Cancer risk for the Cancer risk for the patients undergoing ARTpatients undergoing ART

Is there still a problem? Is there still a problem?

M. AboulgharM. Aboulghar

Cairo - EgyptCairo - Egypt

Women are delaying their first Women are delaying their first childbirth.childbirth.

By the year 2025, between 5.4-7.7 By the year 2025, between 5.4-7.7 million women aged 15-44 will be million women aged 15-44 will be diagnosed in the USA with infertility diagnosed in the USA with infertility (Stephen and Chandra, 1998).(Stephen and Chandra, 1998).

Consequently, ovulation-stimulating Consequently, ovulation-stimulating drugs are among the fastest growing drugs are among the fastest growing groups of drugs (Wysowski, 1993).groups of drugs (Wysowski, 1993).

Ovulation inducing drugs and Ovulation inducing drugs and cancer riskcancer risk

Studies addressing ovulation Studies addressing ovulation inducing drugs and cancer risk have inducing drugs and cancer risk have limitations due to small sample size, limitations due to small sample size, short follow up, imprecise short follow up, imprecise information on drug exposure, information on drug exposure, indications for usage, absence of indications for usage, absence of information of drug exposure that information of drug exposure that could influence cancer and recall could influence cancer and recall bias.bias.

The results of case control studies are The results of case control studies are limited by the fact that information on limited by the fact that information on prior drug use is based on patient prior drug use is based on patient histories. histories.

Most have been further limited by Most have been further limited by small numbers of ovarian cancer cases small numbers of ovarian cancer cases reporting prior drug usage.reporting prior drug usage.

For example, in the largest case-For example, in the largest case-control study (Parazzini et al 2001).control study (Parazzini et al 2001).

Only 15 cases and 26 controls with Only 15 cases and 26 controls with relevant exposures were reported for relevant exposures were reported for analysis.analysis.

Ovulation inducing drugs and Ovulation inducing drugs and cancer riskcancer risk

The principal shortcoming of these case-The principal shortcoming of these case-control and retrospective cohort studies is control and retrospective cohort studies is that infertile women, usually anovulatory that infertile women, usually anovulatory are being compared with the experience of are being compared with the experience of the general population.the general population.

This is done using the calculation of This is done using the calculation of standardized incidence ratios (SIRs). SIRs standardized incidence ratios (SIRs). SIRs compare the numbers of observed cancers compare the numbers of observed cancers in the cohort of interest to the number in the cohort of interest to the number expected on the basis on incidence rates expected on the basis on incidence rates in the general populations.in the general populations.

Fertility drugs and ovarian cancerFertility drugs and ovarian cancer

The life time risk that a woman develops The life time risk that a woman develops ovarian cancer is between 1.4-1.8%.ovarian cancer is between 1.4-1.8%.

In 1992 Whittmore and colleagues In 1992 Whittmore and colleagues conducted a systematic review of 12 case-conducted a systematic review of 12 case-control studies related to the etiology of control studies related to the etiology of ovarian cancer.ovarian cancer.

The data from Whittmore and colleagues The data from Whittmore and colleagues was based upon a comparison of users was based upon a comparison of users (fertility drugs) with the general (fertility drugs) with the general population.population.

The risk of ovarian cancer and the The risk of ovarian cancer and the use of fertility medications was use of fertility medications was heightened by a series of heightened by a series of publications, publications, Whittemore et al. (1992)Whittemore et al. (1992) from the Collaborative Ovarian from the Collaborative Ovarian Cancer Group, which reported that Cancer Group, which reported that infertile women using fertility drugs infertile women using fertility drugs had almost three times the risk had almost three times the risk (RR (RR = 2.8, 95% CI = 1.3 to 6.1)= 2.8, 95% CI = 1.3 to 6.1) for for invasive epithelial ovarian cancer.invasive epithelial ovarian cancer.

Critics of this report have cited: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 Ovulation induction treatment and risk of borderline ovarian tumors borderline ovarian tumors (Cusido et al. 2007)(Cusido et al. 2007)

This was a case-control study in which the study This was a case-control study in which the study group comprised 42 women with a borderline group comprised 42 women with a borderline ovarian tumor and the control group comprised ovarian tumor and the control group comprised 257 women with benign ovarian pathology.257 women with benign ovarian pathology.

