КОК и риски развития рака

[D_Timofeev]

Уважаемые коллеги! Занялся вплотную темой комбинированных оральных контрацептивов, в связи с чем возник ряд вопросов. В первую очередь интересуют последние исследования о рисках развития различных видов рака при употреблении КОК. Пока имеющаяся в распоряжении на сегодняшний день информация позволяет сделать следующие выводы:

– Увеличение риска развития РМЖ среди пользователей КОК;
– Риск снижается через 10 лет после прекращения приема КОК;
– Риск не коррелирует с длительностью приема, типом и дозой препаратов;
– Риск может быть выше у женщин, начавших прием моложе 20 лет;
– Нет увеличения риска среди женщин, использующих чистые гестагены;
– Неоднозначен риск у женщин с наследственной предрасположенностью к РМЖ.

Гормональные контрацептивы и риск развития РЭ:

– Наблюдается снижение риска развития РЭ среди пользователей КОК в два раза (0,5);
– Снижение риска прямо пропорционально длительности приема КОК;
– Снижение риска сохраняется через 15 лет пос ле прекращения приема КОК.

Гормональные контрацептивы и риск развития РШМ:

– Отмечено увеличение риска развития РШМ с увеличением длительности использования КОК;
– Риск несколько выше в отношении рака in situ шейки матки, нежели инвазивного рака шейки матки;
– Риск снижается с увеличением времени прекращения приема КОК;
– У женщин с положительным тестом на HPV риск развития РШМ выше по сравнению с негативными по HPV-статусу.

Гормональные контрацептивы и риск развития РЯ:

– Наблюдается снижение риска развития РЯ среди пользователей КОК в два раза (0,5);
– Снижение риска прямо пропорционально длительности приема КОК;
– Снижение риска сохраняется через 30 лет после прекращения приема КОК;
– Снижение риска пограничных опухолей яичников среди пользователей КОК.

Гормональные контрацептивы и риск развития рака печени:

– Увеличение риска для гепатоцеллюлярного рака печени среди женщин длительно использующих КОК;
– Возможно отсутствие увеличения риска для пользователей КОК из групп риска возникновения рака печени.

Гормональные контрацептивы и риск развития колоректального рака:

– Не получено увеличения риска развития колоректального рака среди пользователей КОК даже при длительном использовании препарата. В двух исследованиях случай-контроль продемонстрировано достоверное снижение риска развития колоректального рака. Таким образом, среди пользователей КОК наблюдается отсутствие либо снижение риска развития колоректального рака.

Гормональные контрацептивы и риск развития меланомы:

– Не подтверждается достоверное увеличение риска для этой опухоли, как при длительном приеме КОК, так и в зависимости от времени начала и прекращения приема КОК. Единичные исследования, предполагающие некоторое увеличение риска, возможно, отражают более тщательное наблюдение за этими женщинами и как следствие более частое удаление пигментных новообразований среди них.

Коллеги! Буду признателен, если кто-то поделится дополнительной информацией, очень желательно, конечно, со ссылками. Заранее благодарен!

[DrTatyana]

http://forums.rusmedserv.com/showthread.php?t=270402

вы бы сами ссылки привели бы, что ли

[DrTatyana]

Risks and side effects associated with estrogen-progestin contraceptives
Authors: Kathryn A Martin, MD Pamela S Douglas, MD
Section Editors Robert L Barbieri, MD William F Crowley, Jr, MD Deputy Editor
Kathryn A Martin, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2013. | This topic last updated: фев 7, 2013.

Overall cancer risk — Oral contraceptive use has been associated with an increased risk of certain types of cancer and a decrease in others. However, it appears that the pill is not associated with an overall increased risk of cancer. This was illustrated in the Royal College of General Practitioners' cohort study, which included nearly 50,000 women followed for a mean of 24 years. In pill users compared with nonusers, risks were significantly lower for colorectal, uterine, and ovarian cancer [85]. The incidence of breast cancer was similar in pill users and never users, but there were significant trends of increasing risk of cervical and central nervous system cancer in pill users. Depending upon the data set used, there was either a nonsignificant or significant reduction in overall cancer risk among users compared with nonusers, with an estimated absolute risk reduction between 10 and 45 per 100,000 woman-years.

