Hisham Ahmed Abou-Taleb, M.D. Ph.D.

Fertility preservation

in cervical cancer patients

Professor of Obstetrics and Gynecology

Clinical Director of Gynecologic Oncology Unit, Vice manager for Health Quality systems

Women Health Hospital, faculty of Medicine, Assuit University

EGOS board member

hishamaboutaleb1@aun.edu.eg

C O I Disclosure

Outline

• Introduction
• Fertility sparing treatment for patients with cervical cancer: Guidelines from ESGO, ESHRE, and ESGE
• Fertility sparing surgery for cervical cancer
• Oncological Outcomes
• Fertility and Obstetrical outcomes

Introduction

Introduction

• The introduction of screening programs and HPV vaccination has led to a marked reduction in the incidence and mortality rates of cervical cancer precursors and invasive lesions

Introduction

Outline

• Introduction
• Fertility sparing treatment for patients with cervical cancer: Guidelines from ESGO, ESHRE, and ESGE
• Fertility sparing surgery for cervical cancer
• Oncological Outcomes
• Obstetrical outcomes

ESGO, ESHRE, ESGE guidelines

The surgical perimeter

• Preservation of the uterus
• Preservation of at least one part of one ovary
• Aim to achieve (spontaneous) pregnancy

General Recommendations

• Counselling with a reproductive specialist who has an in-depth understanding of the patient and couple’s History is recommended before considering Fertility-sparing treatment and pregnancy seeking (level of evidence V, grade of recommendation A)
• Fertility-sparing surgery and treatment planning should be performed exclusively by teams with a strong collaboration between gynaecological oncologists and reproductive medicine specialists (V, A)

General Recommendations

• Pathological expert review is recommended in all patients if the diagnosis and associated treatment could impair fertility (V, A)
• Detailed description of the initial surgery should be provided (endobag, upper abdomen description, etc; (V, A)

Oncological aspects of fertility-sparing strategies:�< Oncological selection criteria >

• Pelvic MRI is mandatory to assess oncological criteria
• It is preferred to be evaluated by a dedicated gynecological radiologist or expert sonography
• The following information is required: tumor size, depth of stromal invasion, distance between cranial edge of tumor and internal os and any extra cervical extension or suspicious nodes (III, A)
• CT or PET-CT is done to exclude any distant metastatic disease (II, B)

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• Cervical conisation is the method of choice for staging in early cervical cancer and should be performed if no gross lesion is noted (III, B)

• This can be associated with lymph node staging according to the ESGO–ESTRO–ESP guidelines (II, B)

Oncological aspects of fertility-sparing strategies:�< Oncological selection criteria >

• A non-fragmented cone is crucial for pathological evaluation
• The base of the cone should encompass the visible gross lesion on the ectocervix
• At least 1 mm free histological margin
• The height of the cone (center of cone base to vertex) should be at least 10 mm
• Cones can be oriented with a suture at the midpoint of the anterior cervical lip (III, A)
• Intraoperative frozen section of cone margins can be considered to tailor the surgery (IV, B)

Oncological aspects of fertility-sparing strategies:�< Surgical and Pathological criteria >

Oncological aspects of fertility-sparing strategies:�< Surgical and Pathological criteria >

• ConCerv trial inclusion criteria:
• Stage IA2-IB1 (defined by 2009 FIGO staging system)
• Squamous cell carcinoma at any grade

or adenocarcinoma at grade 1 or 2

• Tumour size ≤2 cm
• No lymphovascular space invasion [LVSI]
• Negative imaging for metastatic disease
• Depth of invasion ≤10 mm
• Conisation margins and endocervical curettage negative for malignancy or high-grade dysplasia

• Radical trachelectomy with removal of a part of parametria is not recommended for stage IB1 disease fulfilling all the strict inclusion criteria of the ConCerv trial (III, E)

Oncological aspects of fertility-sparing strategies:�< Surgical and Pathological criteria >

• ConCerv trial inclusion criteria:
• Stage IA2-IB1 (defined by 2009 FIGO staging system)
• Squamous cell carcinoma at any grade

or adenocarcinoma at grade 1 or 2

• Tumour size ≤2 cm
• No lymphovascular space invasion [LVSI]
• Negative imaging for metastatic disease
• Depth of invasion ≤10 mm
• Conisation margins and endocervical curettage negative for malignancy or high-grade dysplasia

