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Oncologische Risico’s van fertiliteitsbehandelingen

Oncologische Risico’s van fertiliteitsbehandelingen. Curt Burger. VVOG 1 maart 2008 Mechelen. OMEAGA studie. Divisie Gynaecologische Oncologie Erasmus University Medical Center Rotterdam. Red alert in early nineties.

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Oncologische Risico’s van fertiliteitsbehandelingen

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  1. OncologischeRisico’s van fertiliteitsbehandelingen Curt Burger VVOG 1 maart 2008 Mechelen OMEAGA studie Divisie Gynaecologische Oncologie Erasmus University Medical Center Rotterdam

  2. Red alert in early nineties Whittemore et al. Am J Epidemiol 1992 Case control study Nulligravid women with FD use have RR of 27.0 (CI 2.3-316) of ovarian cancer Risk estimated on 12 cases and 1 control !!!

  3. Ovarian stimulation for IVF and ovarian cancer? • More ovarian damage by multiple ovulations at the same time • Increased levels of gonadotropins • Risk of ovarian cancer related to cumulative number of ovulations

  4. Subfertility, Hormones and Cancer risk • Literatureoverview • Effect of subfertility • Effect of hormonaltreatment • OMEGA study • Cancerincidence in womenafter IVF • Endometriosis and ovariancancer • Conclusions

  5. Rossing, NEJM 94 Modan Am J Epidemiol 98 Venn Lancet 99 Klip 2002 thesis DoyleHumanReprod 02 BrintonObstetGynecol 04

  6. BragaHumanReprod 96 WeissCancer C CDisease 98 RiciHumanReprod 99 BurkumFertilSteril 03

  7. Fertility Drugs and risk of cancer literature review • Helen Klip et al. Cancer Causes Disease Control 2000 • Sonia Kalyab et al. Ob&Gyn 2004

  8. Subfertility and Ovarian Cancer Risk (Cases compared with general population) Author population FU cases exp.cases SIR (CI) yrsRon, 1987 2575 12 4 1,9 2.1 (n.s)Brinton, 1989 233519 11 8,6 1.3 (n.s.)Brinton, 1997 20686 11 29 ---- 1.9 (1.3-2.8) endometriosisRossing, 1994 3837 7 11 4.3 2.5 (1.3-4.5)Venn, 1995 4794 5 3 1.9 1.6 (0.5-5.1)Modan, 1998 2469 21 12 7.2 1.6 (0.8-2.9)Rodriquez, 1998 19827 12 2.2 (1.1-4.6) Cancer risk associated with subfertility and ovulation induction: a review. H. Klip et al. Cancer Causes Control 2000;11:319-3 SIR: standard incidence rate (cases/exp. cases)

  9. Gynaecological and Breast Cancer Risk Authorcases controlsSIR (CI) comment Borderline T Ness, 2002 911 1,137 2.4 (1.01-5.88) FD vs no FD comparison withgeneral population Endom CancerModan, 982,469 ---4.8 (3.0-7.4) Subfertility is risk factor Endom CancerModan, 98 2469 --- 6.8 (3.6-11.5) FD is risk factor Breast Cancer4 studies, no increased risk with subfertility Breast Cancer 8 studies, no increased risk with FD use Adapted from Klip et al. Cancer Causes and Control 2000;11.319-344

  10. Fertility Drugs and the risk of Ovarian CancerReview of the literature from 1987-2007 Rossing, 1994 YES > 12 cycle Clomiphene Citrate Brinton, 2004 NO with CC use, >> 15 yrs F-U ! Adapted from Klip et al. Cancer Causes and Control 2000;11.319-344

  11. Kashyap et al. Ob&Gyn 2004Comparison of ovarian cancer in treated versus untreated (control) subfertile patients (cohort studies)

  12. Literature - discussion • Lack of an internal reference group • Short follow-up • Only few cancer cases • Only one source of information • Almost no confounder control! • All studies but one were related to FD use before the IVF era

  13. Recommendations • Adjustment confounders, more detailed analyses • Examine FD use (clomiphene) given before IVF treatment • More prolonged follow-up

