Young Women Deserve To Know Their Post-Cancer Fertility Options

Young Women Deserve To Know Their Post-Cancer Fertility Options: Young cancer survivors do not receive enough information about their fertility and possible options for preserving it.

Pregnancy Outcome in Male and Female survivors of childhood cancer group

The survival rates for childhood cancer are on rise. This would equate to increase in the number of survivors. It has been shown that around two thirds of survivors will have some kind of late side effect and one of them could be effect on reproductive potential. Reproductive concerns can alter the quality of life in some and can lead to mental health issues. ¹

Fertility counseling and offering options for preserving fertility in this age group depends on whether the child is pre-pubertal or post-pubertal. In pre-pubertal age group, discussion about fertility can be a challenging situation not only for patient but also for treating oncologist and reproductive medicine specialist. The options available at this age group are limited and are mostly offered at present in research settings. Preservation of ovarian or testicular tissue is the options mainly given in this sub-group of patients. In post-pubertal children, the options are same as given to adults in the form of oocyte cryopreservation, sperm cryopreservation, ovarian tissue cryopreservation, and medical therapy with GnRH agonists.

Even if the fertility cannot be preserved, discussion and educating children and their parents about potential risk for infertility is important. In this age group, education at diagnosis may not be sufficient² ; re-enforcement of discussion at end of therapy and in late effect survivor clinic may be needed depending on survivor's needs and developmental stage, hence conversations about the impact

In this issue, we will be discussing recent publication from largest childhood cancer survivor study with regards to the pregnancy outcome in child hood cancer survivors.

Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: 
a report from the Childhood Cancer Survivor Study cohort- Lancet Oncology, 2016³

Eric J Chow, Kayla L Stratton, Wendy M Leisenring, Kevin C Oeffinger, Charles A Sklar, Sarah S Donaldson, Jill P Ginsberg, Lisa B Kenney, Jennifer M Levine, Leslie L Robison, Margarett Shnorhavorian, Marilyn Stovall, Gregory T Armstrong, Daniel M Green

Methods: The data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999, were studied.

 The doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records were analyzed. The independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and live births occurring between ages 15 years and 44 years were analyzed. The siblings of survivors were used as a comparison group.

Findings: There were 10,938 survivors and 3949 siblings. After a median follow-up of 8 years from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years, 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. Overall, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio [HR] 0·63, 95% CI 0·58–0·68; p<0·0001; female survivors: 0·87, 0·81–0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58–0·69; p<0·0001; female survivors: 0·82, 0·76–0·89; p<0·0001)

 In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide, ifosfamide , procarbazine and cisplatin . Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy as compared to females. In female survivors, only busulfan and doses of lomustine equal to or greater than 411 mg/m2 were significantly associated with reduced pregnancy. Results for live birth were similar to those for pregnancy.

Conclusion: The findings from this study have suggested that greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, these findings have provided reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy- specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximize the reproductive potential of all adolescents newly diagnosed with cancer.

References:

1.     Gorman JR, Su HI, Roberts SC, et al: Experiencing reproductive concerns, as a female cancer survivor is associated with depression. Cancer 121: 935-942, 2015

2.     Cherven BO1, Mertens A2, Wasilewski-Masker K2, Williamson R3, Meacham :Infertility Education: Experiences and Preferences of Childhood Cancer Survivors. J Pediatr Oncol Nurs. 2015 Nov 18.

3.     Chow EJ, Stratton KL, Leisenring WM, Oeffinger KC, Sklar CA, Donaldson SS, Ginsberg JP, Kenney LB, Levine JM, Robison LL, Shnorhavorian M, Stovall M, Armstrong GT, Green DM. Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort.

Lancet Oncol. 2016 Mar 22. pii: S1470-2045(16)00086-3

Fertility information leaflets for childhood cancer patients and survivors

Cancer and its treatment have many side-effects, some of which may persister appear years after the treatment has finished. This is known as late effects. One such late effect is the effect on fertility i.e. the ability to have a child.

This issue is very relevant to parents and their children, but often does not figure prominently in the initial discussion a doctor has at the time of diagnosis. Information regarding effect on fertility may either not be imparted or get buried in a pile of other information related to cancer and its treatment. Cankids through their survivor group - Kidscan Konnect have taken the initiative of raising the awareness of this issue and produce information leaflets. It has been my pleasure to partner with KCK in this endeavour and bringing out these leaflets. Such information, which till now has been missing in Indian centres, is very welcome. Well done KCK!

Treatment of Infertility and Cancer Risk : Is there any association?

The use of assisted reproductive technologies is increasing. With advancement in the understanding of reproductive physiology and advancements in the techniques of reproductive medicine, its use is now extended to link this specialty with cancer treatment as well in the form of preserving fertility.

