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JOURNAL OF REPRODUCTIVE MEDICINE. 1996 May; 41(5 Suppl):419-25.This article reviews recent epidemiological data assessing the risk of breast, endometrial, ovarian, and cervical cancer in women using the injectable contraceptive depot medroxyprogesterone acetate (DMPA). A review is also provided of epidemiological and biostatistical concepts which relate to the literature on the relationship between the use of hormonal contraception and cancer. Breast cancer is a common and lethal disease in the US, and evidence suggests that gonadal steroids play a role in the development of breast cancer. Two major case control studies (one in New Zealand and the other under the auspices of the World Health Organization [WHO]) as well as a pooled analysis of these studies found no increased overall breast cancer risk in DMPA users. A currently unexplained pattern of increased risk in recent users mimics that seen with oral contraceptive (OC) use and term pregnancy. A WHO hospital-based study of the relationship between endometrial cancer and DMPA use found a protective effect of DMPA which appeared to be longterm and as great as that associated with OCs. Whereas it is plausible that DMPA, which suppresses ovulation, would lower the risk of ovarian cancer in users, a WHO case-control and hospital-based study failed to uncover such a protective effect. Studies of the routine use of DMPA in nulliparous women (who have higher risk of ovarian cancer) will shed more light on any effect DMPA may have on ovarian cancer. The unique epidemiology of cervical cancer (including number of sexual partners, use of barrier contraception, and frequent screening) makes it difficult to assess any association with contraceptive use. However, a large population-based, case-control study in Costa Rica; a WHO hospital-based, case-control study in Thailand, Mexico, and Kenya; and a study in New Zealand indicate that the risk of cervical neoplasia does not appear to be affected by DMPA use. While some issues regarding DMPA and the risk of reproductive tract carcinoma remain to be resolved, clinicians can be reassured that, for appropriately selected clients, the substantial benefits of DMPA outweigh any risks.
Drs. Thomas and Noonan reply re "Comparison of Recalled and Validated Oral Contraceptive Histories" [letter]
AMERICAN JOURNAL OF EPIDEMIOLOGY. 1995 Apr 15; 141(8):791.Dr. Realini asserts in his letter that the results of the WHO Collaborative Study of Neoplasia and Steroid Contraceptives concerning oral contraceptives and breast cancer could have been biased as a result of better recall of prior oral contraceptive use by cases in comparison to controls. Although this is a possibility in any case-control study based on data collected by interviews, being able to validate positive oral contraceptive histories of more cases than controls does not necessarily mean more cases than controls who were users of oral contraceptives gave a history of such use. The issue of bias due to recall was discussed in the original paper. The medical records of women who claimed contraceptive use were checked for brand names and duration of use; the medical records of women who did not were not checked. This procedure did not alter their classification as users or nonusers. Since few combined oral contraceptives were available, and erroneous reports of use of combined or noncombined preparations were corrected, the estimated values of the relative risk of breast cancer in women who ever used combined oral contraceptives could not be appreciably influenced by any differences in the proportion of cases or controls whose oral contraceptive histories were supplemented by information from medical records. However, such differences could alter estimated values of the relative risk in relation to duration, latency, or recency. Information was obtained from the medical records of users in 27% of cases and 18% of controls. These percentages varied with center (0-94% of cases, 0-89% of controls). Information was most frequently obtained from the medical records of long-term and current or recent users in both groups. Similar results were obtained separately from countries in which information from medical records was obtained for relatively high and low proportions of users, and in individuals whose use was ascertained solely from interviews and from both interviews and medical records.
