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INTERNATIONAL JOURNAL OF
Are we making progress in curing advanced
GYNECOLOGICAL CANCER
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cervical cancer—again?
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Jacob Christian Lindegaard ‍ ‍,1 Primoz Petric,2 Li-­Tee Tan,3 Peter Hoskin,4 Maximilian P Schmid,5
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Ina Jürgenliemk-­Schulz,6 Umesh Mahantshetty,7 Christian Kirisits,5 Richard Pötter5

ABSTRACT imaging based, image guided adaptive brachytherapy

Major improvements in radiotherapy over the past two have resulted in unprecedented local control rates of
decades in the definitive treatment of locally advanced >90% across all stages, while improving pelvic control
cervical cancer have significantly improved loco-­regional and survival rates by about 10% without increasing
For numbered affiliations see control and survival, whereas little progress has been toxicity.1–4 Compared with three-­ dimensional
end of article. made with chemotherapy since the implementation conformal techniques, the implementation of intensity
of concomitant cisplatin 25 years ago. However, the modulated radiotherapy, volumetric arc radiotherapy,
Correspondence to randomized study INTERLACE (A phase III multicenter
and advanced treatment planning techniques have
Dr Jacob Christian Lindegaard, trial of weekly induction chemotherapy followed by
Department of Oncology, allowed more precise delivery of external beam irra-
standard chemoradiation versus standard chemoradiation
Aarhus University Hospital, alone in patients with locally advanced cervical cancer) diation and, in particular, applying higher doses to
8200 Aarhus, Denmark; ​jacob.​ of neoadjuvant chemotherapy presented recently, has involved lymph nodes while decreasing the irradi-
lindegaard@​auh.​rm.d​ k ated volume of normal tissue, which should further
shown significant improvement in survival with the
use of six cycles of weekly carboplatin and paclitaxel. improve survival and decrease late effects.2
Received 9 April 2024 Although INTERLACE is yet to be published, neoadjuvant In contrast, there has been little progress with
Accepted 25 June 2024 chemotherapy is already being advocated as the the chemotherapeutic aspects of treatment since
new standard, and studies are being designed with randomized studies5 led to the implementation of
neoadjuvant chemotherapy followed by chemoradiation concomitant cisplatin with radiotherapy at the turn of
and brachytherapy as the standard arm. It is noteworthy
the century. Certainly, the study by Dueñas-­Gonzáles
that INTERLACE was initiated before the improvements in
radiotherapy mentioned above were broadly implemented.
et al6 comparing concomitant cisplatin with concom-
The survival rate in the standard arm of INTERLACE was itant cisplatin and gemcitabine followed by adjuvant
therefore inferior to the results obtained with the latest treatment with the same doublet (Table 1) did show
state-­of-­the-­art external beam radiotherapy and image significant improvement in progression free survival.
guided adaptive brachytherapy (EMBRACE, Magnetic However, for many reasons highlighted in the editorial
Resonance Imaging (MRI)-­Guided Brachytherapy in Locally ‘Are we making progress in curing advanced cervical
Advanced Cervical Cancer). Moreover, patient selection cancer’ by Thomas from 2011,7 the cisplatin and
impedes the comparison of INTERLACE with other studies gemcitabine combination was never widely adopted,
as the patients included in INTERLACE were younger, had and concomitant cisplatin has remained standard of
better performance status, and had less advanced disease
care for chemoradiation in locally advanced cervical
than in other studies. Notably patients with involved para-­
aortic nodes were excluded. In this review, we discuss
cancer.8
neoadjuvant chemotherapy in the frame of the EMBRACE On this backdrop, it is understandable that a break-
studies and show how the impact of modern radiotherapy through in medical oncology would be highly appre-
and patient selection affects the interpretation of the ciated. With the presentation of the INTERLACE study
results of INTERLACE. This has led us to conclude that at ESMO 20239 showing a significant improvement
neoadjuvant chemotherapy is not needed for the majority in both progression free survival and overall survival
of patients with cervical cancer treated with definitive with the use of a short course of neoadjuvant carbo-
modern radiotherapy, and may cause harm. However, it platin and paclitaxel (Table 1), pressure is rising to
is possible that short course neoadjuvant chemotherapy adopt neoadjuvant chemotherapy as the new stan-
may benefit a minor subgroup of patients who need to be
dard to be combined with definitive radiotherapy.10
identified. Comprehensive understanding, including cost
© IGCS and ESGO 2024. Re-­use
utility analyses, are needed to draw conclusions regarding The full publication of the INTERLACE study is still
permitted under CC BY-­NC. No pending; however, based on the available information,
commercial re-­use. Published the potential benefit of neoadjuvant chemotherapy in
by BMJ. low and middle income countries with limited access to the encouraging results of this study are not consis-
modern radiotherapy. tent with existing evidence on the clinical outcome
To cite: Lindegaard JC,
of advanced image guided definitive radiotherapy in
Petric P, Tan L-­T, et al. Int J
Gynecol Cancer Published cervical cancer,2–4 8 raising the justifiable question
Online First: [please include During the past 20 years, there have been major of whether the demonstrated benefit of neoadjuvant
Day Month Year]. doi:10.1136/ improvements in definitive radiotherapy for cervical chemotherapy in INTERLACE is only valid in compar-
ijgc-2024-005572 cancer. Implementation of magnetic resonance ison with less than optimal radiotherapy.