On the other hand, the possible link between fertility drugs and cancer of reproductive organs remains controversial and there is still an ongoing debate on the long-term effects of assisted reproductive technology techniques such as ovulation induction, in-vitro fertilization on the risk of ovarian, endometrial, cervical and breast cancer and also on risk of melanoma.

Here we discuss few studies which have been conducted worldwide to look into his ongoing controversial issue-

Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large US infertility cohort

Britton Trabert et al, Fertil Steril. 2013 December; 100(6)

 

A retrospective cohort of 9,825 women were evaluated for infertility at five clinical sites in the United States between 1965 and 1988 with follow-up through 2010.

Among women evaluated for infertility, there was no association of ovarian cancer risk with ever use of clomiphene citrate (adjusted RR 1.34, 95% CI 0.86–2.07) or gonadotropins (RR 1.00, 95% CI 0.48–2.08) and no evidence that any of several more detailed subgroups of usage were related to an increased risk. Though it was found in the analysis that women who used Clomiphene citrate and remained nulligravid did demonstrate much higher risks than those who successfully conceived compared with nonusers (respectively, RR 3.63, 95% CI 1.36–9.72 vs. RR 0.88, 95% CI 0.47– 1.63).

IVF and breast cancer: a systematic review and meta-analysis

Theodoros N. et al Human Reproduction Update, Vol.20, No.1 pp. 106–123, 2014

Eight cohort studies were analyzed with a total cohort size of

1 554 332 women among whom 14 961 incident breast cancer cases occurred, encompassing 576 incident breast cancer cases among women exposed to IVF. No significant association between IVF and breast cancer was observed either in the group of studies treating the general population (RR 1⁄4 0.91, 95% confidence interval (CI): 0.74 – 1.11) or infertile women (RR 1⁄4 1.02, 95% CI: 0.88 – 1.18), as a reference group. Though it was noticed that pregnant and/or parous women after IVF (pooled effect estimate 1⁄4 0.86, 95% CI: 0.73–1.01) were marginally protected but it was not protective with those who were 30 years at first IVF treatment (pooled effect estimate 1⁄4 1.64, 95% CI: 0.96–2.80).

the conclusion from this analysis was that in the current scenario COH for IVF does not seem to impart increased breast cancer risk, but still what is needed is longer follow-up periods, comparisons versus infertile women, subgroup analyses aiming to trace vulnerable subgroups, adjustment for various confounders and larger informative data sets before conclusive statements for the safety of the procedure are reached.

Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer—a systematic review and meta-analysis

Charalampos Siristatidis et al , Human Reproduction Update, Vol.19, No.2 pp. 105–123, 2013

Nine cohort studies were synthesized, corresponding to a total size of 109 969 women exposed to IVF, among whom 76 incident cases of ovarian, 18 of endometrial and 207 cases of cervical cancer were studied. The synthesis of studies with general population as the reference group pointed to a statistically significant positive association between IVF and increased risk for ovarian (RR 1⁄4 1.50, 95%

The conclusion from this analysis was that IVF does not seem to be associated with elevated cervical cancer risk, nor with ovarian or endometrial cancer when the confounding effect of infertility was neutralized . Of importance is only one study provided follow-up longer than 10 years for the group exposed to IVF. Hence what is needed is future cohort studies preferably using infertile women as the reference group, rely on IVF-registered valid exposure data, adjust for a variety of meaningful confounders and adopt relatively longer follow-up periods before sound conclusions are drawn.

Melanoma risk after ovarian stimulation for in vitro fertilization.

Spaan M et al. Hum Reprod. 2015 May;30(5):1216-28.

This study was part of OMEGA project group looking into association of ovarian stimulation on development of cancer. The cohort comprised of 19158 women who received IVF between 1983-1995 and a comparison group of 5950 womenwho underwent subfertility treatment other than IVF. . In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles were associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; ≥7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21).

Conclusion – the above reviews have tried to address an important aspect and so far infer that treatment of infertility in the form of ovulation induction, in-vitro fertilization does not confer high risk for cancer in reproductive system. Interestingly studies have also highlighted that patients who remain infertile despite these treatments have shown some increased risk in cancer development though numbers studies in these sub-groups were small and properly designed studies to answer these questions further. Extrapolation of these global studies to Indian context has also to be considered when counseling our patients.



Fertility Treatment and Risk of Cancer

The use of assisted reproductive technologies is increasing. With advancement in the understanding of reproductive physiology and advancements in the techniques of reproductive medicine, its use is now extended to link this specialty with cancer treatment as well in the form of preserving fertility.

On the other hand, the possible link between fertility drugs and cancer of reproductive organs remains controversial and there is still an ongoing debate on the long-term effects of assisted reproductive technology techniques such as ovulation induction, in-vitro fertilization on the risk of ovarian, endometrial, cervical and breast cancer and also on risk of melanoma.

