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Surgical versus clinical staging prior to
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international multicenter (Uterus-11)

intergroup study
Simone Marnitz,1 Audrey Tieko Tsunoda,2 Peter Martus,3 Marcelo Vieira,4
Renato Jose Affonso Junior,5 João Nunes,2,6 Volker Budach,7 Hermann Hertel,8 Alexander Mustea,9
Jalid Sehouli,10 Jens-­Peter Scharf,11 Uwe Ulrich,12 Andreas Ebert,13 Iris Piwonski,14
Christhardt Kohler15,16

►► Additional material is HIGHLIGHTS

published online only. To view, • There was no difference in disease-­free survival between surgical and clinical staging in patients with locally advanced
please visit the journal online cervical cancer.
(http://​dx.​doi.​org/​10.​1136/​ijgc-​
• The Uterus-11 trial is the only completed randomized trial comparing surgical (laparoscopic) versus clinical staging prior
2020-​001973).
to primary chemoradiation.
For numbered affiliations see • Laparoscopic staging was safe, did not delay primary chemoradiation, and led to 33% upstaging in patients with locally
end of article. advanced cervical cancer.

Correspondence to
Professor Simone Marnitz, ABSTRACT were randomized. Of these, 240 patients were eligible for
Department of Radiooncology, Objective  Revised staging of patients with locally analysis. The two groups were comparable with respect
Medical Faculty of the advanced cervical cancer is based on clinical examination, to patient characteristics. The surgical approach was
University of Cologne, Cologne imaging, and potential surgical findings. A known transperitoneal laparoscopy in most patients (96.6%).
50937, Germany; ​simone.​ limitation of imaging techniques is an appreciable rate of Laparoscopic staging led to upstaging in 39 of 120 (33%)
marnitz-​schulze@​uk-k​ oeln.​de
understaging. In contrast, surgical staging may provide patients. After a median follow-­up of 90 months (range
more accurate information on lymph node involvement. 1–123) in both arms, there was no difference in disease-­
The aim of this prospective study was to evaluate the free survival between the groups (p=0.084). For patients
Received 17 August 2020
impact of pre-­treatment surgical staging, including with FIGO stage IIB, surgical staging is superior to clinical
Revised 23 October 2020
removal of bulky lymph nodes, on disease-­free survival in staging with respect to disease-­free survival (HR 0.51,
Accepted 26 October 2020
patients with locally advanced cervical cancer. 95% CI 0.30 to 0.86, p=0.011). In the post-­hoc analysis,
Methods  Uterus-11 was a prospective international surgical staging was associated with better cancer-­specific
multicenter study including patients with locally advanced survival (HR 0.61, 95% CI 0.40 to 0.93, p=0.020).
cervical cancer who were randomized 1:1 to surgical Conclusion  Our study did not show a difference in
staging (experimental arm) or clinical staging (control disease-­free survival between surgical and clinical staging
arm) followed by primary platinum-­based chemoradiation. in patients with locally advanced cervical cancer. There
Patients with histologically proven squamous cell was a significant benefit in disease-­free survival for
carcinoma, adenocarcinoma, or adenosquamous cancer patients with FIGO stage IIB and, in a post-­hoc analysis,
International Federation of Gynecology and Obstetrics a cancer-­specific survival benefit in favor of laparoscopic
(FIGO) 2009 stage IIB–IVA underwent gynecologic staging. The high risk of distant metastases in both arms
examination and pre-­treatment imaging including emphasizes the need for further evaluation.
abdominal computed tomography (CT) and/or abdominal
magnetic resonance imaging (MRI). Patients had chest
© IGCS and ESGO 2020. Re-­use imaging (any of the following: X-­ray, CT, or PET-­CT). INTRODUCTION
permitted under CC BY-­NC. No The primary endpoint was disease-­free survival and
commercial re-­use. Published the secondary endpoint was overall survival. An ad hoc
Tumor stage and lymph node involvement are the most
by BMJ.
analysis was performed after trial completion for cancer-­ important prognostic factors for patients with locally
To cite: Marnitz S, specific survival. Randomization was conducted from advanced cervical cancer. In particular, the detection
Tsunoda AT, Martus P, February 2009 to August 2013. of para-­aortic lymph node metastases is of utmost
et al. Int J Gynecol Cancer Results  A total of 255 patients (surgical arm, n=130; importance in order to adjust target volume definition
2020;30:1855–1861. clinical arm, n=125) with locally advanced cervical cancer of primary chemoradiation. Para-­aortic lymph node