  14. Subfertility, Hormones and Cancer risk • Literature overview • Effect of subfertility • Effect of Hormonal treatment • OMEGA study • Cancer incidence in women after IVF • Endometriosis and ovarian cancer • Conclusions

  15. Participating IVF clinics in the Netherlands AZVU AZR/Dijkzigt AZG AZN/ St.Radboud LUMC UMC Utrecht AZM AMC Sophia Hospital Zwolle Elisabeth Hospital Tilburg Diaconessenhuis Voorburg Catharina Hospital Eindhoven Netherlands Cancer Institute, Dept. of Epidemiology Erasmus university Medical Centre Rotterdam, Division of Gynecologic-Oncology

  16. A cohort study of cancer risk after In Vitro Fertilization Erasmus university Medical Centre Rotterdam Division of Gynecologic Oncology Netherlands Cancer Institute, Dept. of Epidemiology The Netherlands Grants from the Dutch Preventiefonds and the Ministry of Health of the Netherlands

  17. Research question Are women who underwent IVF at higher risk for: • ovarian cancer • breast cancer • endometrial cancer • and/or other hormone-related cancers ascompared with a similar subfertile group of women who never had IVF treatment?

  18. Identification of cohort 26,428 women with subfertility problems IVF cohort: n = 19,840 and at least one completed IVF treatment between 1983 and 1995 Control cohort: n = 6,588 Fertility problems but no IVF treatment between 1980 and 1995 Control group has similar distribution of the subfertility disorders as the IVF group

  19. Subfertility, Hormones and Cancer risk • Literature overview • Effect of subfertility • Effect of Hormonal treatment • OMEGA study • Cancer incidence in women after IVF • Endometriosis and ovarian cancer • Conclusions

  20. Design of the Omega study • Nation-wide historical cohort with prospective follow-up • E D L L • IVF group |--------------|--->|------------|----|----------|----| • non-E D L L • Control group <----------------------|--->|------------|----|----------|----|‘80 ‘83 ‘89 ‘95 ‘96 ‘98 ’99‘00 ’05 ’07 • Follow-up Follow-up Follow-up • 1 2 3 • E =Exposure period • D =Data collection • L =Linkage Netherlands Cancer Registry

  21. Data collection - Netherlands Cancer Registry • Linkage with the Netherlands Cancer Registry • Completeness of the registry: 95-98% • Written permission needed from participants

  22. Data collection - Medical files • Reason of subfertility • History of medical conditions associated with subfertility • Gynaecological surgery/other treatments • Details on fertility treatment • drugs • doses per cycle, etc

  23. Data collection – Mailed questionnaire • Medical history including gynaecological diseases • Menstrual history • Reproductive factors • Hormone use • Subfertility disorders and treatment • Family history of cancer • Lifestyle factors

  24. Results Part 1: Follow-up 5.4 yrs Part 2 Follow-up 11.3 yrs Part 3 Follow-up 14.0 yrs

  25. Results linkage cancer registry IVF group with general population: Follow-Up 1 (5.4 yrs) Breast cancer Ovarian cancer Endom cancer RR -1 0 1 2 3 4 5 6

  26. Results linkage cancer registry Control group with general population. (follow-up: 5.4 yrs) Breast cancer Ovarian cancer Endom cancer RR -1 0 1 2 3 4 5 6

  27. Direct comparisons: Hazard Ratios of cancer risk associated with IVF versus ControlsFollow-Up 5.4 yrs Breast cancer Ovarian cancer + Borderline tumor Endometrial cancer RR -2 -1 0 1 2 3 4 5 6 IVF group: 17.796 (202.795 person yrs, follow-up 5.4 yrs) Controls : 6.594 ( 75.714 person yrs, follow-up 7.0 yrs)

  28. Conclusion Omega-I cohort5.4 yrs follow-up Since the increase in risk in endomtrial cancer was observed in both IVF and Control groups, an effect of subfertility itself is likely. No increased risk of breast and ovarian cancer

