year) clinical trial reported to date, found a significantly lower risk of breast cancer in 84 institutionalized women assigned to a high dose of oestrogen
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(2.5 mg of Premarin) plus 10 mg of medroxyprogesterine for 7 days, compared to 84 women assigned to placebo.30 Since oestrogen is generally believed to be a risk factor for breast cancer, it is less often prescribed in women who have a family or personal history of breast cancer.31 This would tend to artificially reduce a true association. Similarly, women with early oophorectomy are at low risk for breast cancer but are particularly likely to receive hormone replacement, another bias leading to a spuriously low risk. On the other hand, women taking replacement oestrogen have more physician contact that almost certainly results in their being more often examined and more often recommended for mammography.32 The resultant earlier diagnosis could lead to a spuriously high risk of breast cancer, a better prognosis, and a paradoxically lower risk of fatal breast cancer. This possibility is strongly suggested by a British report3 where the relative risk of fatal breast cancer was only 0.55 in oestrogen treated women. Similarly, Bergkvist et al.33 found a significantly better survival in Swedish women with breast cancer who had been treated with oestrogen, compared to women with breast cancer who had not been so treated. It is not surprising, then, that the results of various observational studies have been heterogenous.34 Whether currently recommended doses of oestrogen significantly increase risk of breast cancer in postmenopausal women remains uncertain. At the present time the safety of less than 5 years of any oestrogen in currently recommended doses, with or without a progestin, seems assured. At the same time, accumulating evidence also suggests that longer use of replacement oestrogen causes a 30-50% increase in the risk of breast cancer in postmenopausal women. This risk appears to be higher in women with a family history of breast cancer and with a higher dose of oestrogen than is required to prevent menopausal bone loss. Whether the addition of a progestin augments this risk is unclear. It is also uncertain how much of the apparent increased risk is due to ascertainment bias, because women taking oestrogens are more likely to have breast examinations and mammography. Obviously, women treated with replacement oestrogen should be particularly careful to have annual breast examination and mammography. Breast cancer is the most common of the reproductive cancers and the one most feared by women; the answer to the oestrogenbreast cancer question is tremendously important in helping women to make a decision about hormone replacement therapy.
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CANCER OF THE OVARY Ovarian cancer is less common than either breast or uterine cancer, but nevertheless of considerable concern because of the late stage at diagnosis and poor prognosis. The risk of ovarian cancer is reduced by factors related to ovulation, such as multiparity35 and the use of combined oral contraceptives; the latter reduces the risk of epithelial ovarian cancer for years after use.36 A role for non-contraceptive oestrogen is less clear. At least 10 case-control studies conducted in the United States and Europe found no significant association of ovarian cancer with postmenopausal oestrogen.21 Hartge et al,37 reported a significantly reduced risk of serous cancer in oestrogen-using women. Other observations, however, suggest that it would be premature to exclude an increased risk. Time trends show that the incidence of carcinoma of the ovary between 1969 and 1977 in 4 different geographic areas of the United States paralleled the incidence of endometrial cancer, and the prescription of replacement oestrogen.38 Hoover et al.39 found a 2.5 fold increased risk in ovarian cancer in postmenopausal women treated with oestrogen; the risk ratio of observed to expected cases was almost identical in users of diethylstilbesterol and conjugated equine oestrogen, although only the former was statistically significant. When all types of oestrogen were considered, the risk increased with increasing dose but not