Marnitz S, et al. Int J Gynecol Cancer 2020;30:1855–1861. doi:10.1136/ijgc-2020-001973 1855

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involvement occurs in approximately 10–50% of patients with
locally advanced cervical cancer.1–3 Known limitations of imaging
modalities, even positron emission tomography-­computed tomog-
raphy (PET-­CT), lead to false negative rates of 8–20%,4–6 potentially
advocating surgical staging. However, this has been a controversial
topic among gynecologic oncologists and radiation oncologists for
decades due to contradictory results published in the literature.1 7–12
Unacceptably high treatment-­related toxicity caused the premature
termination of the only previously published randomized trial.13
Another planned randomized study (LiLACs) could not be finished
due to lack of funding.14 Although the principle of upstaging and its
impact on treatment has been confirmed, discussion continues on
morbidity associated with surgical staging, particularly when using
an open approach.6 Consequently, recommendations with regard
to surgical staging are contradictory in national and international
guidelines.15 16
The Uterus-11 randomized intergroup (German Association of Figure 1  Flowchart of the Uterus-11 study design.
Gynecologic Oncology, North-­Eastern German Gynecologic Oncology
Group, and German Association of Radiation Oncology) study was
and/or tumor in the supraclavicular lymph node were confirmed,
designed to evaluate the impact of pre-­treatment surgical staging,
no retroperitoneal lymph node dissection was carried out and the
including removal of bulky lymph nodes, on disease-­free survival for
operation was abandoned. In all other patients, para-­aortic and
patients with locally advanced cervical cancer. First analyses of this
bilateral pelvic lymphadenectomy was performed. The upper limit
trial showed that laparoscopic surgical staging was not associated
of para-­aortic lymphadenectomy was the renal vessels; pelvic
with higher rates of early toxicity during chemoradiation or a delay
lymphadenectomy comprised external iliac and obturator lymph
in treatment.17 18 Furthermore, our study showed that upstaging
nodes. If enlarged/bulky para-­aortic and/or pelvic lymph nodes
occurred in 33% of patients who underwent surgical staging, thus
were identified, removal of these was mandatory in order to reduce
leading to treatment changes.3 The current study reports on the
the burden for subsequent chemoradiation.
prospective comparison of disease-­free survival between surgical
and clinical staging. In addition, we present data on the secondary Chemoradiation
outcome of overall survival and on post-­hoc analysis evaluating Details of primary chemoradiation have been reported elsewhere.18
cancer-­specific survival. Primary chemoradiation in both arms comprised external beam radi-
ation, brachytherapy, and concurrent chemotherapy according to
national and international guidelines. Patients underwent radiation-­
METHODS planning CT using immobilization devices with a full bladder and
Patients with histologically proven squamous cell carcinoma, empty rectum, with 2 mm slices from the 12th thoracic vertebra
adenocarcinoma, or adenosquamous cell cancer International in cases of para-­aortic lymph node metastases for extended fields
Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIB–IVA or from the third lumbar vertebra in cases of only pelvic radia-
underwent gynecologic examination and pre-­treatment imaging tion to trochanter minor. Commercial treatment planning systems
including abdominal CT and/or abdominal magnetic resonance were used for contouring and planning. Radiation treatment was
imaging (MRI) and any of the following chest imaging (X-­ray, CT, performed using intensity modulated radiotherapy (IMRT) tech-
or PET-­CT). There was no central imaging review. Eligible patients niques (volumetric arc, conventional IMRT, or tomotherapy) in 65%
were 1:1 randomized to either the experimental (surgical staging) and three-­dimensional planned conventional techniques in 35% of
arm or the control (clinical staging) arm. For patients with suspicious patients using 6 or 10 MV-­X photons. Five weekly single doses of
para-­aortic lymph nodes in the clinical staging arm, a CT-­guided 1.8 Gy to a total dose of 50.4 Gy with or without a simultaneous or
lymph node biopsy was performed prior to primary chemoradiation, sequential parametric boost to a total dose of 60 Gy to the parame-
and in patients with metastatic disease in those lymph nodes, the tria were applied. Brachytherapy was performed according to the
radiation field was extended (Figure 1). The study was approved by policy of the center. MRI-­based after-­loading was recommended
the institutional review boards of the participating institutions. An according to the GEC-­ESTRO recommendations. The tumor region
independent data safety board evaluated the safety and recruit- (high-­risk area of residual tumor) had to be covered by at least
ment of the trial annually. 80 Gy (EQD2,α/β = 10) taking brachytherapy and external beam radi-
ation together. Cisplatin 40 mg/m2 body surface area was given
Surgical Staging in five weekly applications to a total dose of 200 mg/m2 during
Details of surgical staging have been reported elsewhere17 (see external beam radiation. In case of contraindication to cisplatin,
online supplement). Surgical staging prior to primary chemoradia- carboplatin (area under curve 2-­weekly) was applied.
tion was performed via a transperitoneal laparoscopic, extraperito-
neal laparoscopic, or open transperitoneal approach. After careful Statistical Analysis
inspection of the abdominal cavity, biopsies were taken from any Survival endpoints were defined as the time from randomiza-
suspicious area and sent to frozen section. If peritoneal spread tion to relapse or death from any cause. The primary endpoint was