No differences were found between the borderline No differences were found between the borderline tumor and control groups (14.3% vs 27.2%, tumor and control groups (14.3% vs 27.2%, respectively) in terms of infertility history. And respectively) in terms of infertility history. And type of drug used whether CC (9.5% vs 6.2%, type of drug used whether CC (9.5% vs 6.2%, respectively or gonadotropins (7.1% vs 10.1% respectively or gonadotropins (7.1% vs 10.1% respectively). Analysis in terms of the number of respectively). Analysis in terms of the number of cycles administered also failed to reveal any cycles administered also failed to reveal any differences. This series produced no evidence that differences. This series produced no evidence that ovulation induction treatment predisposes women ovulation induction treatment predisposes women to the development of borderline ovarian tumors.to the development of borderline ovarian tumors.

Potashnik et al. (1999) in a prospective Potashnik et al. (1999) in a prospective cohort study followed 1197 infertile cohort study followed 1197 infertile

women for a mean of 17.9 years. No women for a mean of 17.9 years. No increased risk of ovarian cancer was increased risk of ovarian cancer was

noted among those who had used noted among those who had used fertility drugs compared with the fertility drugs compared with the

unexposed group.unexposed group.

In a cohort of 29700 women, 20656 In a cohort of 29700 women, 20656 were exposed to fertility drugs and were exposed to fertility drugs and 9044 were not. For breast and 9044 were not. For breast and ovarian cancer the incidence was no ovarian cancer the incidence was no greater than expected (SIR 0.91 [95% greater than expected (SIR 0.91 [95% CI 0.74-1.13] for breast cancer and CI 0.74-1.13] for breast cancer and 0.88 [0.42-1.841] for ovarian cancer 0.88 [0.42-1.841] for ovarian cancer in the exposed group and 0.95 [0.73-in the exposed group and 0.95 [0.73-1.23] for breast cancer and 1.16 1.23] for breast cancer and 1.16 [0.52-2.59] for ovarian cancer in the [0.52-2.59] for ovarian cancer in the unexposed group) (Venn et al 1999).unexposed group) (Venn et al 1999).

Venn et al (1999) had a follow-up of 7 Venn et al (1999) had a follow-up of 7 years for the exposed group and 10 years for the exposed group and 10 years for unexposed group. Women years for unexposed group. Women who underwent IVF were not at an who underwent IVF were not at an increased risk for ovarian cancer increased risk for ovarian cancer

compared to the general population. compared to the general population. Again, women with unexplained Again, women with unexplained

infertility had significantly more ovarian infertility had significantly more ovarian cancers than expected (SIR = 2.6).cancers than expected (SIR = 2.6).

A meta-analysis of eight studies involving A meta-analysis of eight studies involving data on 1060 cases and 1337 controls data on 1060 cases and 1337 controls (Ness et al. 2002) also showed no risk (Ness et al. 2002) also showed no risk associations with fertility drug use.associations with fertility drug use.

In this study, after adjustment for types of In this study, after adjustment for types of infertility, the risk associated with drug infertility, the risk associated with drug usage was somewhat higher among usage was somewhat higher among nulligravid women (1.8) and among those nulligravid women (1.8) and among those who had more than 4 months of exposure who had more than 4 months of exposure (relative risk (RR) 1.5-1.7), but none of (relative risk (RR) 1.5-1.7), but none of these risks was statistically significant.these risks was statistically significant.

A study on a total of 12193 A study on a total of 12193 infertile women in five fertility infertile women in five fertility centers in the USA, showed that centers in the USA, showed that the increase in the risk of ovarian the increase in the risk of ovarian cancer was similar for women cancer was similar for women who received fertility drugs and who received fertility drugs and those who did not. The study those who did not. The study included both clomiphene citrate included both clomiphene citrate and/or gonadotrophins. and/or gonadotrophins.

(Brinton et al., 2004)(Brinton et al., 2004)..

Based on the evidence to date, there is Based on the evidence to date, there is no conclusive link between fertility drugs no conclusive link between fertility drugs

use and ovarian cancer. Additional use and ovarian cancer. Additional studies should continue to monitor long-studies should continue to monitor long-term effects and assess whether there term effects and assess whether there

may be distinctive relationships for may be distinctive relationships for borderline ovarian tumors and certain borderline ovarian tumors and certain tumor histologies. Specific attention tumor histologies. Specific attention

should also be focused on effects among should also be focused on effects among nulligravidas. (Brinton et al 2005).nulligravidas. (Brinton et al 2005).