Lindegaard JC, et al. Int J Gynecol Cancer 2024;0:1–6. doi:10.1136/ijgc-2024-005572 1

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Table 1 Comparison of patient and treatment characteristics in the study of Duenas-­Gonzales et al,6 INTERLACE,9 and
EMBRACE-­I3 in relation to progression free survival and overall survival
Dueñas-­Gonzáles INTERLACE EMBRACE-­I
CRT CRT+ACT CRT NACT-­CRT CRT
No of patients 256 259 250 250 1341
Age (years), median 46 45 46 46 49
Performance status (WHO) >0 (%) Unknown Unknown 12 14 28
*
FIGO2009 III–IVA (%) 39 38 14 13 20
N1 (pelvic)† (%) NA NA 43 42 43
†
N2 (para-­aortic) (%) Excluded Excluded 8
EBRT dose (Gy), median and range 50.4 40–50.4 45–50
Nodal EBRT boost Not given Unknown Yes
Elective para-­aortic EBRT Not given Unknown Yes
BT technique IC IC IC or IC/IS
BT target Point A Point A (70%) CTVHR
EBRT+BT dose (Gy), range, minimum, 80–85 >78 EQD2‡ 90 EQD2
median
PFS 3 year (%) 65 74 72 75 72§
PFS 5 year (%) 62 71 64 73 68§
OS 3 year (%) 70 78 80 86 81
OS 5 year (%) 64 75 72 80 74

*Stage according to FIGO200938 which in this context is equivalent to T stage in the American Joint Committee on Cancer Tumor, Node,
Metastasis system.
†N stage according to the American Joint Committee on Cancer, Tumor, Node, Metastasis system39
‡Equivalent dose in 2 Gy fractions.
§Disease free survival (events were persistent/recurrent disease or death from any cause). In EMBRACE-­I, disease free survival was
used as a substitute for progression free survival.
ACT, adjuvant chemotherapy; BT, brachytherapy; CRT, concomitant chemotherapy and radiotherapy; CTVHR, high risk clinical target
volume; EBRT, external beam radiotherapy; EMBRACE-­1, Magnetic Resonance Imaging (MRI)-­Guided Brachytherapy in Locally
Advanced Cervical Cancer trial; FIGO, International Federation of Gynecology and Obstetrics; IC, intracavitary; INTERLACE, A phase
III multicenter trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in
patients with locally advanced cervical cancer; IS, interstitial; NA, not available; NACT, neoadjuvant chemotherapy; OS, overall survival;
PFS, progression free survival.

