Concer V

Original research
Int J Gynecol Cancer: first published as 10.1136/ijgc-2021-002921 on 7 September 2021. Downloaded from http://ijgc.bmj.com/ on September 8, 2021 at International Gynecologic Cancer
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ConCerv: a prospective trial of conservative
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Kathleen M Schmeler ‍ ‍,1 Rene Pareja ‍ ‍,2 Aldo Lopez Blanco,3 Jose Humberto Fregnani,4
Andre Lopes,5 Myriam Perrotta,6 Audrey T Tsunoda,7 David F Cantú-de-León,8 Lois M Ramondetta,1
Tarinee Manchana,9 David R Crotzer,10 Orla M McNally,11 Martin Riege,12 Giovanni Scambia,13
Juan Manuel Carvajal,14 Julian Di Guilmi,15 Gabriel J Rendon ‍ ‍,16 Preetha Ramalingam,17
Bryan M Fellman,18 Robert L Coleman,19 Michael Frumovitz ‍ ‍,1 Pedro T Ramirez1
For numbered affiliations see HIGHLIGHTS

end of article. • Conservative surgery was associated with a 3.5% recurrence rate in women with low-risk cervical cancer.
• The rate of positive lymph nodes was 5%, with lymph node assessment recommended in this low-risk population.
Correspondence to • Further study is needed to determine long-term outcomes and optimal pathologic criteria for conservative surgery.
Dr Kathleen M Schmeler,
Gynecologic Oncology, The
University of Texas MD ABSTRACT Discussion Our prospective data show that select
Anderson Cancer Center,
Objective The objective of the ConCerv Trial was to patients with early-stage, low-risk cervical carcinoma may
Houston, TX 77230, USA;
prospectively evaluate the feasibility of conservative be offered conservative surgery.
KSchmele@mdanderson.org
Society. Protected by copyright.

surgery in women with early-stage, low-risk cervical
cancer.
For ‘Presented at statement’ Methods From April 2010 to March 2019, a prospective, INTRODUCTION
see end of article. single-arm, multicenter study evaluated conservative Approximately 570 000 new cases of cervical cancer
surgery in participants from 16 sites in nine countries. and 311 000 related deaths occur annually world-
Received 3 July 2021
Eligibility criteria included: (1) FIGO 2009 stage IA2–IB1
Accepted 11 August 2021 wide.1 About 85% of these cases and deaths occur in
cervical carcinoma; (2) squamous cell (any grade) or
adenocarcinoma (grade 1 or 2 only) histology; (3) tumor
low- and middle-income countries.2 Cervical cancer
size <2 cm; (4) no lymphovascular space invasion; (5) screening programs have led to a significant reduc-
depth of invasion <10 mm; (6) negative imaging for tion in the incidence and mortality of cervical cancer
metastatic disease; and (7) negative conization margins. in high-income countries. By contrast, the cervical
Cervical conization was performed to determine eligibility, cancer burden remains unchanged in low- and
with one repeat cone permitted. Eligible women desiring middle-income countries, primarily due to a lack of
fertility preservation underwent a second surgery with effective organized programs for cervical screening
pelvic lymph node assessment, consisting of sentinel and treatment of pre- invasive disease. The World
lymph node biopsy and/or full pelvic lymph node Health Organization (WHO) recently implemented a
dissection. Those not desiring fertility preservation global strategy for the elimination of cervical cancer
underwent simple hysterectomy with lymph node
as a public health problem. The 2030 goals of the
assessment. Women who had undergone an ‘inadvertent’
simple hysterectomy with an unexpected post-operative
program include: (1) 90% of girls to receive complete
diagnosis of cancer were also eligible if they met the above human papillomavirus vaccination by age 15, (2) 70%
inclusion criteria and underwent a second surgery with of women to undergo cervical cancer screening with
pelvic lymph node dissection only. a high performance test at 35 and 45 years of age,
Results 100 evaluable patients were enrolled. Median and (3) 90% of women with pre-invasive or invasive
age at surgery was 38 years (range 23–67). Stage was cervical lesions to undergo treatment.3 If successfully
IA2 (33%) and IB1 (67%). Surgery included conization implemented, these aggressive efforts will result in
followed by lymph node assessment in 44 women, the majority of women around the world being diag-
© IGCS and ESGO 2021. No conization followed by simple hysterectomy with lymph nosed with pre-invasive or early-stage cervical cancer
commercial re-use. See rights node assessment in 40 women, and inadvertent simple that can be treated and cured.
and permissions. Published by hysterectomy followed by lymph node dissection in
BMJ. For women with early-stage cervical cancer, the
16 women. Positive lymph nodes were noted in 5 patients
(5%). Residual disease in the post-conization hysterectomy
current standard treatment is a radical hysterectomy
To cite: Schmeler KM,
Pareja R, Lopez Blanco A, et al. specimen was noted in 1/40 patients—that is, an with removal of the uterus, cervix, upper vagina, and
Int J Gynecol Cancer Published immediate failure rate of 2.5%. Median follow-up was parametrium as well as the pelvic lymph nodes.4 In
Online First: [please include 36.3 months (range 0.0–68.3). Three patients developed women who desire fertility preservation, a radical
Day Month Year]. doi:10.1136/ recurrent disease within 2 years of surgery—that is, a trachelectomy is an acceptable alternative, with
ijgc-2021-002921 cumulative incidence of 3.5% (95% CI 0.9% to 9.0%). equivalent oncologic outcomes.5 This consists of
Schmeler KM, et al. Int J Gynecol Cancer 2021;0:1–9. doi:10.1136/ijgc-2021-002921 1

