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Conization and lymph node evaluation as a fertility-sparing treatment for early stage cervical cancer
  1. Fabio Martinelli1,
  2. Antonino Ditto1,
  3. Francesca Filippi2,
  4. Daniele Vinti3,
  5. Giorgio Bogani1,
  6. Umberto Leone Roberti Maggiore1,
  7. Mariateresa Evangelista1,
  8. Mauro Signorelli1,
  9. Valentina Chiappa1,
  10. Salvatore Lopez1,
  11. Edgardo Somigliana2,4 and
  12. Francesco Raspagliesi1
  1. 1 Gynecologic Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
  2. 2 Infertility Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Lombardia, Italy
  3. 3 Obstetrics and Gynecology, ASST Rhodense, Garbagnate Milanese, Italy
  4. 4 Università degli Studi di Milano, Milan, Italy
  1. Correspondence to Dr Fabio Martinelli, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Fabio.Martinelli{at}istitutotumori.mi.it

Abstract

Introduction To evaluate oncological and obstetrical outcomes of early stage cervical cancer patients who underwent conservative management to retain childbearing potential.

Methods Data of women (aged <40 years) who underwent fertility sparing treatment for International Federation of Gynecology and Obstetrics (FIGO) stage IA1 with lymphovascular invasion (LVSI) and IB1 cervical cancer were prospectively collected. All patients underwent cervical conization/s and laparoscopic nodal evaluation (pelvic lymphadenectomy/sentinel node mapping). Oncological and obstetrical outcomes were assessed.

Results Overall, 39 patients met inclusion criteria; 36 (92.3%) women were nulliparous. There were: 3 (7.7%) IA1-LVSI+; 11 (28.2%) IA2; and 25 (64.1%) IB1 cervical cancers, according to 2018 FIGO stage classification. Histological types were 22 (56.4%) squamous carcinoma and 17 (43.6%) adenocarcinoma. Pelvic lymphadenectomy was performed in 29 (74.4%) patients, while 10 (25.6%) patients had only sentinel node mapping. In 4 (10.3%) patients conservative treatment was discontinued due to nodal involvement and 2 (5.1%) patients requested definitive treatment (hysterectomy) after a negative lymph node evaluation. Among 33 (84.6%) patients who retained their childbearing potential, 17 (51.5%) had a second conization. 2 (6.1%) patients relapsed and underwent definitive treatment. After a median follow-up of 51 months (range 1–184) no deaths were reported. 22 (70.9%) patients attempted to conceive. There were 13 natural pregnancies among 12 (54.5%) women who got pregnant. Live birth rate was 76.9%: 9 (69.2%) term and 1 (7.7%) preterm (at 32 weeks) deliveries. 2 (15.4%) miscarriages (first and second trimester) and 1 (7.7%) termination of pregnancy for medical reasons were recorded.

Conclusion Conization plus laparoscopic nodal evaluation may be a safe and feasible conservative option in the setting of fertility-sparing treatment for early-stage cervical cancer patients.

  • cervical cancer
  • surgical procedures
  • operative
  • gynecology
  • SLN and lympadenectomy

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HIGHLIGHTS

  • Two (6.1%) relapses and no deaths were reported after conization and lymph node evaluation.

  • Live birth rate was 76.9%, and 69.2% were term deliveries.

  • Strict inclusion criteria and oncofertilty counseling are of paramount importance as a third of patients are not eligible.

Introduction

Cervical cancer, with an estimated 570 000 cases and 311 000 deaths in 2018, is the fourth most common cancer worldwide and ranks second in incidence and mortality in low-income countries.1 Radical hysterectomy and lymph node evaluation is the standard treatment in early-stage cervical cancer.2 However, in patients with early-stage low-risk cervical cancer desiring to retain their fertility, options are available.3 4 Conization is usually accepted for International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IA1, while for stage IA1 with lymphovascular space invasion (LVSI), IA2-IB1 trachelectomy(radical) and nodal evaluation is the treatment of choice.5 6 For tumors >2 cm the use of neoadjuvant chemotherapy, while attempting a fertility sparing procedure, is an option under evaluation.7 8

In a systematic review including more than 3000 patients with FIGO 2009 stage IA-IB2/IIA (at least 400 patients with tumor >2 cm) treated conservatively, Bentivegna et al found encouraging oncological outcomes with a global recurrence rate <4% and a mortality rate of 1.2%, which varied according to tumor volume/stage and type of surgery (radical/simple trachelectomy) performed.5 Noteworthy, the challenge of the reduction of radicality continues: simple hysterectomy/conization instead of radical hysterectomy/trachelectomy is another topic under evaluation (SHAPE trial, ConCerv trial).6 9 10 Single center retrospective series on less radical procedures such as simple trachelectomy for preserving fertility in early-stage low risk cervical cancer patients showed safe oncological outcomes and excellent obstetrical results.6 11 Further prospective multicenter trials are completed but data on oncologic outcomes are not yet mature (ConCerv trial).12 In this study, we report on a single center experience of conservative treatment (conization/s and lymph node evaluation) in patients with early stage cervical cancer wishing to preserve fertility.