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disease-­free survival and the secondary endpoint was overall survival, Table 1  Demographic and clinical data
measured as the time from randomization to death from any cause.
Surgical arm Clinical arm Significance
As a post-­hoc analysis, we also evaluated cancer-­specific survival.
Death without prior relapse was considered an event in the defini- N 130 125
tion of disease-­free survival. The sample size calculation assumed a ITT: 121 ITT: 119
disease-­free survival of 54% after 5 years in the experimental arm Not eligible: 9 Not eligible: 6
(surgical staging) and 36.5% in the control arm (clinical staging) Evaluable patients 121 119
based on a Gynecologic Oncology Group (GOG) analysis by Gold et Age (years), mean 47.2 49.6 p=0.09
al.7 In total, a sample size of 250 patients including 20% drop-­outs,
Range 20–69 24–71
leading to 200 evaluable patients and a number of events amounting
BMI, mean 26.2 26.2 p=0.83
to 129, was needed to achieve a power of 80%. A recruitment period
of 4 years and a minimum follow-­up of 4 years was planned. The Range 16.4–48.1 15.7–51.4
actual recruitment period was 4 years and 6 months (February 2009 Karnofsky index (%) 90 (70–100) 90 (70–100) p=0.45
to August 2013) and the planned follow-­up ended in August 2017. Co-­morbidity
Follow-­up was prolonged until August 2019 because fewer events  Cardiovascular 24 (19.8%) 24 (20.2%) p=0.95
were observed than the planned number to August 2017. However,  Diabetes 9 (7.4%) 7 (5.9%) p=0.63
even after the prolonged period, there were only 102 events in 240  Prior abdominal 56 (46.3%) 46 (38.7%) p=0.23
evaluable patients (compared with 129 events planned). At this point surgery
it was decided to close the databank and perform primary statistical Stage at randomization*
analysis. Randomization was 1:1 stratified for FIGO 2009 stage (IIB vs
 IIB 85 (70.2%) 80 (67.2%)
III/IV) and study center.
 IIIA 4 (3.3%) 6 (5%)
Survival rates for the primary and secondary endpoints and
related survival curves were estimated using the Kaplan–Meier  IIIB 29 (24%) 24 (20.2%)
method. Hazard ratios (HR) including two-­sided 95% limits of confi-  IVA 3 (2.5%) 9 (7.6%) p=0.44
dence were estimated using the Cox proportional hazard model Tumor size*
including the study arm only. In three sensitivity analyses this model  ≤4 cm 31 (25.6%) 22 (18.5%)
was adjusted, stratified, and calculated separately for FIGO stage.  >4 cm 90 (74.4%) 97 (81.5%) p=0.18
Additionally, interaction terms between the study arm and FIGO
Histology*
stage were tested for each outcome. Note, however, that the study
 Squamous 103 (85.1%) 108 (90.8%)
was not powered for sub-­group analyses. Cancer-­specific survival
was affected by a competing risk (death from other causes) and  Adenocarcinoma 15 (12.4%) 8 (6.7%)
the Fine–Gray method19 was applied to estimate sub-­distribution  Adenosquamous 3 (2.5%) 3 (2.5%) p=0.33
hazard ratios for cumulative incidences and their respective confi- Grade*
dence limits and p values. Sensitivity analyses included adjust-  G1 5 (4.1%) 1 (0.8%)
ment for histology (squamous cell carcinoma vs adenocarcinoma/  G2 85 (70.2%) 76 (63.9%)
adenosquamous cell carcinoma) and tumor size (≤4 cm vs >4 cm).  G3 31 (25.6%) 42 (35.3%) p=0.046
The primary analysis population was the intent-­to-­treat population.
LVSI*
Comparisons of baseline characteristics between study arms were
 Negative 98 (81%) 101 (85%)  
conducted using the χ2 test (categorical variables), the Mann–Whitney
test (ordered or non-­normally distributed variables), and the t-­test for  Positive 21 (17%) 14 (12%)  
independent samples (normally distributed variables). The level of  Indeterminate 2 (2%) 4 (3%) p=0.24
significance was 0.05 (two-­sided) in all analyses. However, only the HVSI*
primary analysis for disease-­free survival was confirmatory; p values  Negative 109 (90%) 111 (94%)
given for the secondary analysis should be interpreted as additional  Positive 10 (8%) 4 (3%)
descriptive parameters. The analysis was performed using SPSS (IBM,  Indeterminate 2 (2%) 4 (3%) p=0.11
Armonk, New York, USA) for Windows, release 25, and R (R Foundation
for Statistical Computing, Vienna, Austria) release 3.01. *Only evaluable patients included in these sections.
HVSI, hemovascular space invasion: tumor cell invasion in
microscopic blood vessels; LVSI, lymphovascular space invasion:
tumor cell invasion in lymphatic vessels.