Original research
removal of the cervix, upper vagina, and parametrium while sparing simple hysterectomy and pelvic lymph node assessment. Patients
the uterine fundus, allowing for future pregnancy. Although radical who had undergone an inadvertent simple hysterectomy with an
hysterectomy and radical trachelectomy result in excellent local unexpected post-operative diagnosis of invasive cancer were also
tumor control, they can be associated with significant morbidity due eligible if they met the above inclusion criteria and had negative
to removal of the parametrium, which contains autonomic nerve margins on the hysterectomy specimen. These patients underwent
fibers associated with bladder, bowel, and sexual function.6–10 a second surgery with pelvic lymph node dissection only. All patho-
These radical procedures are also associated with surgical compli- logic specimens were centrally reviewed by an expert gynecologic
cations, such as hemorrhage, bladder and ureteral injury, and pathologist at MD Anderson Cancer Center (PR). This included
fistula formation. Furthermore, these procedures require a provider review of cone and inadvertent hysterectomy specimens to confirm
with specialized training in gynecologic oncology surgery, often not eligibility prior to undergoing simple hysterectomy and/or lymph
available in many low- and middle-income countries. node assessment. In addition, all final hysterectomy and lymph
In recent years, the usefulness of parametrial resection in women node specimens were centrally reviewed. Frozen section for the
with early-stage cervical cancer has come under question. Several conization specimens was not permitted due to the requirement for
retrospective studies have reported that <1% of women with early- final pathologic analysis, including central pathology review, prior to
stage disease and favorable pathologic characteristics (tumor performing definitive conservative surgery.
<2 cm, depth of invasion <10 mm, and negative pelvic nodes) have Surgery could be performed using an open, laparoscopic, or
parametrial involvement.11–15 In addition, several retrospective robotic approach based on each participating institution’s standard
and small prospective studies have shown favorable results with practice and surgeon preference. Post-operatively, study partici-
conservative surgery consisting of cervical conization or simple pants were followed with pelvic examination and cytology every
hysterectomy, with lymph node assessment in select women with 3 months for 2 years, and then according to local standard of care.
low-risk cervical cancer.16–22 To further evaluate the oncologic Quality of life factors, sexual functioning, and satisfaction with
outcomes of conservative surgery, we performed the ConCerv Trial, healthcare decisions were assessed prior to surgery at 3, 6, 12
the first prospective study of conservative surgery in women with and 24 months following surgery, and will be reported in a separate
early-stage, low-risk cervical cancer. publication.

The primary objective of the study was to evaluate the feasibility
of performing, and oncologic outcomes of, conservative surgery.
We determined the immediate failure rate, defined as residual
METHODS disease in the simple hysterectomy specimen of women who
The ConCerv Trial was a prospective, single- arm, multicenter underwent conization followed by simple hysterectomy and lymph
study to evaluate the feasibility and oncologic outcomes of coni- node assessment. Futility monitoring of feasibility was performed
zation alone or simple hysterectomy in women with early-stage, throughout the study using the Bayesian methods of Thall et al.23
low-risk cervical carcinoma. Institutional review board approval The proposed treatment strategy was considered infeasible if there
was obtained from the University of Texas MD Anderson Cancer was more than an 80% chance that the immediate failure rate
Center (protocol 2008–0118, NCT01048853) and all participating exceeded 3%. If this was reached, the trial would be stopped. We
institutions. Eligibility criteria included: (1) FIGO 2009 stage IA2–IB1 also evaluated the cervical cancer recurrence rate at 2 years, with
cervical carcinoma; (2) squamous cell (any grade) or adenocarci- an additional stopping rule stating that the study would be discon-
noma (grade 1 or 2 only) histology; (3) tumor size <2 cm by physical tinued if two or more patients developed recurrent disease within
examination and/or imaging studies; (4) no lymphovascular space this time period. We assumed a beta (0.15, 4.85) prior distribution
invasion; (5) negative imaging for metastatic disease with CT scan, for the immediate failure rate. The trial was designed with a sample
MRI, and/or positron emission tomography scan; (6) depth of inva- size of 100 subjects to have desirable operating characteristics. We
sion <10 mm; and (7) conization margins and endocervical curet- also evaluated the rate of pelvic lymph node positivity and quality
tage negative for malignancy and high-grade dysplasia. A negative of life outcomes. The overall conduct of the study was monitored
margin was defined as no invasive cancer within 1.0 mm of both by the MD Anderson Cancer Center Data and Safety Monitoring
the endocervical and ectocervical margins and no adenocarci- Committee.
noma in situ, cervical intraepithelial neoplasia 2 or 3 at the inked or Frequencies were used to describe the number of enrolled,
cauterized margin. Inclusion criteria 6 and 7 were added after the eligible and evaluable patients by institutional site. Standard
first year of the study as described in the Results section. summary statistics were used to describe the clinical and demo-
All patients provided informed consent for the study and under- graphic characteristics of the evaluable study population. We esti-
went a cervical conization and endocervical curettage to determine mated the immediate failure rate (residual disease) along with a
eligibility. Of note, women who had undergone conization at an 90% credible interval. We also reported the posterior probability that
outside institution were considered eligible if they met the inclusion the immediate failure rate is 3% or more. We estimated the 2-year
criteria. In all cases, one repeat conization and endocervical curet- cumulative incidence of recurrence in the study population along
tage was permitted if required to meet the inclusion criteria. Eligible with 95% confidence intervals. Cumulative incidence of recurrence
women desiring fertility preservation underwent a second surgery was measured from the date of surgery to the earliest date of the
with pelvic lymph node assessment, consisting of sentinel lymph last clinic visit, date of first recurrence, or date of death. Death was
node biopsy and/or full pelvic lymph node dissection based on each considered a competing event for recurrence. Recurrence- free
participating institution’s guidelines and standard practices. Those survival was estimated using the methods of Kaplan and Meier,
not desiring fertility preservation underwent a second surgery with and was measured from the date of surgery to the earliest date
2 Schmeler KM, et al. Int J Gynecol Cancer 2021;0:1–9. doi:10.1136/ijgc-2021-002921