• Radical trachelectomy is recommended for stage IB2 disease
• Using an abdominal approach (eg, laparotomy or mini-invasive approaches [robotic-assisted or pure laparoscopic approaches] (IV, B)

Oncological aspects of fertility-sparing strategies:�< Surgical and Pathological criteria >

• Silva pattern-based classification for HPV-associated invasive adenocarcinoma

Alvarado-Cabrero & Parra-Herran et al., Int J Gynecol Pathol. 2021 ;40 (Iss 2 Suppl 1):S48–S65

Oncological aspects of fertility-sparing strategies:�< Surgical and Pathological criteria >

• Pathologists are encouraged to assign a Silva pattern classification
• Pattern A is the most favorable
• Pattern B without LVSI is also favorable (IV, C)

• Seven criteria should be met before considering fertility-sparing management
• Assignment of patients to favourable selection criteria is based on all clinicopathological variables (IV, B)
• Confirmed histology on cervical biopsy or conisation is consistent with squamous cell carcinoma (all grades) or usual-type HPV-associated adenocarcinoma (all grades) with no more than 10 mm stromal invasion (IV, B)
• Absence of LVSI is a favourable pathological biomarker (III, B)
• No evidence of any metastasis is required (IV, A)
• Largest measurement of a tumour is 2 cm by imaging or clinical exam (IV, B)
• Free margins on final pathology are mandatory (III, A)
• No evidence of tumour involvement of the internal cervical orifice and cranial extent of cervical tumour is 1 cm or more from the internal cervical orifice on imaging (IV, B).

Favourable oncological selection criteria

At least one of the following criteria should be met:

• Tumour size is 2–4 cm by exam or imaging (IV, C)
• Stromal invasion by conisation is more than 10 mm but has negative margins (IV, C)
• Evidence of deep cervical stromal invasion on MRI or sonography (IV, B)
• Tumour cranial extent is 5–10 mm from internal cervical orifice by imaging (IV, C)
• Trachelectomy specimen margin reveals a 5–10 mm tumour-free margin from the internal cervical orifice (IV, B)
• Silva pattern C of HPV-associated usual-type adenocarcinoma (?data are scarce on pattern B with LVSI) (IV, C)

Oncological selection criteria acceptable in selected cases

Selection of patients�considering fertility-sparing treatment

Selection of patients�considering fertility-sparing treatment

Outline

• Introduction
• Fertility sparing treatment for patients with cervical cancer: Guidelines from ESGO, ESHRE, and ESGE
• Fertility sparing surgery for cervical cancer
• Oncological Outcomes
• Obstetrical outcomes

Types of fertility sparing surgery

• Up to now, in patients interested in future pregnancies and with limited disease, the mainstay of clinical management has been centered in avoiding hysterectomy

Types of fertility sparing surgery

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1. Conization

(B1) Simple trachelectomy.

(B2) Endocervical loop

(C) Vaginal radical trachelectomy

(D) Abdominal radical trachelectomy (laparoscopic, robotic)

• Neoadjuvant chemotherapy has been used as an alternative to radical trachelectomy for selected patients with stage IB2 (2–4 cm) cervical cancer (IV, C)
• Various chemotherapy regimens have been used to reduce cervical tumor burden and allow for a satisfactory resection of the primary tumor with conisation and simple or radical trachelectomy (IV, C)
• Retrospective data suggest that abdominal radical trachelectomy has the lowest recurrence rate for patients with stage IB2 cervical cancer (IV, C)
• Ongoing prospective trials with platinum and paclitaxel will clarify the validity of neoadjuvant chemotherapy in fertility-sparing treatment of stage IB2 disease (IV, C). Including patients with stage IB2 cervical cancer in ongoing trials is encouraged to evaluate the safety of neoadjuvant chemotherapy (V, B)

Neoadjuvant chemotherapy

for patients with stage IB2 cervical cancer

Outline

• Introduction
• Fertility sparing treatment for patients with cervical cancer: Guidelines from ESGO, ESHRE, and ESGE
• Fertility sparing surgery for cervical cancer
• Oncological Outcomes
• Obstetrical outcomes

Cervical Conization

• ConCerv trial by Schmeler et al. is single-arm, international, prospective trial of 100 women
• It demonstrated that conservative surgery in early-stage (IA2–IB1), low-risk (negative LVSI, negative cone margins) cervical cancer was associated with a 3.5% recurrence rate and a positive lymph node rate of 5%