AMERICAN JOURNAL OF EPIDEMIOLOGY. 1994 Nov 15; 140(10):956.A paper by Nischan and colleagues, "Comparison of Recalled and Validated Oral Contraceptive Histories," which examines the accuracy of the histories of oral contraceptive use (defined as agreement with gynecologists' records concerning duration of use, times since first and last use, and individual preparations used) in a WHO case-control study of breast cancer, "WHO Collaborative Study of Neoplasia and Steroid Contraceptives," fails to comment on the more frequent validity of the histories among those persons with breast cancer. Of 253 contraceptive histories from persons with breast cancer, for whom responses from at least 1 gynecologist were available, 234 (92.4%) were confirmed; of those from 621 controls, 524 were. The difference is statistically significant (chi-square test, p < 0.01). This better recall of ever-use of oral contraceptives among breast cancer patients creates a bias that makes an association between breast cancer and ever-use of oral contraceptives stronger than it is. The slight elevation in breast cancer risk associated with ever-use of oral contraceptives found in the WHO study may be due to this. There is no information about the accuracy of negative oral contraceptive histories.
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY. 1992 Oct; 167(4 Pt 2):1171-6.The largest case control study on the association between oral contraceptive (OC) use and cancer is the US Cancer and Steroid Hormone (CASH) study. Since it did not use hospital-based patients as controls, it eliminated some biases. Since OCs suppress ovulation and suppressed ovulation is linked with reduced risk of ovarian cancer, scientists believe OCs may reduce this cancer risk. The CASH study shows that OC use indeed decreases the risk of ovarian cancer 40% (relative risk [RR]=.6 and this protection lasts for more than 10 years after OC discontinuation. Protection increases with duration of OC use (<1 year RR=.6 and >10 years RR=.2). Estrogenic stimulation of the endometrium without ample progestational protection causes endometrial cancer. Thus combined OCs which have estrogen and progestin components should reduce the risk of endometrial cancer. The CASH study reveals OC use for at least 12 months reduces this risk 50%. OCs have a protective effect for at least 15 years after stopping OC use. In addition, UK national mortality data show OC use caused the decline in ovarian cancer mortality and a 40% decrease in endometrial cancer mortality over the last 20 years. A WHO 7-county case control study indicates that OC users in developing countries have the same protective effect against ovarian and endometrial cancer as those in developed countries. Studies of OC use and cervical cancer have had conflicting results due to 3 biases: cervical cancer is associated with sexual behavior and is therefore a sexually transmitted disease; detection bias. A study in Costa Rica conducted by CDC study has addressed the 1st and 3rd biases. It found no increased risk of invasive cervical cancer or carcinoma in situ with OC use. Studies of OC use and breast cancer have also had conflicting results, but the data clearly indicate that OC use does not increase the overall risk of breast cancer. In fact, OC benefits surpass breast cancer risks.
SOUTH AFRICAN MEDICAL JOURNAL. 1992 May 2; 81(9):444-5.The advantages and side effects of the injectable contraceptive, Depo-Provera, are highlighted. It has been available to women in South Africa and in about 90 developing and developed countries for 20 years. It is an effective and convenient contraceptive with no serious side effects. Its failure rate is 0.2-0.6/100 woman years. Nevertheless there is still concern that it may cause breast cancer because original tests of Depo-Provera using beagles indicated that it may increase breast cancer risk. WHO and the UK Committee on Safety of Medicines have since dropped the requirement of testing of beagles since they cannot predict the effects of steroids on women. A 12-year WHO multinational, hospital-based case-control study on neoplasia and hormonal contraceptives reassures Depo-Provera's safety. For example, the risk of breast cancer did not increase with duration or in women who had used it for >5 years. The risk was higher, however, among women who had used it for <4 years, particularly <35-year old women. The same holds true for oral contraceptive (OC) users. It has been suggested that this slight increase is because Depo-Provera and OCs may accelerate growth of some existing, previously undetected breast tumors. The WHO study verifies that the benefits of Depo-Provera surpass the side effects which include disturbed bleeding patterns, weight gain, and headaches. For example, it decreases the risk of ovarian and endometrial cancer. It is even more beneficial in developing countries where women often suffer from anemia because it increases hemoglobin levels. Further since women in developing countries cannot always comply and take their OCs, Depo-Provera can grant them the protection they need against pregnancy thus saving many lives. Depo-Provera should be available in developed as well as in developing countries.