Original research
Table 1 Study accrual by participating site
Institution City Country Number of evaluable participants
MD Anderson Cancer Center Houston USA 36 (36%)
Instituto de Cancerología Medellin Colombia 14 (14%)
Instituto Nacional de Enfermedades Neoplásicas Lima Perú 13 (13%)
Barretos Cancer Hospital Barretos Brazil 8 (8%)
Hospital Italiano Buenos Aires Argentina 6 (6%)
Instituto Brasileiro de Controle do Cancer São Paulo Brazil 6 (6%)
Hospital Erasto Gaertner Curitiba Brazil 5 (5%)
Instituto Nacional de Cancerologia Mexico City México 4 (4%)
Lyndon B. Johnson Hospital/Harris Health Houston USA 3 (3%)
Chulalongkorn University Bangkok Thailand 1 (1%)
Royal Women’s Hospital Melbourne Australia 1 (1%)
Nebraska Methodist Health System Omaha USA 1 (1%)
Instituto de Ginecología de Rosario Rosario Argentina 1 (1%)
Fondazione Policlinico Universitario A. Gemelli IRCCS Rome Italy 1 (1%)
of the last clinic visit, date of first recurrence, or date of death. All hysterectomy with an unexpected post- operative diagnosis of
statistical analyses were performed using Stata/MP version 16.0 cancer, followed by lymph node dissection only. Minimally invasive
(College Station, Texas USA). surgery was performed in 96 patients: laparoscopic surgery in 83
MD Anderson Cancer Center served as the lead site and coor- patients, and robotic surgery in 13 patients. A full pelvic lymph node

dinating center for the ConCerv Trial, providing oversight for all dissection was performed in 58 patients (58%), sentinel lymph
participating sites. All study data were collected and managed node biopsy and full pelvic lymph node dissection in 38 patients
using the Research Electronic Data Capture (REDCap) tools hosted (38%), and sentinel biopsy alone in four patients (4%). Positive
at MD Anderson.24 REDCap is a secure, web-based application lymph nodes were found in 5 patients (5%) (Table 3) who were
designed to support data capture for research studies. Any adverse treated with chemoradiation.
events were reported to the MD Anderson coordinating center One of 40 patients had residual disease in the hysterectomy spec-
and classified according to the National Cancer Institute Common imen after a conization with negative margins, corresponding to an
Terminology Criteria for Adverse Events version 4.0 (CTCAE version immediate failure rate of 2.5% (90% credible interval 0.2−7.2%).
4.0) for Toxicity and Adverse Event reporting. In accordance with the
journal’s guidelines, we will provide our data for the reproducibility
of this study in other centers if such is requested. Table 2 Patient demographic and pathology information
Age at surgery (years):
Mean 39
RESULTS Median 38
A total of 100 evaluable women were enrolled between April 2010 Range 23–67
and January 2019 from 14 institutions in nine countries (Table 1). Of
Stage (FIGO 2009), N (%)
note, 140 patients were enrolled to reach 100 evaluable patients: 31
IA2 33 (33%)
were ineligible after central pathology review; seven withdrew from
the study prior to surgery; and two had a positive pregnancy test at IB1 67 (67%)
the time of surgery. The discrepancies in pathology review included Histology, N (%)
presence of lymphovascular space invasion (n=15, 48.4%); stage Squamous cell carcinoma 48 (48%)
IA1 or pre-invasive disease (n=13, 41.9%); and adenosquamous Adenocarcinoma 52 (52%)
or adenoid basal histology (n=3, 9.7%). Participant demographic
Surgical approach, N (%)
and pathologic information are shown in Table 2. The median age
at surgery was 38 years (range 23–67). Stage at diagnosis was Laparoscopic 83 (83%)
IA2 (33%) and IB1 (67%). Histologic type included squamous cell Robotic 13 (13%)
carcinoma (48%) and adenocarcinoma (52%). Open 4 (4%)
The study results are shown in Figure 1. A total of 44 participants Lymph node assessment, N (%)
(44%) desired fertility preservation and underwent cervical coniza- Full lymph node dissection 58 (58%)
tion followed by lymph node assessment. Forty participants (40%)
Sentinel lymph node biopsy+full lymph 38 (38%)
did not desire fertility preservation and underwent cervical coniza- node dissection
tion followed by simple hysterectomy with lymph node assessment.
Sentinel lymph node biopsy alone 4 (4%)
The remaining 16 participants (16%) had an inadvertent simple

Original research
Figure 1 Study results by treatment type. Lymph node (LN), pelvic lymph node assessment with sentinel lymph node biopsy
and/or full pelvic lymphadenectomy. *Patients with positive lymph nodes or residual disease in the hysterectomy specimen
were excluded from further analyses for rates of recurrent disease.
The posterior probability that the immediate failure rate was greater hysterectomy and pelvic lymph node dissection, which showed a
than 3% is 0.33 indicating that conservative surgery in this popu- 2.0 mm focus of residual adenocarcinoma in the cervix, with nega-
lation is feasible with regards to immediate failure. Of note, this tive margins and negative lymph nodes. She underwent observa-
patient had a long history of adenocarcinoma in situ followed by a tion and was without evidence of disease 5 years following surgery.
cervical conization which showed a grade 2 adenocarcinoma with The median follow- up for all participants was 36.3 months
3.0 mm of invasion with a positive margin. According to protocol, (range 0.0–68.3). Three patients developed recurrent disease for
she underwent a repeat conization and endocervical curettage to a 2-year cumulative incidence of 3.5% (95% CI 0.9% to 9.0%).
determine eligibility and both were negative for adenocarcinoma Median recurrence- free survival was not reached. The 2- year
and adenocarcinoma in situ. She subsequently underwent a simple recurrence-free survival probability was 0.95 (95% CI 0.88 to
Table 3 Participants with positive lymph nodes (5/100, 5%)

