1. Conservative Surgery to Preserve Fertility in Gynaecological Cancers. Sean Kehoe Oxford Gynaecological Cancer Centre Churchill Hospital Oxford

2. Malignancies Cervical Cervical Endometrial Endometrial Ovarian Ovarian Vulval Cancer ? Vulval Cancer ?

3. Counselling Counselling is very important Counselling is very important Often we are deviating from what could be considered the ‘Standard Recommendations’ Often we are deviating from what could be considered the ‘Standard Recommendations’ In essence – experimentation with the patient taking the risk. In essence – experimentation with the patient taking the risk.

4. Cervical Carcinoma Occurs not uncommonly in younger patients [33% < 40 years] A real increase in adenocarcinomas An impression of more cases occurring in nulliparous women – probably due to women delaying pregnancies as compared to previous times.

5. About 33% of cervical carcinomas occur in women <40 years

6. Cervical Carcinoma Severe Dyskaryosis ? Invasion Severe Dyskaryosis ? Invasion ? Invasion on Colposcopy ? Invasion on Colposcopy Requires some form of biopsy Requires some form of biopsy

7. Stage 1A1 – Squamous Carcinoma A loop cone excision of the cervix is sufficient treatment Once all pre-invasive and invasive disease cleared.

8. Stage 1A1 Adenocarcinoma Problem with ‘definition’ Now staging as 1A1 is acceptable Skip lesions can occur : ? Just Pre-invasive For lesions 3 -5 mm x 7 mm, 141 women – only 1 case of lymph node disease [0.73%]

9. Cervical Cancer: Trachelectomy Rules Rules Nulliparous [?] – family incomplete Nulliparous [?] – family incomplete Careful clinical staging Careful clinical staging MRI scan to evaluate tumour extent. MRI scan to evaluate tumour extent. Ib1 [2cms] or less. Ib1 [2cms] or less. Adenocarcinomas ? Adenocarcinomas ? ? Poorly Differentiated ? Poorly Differentiated ?Lymph Vascular Space Invasion ?Lymph Vascular Space Invasion

10. Trachelectomy Excise to Isthmus Insert Cervical Circlage

11. Cervical Circlage Parametrial Tissue But will surgery be further modified? Why parametrial tissue which addresses only 2 of 4 planes ? In tumour <10mm invasion and <2cms diameter – incidence of parametrial involvement is estimates at 0.6% Cervical Cancer

12. Single or 2 stage procedure ? If single – depending on Frozen Section Histology Extra-peritoneal or Intra-peritoneal Lymphadenectomy? If the procedure is about preserving fertility – it seems logical to prevent intra-peritoneal surgery when an alternative is available.

13. Beiner ME and Covens A (2007) Surgery Insight: radical vaginal trachelectomy as a method of fertility preservation for cervical cancer Nat Clin Pract Oncol 4: 353–361 doi:10.1038/ncponc0822 Patients and tumor characteristics for the seven clinical studies of radical vaginal trachelectomy

14. Beiner ME and Covens A (2007) Surgery Insight: radical vaginal trachelectomy as a method of fertility preservation for cervical cancer Nat Clin Pract Oncol 4: 353–361 doi:10.1038/ncponc0822 Table 2 Operative data and complications in the seven clinical studies of radical vaginal trachelectomy

15. Beiner ME and Covens A (2007) Surgery Insight: radical vaginal trachelectomy as a method of fertility preservation for cervical cancer Nat Clin Pract Oncol 4: 353–361 doi:10.1038/ncponc0822 Table 7 Number of obstetric outcomes in patients who underwent trachelectomy

16. Counselling Pregnancy: Pregnancy: If achieved – 30% miscarriage rate Assume – Premature delivery Assume – Operative Delivery

17. Recurrence Rates To date the recurrence rates at about 4% are not in excess of that expected with a radical hysterectomy. The application of this procedure to large tumours is less frequent now.

18. How Safe: Trachelectomy? Case selection very important Case selection very important Probably as safe as Radical Procedures Probably as safe as Radical Procedures Avoid in Large tumours [>2cms ?] Avoid in Large tumours [>2cms ?] Avoid in rare/high risk tumours Avoid in rare/high risk tumours For nulliparous women only? For nulliparous women only?

19. ENDOMETRIAL CANCER

20. Endometrial Cancer A Rare issue in women where fertility is a factor. Histopathology Histopathology Imaging Imaging Both of these are paramount in decision making.