Breast cancer — Available data on breast cancer risk with OC use are conflicting.
Epidemiologic studies have generally not demonstrated an association between OC use and the risk of breast cancer later in life [86-91]. This can be illustrated by the results of three of the largest series:


■In the Nurses' Health Study, in women over age 40 years, neither long-term past OC use, nor use prior to a first full-term pregnancy was associated with an increased breast cancer risk [88].
■A population-based, case-control study evaluated women ages 35 to 64 (4574 women with breast cancer and 4682 controls), over 75 percent of whom were using or had used OCs [89]. The relative risks of breast cancer for current or previous oral contraceptive use were 1.0 (95% CI 0.8-1.2) and 0.9 (95% CI 0.8-1.0), respectively. Breast cancer risk was not associated with estrogen dose, duration of use, initiation at a young age (<age 20), or race.
■In the Royal College of General Practitioners' study described above, the risk of breast cancer was similar in users compared with never users of the pill (RR 0.98, 95% CI 0.87-1.10) [85].

In contrast, an increase in risk has been reported in some pooled and meta-analyses. In one pooled analysis published before the observational studies noted above [88,89], there was a small but significant increase in the overall relative risk of breast cancer (RR = 1.07) in forever versus never users [92]. However, because pill users are young, this represented a very small rise in absolute risk. In addition, concerns have been raised about this meta-analysis because a low percentage of women had ever used oral contraceptives (40 percent), and it lacked the follow-up necessary to determine whether there were long-term effects of OC use [90].

Data on breast cancer risk in OC users with a family history of breast cancer are also conflicting. In the above case-control study, the risk was not increased in women with a family history of breast cancer [89]. In contrast, a review of women taking OCs prior to 1975 (high dose formulations) found an increase in breast cancer risk in those who had a first-degree relative with breast cancer (RR = 3.3; 95% CI 1.6-6.7) [93].

Oral contraceptive use may increase breast cancer risk in carriers of BRCA1 mutations, and possibly BRCA2 mutations.

Cervical cancer — There appears to be an increased risk for developing cervical cancer among women who have taken OCs [85,91,94-96]. A systematic review of 28 studies, including over 12,000 women with cervical cancer, found that the risk increased with increasing duration of oral OC use (table 3) [97]. Although there was considerable variation in study designs, the increased risk of cervical cancer was demonstrated after adjusting for the number of sexual partners, previous cervical smears, smoking, histology (adenocarcinoma or squamous cell), HPV status, and use of barrier methods. Adjustment for HPV status may not have been reliable since HPV testing at regular intervals was not routinely performed; thus, some HPV infections could have been missed [97].

The best available evidence comes from The Collaborative Group on Epidemiological Studies of Cervical Cancer, which reanalyzed and pooled individual participant data from 24 epidemiologic studies that included 16,573 women [98]. The risk of invasive cervical cancer increased with increasing duration of use (RR for five or more years of use 1.90, 95% CI 1.69-2.13). The risk decreased after use ceased, returning to that of nonusers after 10 years.

Similar patterns of risk were seen for invasive and in-situ cancer, and for women who tested positive for high-risk HPV. The absolute increase in risk is very low: the authors estimate that 10 years of use between ages 20 and 30 would increase the cumulative incidence of cervical cancer from 7.3 to 8.3 per 1000 and 3.8 to 4.5 per 1000 in less developed and more developed countries, respectively. It is still unclear whether the relationship between oral contraceptive use and cervical cancer is a causal one because their use is also associated with exposure to human papillomavirus, the known cause of cervical cancer.

Some studies indicate HPV-negative OC users do not have an increased risk of cervical cancer [97,99]. The mechanism for an increased cervical cancer risk in HPV-positive OC users noted in some studies may be related to a metabolite of estradiol, 16 alpha-hydroxyestrone, which can act as a cofactor with oncogenic HPV to promote cell proliferation [96,99-101].