Previous attempts with neoadjuvant chemotherapy followed by technique, which does not comply with current recommendations.8
definitive radiotherapy in locally advanced cervical have largely Nevertheless, the investigators stated in their presentation that the
failed.8 Recently, two randomized phase III studies on neoadjuvant radiotherapy used in both arms of INTERLACE reflected best clinical
carboplatin and paclitaxel administered before surgery in stage practice.
IB–IIB were also negative.11 12 The combination of carboplatin and The investigators also stated that overall survival in the stan-
paclitaxel in the adjuvant setting after chemoradiation likewise dard arm was similar to that reported in the recent published liter-
showed no benefit in the OUTBACK (Cisplatin and Radiation Therapy ature. However, the INTERLACE cohort had fewer locally advanced
With or Without Adjuvant Carboplatin and Paclitaxel in Patients With primary tumors and less extensive nodal disease than, for instance,
Locally Advanced Cervical Cancer) study.13 In addition, platinum– in EMBRACE-­I (Table 1). Moreover, patients with involved para-­
paclitaxel based chemotherapy without bevacizumab or immuno- aortic nodes were excluded. Notably, the relative improvement of
therapy had moderate activity in recurrent, persistent, or metastatic progression free survival in INTERLACE mirrors the results of the
disease.14–17 study of Dueñas-­Gonzáles et al in 2011,6 which more or less was
There are several issues in the INTERLACE study which raise based on the same technique, dose, and fractionation of external
concerns about the applicability of the results in the context of beam radiotherapy and brachytherapy, but performed in patients in
state-­of-­the art radiotherapy. Brachytherapy was by the intracav- a more advanced stage (Table 1). Comparison with state-­of-­the-a­ rt
itary technique only and mainly point A based (70%), with no opti- radiotherapy, as for example in EMBRACE-­I, is difficult mainly due
mization to the actual tumor volume, which is substantially inferior to patient selection. However, by excluding patients with para-­aortic
to the current standard, as defined in the multidisciplinary Euro- nodes (N2 stage) and by calibrating the local tumor stage by the use
pean guidelines.8 We do not yet have detailed information about of the T-s­ core,18 it was possible to create an EMBRACE cohort with
the external beam radiotherapy technique in INTERLACE but in at least a comparable T and N stage distribution as in INTERLACE
59% of patients it was delivered by a three-­dimensional conformal (Table 2). When viewed against this more comparable cohort, it is

2 Lindegaard JC, et al. Int J Gynecol Cancer 2024;0:1–6. doi:10.1136/ijgc-2024-005572

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Table 2 Comparison of INTERLACE9 with EMBRACE-­I4 18 based on patient selection of INTERLACE-­like patients in
EMBRACE-­I by excluding patients with para-­aortic nodes (N2) and with T stage calibration by using the T-­score (ie,
INTERLACE-­like: N2=0 and T-­score <11)
INTERLACE EMBRACE-­I
CRT NACT+CRT INTERLACE-­like CRT Other CRT
No of patients 250 250 1141 177
Age (years) (median) 46 46 49 53
Performance status >0 (WHO) (%) 12 14 25 44
Comorbidity (%) Unknown Unknown 28 31
T3-­T4 (FIGO2009 III–IVA)* (%) 14 13 14 63
N1 (pelvic)* (%) 43 42 48 25
N2 (para-­aortic)* (%) 0 0 57
EBRT dose (Gy) (range/median) 40–50.4 45 45
Nodal EBRT boost (%) Unknown 32 57
Elective para-­aortic EBRT (%) Unknown 11 52
EBRT+BT dose (Gy) (minimum/median) >78 EQD2 90 EQD2 88 EQD2
Completed five weekly cisplatin (%) 79 68 71 55
Total local/pelvic relapse (%) 16 16 12 18
Total distant relapse† (%) 20 12 16 33
Total relapse (%) 28 22 23 41
PFS 3 year (%) 72 75 76‡ 56‡
PFS 5 year (%) 64 73 72‡ 47‡
OS 3 year (%) 80 86 84 68
OS 5 year (%) 72 80 78 57
For this exercise, a cohort of 1318 patients from EMBRACE-­I with complete information on disease stage was used.4 Overall survival was
available for both INTERLACE and EMBRACE-­I, whereas disease free survival was used as a substitute in EMBRACE-­1 to compare with
progression free survival in INTERLACE.
*T and N stage distribution according to the American Joint Committee on Cancer, Tumor, Node, Metastasis system, V.9.39
†Including para-­aortic relapse.
‡Disease free survival (events were persistent/recurrent disease or death from any cause).
BT, brachytherapy; CRT, concomitant chemotherapy and radiotherapy; EBRT, external beam radiotherapy; EMBRACE-­1, Magnetic
Resonance Imaging (MRI)-­Guided Brachytherapy in Locally Advanced Cervical Cancer trial; EQD2, equivalent dose in 2 Gy fractions; FIGO,
International Federation of Gynecology and Obstetrics; INTERLACE, A phase III multicenter trial of weekly induction chemotherapy followed
by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer; NACT, neoadjuvant
chemotherapy; OS, overall survival; PFS, progression free survival.

