Cancer risk for the patients undergoing ART Is there still a problem? M. Aboulghar Cairo - Egypt Women are delaying their first childbirth. By the year 2025, between 5.4-7.7 million women aged 15-44 will be diagnosed in the USA with infertility (Stephen and Chandra, 1998). Consequently, ovulation-stimulating drugs are among the fastest growing groups of drugs (Wysowski, 1993). Ovulation inducing drugs and cancer risk Studies addressing ovulation inducing drugs and cancer risk have limitations due to small sample size, short follow up, imprecise information on drug exposure, indications for usage, absence of information of drug exposure that could influence cancer and recall bias. The results of case control studies are limited by the fact that information on prior drug use is based on patient histories. Most have been further limited by small numbers of ovarian cancer cases reporting prior drug usage. For example, in the largest casecontrol study (Parazzini et al 2001). Only 15 cases and 26 controls with relevant exposures were reported for analysis. Ovulation inducing drugs and cancer risk The principal shortcoming of these casecontrol and retrospective cohort studies is that infertile women, usually anovulatory are being compared with the experience of the general population. This is done using the calculation of standardized incidence ratios (SIRs). SIRs compare the numbers of observed cancers in the cohort of interest to the number expected on the basis on incidence rates in the general populations. Fertility drugs and ovarian cancer The life time risk that a woman develops ovarian cancer is between 1.4-1.8%. In 1992 Whittmore and colleagues conducted a systematic review of 12 casecontrol studies related to the etiology of ovarian cancer. The data from Whittmore and colleagues was based upon a comparison of users (fertility drugs) with the general population. The risk of ovarian cancer and the use of fertility medications was heightened by a series of publications, Whittemore et al. (1992) from the Collaborative Ovarian Cancer Group, which reported that infertile women using fertility drugs had almost three times the risk (RR = 2.8, 95% CI = 1.3 to 6.1) for invasive epithelial ovarian cancer. Critics of this report have cited: Selection bias Wide confidence intervals Lack of a uniform etiology of infertility Temporal incompatibility between treatment for infertility and licensing of modern fertility drugs in the subjects reported. Because of these limitation, the conclusion of a causal link between fertility medications and ovarian cancer cannot be drawn confidently from these data. Ovulation induction treatment and risk of borderline ovarian tumors (Cusido et al. 2007) This was a case-control study in which the study group comprised 42 women with a borderline ovarian tumor and the control group comprised 257 women with benign ovarian pathology. No differences were found between the borderline tumor and control groups (14.3% vs 27.2%, respectively) in terms of infertility history. And type of drug used whether CC (9.5% vs 6.2%, respectively or gonadotropins (7.1% vs 10.1% respectively). Analysis in terms of the number of cycles administered also failed to reveal any differences. This series produced no evidence that ovulation induction treatment predisposes women to the development of borderline ovarian tumors. Potashnik et al. (1999) in a prospective cohort study followed 1197 infertile women for a mean of 17.9 years. No increased risk of ovarian cancer was noted among those who had used fertility drugs compared with the unexposed group. In a cohort of 29700 women, 20656 were exposed to fertility drugs and 9044 were not. For breast and ovarian cancer the incidence was no greater than expected (SIR 0.91 [95% CI 0.74-1.13] for breast cancer and 0.88 [0.42-1.841] for ovarian cancer in the exposed group and 0.95 [0.73-1.23] for breast cancer and 1.16 [0.52-2.59] for ovarian cancer in the unexposed group) (Venn et al 1999). Venn et al (1999) had a follow-up of 7 years for the exposed group and 10 years for unexposed group. Women who underwent IVF were not at an increased risk for ovarian cancer compared to the general population. Again, women with unexplained infertility had significantly more ovarian cancers