Ovarian cancer — Epidemiologic studies have consistently shown that prolonged use of oral contraceptive pills (OCs) reduces the risk of ovarian cancer [91]. An analysis of 45 epidemiological studies from 21 countries found that, compared with women who had never used OCs, any use of OCs was associated with a significant reduction in risk of developing ovarian cancer (RR 0.73, 95% CI 0.70-0.76) [102]. Importantly, the protective effect persisted for 30 years after cessation of OCs. Low dose OCs are as effective as higher dose OCs. This topic is reviewed in detail separately. (See "Epithelial ovarian cancer: Pathology".)

The use of OCs to reduce the risk of ovarian cancer in women at high risk of this disease (BRCA1 or BRCA2 mutations) is reviewed separately.

Endometrial cancer — The use of oral contraceptive pills decreases the risk of endometrial cancer [85,91,103]. In one study, women using combination oral contraceptive pills for at least 12 months had a relative risk of endometrial cancer of 0.6 (95% CI 0.3-0.9) compared with nonusers [103]. The protective effect of oral contraceptives persisted for at least 15 years after cessation of use. This benefit is likely related to the progestin effect of oral contraceptives, which suppress endometrial proliferation. (See "Endometrial carcinoma: Epidemiology and risk factors".)

Melanoma — The impact of oral contraceptives on the risk of melanoma has been unclear. In a prospective cohort study of premenopausal Caucasian women, current oral contraceptive use was associated with a twofold increase in risk, particularly in current users with 10 or more years of use [104]. However, a systematic meta-analysis that included 18 case-control studies showed no evidence for an increased risk of melanoma with the use of OCs [105]. (See "Risk factors for the development of melanoma", section on 'Other factors'.)

OVERALL MORTALITY — As described above, oral contraceptive use in women over age 35 who smoke is associated with an increased risk of death from cardiovascular events. However, overall mortality rates are not increased, and may actually be decreased, among ever users of oral contraceptives compared with never users, as illustrated by the following observations:


■In the Oxford Family Planning cohort study of 17,032 women of reproductive age followed for 32 years, the rate ratio for death from any cause in those who had ever used oral contraceptives was 0.89 compared with never users (after adjusting for smoking, age, parity, social class, and duration of use) [106].
■In the Nurses’ Health Study, there was no adverse effect of oral contraceptive use on overall long-term mortality (relative risk [RR] of mortality 0.93 for ever users versus never users; RR 1.06 for ≥10 years of use) [107].
■A possible mortality benefit was reported in the Royal College of General Practitioners' prospective cohort study of over 46,000 women followed for up to 39 years [108]. Ever users of OCs had a significantly lower rate of death from any cause (RR 0.88). Lower rates of death were also seen for all cancers combined, individual cancers (colorectal, uterine, ovarian), cardiovascular disease, and coronary heart disease. The estimated absolute reduction in all cause mortality for ever users of OCs was 52 per 100,000 woman years.

The majority of women in this study had taken oral contraceptives containing higher doses of estrogen than are typically used today (≥50 mcg versus 20 to 35 mcg ethinyl estradiol). These data should reassure young, nonsmoking women that current use of oral contraceptives is not associated with an increased long-term risk of death, and may actually provide a small benefit.

[DrTatyana]