RESULTS Surgical Staging

A total of 255 patients with cervical cancer FIGO 2009 stage Surgical staging was performed via the laparoscopic approach in
IIB–IVA were randomized, with a subsequent total of 240 evalu- 96.6% of patients. Intra-­operative and post-­operative complica-
able patients, 121 in the surgical arm and 119 in the clinical arm. tion rates were 1.6% and 7.3%, respectively. The median number
There were no significant differences between the two arms with of harvested pelvic and para-­aortic lymph nodes was 19 (range
respect to clinical parameters, except for a higher number of grade 1–70) and 17 (range 3–74), respectively. In the surgical arm, posi-
3 tumors in the control arm (Table 1). tive pelvic lymph nodes were confirmed in 51% of patients and

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Table 2  Reasons for non-­cervical cancer-­related death
Surgical staging arm Clinical staging arm
Suicide (n=1) Liver cirrhosis (n=1)
Other malignancy (n=1) Other malignancy (n=1)
Urosepis non-­cancer related (n=1) Apoplectic stroke (n=1)
Abdominal sepsis non-­cancer  
related (n=1)
Non-­cancer related, not specified  
(n=2)

survival compared with clinical staging in patients with FIGO stage

IIB (HR 0.51, 95% CI 0.30 to 0.86, p=0.011), but not in patients
with FIGO stage III (HR 1.24, 95% CI 0.67 to 2.28, p=0.50). The
difference between the HRs (0.51 vs 1.24) was significant (statis-
Figure 2  CONSORT diagram. EBRT, external beam tical interaction between study arm and FIGO stage p=0.031). In
radiation therapy; FIGO, International Federation of 41 (34%) of 121 patients in the surgical staging arm and 54 (45%)
Gynecology and Obstetrics; RCT, chemoradiation. of 119 patients in the clinical staging arm there was recurrence
of disease at study completion. In the post-­hoc analysis evalu-
ating cancer-­specific survival, patients in the surgical staging arm
positive para-­aortic lymph nodes in 24% of patients.3 The median had improved outcomes (HR 0.61, 95% CI 0.40 to 0.93, p=0.020;
time between surgical staging and the start of chemoradiation was FIGO IIB: HR 0.35, 95% CI 0.19 to 0.64, p<0.001; FIGO III: HR 1.27,
13 days (range 7–21),17 and the median time interval between 95% CI 0.69 to 2.33, p<0.44; Figure 3). A sub-­analysis of patients
randomization and the start of chemoradiation in the clinical arm who underwent extended field radiation (6%) in either group was
was 13.5 days (range 3–30). Histology results led to upstaging in not possible due to the small number of patients.
33% of patients in the surgical arm compared with 8% in the clin- The most important risk factor was the FIGO stage for each of
ical arm (CT-­guided lymph node biopsy) (p<0.001).3 Of note, a total the outcomes. For FIGO stage III/IV, HR was 1.89 (95% CI 1.27 to
of 47 patients underwent PET/CT scans; however, the number of 2.83, p=0.002) for overall survival, 1.81 (95% CI 1.22 to 2.69,
patients was considered too small to derive definitive conclusions p=0.003) for disease-­free survival, and 2.21 (95% CI 1.45 to 3.35,
on analysis of comparison. p=0.0002) for cancer-­specific survival. In contrast, patients with