than expected (SIR = 2.6). A meta-analysis of eight studies involving data on 1060 cases and 1337 controls (Ness et al. 2002) also showed no risk associations with fertility drug use. In this study, after adjustment for types of infertility, the risk associated with drug usage was somewhat higher among nulligravid women (1.8) and among those who had more than 4 months of exposure (relative risk (RR) 1.5-1.7), but none of these risks was statistically significant. A study on a total of 12193 infertile women in five fertility centers in the USA, showed that the increase in the risk of ovarian cancer was similar for women who received fertility drugs and those who did not. The study included both clomiphene citrate and/or gonadotrophins. (Brinton et al., 2004). Based on the evidence to date, there is no conclusive link between fertility drugs use and ovarian cancer. Additional studies should continue to monitor longterm effects and assess whether there may be distinctive relationships for borderline ovarian tumors and certain tumor histologies. Specific attention should also be focused on effects among nulligravidas. (Brinton et al 2005). The recent multicenter US study of gonadotropin and clomid users did not find an increase in ovarian cancer in this cohort (Althius et al 2005; Brinton et al 2004). A pooled analysis of 8 case controled studies by Ness et al 2002 suggested that infertility per se, but not the use of fertility medications, elevates the overall risk of ovarian cancer. Case control studies of ovarian cancer risk and fertility drugs versus no drugs (Mahdavi 2006) Author Whittemore et al. (1992) No. of cases (% treated) No. of controls OR (95% CI) (% treated) 718 (2.8) 1,236 (0.9) 2.8 (1.3-6.1) 1,060 (14.1) 1,337 (15.0) 1.0 (0.8 – 1.3) Franceschi et al. (1994) 195 (1.0) 1,339 (1.1) 0.7 (0.2-3.3) Shushan et al. (1996) 164 (12) 408 (7.1) 1.3 (0.6278) Mosgaard et al. (1997) 684 (20.7) 1,721 (23.8) 0.8 (0.4-2.0) Parazzini et al. (1997) 971 (0.5) 2758 (0.4) 1.1 (0.4-3.3) Parazzini et al. (2001) 10.31 (1.5) 2,411 (1.1) 1.3 (0.7-2.5) Ness et al. (2002) Rossing et al (1994) examined a cohort of 3837 infertile women from 1974 to 1985. The ratio of the observed to the expected new cases for invasive epithelial ovarian cancer was 1.5 (95% CI 0.4-3.7) and was 3.3 (95% CI 1.1-7.8) for borderline tumors. Fertility drugs and breast cancer Among 92555 women from the study population 6602 women were treated for infertility. During the 10 year follow-up period, 2571 cases of primary invasive breast cancer were diagnosed (183 in treated women). The study showed no overall significant association between breast cancer risk and treatment for infertility (RR = 0.85, confidence interval 0.82-1.11). (Gauthier et al 2004) Overall, the findings on ovarian cancer (especially invasive epithelial and non-epithlial) risk associated with fertility drug treatment are reassuring. However, a stronger association between fertility drug use and borderline tumors of the ovary has been observed. (Mahdavi et al 2006) That ovulation-stimulating drugs might preferentially affect the risk of borderline ovarian tumours is also suggested by several studies (Ness et al 2002). Ovarian stimulation may induce growth in existing highly differentiated indolent tumours. Alternatively, the findings simply could reflect more intensive medical surveillance among infertile women. Among women who participated in the Nurses’ Health Study II, Terry et al (1006) observed an inverse association between infertility due to ovulatory disorder and breast cancer incidence. We observed the greatest reduction in the incidence of breast cancer for women who reported ovulatory disorder and use of ovulation induction therapy, but these results should be interpreted with caution because these women may be the most infertile. Infertile patients had a significantly higher breast cancer risk than the general population [SIR = 1.29, 95% confidence interval 1.1 -1.4]. Analysis within the cohort showed adjusted RRs of 1.02 for clomiphene citrate and 1.07 for gonadotrophins, and no substantial relationships to dosage or cycles of use. Although there was no overall increase in breast cancer risk associated with use of ovulationstimulation drugs, long-term effects should continue