Here we discuss few studies which have been conducted worldwide to look into his ongoing controversial issue-

Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large US infertility cohort

Britton Trabert et al, Fertil Steril. 2013 December; 100(6)

 

A retrospective cohort of 9,825 women were evaluated for infertility at five clinical sites in the United States between 1965 and 1988 with follow-up through 2010.

Among women evaluated for infertility, there was no association of ovarian cancer risk with ever use of clomiphene citrate (adjusted RR 1.34, 95% CI 0.86–2.07) or gonadotropins (RR 1.00, 95% CI 0.48–2.08) and no evidence that any of several more detailed subgroups of usage were related to an increased risk. Though it was found in the analysis that women who used Clomiphene citrate and remained nulligravid did demonstrate much higher risks than those who successfully conceived compared with nonusers (respectively, RR 3.63, 95% CI 1.36–9.72 vs. RR 0.88, 95% CI 0.47– 1.63).

IVF and breast cancer: a systematic review and meta-analysis

Theodoros N. et al Human Reproduction Update, Vol.20, No.1 pp. 106–123, 2014

Eight cohort studies were analyzed with a total cohort size of

1 554 332 women among whom 14 961 incident breast cancer cases occurred, encompassing 576 incident breast cancer cases among women exposed to IVF. No significant association between IVF and breast cancer was observed either in the group of studies treating the general population (RR 1⁄4 0.91, 95% confidence interval (CI): 0.74 – 1.11) or infertile women (RR 1⁄4 1.02, 95% CI: 0.88 – 1.18), as a reference group. Though it was noticed that pregnant and/or parous women after IVF (pooled effect estimate 1⁄4 0.86, 95% CI: 0.73–1.01) were marginally protected but it was not protective with those who were 30 years at first IVF treatment (pooled effect estimate 1⁄4 1.64, 95% CI: 0.96–2.80).

the conclusion from this analysis was that in the current scenario COH for IVF does not seem to impart increased breast cancer risk, but still what is needed is longer follow-up periods, comparisons versus infertile women, subgroup analyses aiming to trace vulnerable subgroups, adjustment for various confounders and larger informative data sets before conclusive statements for the safety of the procedure are reached.

Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer—a systematic review and meta-analysis

Charalampos Siristatidis et al , Human Reproduction Update, Vol.19, No.2 pp. 105–123, 2013

Nine cohort studies were synthesized, corresponding to a total size of 109 969 women exposed to IVF, among whom 76 incident cases of ovarian, 18 of endometrial and 207 cases of cervical cancer were studied. The synthesis of studies with general population as the reference group pointed to a statistically significant positive association between IVF and increased risk for ovarian (RR 1⁄4 1.50, 95%

The conclusion from this analysis was that IVF does not seem to be associated with elevated cervical cancer risk, nor with ovarian or endometrial cancer when the confounding effect of infertility was neutralized . Of importance is only one study provided follow-up longer than 10 years for the group exposed to IVF. Hence what is needed is future cohort studies preferably using infertile women as the reference group, rely on IVF-registered valid exposure data, adjust for a variety of meaningful confounders and adopt relatively longer follow-up periods before sound conclusions are drawn.

Melanoma risk after ovarian stimulation for in vitro fertilization.

Spaan M et al. Hum Reprod. 2015 May;30(5):1216-28.

This study was part of OMEGA project group looking into association of ovarian stimulation on development of cancer. The cohort comprised of 19158 women who received IVF between 1983-1995 and a comparison group of 5950 womenwho underwent subfertility treatment other than IVF. . In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles were associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; ≥7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21).

Conclusion – the above reviews have tried to address an important aspect and so far infer that treatment of infertility in the form of ovulation induction, in-vitro fertilization does not confer high risk for cancer in reproductive system. Interestingly studies have also highlighted that patients who remain infertile despite these treatments have shown some increased risk in cancer development though numbers studies in these sub-groups were small and properly designed studies to answer these questions further. Extrapolation of these global studies to Indian context has also to be considered when counseling our patients.



Cancer Treatment and fertility - 7 questions which patient need to think about and ask

Patients undergoing cancer treatment are at emotional cross roads where on one hand they are receiving counselling for treatment for life threatening condition-CANCER and on the other hand they are having discussions about long term effects of treatment of cancer on REPRODUCTIVE ORGANS and FERTILITY. This can be very difficult and challenging at times not only for patient but also for treating oncologist. 

Patient need to think and ask following questions to their oncologist/fertility specialist regarding fertility which will help them to make a right decision with regards to their treatment-

·       Will any of my cancer treatments affect my fertility?

·       Are there effective cancer treatment options for me that are less likely to cause infertility?

·       Are there any options for preserving fertility prior to cancer treatment?

·       How will I know if I am fertile after treatment?

·       If I don’t preserve my fertility before my cancer treatment, what are my parenthood options after treatment?

·       Do I have a type of cancer that can be inherited by my children?

·       How long do I need to wait after cancer treatment ends to start a family?

Courtesy- Fertilehope