Chemoradiation adenocarcinoma or adenosquamous carcinoma had no increased
A total of 236 of the 240 patients (98.3%) underwent external beam risk for progression compared with patients with squamous cell
radiation therapy with a median total dose of 50.4 Gy (117 patients carcinoma, with HR 1.28 (95% CI 0.73 to 2.26, p=0.39) for overall
in the surgical arm and 119 patients in the clinical arm, Figure 2). survival, 1.23 (95% CI 0.70 to 2.15, p=0.48) for disease-­free
The radiation technique used was IMRT in 65% of patients and survival, and 1.16 (95% CI 0.63 to 2.13, p=0.63) for cancer-­specific
three-­dimensional radiation therapy in 35% of patients. The mean survival. Patients with bulky tumors (>4 cm) had no significant
total treatment time was 53.7±8.9 days in the experimental arm difference in overall survival (HR 1.67, 95% CI 0.98 to 2.86, p=0.06)
and 53.0±9.8 days in the clinical arm. Patients in the surgical arm and disease-­free survival (HR 1.52, 95% CI 0.91 to 2.52, p=0.096)
received extended field radiation more frequently than those in compared with patients with tumors ≤4 cm. However, there was a
the clinical arm (23% vs 12%, p=0.02). In 234 patients (97.5%) difference in cancer-­specific survival (HR 1.92, 95% CI 1.07 to 3.45,
platinum-­based chemotherapy was administered. High dose rate p=0.028). Lymph node status could only be evaluated in patients
(HDR)-192Ir brachytherapy was performed in 227 of the 240 patients with surgical staging. The presence of para-­aortic lymph metas-
(94.5%), with a median single dose of 6 Gy to a median nominal tases (overall survival: HR 3.14, 95% CI 1.67 to 5.90; disease-­free
total dose of 28 Gy. Chemotherapy and radiation were well toler- survival: HR 3.03, 95% CI 1.63 to 5.62; cancer-­specific survival:
ated in both arms without early genitourinary and gastrointestinal HR 3.53, 95% CI 1.84 to 6.79; p<0.001 for each outcome) and
toxicity grade >3. No chemoradiation-­related death occurred in pelvic±para-­aortic lymph nodes (overall survival: HR 3.30, 95% CI
either arm.18 1.61 to 6.76; disease-­free survival: HR 2.79, 95% CI 1.43 to 5.46;
cancer-­specific survival: HR 3.79, 95% CI 1.72 to 8.33; p<0.001 for
Oncologic Results each outcome) were negative prognostic factors. When recurrence
Overall, 102 patients relapsed or died. In 90 patients death was was detected, it was distant or distant in combination with local in
cancer-­related (Table 2). There was no difference in disease-­free 87% in the surgical arm and 91% in the clinical arm.
survival between the surgical staging and clinical staging arms
(95% CI 0.48 to 1.05, p=0.084). Analyses adjusted (HR 0.73, 95% CI
0.49 to 1.08, p=0.12) or stratified (HR 0.74, 95% CI 0.50 to 1.10, DISCUSSION
p=0.13) for FIGO stage showed similar results. Moreover, surgical Our study showed that there was no difference in disease-­free
staging was associated with significantly improved disease-­free survival between surgical staging and clinical staging in patients

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Figure 3  (A) Disease-­free survival, (B) overall survival, (C) disease-­free survival FIGO stage IIB, and (D) cancer-­specific death
rate (mortality).