duration of use. Weiss et al.40 reported an increased risk of endometroid cancers, but no trend with dose or duration of oestrogen use. In Britain, using cancer registry data for comparison, a modest but not statistically significant 1.4 fold increased risk of fatal ovarian cancer was seen in women who had used replacement oestrogen.3 In this study, cancer incidence by years since first use of oestrogen showed a stepwise trend (estimated risk 0.41 for 0-4 years; 1.70 for 5-9 years and 2.38 for 10+ years); this trend was based on only 6 cases, and was not statistically significant. Small numbers of cases of different histological types in women exposed to different hormone replacement regimens characterize many published studies. It is not possible to preclude an effect of long-term replacement oestrogen on ovarian cancer risk. CONCLUSIONS Essentially all of the data on oestrogen therapy and cancer in postmenopausal women are based on observational studies, subject
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to the usual caveats of interpretation. Factors related to who receives replacement oestrogen, who remains on it, and consequent differences in symptoms and health care all confound the associations. The only unequivocal association is the increased risk of endometrial cancer with and after the use of unopposed oestrogen. The risk, especially with long-term use, is too large and the results are too consistent to be explained by chance, confounding or bias. Because endometnal hyperplasia precedes cancer in most cases, randomized trials have been able to study the (relatively short term) effect of different oestrogens with and without different progestins. In this instance, two major questions remain: what is the optimal progestin regimen; and is a program of unopposed estrogen either necessary or feasible? Whether replacement oestrogen alone or with a progestin increases the risk of breast or ovarian cancer remains an unanswered question, one that is not likely to be resolved by clinical trials with cancer as an outcome. Because widespread oestrogen replacement is a recent addition to medical practice, relatively few studies have included many long-term oestrogen users. All these reports are compatible with the possibility that non-contraceptive oestrogen increases the risk of breast cancer by 30-50%. These studies do not exclude other explanations for the observed oestrogen-breast cancer association, however. In the meantime, physicians need to help their patients make informed choices about when, whether and how to use oestrogen replacement. These choices must consider more than the possible prevention of one specific disease, but also issues of the individual woman's risk pattern, fears and quality of life. REFERENCES 1 Barrett-Connor EL. Postmenopausal estrogen, cancer and other considerations. Women Health 1986; 11(3-4): 179-195 2 Hemminki E, Kennedy DL, Baum C, McKinlay SM. Precursing of noncontraceptive estrogen and progestins in the United States, 1974-1986. Am J Public Health 1988; 78:1479-1481 3 Hunt K, Vessey MP, MacPherson K, Colcman M. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Gynecol 1987; 94: 620-635 4 Henderson BE. The cancer question: An overview of recent epidemiologic and retrospective data. Am J Obstet Gynecol 1989; 161:1859-1864 5 Etringer B, Golditch IM, Friedman G. Gynecologic consequences of longterm, unopposed estrogen replacement therapy. Mflturitis 1988; 10: 271-282 6 Shapiro S, Kelly JP, Rosenberg L, et al. Risk of localized and widespread
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endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med 1985; 313:969-972 7 Rubin GL, Peterson HB, Lee NC, Maes EF, Wingo PA, Becker S. Estrogen replacement therapy and the risk of endometrial cancer: remaining controversies. Am J Obstet Gynecol 1990; 162: 148-154 8 Paganini-Hill A, Ross RK, Henderson BE. Endometrial cancer and patterns of use of estrogen replacement therapy: a cohort study. Br J Cancer 1989; 59: 445-447 9 Collins J, Allen LH, Dormer A, Adams O. Oestrogen use and survival in endometrial cancer. Lancet 1980: ii 961-963 10 Schwartzbaum JA, Hulka BS, Fowler WC, et al. The influence of exogenous estrogen use on survival after diagnosis of endometrial cancer. Am J Epidemiol 1987; 126(5): 851-860 11 Hammond CB, Jelovsek FR, Lee KL, et al. Effects of long-term estrogen replacement therapy. Am J Obstet Gynecol 1979; 133: 537 12 Paterson MEL, Wade-Evans T, Sturdee DW, Thorn MH, Studd JWW. Endometrial disease after treatment with oestrogens and progestogens in the climacteric. Br Med J 1980; 22 March: 822-824 13 Whitehead MI, Hillard TC, Crook D. The role and use of progestogens. Obstet Gynecol 1990; 75: 59S-80S 14 Endometrial cancer and combined oral contraceptives. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Epidemiol 1988; 17: 263-269 15 Van Leeuwen FE, Rookus MA. The role of exogenous hormones in the epidemiology of breast, ovarian and endometrial cancer. Eur J Cancer Clin Oncol 1989; 25: 1961-1972 16 Persson IR, Adami HO, Bergkvist L, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: Results of a prospective study. Br Med J 1989; 278: 147-151 17 Kurman RJ, Karainski PF, Norris HJ. The behavior of endometrial hyperplasia: a long-study of 'untreated' hyperplasia in 170 patients. Cancer 1985; 56: 403-412 18 Gusberg SB, Kaplan AL. Precursor of corpus cancer IV adenomatous hyperplasia as stage O carcinoma of the endometrium. Am J Obstet Gynecol 1963; 87: 662-678 19 King A, Seraj IM, Wagner RJ. Stomal invasion in endometrial carcinoma. Am J Obstet Gynecol 1984; 149: 10-14 20 Granberg S, Wikland M, Karlsson B, et al. Endometrial thickness as measured by endovaginal ultrasonography for identifying endometrial abnormality. Am J Obstet Gynecol 1991; 164(1): 47-52 21 Thomas DB, Chu J. Nutritional and endocrine factors in reproductive organ cancers: Opportunities for primary prevention. J Chron Dis, 1986; 39(12): 1031-1050 22 Hulka BS. Hormone-replacement therapy and the risk of breast cancer. CA 1990; 40: 289-296 23 Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer, Arch Intern Med 1991; 151: 67-72 24 Steinberg KK, Thacker SB, Smith SJ, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. J Am Med Assoc 1991; 265(15): 1985-1990 25 Ewertz M. Influence of non-contraceptive oxogenous and endogenous sex hormones on breast cancer risk in Denmark. Int J Cancer 1988; 42: 832-838 26 Bergkvist L, Adami H-O, Persson I, Hoover R, Schairer C. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 1989; 321: 293-297 27 Mills PK, Beeson WL, Phillips RL, Fraser GE. Prospective study of exogenous
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hormone use and breast cancer in Seventh-Day Adventists. Cancer 1989; 64: 591-597 Colditz GA, Stampfer MJ, Willctt WC, Hennekens CH, Rosner B, Speizer FE. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. J Am Med Assoc 1991; 264(20): 2648-2653 Kay TJ, Pike M. The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 1988; 24: 29-43 Nachtigall LE, Nachtigall RH, NachtigaU RD, Beckman EM. Estrogen replacement therapy. II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979; 54: 74-79 Bergkvist L, Persson I, Adami HO, Schairer C. Risk factors for breast and endometria] cancer in a cohort of women treated with menopausal oestrogens. Int J Epi 1988; 17 (4): 732-737 Barrett-Connor, EL. Postmenopausal estrogen and prevention bias. Ann Intern Med 1991; 115: 455-456 Bergkvist L, Adami HO, Persson I, Bergstrom R, Krusemo UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogenprogestogen replacement therapy. Am J Epidemiol 1989; 130: 221-8 Armstrong BK. Estrogen therapy after the menopause—boom or bane? Med J Aust 1988; 148: 213-214 Henderson BH, Ross RK, Pike MC, Casagrande JT. Endogenous hormones as a major factor in human cancer, Cancer Res 1982; 42: 3232-3239 Ory HW. The reduction in risk of ovarian cancer associated with oralcontraceptive use. N Engl J Med 1987; 316: 650-655 Hartge P, Hoover R, McGowan L, Lcsher L, Norris HJ. Menopause and ovarian cancer. Am J Epidemiol 1988; 127(5): 990-998 Cramer DW, Devesa SS, Welch WR. Trends in the incidence of endometroid and clear cell cancers of the ovary in the United States. Am J Epidemiol 1981; 114: 201-208 Hoover R, Gray LA, Fraumeni JF Jr. Stilbestrol and the risk of ovarian cancer. Lancet 1977; 2: 533-534 Weiss NS, Lyon JL, Krishnamurthy S, Dietert SE, Liff JM, Daling JR. Noncontraceptive estrogen use and the occurrence of ovarian cancer. J Nad Cancer Instit 1982; 68(1): 95-98