obvious that the results obtained in the standard arm of INTERLACE of clonogenic cells occurring simultaneously after a limited dose
were inferior to EMBRACE-­I.3 Thus neoadjuvant chemotherapy is of radiotherapy,20 which is likely to also be relevant for chemo-
merely compensating for suboptimal radiotherapy (Figure 1), which therapy.21 In addition, for the 30% of patients with no response to or
will be further evident with the imminent results of EMBRACE-­II2, progressive disease after neoadjuvant chemotherapy, the outlook
entailing full integration of intensity modulated external beam for obtaining loco-­ regional control with radiotherapy is clearly
radiotherapy, including simultaneous integrated nodal boost and diminished in a tumor environment with acquired resistance and an
risk adapted elective para-­aortic irradiation as well as magnetic increased number of clonogenic cells.
resonance image guided adaptive brachytherapy with combined A reduction in the event rate of total systemic/para-­aortic relapse
intracavitary/interstitial implantation techniques. from 16% in the 'Interlike' cohort of EMBRACE-­I to 12%, as reported
From the relapse pattern, it appears that the effect of neoad- for the neoadjuvant chemotherapy arm in INTERLACE (Table 2), will
juvant chemotherapy on survival in INTERLACE likely is due to a require that 25 patients receiving optimal radiotherapy are treated
reduction in systemic relapse from 20% to 12%, whereas neoadju- with neoadjuvant chemotherapy to prevent one systemic/para-­
vant chemotherapy had no impact on overall loco-­regional control aortic event, and that neoadjuvant chemotherapy is needlessly
(Table 2). From the phase II study preceding INTERLACE, a 70% given to 96% of patients.22 From the EMBRACE-­I data, subgroups
response rate is expected from dose dense neoadjuvant chemo- with a very low risk of recurrence (including systemic) have been
therapy, as used in INTERLACE.19 The lack of impact of response to identified where treatment de-­escalation is even being considered.
chemotherapy on loco-­regional control is in line with the preclin- For this low risk group, the percentage of needless use of neoadju-
ical observation of volume regression and accelerated repopulation vant chemotherapy will likely approach 100%. As we can assume

Lindegaard JC, et al. Int J Gynecol Cancer 2024;0:1–6. doi:10.1136/ijgc-2024-005572 3

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Figure 1 Progression free survival and overall survival in INTERLACE (a phase III multicenter trial of weekly induction
chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced
cervical cancer), reconstructed from the graphics presented at the 2023 ESMO congress. The reconstructed curves are not
based on actual numeric data. Data points of the EMBRACE 1 (Magnetic Resonance Imaging (MRI)-­Guided Brachytherapy
in Locally Advanced Cervical Cancer) 'Interlike' cohort are projected over the INTERLACE curve sketches. The EMBRACE 1
'Interlike' cohort was selected to mirror the INTERLACE patients, specifically with regard to the absence of para-­aortic nodal
metastases. However, the 'Interlike' patients were older, and had more advanced stages and worse performance status than
INTERLACE patients. Nevertheless, the EMBRACE 1 'Interlike' data points overlap with the sketched INTERLACE curve for
induction chemotherapy up to the 5 year mark, before deviating downwards. Notably, the number of patients remaining for
analysis after 5 years is low, and only a small proportion of events occurred after 5 years in EMBRACE 1. It can be argued
that the neoadjuvant chemotherapy is merely compensating for suboptimal radiotherapy of the INTERLACE study. NACT,
neoadjuvant chemotherapy; CRT, chemoradiation; pts, patients.

that para-­aortic recurrences are included as systemic in INTER- and local tumor burden,25–27 as is also demonstrated by the 'non-­
LACE and knowing that para-­aortic recurrence was a common site INTERLACE like' EMBRACE-­I cohort (Table 2). Thus normal tissue
of recurrence in EMBRACE-­I,23 it is also likely that the increased reserves, including bone marrow, are limited in real world patients.
use of elective para-­aortic radiotherapy in high risk N1 patients By expending these reserves on unnecessary neoadjuvant chemo-
in EMBRACE-­II will address this problem in a more selective and therapy, we run the risk of compromising the curative treatment for
better tolerated way.24 Thus preliminary data from EMBRACE-­II are the many patients who are not fit for trials. In addition, prolonged
showing a 5% reduction in the event rate of extra-­pelvic recur- leukopenia and thrombocytopenia may prevent timely delivery of
rences compared with EMBRACE-­I. Results for distant control after image guided brachytherapy with interstitial needles, leading to
optimal radiotherapy, as in EMBRACE-­II, are then comparable with further prolongation of overall treatment time with additional nega-
those achieved in the experimental arm of INTERLACE. tive impact on local tumor control.
We acknowledge that it is unusual to comment on a study which The notion of using neoadjuvant chemotherapy as a strategy
at the moment is available only as an abstract9 and from a meeting to bridge long waiting times for radiotherapy and/or compen-
presentation. But there is increasing pressure in our clinical prac- sate for the absence of advanced external beam radiotherapy
tice to immediately incorporate neoadjuvant chemotherapy as the and brachytherapy in low and middle income countries, but also
new standard before the publication of INTERLACE.10 In our view, some high income countries, is appealing. The INTERLACE study
this is a premature and retrograde step which is not consistent with concluded that neoadjuvant chemotherapy was feasible in all
evidence based medicine. Like many trials, the INTERLACE cohort countries, including low and middle income countries.9 However,
was a highly selected cohort of young patients with good perfor- INTERLACE was not designed to address the question of world-
mance status and limited tumor load. Despite this, there was a 11% wide feasibility of neoadjuvant chemotherapy. Only 112 (22%) of
drop in the percentage of patients being able to complete five cycles the included patients were from low and middle income countries
of concomitant cisplatin after neoadjuvant chemotherapy. In the and 100 (89%) of them were from the National Cancer Institute
real world, use of concomitant cisplatin in patients not participating in Mexico (upper middle income country). In fact, the outcome
in studies is highly variable (40–77%) and there is a high dropout of neoadjuvant chemotherapy in the real world settings of low
rate (30–60%) depending on age, performance status, comorbidity, and middle income countries would likely be inferior to standard