with locally advanced cervical cancer. In patients with locally occurs in up to 34% of patients.23 Using a laparoscopic approach, the
advanced cervical cancer and any pelvic±para-­aortic, any para-­ complication rate is between 1.6% and 7% without delay of primary
aortic, or any histologically confirmed lymph node metastases, chemoradiation.2 4 5 9 17 20 22 23 25 26 It is not finally decided whether a
false negative imaging occurs in 30–50%, 10–37%, and 8–25% transperitoneal or retroperitoneal approach, a conventional or robotic
of cases, respectively.6 20–23 In their meta-­ analysis, Choi et al laparoscopy, and the infra-­renal or infra-­mesenteric extent of para-­
derived pooled sensitivities and specificities for detecting lymph aortic lymphadenectomy should be preferred.2 4 9 12 25 The surgical
node metastases for CT (50% and 92%), MRI (56% and 91%), and approach used in the Uterus-11 trial was conventional laparoscopy
PET-­CT (82% and 95%).24 Detection of lymph node metastases is of extending to the renal vessels in 96.6% of patients. Furthermore, Lee
utmost importance for defining the personalized treatment volume et al showed that nodal staging surgery before definitive chemoradi-
and achieving subsequent improved outcomes after chemora- ation may be cost effective, especially in patients with negative PET-­
diation. Although patients in the Uterus-11 trial did not routinely CT.27 Well-­designed randomized trials comparing PET-­CT with surgical
undergo pre-­operative PET-­CT, study results need to be compared staging (PALDISC trial) are ongoing.28 Minimally invasive surgical
with PET-­CT, which is considered the standard-­of-­care for pre-­ staging in patients with locally advanced cervical cancer has demon-
operative work-­up today in many centers, rather than surgical strated upstaging rates between 22% and 43% compared with clinical
staging.8 The main arguments for PET-­CT are avoiding potential staging.1 7 At 33%, the rate of upstaging in Uterus-11 is exactly within
surgical morbidity, delay in starting chemoradiation, and the lack this range.3
of evidence for improved survival following performance of surgical Another important aspect of surgical staging is the potential onco-
staging.8 23 However, as demonstrated in several retrospective and logic benefit of removing bulky pelvic and para-­aortic lymph node
prospective studies, in patients with negative PET-­CT who under- metastases prior to primary chemoradiation. Thus, from a radiobiolog-
went minimally invasive para-­aortic lymph node staging, the false ical point of view, one should consider removal of larger lymph nodes
negative rate for para-­aortic lymph node involvement is between in order to provide higher locoregional control. Wakatsuki et al have
8% and 22%, especially in those patients with PET-­CT positive described a 97% control rate with 50 Gy radiotherapy for lymph nodes
pelvic nodes20 or small tumor volume in para-­aortic lymph nodes.5 <10 mm in patients with cervical cancer in contrast to 76% for nodes
Surgical staging should not be performed via laparotomy in order to >10 mm.29 Similar results were found by Oh et al in 310 patients with
avoid the subsequent severe morbidity or mortality during radiation that locally advanced cervical cancer with a follow-­up of 83 months. In-­field

