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

Malignancies Cervical Cervical Endometrial Endometrial Ovarian Ovarian Vulval Cancer ? Vulval Cancer ?

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.

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.

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

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

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

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%]

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

Trachelectomy Excise to Isthmus Insert Cervical Circlage

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

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.

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: /ncponc0822 Patients and tumor characteristics for the seven clinical studies of radical vaginal trachelectomy

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: /ncponc0822 Table 2 Operative data and complications in the seven clinical studies of radical vaginal trachelectomy

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: /ncponc0822 Table 7 Number of obstetric outcomes in patients who underwent trachelectomy

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

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.

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?

ENDOMETRIAL CANCER

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

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

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

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

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

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

RefCasesResponsePregnancies Kaku %2 Imai %2 Randall %? Gotlieb %9 babies Signorelli, %13 pregnancies Laurelli %1 baby Miniq, %11 pregnancies Endometrial Cancer

Ushijima et al. J. Clinical Oncology 2007 Ushijima et al. J. Clinical Oncology 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

Taiwan J Obstet Gynecol.Taiwan J Obstet Gynecol 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) , 4.1 (n = 14) 29.5, 5.3 (n = 36) 0.05 Age at pregnancy, yr (mean SD) , 4.0 (n = 13)30.9, 5.3 (n = 30) 0.05 Histology type Adenocarcinoma Adenosquamous Grade of differentiation Well Moderate and poor Hysterectomy after childbearing Yes No Metastasis/recurrence Yes No

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) Cesarean rate 14 (93.3) 11 (22.0) <0.001 Primigravida 14 (93.3) 36 (72.0) Multiple pregnancy 6 (40.0) 3 (6.0) Taiwan J Obstet Gynecol.Taiwan J Obstet Gynecol 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

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.

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 !!

Invasive Early stage disease Schilder et al, Gynecol Oncol, 2002 N = 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%

Fertility-sparing surgery in young women with mucinous adenocarcinoma of the ovary. Gynecol Oncol Aug;122(2): 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 ( ) 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.

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

Borderline Ovarian Tumours RefCasesRecurrencePregnancies Gotlieb, %22 in 15 women Zanetta, %41in 21 women Demeter, ?50% Donnez, %64% Boran %13 in 10 women Rao, %6 in 5 women

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

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

Fertility Sparing Radical Recurrence Fertility Sparing Radical Recurrence Boran % vs 0.0% Zanetta * % 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

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

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

A Healthy Mother and Child