4 Lindegaard JC, et al. Int J Gynecol Cancer 2024;0:1–6. doi:10.1136/ijgc-2024-005572

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treatment, since the success of neoadjuvant chemotherapy criti- Author affiliations
1
cally depends on chemotherapy compliance and uninterrupted Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
2
Department of Radiation Oncology, University Hospital Zürich, Zürich, Switzerland
transition from neoadjuvant chemotherapy to chemoradiation, 3
Department of Oncology, Cambridge University Hospitals NHS Foundation Trust,
which are both more than challenging in low and middle income Cambridge, UK
countries.28 29 4
Mount Vernon Cancer Centre, Northwood, UK
5
Furthermore, the INTERLACE study did not address cost utility Department of Radiation Oncology, Comprehensive Cancer Center, Medical
University of Vienna, Vienna, Austria
aspects. Access to external beam radiotherapy and brachytherapy 6
Department of Radiation Oncology, University Medical Center Utrecht, Utrecht,
is essential for cervical cancer treatment but remains restricted Netherlands
in low and middle income countries despite international 7
Radiation Oncology, Homi Bhabha Cancer Hospital and Research Center,
efforts28 30 and the fact that even simple external beam radio- Visakhapatnam, India
therapy and brachytherapy with optimal overall treatment time can
Contributors Planning of the manuscript was done by JCL, PP, and RP. Figure 1
yield good results.31 Likewise, in our experience with educational
was drawn by PP and JCL. The tables were produced by JCL, RP, and CK. The
work through the European Society for Radiotherapy and Oncology manuscript was written by JCL with substantial contribution and support from all
(https://www.estro.org), the Groupe Européen de Curiethérapie co-­authors: PP, LTT, PH, MPS, IJ-­S, UM, CK, and RP.
(https://www.estro.org/About/ESTRO-Organisation-Structure/​ Funding The authors have not declared a specific grant for this research from any
Committees/GEC-ESTRO-Committee), EMBRACE,32 International funding agency in the public, commercial, or not-­for-­profit sectors.
Commission on Radiation Units and Measurements,1 and Brachy- Competing interests None declared.
Terra (https://brachyterra.thinkific.com/), experts from low and Patient consent for publication Not applicable.
middle income countries are keen and able to adopt modern Ethics approval Not applicable.
external beam radiotherapy and brachytherapy, achieving excel-
Provenance and peer review Not commissioned; externally peer reviewed.
lent outcomes and cost effectiveness,33 34 but often face the barrier
Open access This is an open access article distributed in accordance with the
of costly and scarce training opportunities.35 In this context, and Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
despite the comparatively low per patient cost of the INTERLACE permits others to distribute, remix, adapt, build upon this work non-­commercially,
drug regimen, the cumulative expenditure due to the high incidence and license their derivative works on different terms, provided the original work is
of cervical cancer could strain the already limited oncology budgets properly cited, an indication of whether changes were made, and the use is non-­
commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
of low and middle income countries. Therefore, the use of neoadju-
vant chemotherapy to bridge waiting times, compensate for subop- ORCID iD
timal radiotherapy, or as a shortcut to bypass training, introduces Jacob Christian Lindegaard http://orcid.org/0000-0003-2426-7255
the risk of diverting funds from the critically needed long term
investments into radiotherapy infrastructure and education. More- REFERENCES
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