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failure rates for pelvic as well as para-­aortic lymph nodes >10 mm Uterus-11 trial were 77%, 80%, and 86% for surgical staging and
were significantly higher than for smaller lymph nodes.30 This has been 59%, 60%, and 61% for clinical staging, which is in the upper range
confirmed by retrospective clinical data.1 7 of previously reported oncologic results.7 26 32
Primary chemoradiation in both arms of the Uterus-11 trial Although negative for the primary endpoint, our study results
fulfilled high-­quality treatment standards with respect to radiation suggest that surgical staging prior to primary chemoradiation
treatment duration, use of brachytherapy, application of concom- might be beneficial for patients with FIGO stage IIB tumors (HR
itant chemotherapy, and use of modern techniques for external 0.51). Thus, further studies in patients with FIGO stage IIB tumors
beam radiation therapy and brachytherapy. Consequently, over should be considered. The fact that in cases of recurrence there
92% of the patients in the Uterus-11 study received a biologi- were >85% distant metastases underlines the need for more effec-
cally sufficient tumor dose (external beam radiation therapy + tive systemic (maintenance) treatments such as sequential chemo-
brachytherapy), which is much better than general chemoradi- therapy following primary chemoradiation, immunotherapy, or a
ation practice.31 Moreover, early chemoradiation-­related toxicity combination of both.32
in Uterus-11 was moderate with 0% grade >3 genitourinary and Among the strengths of our study is the fact that it is the
gastrointestinal toxicity, 6% grade 3 nausea, 3% grade 3 vomiting, largest investigator-­initiated randomized trial comparing surgical
and <2% grade 3 diarrhea. In contrast, within the small prema- staging with clinical staging in patients with locally advanced
turely closed randomized study by Lai et al using outdated radi- cervical cancer. Nearly all patients underwent surgical staging by
ation techniques, toxicity grade ≥3 occurred in 45% of patients in a minimally invasive approach and modern radiation techniques.
the clinical arm and 38% in the surgical arm, which demonstrated Long-­term follow-­up and a high level of data completeness was
that radiation technique, not surgery, contributed to the unfavorable achieved. However, PET-­CT could not be routinely implemented in
results.13 pre-­operative work-­up due to lack of reimbursement. Patients with
Para-­aortic lymph node metastases significantly impair survival stage IB2 (FIGO 2009) could not be included in the protocol. Finally,
of patients with locally advanced cervical cancer, as demonstrated with only 102 instead of 129 observed events, the power of our
in several retrospective publications.1 7 Benito et al reported a study was 70% instead of 80% as initially planned.
mean survival time in 139 patients of 77 months and 21 months,
respectively, for patients without (N0) and with (N1) proven para-­
aortic lymph node metastasis. Mezquita et al found a 5-­year overall CONCLUSION
survival rate in 67 patients of 71% (N0) and 21% (N1).22 26 Similar
The Uterus-11 trial showed that laparoscopic staging prior to
results were described by Gouy et al with 3-­year event-­free survival
primary chemoradiation in patients with locally advanced cervical
of 74%, 69%, and 17% for para-­aortic N0, N1 <5 mm, and N1
cancer was not associated with improved disease-­free survival or
>5 mm, respectively.12 However, further oncologic results of studies
overall survival. Patients with FIGO stage IIB benefit from surgical
comparing clinical staging versus surgical staging in patients with
staging prior to primary chemoradiation. We showed that surgical
locally advanced cervical cancer differ considerably. Analyzing the
staging is safe and leads to an upstaging in more than 30% of
data of GOG 85, GOG 120, and GOG 165 trials, Gold et al showed
patients. Primary chemoradiation was not delayed nor associated
a benefit in progression-­free survival (50% vs 36%) and overall
with higher rates of early complications following surgical staging.
survival (54% vs 40%) in favor of surgical staging, which was more
beneficial for stage III/IV than for stage II.7 Dabi et al10 compared Author affiliations
377 patients who underwent surgical staging with 270 patients 1
Department of Radiooncology, Medical Faculty of the University of Cologne,
who had clinical staging. After a mean follow-­up of 38 months, Cologne, Germany
2
patients in the surgical group had a better prognosis with respect Gynecologic Oncology Department, Hospital Erasto Gaertner, Curitiba, Brazil
3
Institute for Clinical Epidemiology and Biometry, Eberhard Karls University
to disease-­free survival (OR 0.64) and overall survival (OR 0.43).
Tübingen Faculty of Medicine, Tubingen, Germany
However, a study by Yang et al in 148 patients with locally advanced 4
Department for Gynecologic Oncology, Hospital de Amor de Barretos, Barretos,
cervical cancer showed no significant survival differences between Brazil
the surgical and imaging group after a mean follow-­up of 41 5
Department of Radiooncology, Hospital de Amor de Barretos, Barretos, Brazil
6
months.32 Gynecologic Oncology Department, Instituto de Oncologia do Paraná, Curitiba,
Brazil
The only prospective randomized trial so far has to be interpreted 7
Department of Radiooncology, Charité Universitätsmedizin Berlin, Berlin, Germany
with caution due to the small number of patients (n=29 clinical arm, 8
Department of Obstetrics and Gynecology, Hannover Medical School, Hannover,
n=32 surgical arm) and also because it was prematurely stopped Germany
due to significantly worse disease-­free survival in the surgical arm 9
Department of Gynecology and Gynecologic Oncology, University of Bonn, Bonn,
with an HR of 3.13 for recurrence and HR 1.76 for death. However, Germany
10
Department of Gynecology with Center for Oncological Surgery, Campus
all eight patients with histologically confirmed para-­aortic lymph
Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie
node metastasis died due to treatment failure or complications. Universität Berlin, Humboldt-­Universität zu Berlin and Berlin Institute of Health,
Given the low number of events, this probably influenced survival Berlin, Germany
curves.13 11
Department of Gynecology and Obstetrics, Sana-­Clinics Berlin Lichtenberg, Berlin,
The rates of 5-­year disease-­free survival, 5-­year overall survival, Germany
12
Department of Gynecology and Obstetrics, Martin-­Luther-­Hospital Berlin, Berlin,
and 5-­year cancer-­specific survival in the Uterus-11 trial were 67%,
Germany
68%, and 73% for surgical staging and 57%, 58%, and 58% for 13
Outpatient Clinics for Women’s Health, Berlin, Germany
clinical staging. For FIGO stage II, the 5-­year disease-­free survival, 14
Institute of Pathology, Charite Medical Faculty Berlin, Berlin, Germany
5-­year overall survival, and 5-­year cancer-­specific survival in the 15
Department of Gynecology, University of Cologne, Koln, Germany