CONTRACEPTION. 1992 Apr; 45(4):363-8.Researchers analyzed interview and physician records' data on 45 women with breast cancer (cases) admitted to the Central Institute of Cancer Research in Berlin, East Germany between November 1982-June 1986 and born in 1983 or later and 194 women (controls) admitted to the Klinikum Berlin-Buch also in East Germany for conditions other than breast cancer to compare recall accuracy in women who had ever used an IUD. These women were drawn from case control study of the relationship between breast cancer and oral contraceptive use was part of the WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Agreement between patient recall and physician records was exceptional for duration of IUD use (p<.001), number of IUD episodes (kappa=0.79), time since 1st IUD and time since last IUD use (p<.001). Agreement rates did not differ between cases and controls. 75% of the women could not name the IUD brand used so the researcher could not examine agreement of brand name. Thus, other than brand name, this study showed that validity of information on IUD use obtained from interviews is significant. In fact, it also pointed out that case control studies probably yield sound relative risk estimates.
The WHO Collaborative Study of Neoplasia and Steroid Contraceptives: the influence of combined oral contraceptives on risk of neoplasms in developing and developed countries.
CONTRACEPTION. 1991 Jun; 43(6):695-710.A hospital-based case-control study was conducted in 8 developing and 3 developed countries to determine whether use of combined oral contraceptives (OCs) alters risks of various cancers. An observed trend of increasing risk of invasive cervical cancer with duration of use may not represent a causal relationship and is the subject of further study. Decreased risks of ovarian and endometrial carcinomas in users likely indicate a protective effect of OCs, the degree of which was similar in developing and developed countries. A small increase in risk of breast cancer in recent and current users was found to be somewhat greater in developing countries. Both causal and noncausal interpretations of this finding have been offered. No associations were found between OCs and in situ cervical, hepatocellular, cholangio, or gallbladder carcinomas, or uterine sarcomas. However, the ability of this study to detect alterations in risks for these neoplasms in longterm users was low. (author's)
CANCER CAUSES AND CONTROL. 1991 Nov; 2(6):389-94.As part of the Who Collaborative Study of Neoplasia and Steroid Contraceptives, physicians gathered data from 2796 cases and 18,900 controls from at least 1 hospital in each country between 1979-1982 and stopped between 1982-1988 to examine the association between breast cancer in women and combined oral contraceptives (COCs), particularly around menopause. The countries included Australia, Democratic Republic of Germany, Israel, Chile, China, Colombia, Kenya, Mexico, the Philippines, and Thailand. The relative risk (RR) was higher in women who had used COCs in the last year, but the increased RR was no greater for women who would be near menopause (45-49 years) than it was for women <40 years old (1.3 vs. 1.4). In fact, the RR was highest in 40-44 year old women (2.1). Further the RRs were greater in women who began using a COC >45 years of age than they were for women who began using it <45 years of age, but the RR did not increase with duration. For example, the RR for women who began to take the COC <45 years for 12-48 months was 0.86 compared to 1.4 for those who began >45 years. The RR for women who began to take the COC at >45 years old remained at 1.4 for the other durations. In addition, the RR in women who ever used COCs was greater in women who underwent an artificially induced menopause than those who underwent a natural menopause (1.7 vs. 1.04). This higher risk in COC users occurred no matter the duration between last use of COCs and induced menopause and the method of artificial menopause. In conclusion, this study did not support the hypothesis that COCs increase the risk of breast cancer in women who use them around the time of menopause.