Methods

After Institutional Review Board approval, data of the National Cancer Institute of Milan prospectively maintained database on conservative treatment for early cervical cancer patients were retrieved. Data of consecutive patients evaluated for a fertility sparing treatment from May 2003 to March 2020 were analyzed. Included patients were women aged ≥18 and <40 years; diagnosed with early stage cervical cancer and no concomitant and/or previous cancer; without any radiological evidence of lymph node or extracervical disease; and a strong desire to preserve their fertility. Patients diagnosed with adenocarcinoma, adenosquamous, and squamous histology were included, while neuroendocrine cervical tumors or other rare histologies were excluded.

All recruited patients underwent preoperative evaluation including: chest and abdomen computed tomography (CT) scan or positron emission tomography (PET) scan to exclude lymph node/distant disease; pelvic magnetic resonance imaging (MRI) and/or transvaginal ultrasound to exclude local spread of disease. Stage and grading of disease were assessed using the 2018 FIGO system.2 Early stage of disease was defined as FIGO stage IA1 with lymphovascular space invasion (LVSI), IA2, IB1 (tumor <2 cm), and IB2 (tumor ≥2 and<4 cm) according to FIGO 2018 staging system. All patients gave written informed consent. Patients were thoroughly counseled about different treatment modalities. Patients were informed that conservative treatment was an experimental option and that hysterectomy (simple/radical) was the standard of care for early-stage cervical cancer. Since 2012, oncofertility counseling and evaluation with a specialist in infertility is mandatory before attempting a conservative approach.

Eligible patients underwent conization/s plus laparoscopic pelvic node assessment. Systematic pelvic lymphadenectomy was performed until 2017, thereafter sentinel node mapping was used according to the SENTIX (Sentinel Lymph Node Biopsy in Patients With Early Stages Cervical Cancer) trial protocol.13 As per the SENTIX protocol, if mapping was successful bilaterally, no further node dissection was performed. In case of positive lymph nodes, patients were excluded from the conservative approach and underwent standard treatment (chemoradiation) or were enrolled in ongoing clinical trials (neoadjuvant chemotherapy followed by radical hysterectomy and pelvic lymphadenectomy).14 15 A laser conization was repeated only when margins were involved by invasive tumor or there were minimal free margins (<2 mm free margins).

Follow-up evaluations were scheduled every 3–4 months for the first 2 years after surgery, every 6 months between 2 and 5 years after surgery, and annually thereafter. Pap smear with endocervical brushing and/or endocervical sampling was performed at every visit. Patients were also tested for human papillomavirus (HPV). Abdominal ultrasound was requested for the first follow-up visit. MRI, CT scan or PET scan were performed once a year. Oncological and obstetrical outcomes were assessed. Descriptive statistics were performed using Statistical Package for the Social Science (SPSS) 15.0 (SPSS, Inc, Chicago, IL).

In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if requested.

Results

Overall, 51 patients were interested in a conservative treatment and were counseled. Seven (13.7%) patients did not meet the inclusion criteria: four patients had rare histology/neuroendocrine, and three patients withdrew after a thorough counseling. Globally 44 patients underwent a conservative treatment. Five (11.4%) patients, diagnosed with a FIGO stage IB2 cervical cancer, were excluded from the present analysis, with the natural history and clinical behavior of IB2 lesions being different to real early stages (IA1-LVSI+; IA2; IB1). Clinical characteristics of the 39 (IA1-LVSI+; IA2; IB1) evaluated patients are reported in Table 1. Thirty-six (92.3%) patients were nulliparous. The majority of patients had FIGO stage IB1 (64.1%) cervical cancer, with squamous cell carcinoma the most frequent histology (56.4%). The majority (84.6%) of patients underwent a conization as diagnostic procedure. No evidence of distant metastases at CT/PET-CT scan was reported in any patients. MRI was performed in 19 (48.7%) cases without evidence of local spread of disease.