21. Histology: Differentiation between Atypical Hyperplasia and Frank Carcinoma Histology: Differentiation between Atypical Hyperplasia and Frank Carcinoma Remember – when tissue confirms Atypical Hyperplasia – Frank Malignancy is found in the Hysterectomy specimen in 40-50% of cases [Cancer 2006,GOG study] Remember – when tissue confirms Atypical Hyperplasia – Frank Malignancy is found in the Hysterectomy specimen in 40-50% of cases [Cancer 2006,GOG study] Most would agree that fertility preservation should be limited to those with well differentiated tumours [stage 1A] Most would agree that fertility preservation should be limited to those with well differentiated tumours [stage 1A] Endometrial Cancer

22. Imaging: Imaging: This is important for the ‘staging’ process. CT/MTI/Ultrasound? Kinkel et al,Radiology 1999: Meta- analysis Contrast enhanced MRI best – BUT of note myometrial invasion detected correctly in 90% of cases – i.e. 10% false negative rate. Endometrial Cancer

23. In the main – progestagens used as therapy. Treatment time to regression ranges from 3.5 – 9 months Recurrence occurs in about 20% of responders This approach requires careful surveillance – and repeated endometrial curettage. Endometrial Cancer

24. How to manage?? How to manage?? Endometrial Cancer Mirena IUCD Progestogens: GnRH analogues All the above have been used with reasonable success [responses about 70%]. Tamoxifen can increase the PR, and hence potentially enhance the efficacy of progestagenic agents

25. Endometrial Cancer Curettage at 3/12 Curettage at 6/12 If - If + Attempt pregnancy Offer Hysterectomy Intervene If Any concerns Stage 1a Treatment

26. RefCasesResponsePregnancies Kaku 20011275%2 Imai 20011550%2 Randall19971475%? Gotlieb 200313100%9 babies Signorelli, 20092157%13 pregnancies Laurelli 20111490%1 baby Miniq, 20111457%11 pregnancies Endometrial Cancer

27. Ushijima et al. J. Clinical Oncology 2007 Ushijima et al. J. Clinical Oncology 2007 28 Stage 1 A, 17 Atypical hyperplasia, all < 40 years 28 Stage 1 A, 17 Atypical hyperplasia, all < 40 years 600mgs MPA with low dose aspirin 600mgs MPA with low dose aspirin Continued for 28 weeks once responding Continued for 28 weeks once responding Endometrium checked 8 and 16 weeks Endometrium checked 8 and 16 weeks CR 55% Endometrial CA, and 82% AH CR 55% Endometrial CA, and 82% AH In responders– either oestrogen/progesterone therapy or Fertility therapy. In responders– either oestrogen/progesterone therapy or Fertility therapy. 36 months follow-up – 12 pregnancies and 7 deliveries 36 months follow-up – 12 pregnancies and 7 deliveries However 47% recurrence rate – need careful monitoring However 47% recurrence rate – need careful monitoring Endometrial Cancer

28. Taiwan J Obstet Gynecol.Taiwan J Obstet Gynecol. 2011 Mar;50(1):62-6. Obstetric outcomes of pregnancy after conservative treatment of endometrial cancer: case series and literature review. Chao ASChao AS, Chao A, Wang CJ, Lai CH, Wang HSChao AWang CJLai CHWang HS Distribution of clinicopathological characteristics in the endometrial cancer patients with conception in the meta-analysis Characteristics Patients no. Group 1 Group 2 p Age at diagnosis, yr (mean SD) 50 32.8, 4.1 (n = 14) 29.5, 5.3 (n = 36) 0.05 Age at pregnancy, yr (mean SD) 43 34.3, 4.0 (n = 13)30.9, 5.3 (n = 30) 0.05 Histology type 4514 31 1.0 Adenocarcinoma 44 14 30 Adenosquamous 1 0 1 Grade of differentiation 4114 27 1.0 Well 3813 25 Moderate and poor 3 1 2 Hysterectomy after childbearing 50 1436 0.70 Yes 9 3 6 No 41 11 30 Metastasis/recurrence 50 14 36 0.57 Yes 4 0 4 No 46 14 32

29. Analyses of obstetric outcomes according to undergoing: IVF, ICSI, gamete intrafallopian transfer, or zygote intrafallopian transfer (Group 1) and spontaneous conception/intrauterine insemination (Group 2) Group 1 (n=15) Group 2 (n=50) p Preterm labor 7 (46.7) 3 (6.0) 0.001 Cesarean rate 14 (93.3) 11 (22.0) <0.001 Primigravida 14 (93.3) 36 (72.0) 0.160 Multiple pregnancy 6 (40.0) 3 (6.0) 0.003 Taiwan J Obstet Gynecol.Taiwan J Obstet Gynecol. 2011 Mar;50(1):62-6. Obstetric outcomes of pregnancy after conservative treatment of endometrial cancer: case series and literature review. Chao ASChao AS, Chao A, Wang CJ, Lai CH, Wang HSChao AWang CJLai CHWang HS

30. How safe : Endometrial cancer? Numbers are too small to make any dogmatic statements. Numbers are too small to make any dogmatic statements. We can preserve fertility We can preserve fertility After single delivery – most recommend hysterectomy. After single delivery – most recommend hysterectomy.