Schmeler et al ., Int J Gynecol Cancer, 2021 

Cervical Conization

• GOG 278 is a large, prospective cohort study that aims to examine the changes in bladder, bowel, and sexual function among women who undergo conservative treatment for early-stage cervical cancer including a fertility preservation arm (conization and pelvic lymphadenectomy)
• Results showed that non-radical surgery for early-stage cervical cancer was associated with small decreases in sexual function and bladder/bowel function at 4–6 weeks postoperative but quickly improved to baseline after 6 months
• An improvement in QOL and decreased cancer worry postoperatively was also seen

Covens & Huang et al., Gynecol Oncol, 2024, 190(1)58-59

Cervical Conization

• The SHAPE trial (Radical Versus Simple Hysterectomy and Pelvic Node Dissection With Low-risk Early Stage Cervical Cancer)
• Although not focused on fertility preservation, similarly seeks to add to the growing body of evidence evaluating the overall safety of conservative surgery in this group of patients by assessing the oncologic outcomes of less radical procedures

Plante & Kwon et al., N Engl J Med 2024;390:819-829

Cervical Conization

Simple Trachelectomy

• Many of these complications are related to parametrial. However, in a select group of patients, parametrectomy may not be necessary
• Frumovitz et al. found that 0% of women with tumor size of 2 cm or less without lymphovascular space invasion (LVSI) had parametrial involvement, while 0.7% of patients had a positive pelvic lymph node with a negative parametrium

(Frumovitz et al., Obstet Gynecol. 2009)

Simple Trachelectomy

A more recent report addressed a more promising results

• The rate of DFS at 2 and 5 years was 89%, and the 5- year OS was 96%.
• Early complications were grade 1–2 in 90% of cases.
• Late postoperative complications were seen in 15 patients (31.2%).
• 60.4% of patients intended to get pregnant. The pregnancy rate was 41.4%, and the live birth rate 88.2%

Valzacchati & Odetto et al., Gynecol. Oncol. Reports, 2023

Simple Trachelectomy

Radical Trachelectomy

• Machida et al. demonstrated a 5-year recurrence rate of 2.8% following trachelectomy

Machida et al Gynecol Oncol. , 2021

Radical Trachelectomy

• RT is associated with similar risks to radical hysterectomy including bladder dysfunction, lymphocele, hematoma, and lymphedema
• Furthermore, obstetric and pregnancy outcomes are compromised depending on route of radical trachelectomy
• One study showed that 22 of 37 patients (60%) had complications 6 had cervical stenosis requiring surgical dilation, 4 had ovarian insufficiency, and 14 had Asherman’s syndrome

(Egashira et al. Acta Obstet Gynecol Scand, 2017)

Radical Trachelectomy

Oncologic results of fertility sparing surgery of cervical cancer

Morice et al., Gynecologic Oncology 165 (2022) 169–183

Oncologic results of fertility sparing surgery of cervical cancer

Morice et al., Gynecologic Oncology 165 (2022) 169–183

Outline

• Introduction
• Fertility sparing treatment for patients with cervical cancer: Guidelines from ESGO, ESHRE, and ESGE
• Fertility sparing surgery for cervical cancer
• Oncological Outcomes
• Fertility and Obstetrical outcomes

Natural fertility after conservative surgery

• The cervix plays a crucial role in defending the upper genital tract from infections. However, it also has an active role in ensuring fertility.
• The modification of the cervical mucus with sex steroids fluctuations functions as a gatekeeper, allowing spermatozoa to overcome this functional barrier only when ovulation approaches
• In addition, the cervix has a role of sperm reservoir so that during the days preceding ovulation spermatozoa can be stored and gradually released to better cover the time of ovulation

Harris-Glocker and McLaren, 2013

Natural fertility after conservative surgery

• A systematic review showed that stage I patients who attempted to become pregnant, 55% conceived, of whom 70% achieved a live birth
• The highest fertility rate (77%) and live birth rate (76%) were observed among women treated with neoadjuvant chemotherapy prior to surgery
• The poorest outcome was documented in patient who underwent abdominal laparotomic radical trachelectomy (fertility rate of 44% and live birth rate of 68%)