Number of positive
Patient Histology Stage Visible lesion Procedure Depth of invasion lymph nodes
1 Grade 2 IA2 No Cone x 2 4 mm 1/17
squamous LND only 0 mm
2 Grade 2 IB1 No Cone x 2 6.5 mm 1/7
squamous LND only 3.1 mm
3 Grade 2 squamous IA2 No Cone x 1 3.0 mm 1/21
SH +LND
4 Grade 3 IB1 Yes Cone x 1 2.2 mm 2/16
squamous 1.0 cm SH +LND
5 Grade 2 squamous IB1 Yes Cone x 1 3.5 mm 2/28
1.8 cm SH +LND
All participants with positive lymph nodes were treated with chemoradiation.
LND, lymph node dissection; SH, simple hysterectomy.

Original research
0.98). As shown in Figure 1, the recurrence rate was 1/42 (2.4%) To date, 14 pregnancies have been reported among 11 of
for evaluable women who underwent cone biopsy alone followed 40 women (27.5%) who underwent cervical conization and lymph
by lymph node assessment; 0/36 (0.0%) for women who under- node assessment for fertility preservation and remain in the study.
went conization followed by simple hysterectomy and lymph node Of these 14 pregnancies, 13 (92.9%) delivered at term and one
assessment; and 2/16 (12.5%) for women who underwent inadver- (7.1%) resulted in a fetal demise at 22 weeks of gestation. It is
tent simple hysterectomy followed by lymph node dissection. The unknown how many additional women attempted to become
first recurrence occurred in a patient who desired fertility preser- pregnant.
vation. She underwent cervical conization and was found to have
a grade 2 squamous cell carcinoma with 13 mm of invasion and
positive margins. She underwent a second conization, which was
negative for invasive cancer but showed cervical intraepithelial DISCUSSION
neoplasia 3, which was present at the cone margin. She under- Summary of Main Results
went a laparoscopic pelvic lymphadenectomy with 15 negative The ConCerv Trial showed that conservative surgery with conization
lymph nodes. At her 3-month follow-up visit, her cervix appeared and simple hysterectomy is feasible in patients with early-stage,
normal but cytology showed a high-grade squamous intraepithelial low-risk cervical carcinoma. The rate of positive lymph nodes was
lesion. A cold knife cone biopsy was performed revealing recurrent 5% and the rate of residual disease in the hysterectomy specimen
invasive squamous cell cancer with positive margins. She there- following conization was 2.5%. The 2-year recurrence rate was
fore underwent a radical trachelectomy, which was converted to 3.5% overall; 2.4% (1/42) among patients who had conization; 0%
a radical hysterectomy due to a positive endocervical margin on (0/36) among patients who had conization followed by hysterec-
frozen section. She received adjuvant chemoradiation for high- tomy; and 12.5% (2/16) among women who had an inadvertent
risk features. She was without evidence of disease at her 5-year simple hysterectomy. These results are similar to the findings from
follow-up visit. This occurred in the first year of the study and previous retrospective and small prospective studies described
was reviewed by the Data and Safety Monitoring Committee. The below.17 19–22 25 26
inclusion criteria were amended to become more conservative and

include a depth of invasion <10 mm and negative cone margins for Results in Context of Published Literature
high-grade dysplasia including cervical intraepithelial neoplasia 2/3 Early studies by Rob et al19 20 reported the feasibility and safety
and adenocarcinoma in situ. of performing less radical, fertility-sparing surgery in women with
The other two recurrences were in women who underwent an FIGO 2009 stage IA1–IB1 cervical carcinoma. All patients under-
inadvertent simple hysterectomy. One patient had adenocarcinoma went laparoscopic sentinel lymph node identification with frozen
in situ and underwent a cone with negative margins followed by section. Of the 40 patients enrolled, 6 (15%) had positive sentinel
laparoscopic simple hysterectomy which showed an unexpected lymph nodes on frozen section, and radical hysterectomy with
grade 2 adenocarcinoma with 4.2 mm of invasion and negative pelvic lymphadenectomy was immediately performed according to
margins. She was enrolled in the trial and underwent laparo- the local standard of care. In the remaining patients, only a pelvic
scopic lymph node dissection with three negative lymph nodes. lymphadenectomy was performed. Following a 7-day interval to
Her cancer recurred 11 months later with biopsy-proven disease allow pathologic confirmation of negative lymph nodes, a large
in the pelvis and lungs. She was treated with chemotherapy but cone or simple vaginal trachelectomy was performed. With a mean
died of disease 6 years later. The other recurrence was in a woman follow-up of 47 months, one recurrence was reported in a patient
who had a conization with <1 mm of squamous cell carcinoma. with a stage IB1 tumor with 8 mm of cervical stromal invasion and
She subsequently underwent a laparoscopic simple hysterectomy, lymphovascular space invasion present. Of the 24 women who
which showed 6 mm of invasion and negative margins. She was tried to conceive, 17 (71%) became pregnant with 11 births. The
enrolled in the trial and underwent laparoscopic lymphadenec- authors concluded that large cone or simple trachelectomy with
tomy with 11 negative lymph nodes. She was diagnosed with a laparoscopic pelvic lymph node dissection was safe and feasible
biopsy-proven inguinal lymph node recurrence 10 months later. with a high pregnancy rate in women with early-stage cervical
She was treated with chemoradiation and is without evidence of cancer.19 20 The same group evaluated less radical surgery in
disease after 4 years of follow-up. Following these two additional 60 women not desiring fertility preservation.21 All participants had
recurrences, the study was closed in 2016 according to the above FIGO 2009 stage IA1–IB1 cervical cancer with favorable pathologic
noted stopping rule. The data were reviewed by the Data and Safety characteristics (tumor size <2 cm and <50% stromal invasion) and
Monitoring Committee and the study was deemed safe to reopen underwent laparoscopic sentinel lymph node identification with
provided that women who had an inadvertent simple hysterectomy frozen section. Five patients (8.3%) had positive sentinel lymph
were excluded due to their high recurrence rate (2/16, 12.5%). Of nodes on frozen section and underwent radical hysterectomy
note, none of the recurrences occurred in the parametria. with pelvic lymphadenectomy according to the local standard of
Significant adverse events (CTCAE version 4.0 grade 4 to 5) care. In the remaining 55 patients, a complete pelvic lymphad-
were noted in two patients (2.0%). One patient died 26 days after enectomy and simple vaginal hysterectomy was performed. With
surgery (laparoscopic lymph node dissection) of a presumed post- a median follow-up of 47 months, no recurrences were reported.
operative venous thromboembolism. A second patient had signif- The authors concluded that simple hysterectomy with pelvic lymph
icant bleeding 12 days post-operatively from conization, which node dissection was safe and feasible in select women with early-
required transfusion and reoperation with sutures placed in the stage cervical cancer who did not desire fertility preservation.21 The
cervix to control the bleeding. ConCerv Trial showed similar findings, with no recurrences noted