1860 Marnitz S, et al. Int J Gynecol Cancer 2020;30:1855–1861. doi:10.1136/ijgc-2020-001973

 Original research

Int J Gynecol Cancer: first published as 10.1136/ijgc-2020-001973 on 8 December 2020. Downloaded from http://ijgc.bmj.com/ on January 7, 2021 by guest. Protected by copyright.
16
Department of Special Operative and Oncologic Gynecology, Asklepios-­Clinic cancer undergoing laparoscopic para-­aortic lymphadenectomy
Hamburg-­Altona, Asklepios Hospital Group, Hamburg, Germany before chemoradiotherapy in the era of positron emission
tomography imaging. J Clin Oncol 2013;31:3026–33.
13 Lai C-­H, Huang K-­G, Hong Ji-­H, et al. Randomized trial of surgical
Acknowledgements  We thank Talita Garcia do Nascimento and Sylvia Blass for staging (extraperitoneal or laparoscopic) versus clinical staging in
excellent technical support. locally advanced cervical cancer☆. Gynecol Oncol 2003;89:160–7.
Contributors  All authors contributed substantially to this manuscript. 14 Frumovitz M, Querleu D, Gil-­Moreno A, et al. Lymphadenectomy
in locally advanced cervical cancer study (LiLACS): phase III
Funding  This study was funded by Deutsche Krebshilfe. clinical trial comparing surgical with radiologic staging in patients
with stages IB2-­IVA cervical cancer. J Minim Invasive Gynecol
Competing interests  None declared. 2014;21:3–8.
Patient consent for publication  Not required. 15 Koh W-­J, Abu-­Rustum NR, Bean S, et al. Cervical cancer, version
3.2019, NCCN clinical practice guidelines in oncology. J Natl Compr
Provenance and peer review  Not commissioned; externally peer reviewed. Canc Netw 2019;17:64–84.
Data availability statement  Data are available upon reasonable request. 16 Cibula D, Pötter R, Planchamp F, et al. The European Society of
Gynaecological Oncology/European Society for Radiotherapy
Supplemental material  This content has been supplied by the author(s). It has and Oncology/European Society of Pathology guidelines for the
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been management of patients with cervical cancer. Int J Gynecol Cancer
peer-­reviewed. Any opinions or recommendations discussed are solely those 2018;28:641–55.
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and 17 Köhler C, Mustea A, Marnitz S, et al. Perioperative morbidity and
responsibility arising from any reliance placed on the content. Where the content rate of upstaging after laparoscopic staging for patients with locally
advanced cervical cancer: results of a prospective randomized trial.
includes any translated material, BMJ does not warrant the accuracy and reliability
Am J Obstet Gynecol 2015;213:503.e1–7.
of the translations (including but not limited to local regulations, clinical guidelines, 18 Marnitz S, Martus P, Köhler C, et al. Role of surgical versus clinical
terminology, drug names and drug dosages), and is not responsible for any error staging in chemoradiated FIGO stage IIB-­IVA cervical cancer
and/or omissions arising from translation and adaptation or otherwise. patients–acute toxicity and treatment quality of the Uterus-11
Open access  This is an open access article distributed in accordance with the multicenter phase III intergroup trial of the German Radiation
Oncology Group and the Gynecologic Cancer Group. Int J Radiat
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
Oncol Biol Phys 2016;94:243–53.
permits others to distribute, remix, adapt, build upon this work non-­commercially, 19 Fine JP, Gray RJ. A proportional hazards model for the
and license their derivative works on different terms, provided the original work is subdistribution of a competing risk. J Am Stat Assoc
properly cited, an indication of whether changes were made, and the use is non-­ 1999;94:496–509.
commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. 20 Uzan C, Souadka A, Gouy S, et al. Analysis of morbidity and clinical
implications of laparoscopic para-­aortic lymphadenectomy in a
continuous series of 98 patients with advanced-­stage cervical
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Marnitz S, et al. Int J Gynecol Cancer 2020;30:1855–1861. doi:10.1136/ijgc-2020-001973 1861