Bentivegna et al., Lancet Oncol 2016b

Natural fertility after conservative surgery

• There is an increased risk of infertility if the cervix or lower uterus is scarred or narrowed from conization or trachelectomy.
• This could potentially prevent sperm from entering the uterus. If this happens, infertility treatment, such as dilatation of the cervical opening &/or intrauterine insemination (IUI) might be beneficial
• If it is not possible to dilate the cervical opening or if IUI is unsuccessful, in vitro fertilization (IVF) with embryo transfer is considered

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Obstetrical outcomes

• Surgical procedures might cause the removal of a substantial portion of cervical connective tissue, thereby weakening the supportive function of the cervix as pregnancy progresses resulting in preterm labor

Bevis and Biggio, 2011

• Removal of cervical tissue of 12.6 mm in height with average residual cervix 28.7 will not increase the risk of preterm labor

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Zebiaty et al., J clin diagn Res, 2017

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Obstetrical outcomes

• Cervical excisional treatment increases the risk of intraamniotic infection in subsequent pregnancy. The risk increases with the length of the excised cone.
• Cone length of ≥18 mm was associated with higher rates of
• intraamniotic infection (29% [5/15] vs without, 12% [85/689]; adjusted odds ratio, 3.0; adjusted P=.05)
• microbial invasion of the amniotic cavity without inflammation (with, 40% [6/15] vs without, 11% [74/689]; adjusted odds ratio, 6.1; adjusted P=.003)
• early-onset neonatal sepsis (with, 20% [3/15] vs without, 3% [23/689]; adjusted odds ratio, 5.7; adjusted P=.02).

Kacerovsky et al., Am J obst Gynecol, 2023

Ramirez et al., Gynecol Oncol. 2014

Obstetrical outcomes

Obstetrical outcomes

• Several strategies to prevent preterm birth have been proposed. They include:
• cervical cerclage (Kim et al., 2012)
• prophylactic antibiotics during pregnancy (Shepherd et al., 2006)
• corticosteroids to accelerate lung maturation of the fetus (Bernardini et al., 2003)
• routinely transvaginal monitoring of cervical length (Petignat et al., 2004)
• Strict bed rest with vaginal irrigation and tocolytics (Ishioka et al., 2007)
• Unfortunately, the available data are limited and no definitive recommendations can be drawn.

Risk of congenital abnormalities  

• Case-control study of congenital anomalies in children of cancer patients by Dodds & Marrett et al., BMJ 1993 which included 45,200 mothers of children who had a congenital anomaly and a matched sample of parents whose children did not have a congenital anomaly.
• 54 cases and 52 controls were identified as having cancer (RR = 1.04, 95% CI 0.7 to 1.5)
• No significant associations were found between congenital anomalies in the offspring and any type of cancer treatment

Cancer risk in offspring

• No excess risk of cancer in offspring of cancer survivors has been demonstrated.
• Stensheim et al, Int J Cancer. 2013
• Sankila et al., N Engl J Med. 1998
• Mulvihill et al., Lancet. 1987
• Unless the parent’s tumor is a component of an inherited syndrome, such as retinoblastoma
• Survivors of ovarian or breast cancer who are positive for BRCA 1 or 2 mutation have a 50 percent chance of passing the mutation to their offspring. 

Conclusions

• Cervical cancer is a treatable condition and more cases are now being diagnosed in the reproductive age
• Surgery is the standard of care especially when performed through laparotomy
• There are many safe treatment options for patients with early stage cervical cancer who wish to preserve their fertility
• Conization and simple hysterectomy can be used for fertility preservation in early stage cervical cancer with favorable histology and tumor size <2cm
• Radical trachelectomy can be used for larger tumor sizes 2-4 cm

Conclusions

• Natural conception can reach up to 55% in cancer survivors
• Cervical excisional treatment increases the risk of intraamniotic infection in subsequent pregnancy. The risk increases with the length of the excised cone
• No significant associations were found between congenital anomalies in the offspring and any type of cancer treatment
• No excess risk of cancer in offspring of cancer survivors has been demonstrated.

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Thank You

• Uterus transplantation has been attempted 11 times worldwide, but until now no live births have resulted from the procedure until recently.
• A 36-year-old woman who received a uterus transplant from a postmenopausal woman aged 61 years, who had previously born two children in 2013 gave birth to a healthy baby boy in September 2014.
• The recipient and her partner underwent in-vitro fertilization prior to the transplant, and had 11 cryopreserved embryos. 

Mats Brännström et al., Lancet., 2014

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