Original research
in the 40 women who underwent conization followed by simple as positive cone margins for high-grade dysplasia and the other
hysterectomy and negative lymph node assessment. two patients had an inadvertent simple hysterectomy. The inclu-
A subsequent study by Plante et al17 evaluated 50 patients with sion criteria for the trial were changed based on these findings as
early-stage low- risk cervical cancer who underwent a simple described above. Of note, none of the recurrences occurred in the
vaginal trachelectomy/conization with laparoscopic lymph node parametria. Five per cent of patients had positive lymph nodes. This
evaluation. Lymph nodes were negative in 46 patients (92%), three is similar to the findings of Park et al,30 suggesting that lymph node
patients had isolated tumor cells, and one patient had microme- assessment with sentinel lymph node biopsy and/or full lymph node
tastasis. Thirty patients (60%) had either no residual disease or dissection should be performed in this population. This is in accor-
cervical dysplasia only in the simple trachelectomy specimen. With dance with current guidelines from the National Comprehensive
a median follow-up of 76 months, only one local recurrence was Cancer Network and the European Society for Medical Oncology,
seen, which was treated initially with chemoradiation. This patient which recommend lymph node assessment in all patients under-
again had a local recurrence and underwent a pelvic exenteration, going hysterectomy for cervical cancer.31 32
but the disease progressed and she died of disease. Forty preg- The publication of the Laparoscopic Approach to Cervical Cancer
nancies were reported and 75% delivered at term.17 Several recent (LACC) Trial33 occurred during the last year of enrollment of the
retrospective analyses have also shown the safety and efficacy of ConCerv Trial. The LACC Trial was a prospective, randomized study
conservative surgery.22 25 26 which showed that minimally invasive radical hysterectomy is
Two large database studies and a systematic review evalu- associated with lower rates of disease-free survival and overall
ating conservative surgery in early-stage, low-risk cervical cancer survival compared with open abdominal radical hysterectomy
have recently been published.27–29 Tseng et al27 used the Surveil- among women with early-stage cervical cancer. The results of the
lance, Epidemiology, and End Results (SEER) database to evaluate LACC Trial have changed the standard of care for women with early-
2717 patients with FIGO 2009 stage IB1 disease, all of whom had stage cervical cancer, with minimally invasive surgery no longer
pelvic lymphadenectomy performed. They compared women who recommended in women undergoing radical hysterectomy.33 These
underwent uterine preserving surgery (n=125) with conization results did not significantly impact the ConCerv Trial or require a
or simple trachelectomy with women who underwent hysterec- change in our protocol as almost all study procedures were already