Table 1

Clinical and pathological characteristics of 39 patients who underwent conservative treatment

Pelvic lymphadenectomy was performed in 29 (74.4%) patients, while 10 (29.6%) of 11 (90.1%) patients had only sentinel node mapping, having had bilateral nodal detection following indocyanine green injection. All lymph node staging procedures were performed laparoscopically. Three patients had post-operative complications: two had a lymphocele (one requiring a drainage) and one patient had lymphedema. All complications were in patients who underwent lymphadenectomy. No complications were reported among patients who underwent sentinel node mapping.

In four (10.3%) patients conservative treatment was discontinued. Specifically, in three FIGO stage IB1 (two squamous cell cancer grade 3 and one adenocarcinoma grade 1) patients, and one IA2 (squamous, grade 3) patient, all with LVSI, lymph node involvement was found. Among these, two FIGO stage IB1 patients had only micrometastasis. All underwent a definitive treatment (two chemoradiation, two chemotherapy plus radical surgery). Furthermore, two (5.1%) patients reconsidered their initial decision and asked for definitive treatment (hysterectomy) despite a negative nodal evaluation (Figure 1).

Figure 1

Flow chart of patients asking for a fertility sparing treatment and completing the conservative approach. FIGO, International Federation of Gynecology and Obstetrics; LVSI, lymphovascular space invasion.

Among 33 (84.6%) patients who retained their fertility, 17 (51.5%) patients had a second laser conization. In eight (47%) there was no evidence of further invasive disease on the cone specimen, and the remaining patients presented with invasive cancer with clear margins. One (3%) patient suffered from cervical stenosis, following conization, requiring dilatation.

There were two (6.1%) patients who relapsed, both on the cervix. Both were FIGO stage IB1, grade 2, squamous cell cervical cancer. The first patients had a 9 mm LVSI invasive cancer with positive margins at first conization and no evidence of residual disease at second laser conization. She underwent a full pelvic lymphadenectomy (40 nodes harvested). Due to post-coital bleeding she anticipated the second scheduled follow-up visit, and 7 months after the fertility sparing procedure a 2 cm relapse (HPV 18+) was found. She underwent radical hysterectomy followed by chemoradiation due to parametrial nodal involvement. She is alive without disease after 72 months. The second patient had a 9 mm LVSI negative invasive cancer with negative margins at laser conization. She underwent sentinel node procedure (two nodes harvested). Five months following the fertility sparing procedure, at first follow-up visit, an invasive relapse (HPV 16+) was found. She underwent radical hysterectomy and pelvic lymphadenectomy with evidence of invasive cancer on the cervix. She is alive without disease after 17 months.

After a median follow-up of 51 months (range 1–184) no deaths were reported among the 31 patients who retained fertility. A total of 22 (66.7%) patients attempted to conceive. There were 13 natural pregnancies among 12 (54.5%) patients who got pregnant. In two patients, a cervical cerclage was placed during pregnancy for cervical incompetency. The live birth rate was 76.9%: there were nine (69.2%) term and one (7.7%) preterm (at 32 weeks) deliveries. Only two patients delivered vaginally. Two (15.4%) miscarriages (first and second trimester) and one (7.7%) termination of pregnancy for medical reasons were also recorded. (Figure 2) Only one (3%) patient asked for definitive treatment (hysterectomy) after childbearing completion. No evidence of disease was found in the specimen.

Figure 2

Flow chart of oncological and obstetrical outcomes of patients who underwent fertility-sparing treatment.

Discussion

Our study showed that only two thirds of patients who sought a fertility sparing approach for early stage cervical cancer succeeded. When strict criteria are applied a conservative (conization plus lymph node evaluation) treatment provides satisfactory oncological outcomes (6.1% relapse rate, with no reported death) as well as obstetrical outcomes (76.9% live birth rate). Reducing surgical radicality and tailoring treatments has become a key point in the treatment of early stage cervical cancers.3 Even if screening programs and HPV vaccination have reduced the incidence of cervical cancer, many women elect to seek pregnancy later in life.6

Selection of patients is of the utmost importance. In the present series, conservative treatment was ultimately not performed in 13.7% of patients despite being initially considered as potential candidates. In four cases, this was due to the histological characteristics of the tumor (three neuroendocrine and one glassy cell carcinoma). The remaining three patients declined a fertility sparing approach after thorough oncofertility counseling, which is mandatory in this setting. Furthermore, among patients who attempted the conservative approach, 10.3% of patients could not maintain their fertility as tumor stage was more advanced than expected (had lymph node involvement). Whether or not this reflects a more aggressive biology of tumor discovered in areas where screening programs and preventive strategies (HPV vaccination) are highly implemented needs further investigation.