Ссылки, собственно говоря

85.Hannaford PC, Selvaraj S, Elliott AM, et al. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study. BMJ 2007; 335:651.
86.Long-term oral contraceptive use and the risk of breast cancer. The centers for Disease Control Cancer and Steroid Hormone Study. JAMA 1983; 249:1591.
87.Oral-contraceptive use and the risk of breast cancer. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med 1986; 315:405.
88.Hankinson SE, Colditz GA, Manson JE, et al. A prospective study of oral contraceptive use and risk of breast cancer (Nurses' Health Study, United States). Cancer Causes Control 1997; 8:65.
89.Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med 2002; 346:2025.
90.Davidson NE, Helzlsouer KJ. Good news about oral contraceptives. N Engl J Med 2002; 346:2078.
91.Vessey M, Painter R. Oral contraceptive use and cancer. Findings in a large cohort study, 1968-2004. Br J Cancer 2006; 95:385.
92.Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1996; 347:1713.
93.Grabrick DM, Hartmann LC, Cerhan JR, et al. Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA 2000; 284:1791.
94.Ursin G, Peters RK, Henderson BE, et al. Oral contraceptive use and adenocarcinoma of cervix. Lancet 1994; 344:1390.
95.Thomas DB, Ray RM. Oral contraceptives and invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Am J Epidemiol 1996; 144:281.
96.Moreno V, Bosch FX, Muñoz N, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 2002; 359:1085.
97.Smith JS, Green J, Berrington de Gonzalez A, et al. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet 2003; 361:1159.
98.International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, et al. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 2007; 370:1609.
99.de Villiers EM. Relationship between steroid hormone contraceptives and HPV, cervical intraepithelial neoplasia and cervical carcinoma. Int J Cancer 2003; 103:705.
100.Auborn KJ, Woodworth C, DiPaolo JA, Bradlow HL. The interaction between HPV infection and estrogen metabolism in cervical carcinogenesis. Int J Cancer 1991; 49:867.
101.Newfield L, Bradlow HL, Sepkovic DW, Auborn K. Estrogen metabolism and the malignant potential of human papillomavirus immortalized keratinocytes. Proc Soc Exp Biol Med 1998; 217:322.
102.Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Doll R, et al. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 2008; 371:303.
103.Combination oral contraceptive use and the risk of endometrial cancer. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. JAMA 1987; 257:796.
104.Feskanich D, Hunter DJ, Willett WC, et al. Oral contraceptive use and risk of melanoma in premenopausal women. Br J Cancer 1999; 81:918.
105.Pfahlberg A, Hassan K, Wille L, et al. Systematic review of case-control studies: oral contraceptives show no effect on melanoma risk. Public Health Rev 1997; 25:309.
106.Vessey M, Painter R, Yeates D. Mortality in relation to oral contraceptive use and cigarette smoking. Lancet 2003; 362:185.
107.Colditz GA. Oral contraceptive use and mortality during 12 years of follow-up: the Nurses' Health Study. Ann Intern Med 1994; 120:821.
108.Hannaford PC, Iversen L, Macfarlane TV, et al. Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners' Oral Contraception Study. BMJ 2010; 340:c927.OTE]

UpToDate, 2013

[D_Timofeev]

Огромное спасибо!

[DrTatyana]

36 эпидемиологических исследований
- 27 276 женщин, у которых был диагностирован эндометриальный рак (случаи заболевания)
- 115 743 женщин, у которых не было эндометриального рака (контроль)

Медиана возраста пациенток составила 63 года

Чем дольше женщины использовали оральные контрацептивы, тем выше было снижение риска развития эндометриального рака; каждым 5 годам использования контрацептивов соответствовало отношение рисков 0,76 (95% ДИ 0,73–0,78; p < 0,0001). Это снижение риска сохранялось в течение более 30 лет после прекращения использования оральных контрацептивов без видимого снижения ОР при использовании их в течение 1960-х, 1970-х и 1980-х годов, несмотря на более высокие дозы эстрогенов в таблетках, используемых в первые годы. Тем не менее степень снижения риска, связанная с применением оральных контрацептивов, различалась в зависимости от типа опухоли, и была более выраженной для карцином (ОР 0,69; 95% ДИ 0,66–0,71), чем для сарком (0,83; 0,67–1,04; сравнение случай-случай: р = 0,02). В странах с высоким уровнем дохода 10 лет использования оральных контрацептивов, по оценкам, снижает абсолютный риск развития эндометриального рака, возникающего в возрасте до 75 лет, с 2,3 до 1,3 на 100 женщин.

Полученные результаты указывают на то, что в развитых странах благодаря использованию оральных контрацептивов было предотвращено около 400 000 случаев эндометриального рака у женщин в возрасте до 75 лет в течение последних 50 лет (1965–2014 гг.), в том числе 200 000 случаев в прошлом десятилетии (2005–2014 гг.).


Collaborative Group on Epidemiological Studies on Endometrial Cancer. Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies. Lancet Oncol. 2015;16(9):1061-70.

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