tomy of any type (n=2592). They noted no differences in 10-year completed at the time of the LACC Trial publication. However, it is
disease-specific survival between the two groups.27 A subsequent important to note that 96% of the patients on the ConCerv Trial
study by Sia and colleagues28 used the National Cancer Database underwent minimally invasive surgery. Of the 56 patients who
to compare outcomes between simple and radical hysterectomy underwent a simple hysterectomy, the majority (40/56, 71.4%)
for 1530 women with stage IA2 and 3931 women with stage IB1 had a cone with removal of all tumor prior to undergoing hysterec-
disease. They noted no association between surgical radicality and tomy and lymph node assessment. As shown in Figure 1, none of
survival for women with stage IA2 tumors. However, there was a these patients developed a recurrence within the 2-year follow-up
55% increase in mortality for women with stage IB1 disease who period. However, of the 16 patients who had undergone an inad-
underwent simple compared with radical hysterectomy.28 A lymph vertent simple hysterectomy prior to study enrollment, two (12.5%)
node evaluation was not performed in 19% of patients with stage developed recurrent disease. Both patients underwent minimally
IB1 disease who underwent simple hysterectomy versus 2% of invasive surgery for both the simple hysterectomy and the pelvic
women with stage IB1 disease who underwent radical hysterec- lymph node dissection. The role of minimally invasive surgery for
tomy, raising the possibility of undiagnosed lymph node metas- conservative surgery, including both simple hysterectomy after a
tases and undertreatment in the adjuvant setting. After adjusting conization with negative margins as well as for lymph node assess-
for nodal assessment, the difference in survival was no longer ment (sentinel lymph node biopsy and/or full pelvic lymph node
statistically significant. It is unknown how many women in this
dissection), remains unclear and requires further study.
study had an inadvertent simple hysterectomy with an unexpected
post-operative diagnosis of invasive cancer, potentially affecting
the recurrence and survival rates as seen in the ConCerv Trial.28 Strengths and Weaknesses
A recently reported systematic review by Wu et al29 examined the The strengths of our study include that it is the first comprehensive
outcomes of simple hysterectomy for low-risk, early-stage cervical prospective evaluation of conservative surgery in patients with low-
cancer from 21 studies with a total of 2662 women. Most women risk cervical cancer. Furthermore, all surgical specimens underwent
(96.8%) had tumors <2 cm, and 15.4% had tumors with lympho- central pathology review by an expert gynecologic pathologist. In
vascular space invasion. FIGO stage was IA1 in 36.1% and IB1 in addition, all study data were entered into a central REDCap data-
61.0% of patients. The recurrence rate for the 19 studies reporting base and the quality and safety of the study procedures were closely
recurrence data was 5.4%. The total death rate for the 20 studies monitored by the MD Anderson coordinating center as well as the
reporting survival data was 5.5%, encompassing 2.7% of patients Data and Safety Monitoring Committee. An additional strength is
with stage IA2 disease and 7.3% with stage IB1 disease. However, that the trial included multiple sites from low-resource regions,
only 71.8% of patients had a lymph node assessment, with 3.2% which have a high prevalence of cervical cancer. This allowed us to
exhibiting positive lymph nodes, limiting the conclusions that could show that conservative surgery is safe and feasible in both high-
be drawn from the study.29 and low-resource settings. Furthermore, the study allowed us to
In the ConCerv Trial, three patients developed recurrent disease, build a robust network of collaborators around the globe, facilitating
two patients with stage IB1 disease and one patient with stage a pathway for future treatment trials with participants from regions
IA2 disease. However, one patient had invasion >10.0 mm as well with a high burden of disease.

Original research
Our study is limited by a prolonged study period of almost 9 in patients with FIGO 2009 stage IA2–IB1 disease (tumors <2 cm).
years. This was primarily due to the strict inclusion criteria, require- The primary outcomes are safety and pelvic relapse-free survival.
ment for central pathology review, and limited number of women The Gynecologic Oncology Group (GOG) 278 Trial (NCT01649089)
meeting the strict eligibility criteria. To overcome these barriers, is assessing the impact of non-radical surgery (simple hysterec-
the study was opened in several sites with the associated chal- tomy or cone biopsy, both with lymphadenectomy) on functional
lenges of working across multiple countries with different time outcomes of lymphedema, bladder, bowel, and sexual function in
zones, languages, and regulations related to securing contracts and women with FIGO 2009 stage IA2–IB1 (tumors <2 cm) cervical
obtaining institutional review board approvals. Every amendment to cancer. Secondary outcomes include recurrence and survival rates.
the protocol or informed consent required translation and approval Both of these studies are nearing completion and will be reported
from each participating site, often resulting in delays and pauses in in the near future.
the study. During this long study period, there were changes in the The results of the ConCerv Trial have shown that conservative
standard of care for the management of cervical cancer, including surgery in patients with low-risk cervical cancer may be a feasible
the introduction of sentinel lymph node biopsy.34 This change in and oncologically safe option. This includes conization alone or
practice was implemented at some, but not all, participating sites, conization followed by simple hysterectomy, both with lymph node
and at different time points based on local guidelines, availability assessment. As such, these results should be considered and
of specialized equipment/dyes and surgeon training. As a result, discussed with patients who meet low-risk criteria as outlined
the lymph node assessment (sentinel lymph node biopsy and/or in our study. If the SHAPE and GOG 278 studies show similar
full pelvic lymph node dissection) was not consistent across sites. results, the standard of care may change from radical hysterec-
Similarly, the choice of surgical approach (open, laparoscopic, or tomy to conservative surgery with conization in women desiring
robotic) for both the simple hysterectomy and lymph node assess- fertility preservation, and simple hysterectomy in women who have
ment was based on surgeon preference and training, and also completed childbearing. In all cases, pelvic lymph node assess-
not consistent across sites. Our study protocol required at least ment with sentinel lymph node biopsy and/or full pelvic lymph node
two separate surgeries with one (and sometimes two) conization dissection is still recommended based on the results of the ConCerv
procedures to confirm eligibility for conservative surgery, followed Trial and others.