The recent multicenter US study of The recent multicenter US study of gonadotropin and clomid users did gonadotropin and clomid users did not find an increase in ovarian not find an increase in ovarian cancer in this cohort (Althius et al cancer in this cohort (Althius et al 2005; Brinton et al 2004).2005; Brinton et al 2004).

A pooled analysis of 8 case controled A pooled analysis of 8 case controled studies by Ness et al 2002 suggested studies by Ness et al 2002 suggested that infertility per se, but not the use that infertility per se, but not the use of fertility medications, elevates the of fertility medications, elevates the overall risk of ovarian cancer.overall risk of ovarian cancer.

Case control studies of ovarian cancer Case control studies of ovarian cancer risk and fertility drugs versus no drugsrisk and fertility drugs versus no drugs

(Mahdavi 2006)(Mahdavi 2006)

AuthorAuthor No. of cases No. of cases (% treated)(% treated)

No. of controls No. of controls (% treated)(% treated)

OR (95% CI)OR (95% CI)

Whittemore et al. (1992)Whittemore et al. (1992) 718 (2.8)718 (2.8) 1,236 (0.9)1,236 (0.9) 2.8 (1.3-6.1)2.8 (1.3-6.1)

Ness et al. (2002)Ness et al. (2002) 1,060 (14.1)1,060 (14.1) 1,337 (15.0)1,337 (15.0) 1.0 (0.8 –1.3)1.0 (0.8 –1.3)

Franceschi et al. (1994)Franceschi et al. (1994) 195 (1.0)195 (1.0) 1,339 (1.1)1,339 (1.1) 0.7 (0.2-3.3)0.7 (0.2-3.3)

Shushan et al. (1996)Shushan et al. (1996) 164 (12)164 (12) 408 (7.1)408 (7.1) 1.3 (0.6-278)1.3 (0.6-278)

Mosgaard et al. (1997)Mosgaard et al. (1997) 684 (20.7)684 (20.7) 1,721 (23.8)1,721 (23.8) 0.8 (0.4-2.0)0.8 (0.4-2.0)

Parazzini et al. (1997)Parazzini et al. (1997) 971 (0.5)971 (0.5) 2758 (0.4)2758 (0.4) 1.1 (0.4-3.3)1.1 (0.4-3.3)

Parazzini et al. (2001)Parazzini et al. (2001) 10.31 (1.5)10.31 (1.5) 2,411 (1.1)2,411 (1.1) 1.3 (0.7-2.5)1.3 (0.7-2.5)

Rossing et al (1994) examined a Rossing et al (1994) examined a

cohort of 3837 infertile women from cohort of 3837 infertile women from 1974 to 1985.1974 to 1985.

The ratio of the observed to the The ratio of the observed to the expected new cases for invasive expected new cases for invasive epithelial ovarian cancer was 1.5 epithelial ovarian cancer was 1.5 (95% CI 0.4-3.7) and was 3.3 (95% CI (95% CI 0.4-3.7) and was 3.3 (95% CI 1.1-7.8) for borderline tumors.1.1-7.8) for borderline tumors.

Fertility drugs and breast cancerFertility drugs and breast cancer

Among 92555 women from the study Among 92555 women from the study population 6602 women were treated for population 6602 women were treated for infertility. During the 10 year follow-up infertility. During the 10 year follow-up period, 2571 cases of primary invasive period, 2571 cases of primary invasive breast cancer were diagnosed (183 in breast cancer were diagnosed (183 in treated women). The study showed no treated women). The study showed no overall significant association between overall significant association between breast cancer risk and treatment for breast cancer risk and treatment for infertility (RR = 0.85, confidence interval infertility (RR = 0.85, confidence interval 0.82-1.11). (Gauthier et al 2004)0.82-1.11). (Gauthier et al 2004)

Overall, the findings on ovarian Overall, the findings on ovarian cancer (especially invasive cancer (especially invasive

epithelial and non-epithlial) risk epithelial and non-epithlial) risk associated with fertility drug associated with fertility drug

treatment are reassuring. However, treatment are reassuring. However, a stronger association between a stronger association between fertility drug use and borderline fertility drug use and borderline tumors of the ovary has been tumors of the ovary has been

observed. (Mahdavi et al 2006)observed. (Mahdavi et al 2006)

That ovulation-stimulating drugs That ovulation-stimulating drugs might preferentially affect the risk of might preferentially affect the risk of borderline ovarian tumours is also borderline ovarian tumours is also suggested by several studies (Ness suggested by several studies (Ness et al 2002).et al 2002).