Even following strict selection criteria, patients and physicians have to bear in mind the need for a thorough follow-up because the risk of relapse is not insignificant. Data from the literature report a recurrence rate ranging from 0% to 17% depending on the tumor characteristics and surgical approach performed.5 6 16 In our series, we registered two (6.1%) relapses on the cervical stump in patients treated with two previous conizations with negative margins. Relapses appeared early (at 5 and 7 months) and we consider the persistence of high-risk HPV (16-18) could have played a role. Both patients were salvaged and no deaths occurred. An intensive follow-up is mandatory for patients treated conservatively and any “suspicious” symptoms need to be promptly evaluated. A completion surgery (hysterectomy) is not routinely indicated once childbearing is completed, but no definitive data are available in the literature. In our series, only one (3%) patient requested definitive treatment (hysterectomy) after childbearing completion. No evidence of disease on the specimen was found.

The reduction of surgical radicality, both for lymph node assessment (sentinel node procedure vs lymphadenectomy) and tumor removal (conization vs trachelectomy), is performed with the aim to improve reproductive results.6 7 11 17 Studies on oncological safety and side effects of sentinel node procedure are ongoing.13 18 The main issues with trachelectomy are the high risk (up to 60%) compromising natural fertility and the increased rate of first and second trimester fetal loss (nearly 20%).5 11 In our series, 76.9% of pregnancies after conization and nodal assessment resulted in the delivery of a living newborn, in line with data reported on conization/simple trachelectomy.5 6 11 All pregnancies occurred naturally; only two patients required a cervical cerclage and only two (15.4%) patients had a first-second trimester miscarriage, in line with recently reported data.11

Among 31 patients who had preserved their fertility, nine did not attempt to conceive. Excluding two patients whose follow-up was shorter than 6 months, the remaining seven (22.6%) patients did not attempt to conceive. This point deserve attention. In fact, unless new data on the treatment of early stage cervical cancer reveals otherwise, the conization plus lymph node evaluation is not to be considered the standard treatment. It is experimental and its adoption should be restricted to motivated and well-informed patients. It is important to be aware that the goal is to retain the uterus for immediate attempts at pregnancy and not for the future potential possibility of pregnancy.

Our study corroborates the idea that a conservative treatment (conization plus laparoscopic lymph node evaluation) could be considered a valid approach in the setting of fertility-sparing treatment for early-stage cervical cancer patients. It is of the utmost importance to underline the need for patient-centered counseling. Points to be addressed are: thorough selection of eligible patients (in this series 13.7% were not eligible); adequate counseling on the possibility of aborting the procedure (in our study, 10.3% of patients had to discontinue the planned conservative program because of lymph node involvement); the event of a relapse (6.1% in this series), a situation that requires radical treatment; fertility and obstetrical outcomes, which, following conization, are favorable compared with those of more radical procedures such as radical trachelectomy; and patient awareness that conservative treatment is still experimental.

The accrual of less than three patients per year is one of the main limitations of this single center series. However, this highlights real life practice in a country where primary and secondary prevention have greatly reduced cervical cancer incidence. Furthermore, patients were counseled, treated, and followed after strict and reproducible procedures (conization and laparoscopic lymph node evaluation).

In conclusion, following strict criteria, conization plus laparoscopic lymph node evaluation may be considered in the setting of fertility-sparing treatment for early-stage cervical cancer patients. Further evidence is, however, needed for more robust conclusions.

References

Footnotes

  • Twitter @DrFMartinelli

  • Contributors Conception or design of the work (FM, AD, FF, FR). Data collection (FM, FF, DV, GB, ULRM, ME, MS, VC). Data analysis and interpretation (FM, FF, DV, AD). Drafting the article (FM, FF). Critical revision of the article (ES, FR). Final approval of the version to be published (FM, ES, FR).

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests ES has received honoraria from Theramex, Merck-Serono and HRA. He also handles grants of research from Theramex, Merck-Serono and Ferring.

  • Patient consent for publication Not required.

  • Ethics approval Ethical Committee of Fondazione IRCCS Istituto Nazionale Tumori of Milan, protocol INT 68/12.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data are available upon reasonable request fabio.martinelli@istitutotumori.mi.it.

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