by definitive therapy with simple hysterectomy and/or lymph node
assessment. Our group previously reported a single-step proce- CONCLUSIONS
dure with conization and frozen section for intra-operative triage In summary, the results of the ConCerv Trial suggest that conserv-
of simple versus radical hysterectomy in 150 women with stage IA1 ative surgery for women with early-stage, low-risk cervical cancer
disease.35 However, further study is needed to determine the safety is safe and feasible. Further investigation is still needed to address
of this single-step approach for patients potentially eligible for several unanswered questions including the long-term outcomes
conservative surgery, particularly in institutions without specialized of conservative surgery; the role of a minimally invasive approach
pathology services as well as in low- and middle-income countries. in conservative surgery; the impact on quality of life; and the best
Another important limitation of the ConCerv Trial is that the management for women who undergo an inadvertent simple
inclusion criteria were amended during the course of the trial. As hysterectomy with a post-operative diagnosis of cervical cancer.
described above, this was prompted by three patients developing Furthermore, we need to continue to study and refine the optimal
recurrent disease. The first recurrence occurred very early in the pathologic criteria for conservative surgery. Findings from the
study (2010) and was felt to be a study design flaw, with inadequate ConCerv Trial offer prospective data supporting a more conserva-
inclusion criteria. The requirements for depth of invasion <10 mm tive approach to low-risk patients, sparing them the early and late
and negative cone margins for high-grade dysplasia were added. morbidity associated with radical procedures. It will also allow for
In 2016, the study was stopped because two additional patients safer cervical cancer surgery in low- and middle-income countries,
developed recurrent disease, both of whom had undergone an where the burden of cervical cancer is highest.
inadvertent simple hysterectomy. After extensive review, the Data
and Safety Monitoring Committee approved reopening the study Author affiliations
1
provided that we excluded women who had undergone a simple Department of Gynecologic Oncology and Reproductive Medicine, The University of
Texas MD Anderson Cancer Center, Houston, Texas, USA
hysterectomy without a prior cone with negative margins. There is 2
Instituto Nacional de Cancerología, Bogotá, and Clínica de Oncología Astorga,
no current standard of care for this group of patients who undergo Medellin, Colombia
inadvertent simple hysterectomy, and the role of conservative 3
Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
surgery with lymphadenectomy remains unclear in this patient 4
A.C. Camargo Cancer Center, A.C. Camargo Cancer Center, Sao Paulo, Brazil
5
population. Instituto Brasileiro de Controle do Cancer, Sao Paulo, Brazil
6
Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
7
Hospital Erasto Gaertner, Curitiba, Brazil
Implications for Practice and Future Research 8
Instituto Nacional de Cancerologia, Mexico, Mexico
In addition to the ConCerv Trial, two ongoing prospective studies 9
Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok,
are evaluating conservative surgery in low-risk cervical cancer. Thailand
10
The Radical versus Simple Hysterectomy and Pelvic Node Dissec- Nebraska Methodist Health System, Omaha, Nebraska, USA
11
Royal Women's Hospital and University of Melbourne, Melbourne, Victoria,
tion with Low- Risk Early-
Stage Cervical Cancer (SHAPE) Trial
Australia
(NCT01658930) is a non-inferiority randomized phase III study 12
Instituto de Ginecología de Rosario, Rosario, Argentina
comparing simple hysterectomy plus pelvic lymph node dissec- 13
Fondazione Policlinico Universitario A. Gemelli IRCCS and Catholic University of
tion with radical hysterectomy plus pelvic lymph node dissection the Sacred Heart, Rome, Italy

Original research
14
Matamoros General Hospital Alfredo Pumarejo, Matamoros, Mexico 2 Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics
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Hospital Británico de Buenos Aires, Buenos Aires, Argentina 2018: GLOBOCAN estimates of incidence and mortality
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Instituto de Cancerologia - Las Américas - AUNA, Medellin, Colombia worldwide for 36 cancers in 185 countries. CA Cancer J Clin
17 2018;68:394–424.
Department of Pathology, University of Texas MD Anderson Cancer Center, 3 Organization TWH. Global strategy to accelerate the elimination of
Houston, Texas, USA cervical cancer as a public health problem, 2018. Available: https://
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Department of Biostatistics, University of Texas MD Anderson Cancer Center, www.who.int/publications/i/item/9789240014107
Houston, Texas, USA 4 Piver MS, Rutledge F, Smith JP. Five classes of extended
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US Oncology Research, The Woodlands, Texas, USA hysterectomy for women with cervical cancer. Obstet Gynecol
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Presented at 5 Plante M, Gregoire J, Renaud M-C, et al. The vaginal radical
This study was presented in part at the annual meeting of the International trachelectomy: an update of a series of 125 cases and 106
Gynecologic Cancer Society (IGCS), Rio de Janeiro, Brazil, September 2019. pregnancies. Gynecol Oncol 2011;121:290–7.
6 Low JA, Mauger GM, Carmichael JA. The effect of Wertheim
hysterectomy upon bladder and urethral function. Am J Obstet
Twitter Andre Lopes @Andrelopes1002, Michael Frumovitz @frumovitz and Pedro Gynecol 1981;139:826–30.
T Ramirez @pedroramirezMD 7 Kadar N, Saliba N, Nelson JH. The frequency, causes and prevention
Acknowledgements The authors would like to thank the following research of severe urinary dysfunction after radical hysterectomy. Br J Obstet
Gynaecol 1983;90:858–63.
personnel and collaborators for their assistance in recruiting patients, collecting/ 8 Sood AK, Nygaard I, Shahin MS, et al. Anorectal dysfunction
entering data, and working across different countries, languages, and time zones after surgical treatment for cervical cancer. J Am Coll Surg
to complete this study: MD Anderson Cancer Center, Houston, Texas, USA: Cindy 2002;195:513–9.
Melendez, Jessica Gallegos, Juana Rayo, Ana Lopez, Keiry Paiz, and Mark Munsell; 9 Bergmark K, Avall-Lundqvist E, Dickman PW, et al. Vaginal changes
Instituto de de Cancerología - Las Américas - AUNA, Medellín, Colombia: Natalia and sexuality in women with a history of cervical cancer. N Engl J
Escobar; Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú: Med 1999;340:1383–9.
Ninoska Macavilca; Barretos Cancer Hospital, Barretos, Brazil: Talita Garcia, Julio 10 Frumovitz M, Sun CC, Schover LR, et al. Quality of life and
Cesar Souza, Ligia Zampieri, Carlos Andrade, Georgia Fontes-Cintra, Marcelo sexual functioning in cervical cancer survivors. J Clin Oncol
2005;23:7428–36.
Viera, Ricardo dos Reis, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina:
11 Kinney WK, Hodge DO, Egorshin EV, et al. Identification of a low-risk
Mariana Prada, Marina Lamm, and Ana Jaen; Instituto Nacional de Cancerologia, subset of patients with stage Ib invasive squamous cancer of the
México City, México: Lenny Gallardo, Instituto Brasileiro de Controle do Cancer cervix possibly suited to less radical surgical treatment. Gynecol
(IBCC), São Paulo, Brazil: Alayne Domingues Yamada; Hospital Erasto Gaertner, Oncol 1995;57:3–6.
Curitiba, Brazil: Nathalia Carneiro, Fernanda Schamne; Chulalongkorn University 12 Covens A, Rosen B, Murphy J, et al. How important is removal of the
and King Chulalongkorn Memorial Hospital, Bangkok, Thailand: Patou Tantbirojn, parametrium at surgery for carcinoma of the cervix? Gynecol Oncol