Family Planning Perspectives. 1992 Jan-Feb; 24(1):43-4.1 hospital in Nairobi, Kenya; Mexico City, Mexico, and Chiang Mai, Thailand and 2 hospitals in Bangkok, Thailand took part in a WHO sponsored collaborative study to examine the association between depomedroxyprogesterone acetate (DMPA) and breast cancer. The researchers compared 1979-1988 data on 869 hospitalized women with breast cancer with 11,890 hospitalized women with unrelated conditions. 12.5% of cases and 12.2% of controls had ever had an injection of DMPA. Overall ever users had no significant increased risk of breast cancer (relative risk [RR], 1.2) In addition, risk did not rise with duration. Nevertheless current users who began receiving DMPA within the past 4 years did have a significantly higher risk (RR 2.6). On the other hand, current users who began receiving DMPA >5 years earlier were not at increased risk at all. For example, the RR for those who began 8-12 years earlier was 0.8 and for those who began >12 years earlier was 0.5. Further even though the current users <35 years old who began receiving DMPA within the past 4 years were >2 times as likely to have breast cancer than their corresponding counterparts who did not use DMPA (RR 2.2), the risk according to duration was not significant. The researchers listed some possible reasons for the discrepancies. They concluded that there is only a weak association between DMPA and breast cancer--comparable to that between oral contraceptives and breast cancer. In New Zealand, a case control study of 30 25-51 year old women who used DMPA for at least 5 years showed that long term use of DMPA significantly reduced bone density. For example, for DMPA users, the spine and femoral neck bone densities were 8% and 7% respectively lower than the premenopausal controls. The researchers found the same effect even when they restricted the analysis to nonsmokers.
PACIFIC BASIN MATERNAL AND CHILD HEALTH RESOURCE CENTER WHAT'S NEW IN.... 1991 Dec; 3(58):1-2.The WHO has published partial results of an epidemiological study of the safety with respect to breast cancer of the injectable contraceptive depomedroxyprogesterone acetate, known as DMPA or Depo-Provera. The WHO Special Program of Research, Development and Research Training in Human Reproduction has been conducting a collaborative retrospective study of cancer and DMPA in 3 developed and 8 developing countries. Results from Kenya, Mexico and Thailand are published in Lancet on October 5, 1991. Comparing 869 women with breast cancer <64 years old and 11,890 matched hospital-based controls, the relative risk was 1.21, not statistically significant. 12.5% of the cases and 12.2% of the controls had used DMPA. Fine analysis pointed to a possibility of increased risk over the 1st 4 years of use. The data were not compatible with the hypothesis that DMPA. Fine analysis pointed to a possibility of increased risk over the 1st 4 years of use. The data were not compatible with the hypothesis that DMPA causes cancer, but only that it may speed the growth of early pre-existing cancer. When contemplating the choice of DMPA, people should evaluate their risks relative to the excellence of DMPA as a highly effective, convenient, long-acting, but reversible method.
Histologic types of breast carcinoma in relation to international variation and breast cancer risk factors. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.
INTERNATIONAL JOURNAL OF CANCER. 1989 Sep 15; 44(3):399-409.Associations between breast cancer risk factors and histologic types of invasive breast carcinoma were studied in 2728 patients. Lobular and tubular carcinomas occurred with increased relative frequency in most high risk groups. The proportion of these types increased with age to a maximum at 45-49 years and decreased in the following decade. Significantly increased proportions of lobular and tubular carcinomas were also associated with high risk countries, prior benign breast biopsy, bilateral breast cancer, concurrent mammary dysplasia, high age at 1st livebirth, never-pregnant patients compared to those with a 1st livebirth before age 20, private pay status, and length of education. Nonsignificant increases were associated with family history of breast cancer, less than 5 livebirths, less than 25 months total breastfeeding, use of oral contraceptives or IUD, and high occupational class. As a general trend, the higher the overall relative risk, the higher the proportion of lobular and tubular carcinomas. The occurrence of other histologic types also increased breast cancer risk, but to a smaller degree than for lobular/tubular carcinomas. It is suggested that all hormonally related, socioeconomic, and geographic risk factors enter their effect by selectively increasing the number of lobular cells at risk. Family history of breast cancer and age over 49 years did not follow the general trend of parallel increases in the proportion of lobular/tubular carcinomas and breast cancer risk, and may operate through other mechanisms. (author's)