  29. Results Part 1: Follow-up 5.4 yrs Part 2 Follow-up 11.6 yrs Part 3 Follow-up 14.0 yrs

  30. Linkage with cancer registry and Pathology Registry IVF and control group Ovarian Cancer IVF Group N=20 Ovarian Cancer Control Group N= 8 N=26 Borderline Tumor Ovary IVF Group Borderline Tumor Ovary Control Group N= 5 RR -2 -1 0 1 2 3 4 5 6 (follow-up: 11.3 yrs) CWB april 2007

  31. Linkage with cancer registry and Pathology Registry IVF and control group (april 2007) Blue dotted line is < 1 yr excl Ovarian Cancer IVF Group Ovarian Cancer Control Group Borderline Tumor Ovary IVF Group Borderline Tumor Ovary Control Group RR -2 -1 0 1 2 3 4 5 6 (follow-up: 11.3 yrs) CWB april 2007

  32. Results Part 1: Follow-up 5.4 yrs Part 2 Follow-up 11.3 yrs Part 3 Follow-up 14.0 yrs

  33. Results linkage cancer registry withIVF and control group (data october 2007)EXCLUDED ALL TUMORS FOUND < 1 YR (follow-up: 14.0 yrs) CWB apri2007

  34. Linkage with cancer registry and Pathology Registry IVF and control group [tumors excluded < 1 yr] (oct 2007) Ovarian Cancer IVF Group N=18 N=27 N= 6 Ovarian Cancer Control Group N= 10 Borderline Tumor Ovary IVF Group N=22 N=26 Borderline Tumor Ovary Control Group N= 4 N= 4 RR -2 -1 0 1 2 3 4 5 6 (follow-up: 14.0 yrs CWB october 2007

  35. Linkage with cancer registry and Pathology Registry IVF and control group [tumors excluded < 1 yr] (oct 2007) Ovarian Cancer IVF Group N=18 N=27 N= 6 Ovarian Cancer Control Group N= 10 Borderline Tumor Ovary IVF Group N=22 N=26 Borderline Tumor Ovary Control Group N= 4 N= 4 RR -2 -1 0 1 2 3 4 5 6 (follow-up: 11.3 (green) and 14.0 yrs(white/yellow) CWB october 2007

  36. Hazard RatioIVF and control group [tumors excluded < 1 yr] (19 nov 2007) All ovarian cancers IVF n=53 Ovarian cancer Borderline tumor ovary RR -2 -1 0 1 2 3 4 5 15 CWB nov 2007

  37. OMEGA study: effect of

  38. Years after IVF and risk (RR)

  39. Levels of evidence Level I Randomized controlled trials Level II-1 Non-randomized controlled trials Level II-2 Cohort and case-control studies Level II-3 Cross-sectional studies Level III Case reports and opinions In vitro and animal research

  40. Conclusion 1: • No increased risk for breast cancer in comparison with the general population and the control group • risk of endometrial cancer is probably related to subfertility itself

  41. Conclusion 2 • Increased risk of borderline tumors is striking • After  10 yrs a possible increase of ovarian malignancies in IVF group compared to controls • The risk appears to becorrelatedwith the IVF procedure • Small numbers

  42. Is endometriosis a risk factor of cancer, and what is the effect of IVF on that risk?

  43. Link between Endometriosis and ovarian cancer(in all studies endometriosis was reported by the women after the diagnosis ovarian cancer) CWB april 2007

  44. From Giudice and Koa. Lancet 2004, 364:1789-99

  45. Endometriosis Group N=3,658 BTO n=10 Ov Cancer n=13 Controls n= 4,442 BTO n=2 Ov Cancer n=2 Ovarian Cancer risk and Endometriosis CWB april 2007

  46. Risk of ovarian cancer and BTO associated with endometriosis (june 2007) (follow-up: 11.3 yrs) Ovarian Cancer Borderline Tumor Ovary Increased risk RR -5 1 5 10 15 20 25 30 35 So far, there is no negative effect of IVF CWB nov 2007

  47. Anatomic localization of endometriosis CWB april 2007

  48. Conclusion 3: • Endometriosis is a risk factor of ovariancancer and is notcorrelatedwith IVF

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