MD; Nebraska Methodist Health System, Omaha, Nebraska, USA: Kathryn Bartz, 2002;84:145–9.
RN; Royal Women’s Hospital, Melbourne, Australia: Julie Silvers; Fondazione 13 Stegeman M, Louwen M, van der Velden J, et al. The incidence
of parametrial tumor involvement in select patients with early
Policlinico Universitario A. Gemelli IRCCS and Catholic University of the Sacred
cervix cancer is too low to justify parametrectomy. Gynecol Oncol
Heart, Rome, Italy: Luigi Carlo Turco, Anna Fagotti, Francesco Cosentino, Instituto 2007;105:475–80.
de Ginecología de Rosario, Rosario, Argentina: Gabriela Santillan, and Jeronimo 14 Wright JD, Grigsby PW, Brooks R, et al. Utility of parametrectomy for
Costa. The authors would also like to thank all the women who entrusted us with early stage cervical cancer treated with radical hysterectomy. Cancer
their care and participated in the study in order to improve the care of women with 2007;110:1281–6.
cervical cancer globally. 15 Frumovitz M, Sun CC, Schmeler KM, et al. Parametrial involvement
in radical hysterectomy specimens for women with early-stage
Contributors Conception and design: KMS, PTR, MF, RP, RLC. Administrative cervical cancer. Obstet Gynecol 2009;114:93–9.
support: KMS, PTR, RLC. Provision of study material or patients: all authors. 16 Smith AL, Frumovitz M, Schmeler KM, et al. Conservative surgery
Collection and assembly of data: KMS, BMF, PR, PTR, RP, RLC. Data analysis and in early-stage cervical cancer: what percentage of patients may
interpretation: BMF, KMS, PTR, MF, RP, RLC. Manuscript writing: all authors. Final be eligible for conization and lymphadenectomy? Gynecol Oncol
approval of manuscript: all authors. Accountable for all aspects of the work: all 2010;119:183–6.
authors. 17 Plante M, Renaud M-C, Sebastianelli A, et al. Simple vaginal
trachelectomy in women with early-stage low-risk cervical cancer
Funding This research was supported in part by the National Institutes of Health who wish to preserve fertility: the new standard of care? Int J
(NIH) through MD Anderson’s Cancer Center Support Grant P30CA016672 and the Gynecol Cancer 2020;30:981–6.
MD Anderson Sister Institution Network Fund. 18 Ramirez PT, Pareja R, Rendón GJ, et al. Management of low-risk
early-stage cervical cancer: should conization, simple trachelectomy,
Competing interests The authors have the following disclosures: MH: consulting/ or simple hysterectomy replace radical surgery as the new standard
speaker for Stryker and research support from GlaxoSmithKline and Astra Zeneca. of care? Gynecol Oncol 2014;132:254–9.
19 Rob L, Charvat M, Robova H, et al. Less radical fertility-sparing
Patient consent for publication Not required.
surgery than radical trachelectomy in early cervical cancer. Int J
Provenance and peer review Not commissioned; externally peer reviewed. Gynecol Cancer 2007;17:304–10.
20 Rob L, Pluta M, Strnad P, et al. A less radical treatment option to the
Data availability statement Data are available upon reasonable request. fertility-sparing radical trachelectomy in patients with stage I cervical
In accordance with the journal’s guidelines, we will provide our data for the cancer. Gynecol Oncol 2008;111:S116–20.
reproducibility of this study in other centers if such is requested. The data are in 21 Pluta M, Rob L, Charvat M, et al. Less radical surgery than radical
a REDCap database at MD Anderson Cancer Center and are available from the hysterectomy in early stage cervical cancer: a pilot study. Gynecol
principal investigator, Dr. Kathleen Schmeler. Oncol 2009;113:181–4.
22 Martinelli F, Ditto A, Filippi F, et al. Conization and lymph node
ORCID iDs evaluation as a fertility-sparing treatment for early stage cervical
Kathleen M Schmeler http://orcid.org/0 000-0002-9670-4189 cancer. Int J Gynecol Cancer 2021;31:457–61.
23 Thall PF, Wathen JK, Bekele BN, et al. Hierarchical Bayesian
Rene Pareja http://orcid.org/0000-0003-0093-0438
approaches to phase II trials in diseases with multiple subtypes. Stat
Gabriel J Rendon http://orcid.org/0000-0002-7536-0567 Med 2003;22:763–80.
Michael Frumovitz http://orcid.org/0 000-0002-0810-2648 24 Harris PA, Taylor R, Thielke R, et al. Research electronic data capture
(REDCap)--a metadata-driven methodology and workflow process
for providing translational research informatics support. J Biomed
Inform 2009;42:377–81.
25 Nica A, Marchocki Z, Gien LT, et al. Cervical conization and lymph
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Table 3 Participants with positive lymph nodes (5/100, 5%)

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