Ovarian stimulation may induce Ovarian stimulation may induce growth in existing highly growth in existing highly differentiated indolent tumours. differentiated indolent tumours. Alternatively, the findings simply Alternatively, the findings simply could reflect more intensive medical could reflect more intensive medical surveillance among infertile women.surveillance among infertile women.

Among women who participated in the Among women who participated in the Nurses’ Health Study II, Terry et al (1006) Nurses’ Health Study II, Terry et al (1006) observed an inverse association between observed an inverse association between

infertility due to ovulatory disorder and infertility due to ovulatory disorder and breast cancer incidence. We observed the breast cancer incidence. We observed the

greatest reduction in the incidence of breast greatest reduction in the incidence of breast cancer for women who reported ovulatory cancer for women who reported ovulatory

disorder and use of ovulation induction disorder and use of ovulation induction therapy, but these results should be therapy, but these results should be

interpreted with caution because these interpreted with caution because these women may be the most infertile.women may be the most infertile.

Infertile patients had a significantly higher Infertile patients had a significantly higher breast cancer risk than the general population breast cancer risk than the general population [SIR = 1.29, 95% confidence interval 1.1 -1.4]. [SIR = 1.29, 95% confidence interval 1.1 -1.4].

Analysis within the cohort showed adjusted RRs Analysis within the cohort showed adjusted RRs of 1.02 for clomiphene citrate and 1.07 for of 1.02 for clomiphene citrate and 1.07 for

gonadotrophins, and no substantial gonadotrophins, and no substantial relationships to dosage or cycles of use. relationships to dosage or cycles of use.

Although there was no overall increase in breast Although there was no overall increase in breast cancer risk associated with use of ovulation-cancer risk associated with use of ovulation-stimulation drugs, long-term effects should stimulation drugs, long-term effects should

continue to be monitored (Brinton et al 2004).continue to be monitored (Brinton et al 2004).

Infertility, ovulation induction treatments and Infertility, ovulation induction treatments and the incidence of breast cancer--a historical the incidence of breast cancer--a historical

prospective cohort of Israeli women prospective cohort of Israeli women The study cohort included 120,895 women years The study cohort included 120,895 women years

of follow-up. Compared to 115.2 expected breast of follow-up. Compared to 115.2 expected breast cancer cases, 131 cases were observed (SIR = cancer cases, 131 cases were observed (SIR = 1.1; 95% CI 0.9-1.4). Risk for breast cancer was 1.1; 95% CI 0.9-1.4). Risk for breast cancer was significantly higher for women treated with significantly higher for women treated with clomiphene citrate (SIR = 1.4; 95% CI 1.0-1.8). clomiphene citrate (SIR = 1.4; 95% CI 1.0-1.8).

Infertility and usage of infertility drugs in general Infertility and usage of infertility drugs in general are not associated with increased risk for breast are not associated with increased risk for breast cancer. However, for infertile women treated with cancer. However, for infertile women treated with clomiphene citrate, breast cancer risk is clomiphene citrate, breast cancer risk is elevated. elevated.

IVF and breast cancer IVF and breast cancer (Salhab et al 2005)(Salhab et al 2005)

Fifteen studies were identified, of these, Fifteen studies were identified, of these, 11 were cohort studies and 4 were case-11 were cohort studies and 4 were case-control studies. None of the individual control studies. None of the individual studies showed an overall significant studies showed an overall significant association between IVF and breast association between IVF and breast cancer and, in fact, one study showed cancer and, in fact, one study showed that treatment with hCG significantly that treatment with hCG significantly reduced the risk of breast cancer in reduced the risk of breast cancer in women whose maximum non-pregnant women whose maximum non-pregnant body mass index was less than 27.5.body mass index was less than 27.5.

IVF and breast cancer IVF and breast cancer (Salhab et al 2005)(Salhab et al 2005)

CONCLUSION: Overall, there is no CONCLUSION: Overall, there is no clear evidence that ovulation clear evidence that ovulation induction or IVF increases the risk of induction or IVF increases the risk of breast cancer. However, there may be breast cancer. However, there may be a transient increase in the incidence a transient increase in the incidence of breast cancer in the first year due of breast cancer in the first year due to earlier diagnosis. Furthermore, the to earlier diagnosis. Furthermore, the risk may be increased in women with risk may be increased in women with a positive family history. a positive family history.