31. Ovarian Cancer Agreed fertility preservation in all young patients [?<40 years]- as: Agreed fertility preservation in all young patients [?<40 years]- as: 1. Germ cell tumours very chemosensitive 1. Germ cell tumours very chemosensitive 2. Borderline tumours – normally cured with local excision [ if early stage] 2. Borderline tumours – normally cured with local excision [ if early stage] 3. If advanced ovarian cancer – then can always re-operate. 3. If advanced ovarian cancer – then can always re-operate. 4. May be another condition – eg Hodgkins !! 4. May be another condition – eg Hodgkins !!

32. Invasive Early stage disease Schilder et al, Gynecol Oncol, 2002 N = 52 42 stage 1A 10 stage 1C Grade 1 = 35Grade 2= 9Grade 3 = 5 20 had adjuvant chemotherapy 5 recurrences [8-78 months after first surgery] Sites : Contralateral ovary – 3, peritoneum 1 and lung 1. 2 deaths 24 attempted pregnancies – 71% conceived. Survival at 5 years 98% and 10 years 93%

33. Fertility-sparing surgery in young women with mucinous adenocarcinoma of the ovary. Gynecol Oncol. 2011 Aug;122(2):334-8. Kajiyama H et al,Japan Gynecol Oncol.Kajiyama H Gynecol Oncol.Kajiyama H N=148,The median follow-up time of all mEOC patients was 71.6 (4.8-448.3) months 41 patients with Fertility Sparing, 27 = Stage 1a, 14 Stage 1c 5 year overall survival was 97.3% Compared with 101 women who underwent Radical surgery for the Same disease – there was no difference in outcome.

34. Germ Cell Tumours RefCasesChemoPregSurvival Perrin 199945297 babies2 deaths Sagae 200326234 pregnancies – no deaths Zanetta 20011388140 babies95% 5 year For Germ cell tumours – outcome excellent. Most problems were in the more advanced stage diseases. Fertility can be retained.

35. Borderline Ovarian Tumours RefCasesRecurrencePregnancies Gotlieb, 2003398%22 in 15 women Zanetta,200118918%41in 21 women Demeter, 200212?50% Donnez,20031618.7%64% Boran 2004626.5%13 in 10 women Rao, 20053816%6 in 5 women

36. What if Cystectomy performed ? What if Cystectomy performed ? A. If malignant – proceed to oophorectomy and full staging A. If malignant – proceed to oophorectomy and full staging B. If borderline – oophorectomy – reduces recurrence rates B. If borderline – oophorectomy – reduces recurrence rates Ovarian Cancer

37. Must Monitor the Contra-lateral ovary. Must Monitor the Contra-lateral ovary. Ultrasound/tumour markers. Ultrasound/tumour markers. Ovarian Cancer

38. Fertility Sparing Radical Recurrence Fertility Sparing Radical Recurrence Boran 200562806.5% vs 0.0% Zanetta 2001189*15018.5 % vs 4.6% 7 cases progressed to ‘invasive’ carcinoma 7 cases progressed to ‘invasive’ carcinoma Important to counsel the patient and is this evidence to support routine pelvic clearance after completion of the family ?? Borderline Ovarian Cancer

39. Fertility conservation safe for Borderline tumours. Fertility conservation safe for Borderline tumours. In invasive tumours – probably best to restrict fertility preservation surgery to properly staged, Stage 1 disease. In invasive tumours – probably best to restrict fertility preservation surgery to properly staged, Stage 1 disease. Following completion of family – pelvic clearance seems a logical approach to reduce recurrences, and considering the limitations of screening such women. Following completion of family – pelvic clearance seems a logical approach to reduce recurrences, and considering the limitations of screening such women. Ovarian Cancer

40. Yes it can be done – but always the question is :Should it be done? Yes it can be done – but always the question is :Should it be done? Need the full Multidisciplinary Team – Oncological and Fertility Working together. [?Obstetric/Neonatal?] Need the full Multidisciplinary Team – Oncological and Fertility Working together. [?Obstetric/Neonatal?] Counsell– Counsell and Counsell Counsell– Counsell and Counsell Conclusions

41. A Healthy Mother and Child