to be monitored (Brinton et al 2004). Infertility, ovulation induction treatments and the incidence of breast cancer--a historical prospective cohort of Israeli women The study cohort included 120,895 women years of follow-up. Compared to 115.2 expected breast cancer cases, 131 cases were observed (SIR = 1.1; 95% CI 0.91.4). Risk for breast cancer was significantly higher for women treated with clomiphene citrate (SIR = 1.4; 95% CI 1.0-1.8). Infertility and usage of infertility drugs in general are not associated with increased risk for breast cancer. However, for infertile women treated with clomiphene citrate, breast cancer risk is elevated. IVF and breast cancer (Salhab et al 2005) Fifteen studies were identified, of these, 11 were cohort studies and 4 were case-control studies. None of the individual studies showed an overall significant association between IVF and breast cancer and, in fact, one study showed that treatment with hCG significantly reduced the risk of breast cancer in women whose maximum non-pregnant body mass index was less than 27.5. IVF and breast cancer (Salhab et al 2005) CONCLUSION: Overall, there is no clear evidence that ovulation induction or IVF increases the risk of breast cancer. However, there may be a transient increase in the incidence of breast cancer in the first year due to earlier diagnosis. Furthermore, the risk may be increased in women with a positive family history. IVF and breast cancer (Salhab et al 2005) A combined analysis of the cohort studies including a total of 60,050 women treated with ovulation induction/IVF showed no significant association between these treatments and increased risk of breast cancer (observed vs. expected: 601 vs. 568, pooled relative risk [RR] = 1.06, P = 0.337). The case-control studies included a total of 11,303 women in the breast cancer groups and 10,930 controls. Women in the breast cancer groups were slightly less likely to have received IVF (2.2% vs. 2.5%, pooled RR = 0.88, P = 0.231). Fertility drugs and endometrial cancer The most recently published study was a multicenter retrospective cohort conducted in 5 US centers. This study initiated from medical records followed 12193 infertile women for a median of 18.8 years of follow up. The multicenter US cohort study which detected 39 cases of endometrial cancer among a cohort of clomid users found a non-significant increase in relative risk (RR = 1.79 CI 0.9-3.4) The data from this study was based primarily upon a comparison of fertiltiy drug users with the general population. An accurate assessment requires a randomized placebo controlled trial in a uniform population of anovulatory women (Athuis et al 2005). Risk of thyroid cancer after exposure to fertility drugs: results from a large Danish cohort study (Hannibal et al. 2008) A cohort of 54362 women with infertility problems calculated rate ratios (RRs) of thyroid cancer associated with different fertility drugs after adjustment for age at first live birth. Use of clomiphene [RR= 2.28; 95% CI: 1.08-4.82] or progesterone [RR=10.14; 95% CI: 1.93-53.33] was associated with an increased thyroid cancer risk. Longer follow-up is needed to confirm these findings. Future Need more thoughtful planning Need to link data bases in different countries. Need improved long-term followup Need continued investigation of fertility drugs and ovarian cancer among nulligravida women. The Egyptian IVF-ET Center Clinical directors: • M. Aboulghar, M. D. • G. Serour, M. D. - Clinical associates: • Y. Amin, M. D. • M. Sattar, M. D. • A. Ramzy, M. D. • L. Mansour, M. D. • M. Metwally, M. D. • H. Aboulghar, M. D. • M. Aboulghar, M. D. • H. Al Inany, M. D. • A. Abou-Setta, M. D. - Andrology: • I. Fahmy, M. D. • A. El-Gindy Scientific director & Program manager: • Ragaa Mansour, M. D., Ph. D. • • • • • • • - Embryology and micromanipulation • S. Mansour, M. D. • A. Kamal, M. D. • A. Mostafa, M. D. • N. Tawab, B.Sc. • M. Serour, B.Sc. • G. Afifi, B.Sc. • M. Hammam, B.A. - Cytogenetics - Cryobiology & andrrology H. Fayek, Ph. D. • D. Saad, B.Sc. A. Abdel-Razek, M. D. • Y. Demery, B.Sc. A. Amer, B.Sc. • A. Barakat, B.Sc. A. Khalil, Ph. D. • M. Serour , B.Sc. A. Naser, Ph. D. • N. Salah , B.Sc. O. Kamal, B.S. • H. Fanous , B.Sc. S. Mostafa • A. Mohamed , B.Sc.