IVF and breast cancer IVF and breast cancer (Salhab et al 2005)(Salhab et al 2005)

A combined analysis of the cohort studies A combined analysis of the cohort studies including a total of 60,050 women treated including a total of 60,050 women treated with ovulation induction/IVF showed no with ovulation induction/IVF showed no significant association between these significant association between these treatments and increased risk of breast treatments and increased risk of breast cancer (observed vs. expected: 601 vs. 568, cancer (observed vs. expected: 601 vs. 568, pooled relative risk [RR] = 1.06, P = 0.337). pooled relative risk [RR] = 1.06, P = 0.337). The case-control studies included a total of The case-control studies included a total of 11,303 women in the breast cancer groups 11,303 women in the breast cancer groups and 10,930 controls. Women in the breast and 10,930 controls. Women in the breast cancer groups were slightly less likely to cancer groups were slightly less likely to have received IVF (2.2% vs. 2.5%, pooled RR have received IVF (2.2% vs. 2.5%, pooled RR = 0.88, P = 0.231). = 0.88, P = 0.231).

Fertility drugs and endometrial cancerFertility drugs and endometrial cancer The most recently published study was a The most recently published study was a

multicenter retrospective cohort conducted in 5 US multicenter retrospective cohort conducted in 5 US centers.centers.

This study initiated from medical records followed This study initiated from medical records followed 12193 infertile women for a median of 18.8 years 12193 infertile women for a median of 18.8 years of follow up. The multicenter US cohort study which of follow up. The multicenter US cohort study which detected 39 cases of endometrial cancer among a detected 39 cases of endometrial cancer among a cohort of clomid users found a non-significant cohort of clomid users found a non-significant increase in relative risk (RR = 1.79 CI 0.9-3.4)increase in relative risk (RR = 1.79 CI 0.9-3.4)

The data from this study was based primarily upon The data from this study was based primarily upon a comparison of fertiltiy drug users with the a comparison of fertiltiy drug users with the general population.general population.

An accurate assessment requires a randomized An accurate assessment requires a randomized placebo controlled trial in a uniform population of placebo controlled trial in a uniform population of anovulatory women (Athuis et al 2005).anovulatory women (Athuis et al 2005).

Risk of thyroid cancer after exposure to Risk of thyroid cancer after exposure to fertility drugs: results from a large fertility drugs: results from a large

Danish cohort study Danish cohort study (Hannibal et al. 2008)(Hannibal et al. 2008) A cohort of 54362 women with infertility A cohort of 54362 women with infertility

problems calculated rate ratios (RRs) of problems calculated rate ratios (RRs) of thyroid cancer associated with different thyroid cancer associated with different fertility drugs after adjustment for age at fertility drugs after adjustment for age at first live birth.first live birth.

Use of clomiphene [RR= 2.28; 95% CI: Use of clomiphene [RR= 2.28; 95% CI: 1.08-4.82] or progesterone [RR=10.14; 1.08-4.82] or progesterone [RR=10.14; 95% CI: 1.93-53.33] was associated with 95% CI: 1.93-53.33] was associated with an increased thyroid cancer risk.an increased thyroid cancer risk.

Longer follow-up is needed to confirm Longer follow-up is needed to confirm these findings.these findings.

FutureFuture

Need more thoughtful planningNeed more thoughtful planning Need to link data bases in Need to link data bases in

different countries.different countries. Need improved long-term follow-Need improved long-term follow-

upup Need continued investigation of Need continued investigation of

fertility drugs and ovarian cancer fertility drugs and ovarian cancer among nulligravida women.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

• H. Fayek, Ph. D.• A. Abdel-Razek, M. D.• A. Amer, B.Sc.• A. Khalil, Ph. D.• A. Naser, Ph. D.• O. Kamal, B.S.• S. Mostafa

- Cryobiology & andrrology • D. Saad, B.Sc.• Y. Demery, B.Sc.• A. Barakat, B.Sc.• M. Serour , B.Sc.• N. Salah , B.Sc.• H. Fanous , B.Sc.• A. Mohamed , B.Sc.