Gynecologic Oncology 168 (2023) 32–38

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Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Image-guided adaptive brachytherapy for advanced cervical cancer

spreading to the bladder and/or rectum: Clinical outcome and
prognostic factors
Kanta KA a, Adrien Laville a, Elie Rassy b, Radouane EL Ayachi a, Patricia Pautier b, Mouhamadou Bachir BA a,
Sophie Bockel a, Samir Achkar a, Sophie Espenel a, Amandine Maulard c, Philippe Morice c, Sébastien Gouy c,
Christine Haie-Meder a, Roger Sun a, Cyrus Chargari a,⁎
a
Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France
b
Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France
c
Surgical Oncology, Gustave Roussy Cancer Campus, Villejuif, France

H I G H L I G H T S

• Dose escalation through combined intracavity/interstitial brachytherapy techniques improves local control in locally advanced cervical cancer
• In this study, the following factors were associated with poorer survival without local failure: moderately to poorly differentiated grade, a D90 CTVIR dose <63.5
GyEQD2 and a vesico-vaginal fistula formation
• A transverse tumor dimension >55 mm was predictive of fistula during external radiotherapy

a r t i c l e i n f o a b s t r a c t

Article history: Introduction. Refinements of brachytherapy techniques have led to better local control of locally advanced
Received 16 September 2022 cervical cancer (LACC), especially with the development of image-guided adaptive brachytherapy (IGABT).
Received in revised form 29 October 2022 Data on the efficacy of brachytherapy in cervical cancer spreading to adjacent organs are scarce. We report the
Accepted 1 November 2022
experience of our institution in the treatment of these advanced tumors with IGABT.
Available online 9 November 2022
Materials and methods. Medical records of patients treated for a LACC spreading to the bladder and/or rectum
Keywords:
between 2006 and 2020 at Gustave Roussy Institute were analyzed. Dosimetric parameters were collected and
Cervical cancer, image-guided brachytherapy, converted into 2 Gy per fraction equivalent doses, including the minimal dose received by 90% of the high-risk
prognostic factors target volume (D90 CTVHR) and intermediate-risk target volume (D90 CTVIR), as well as the dose received by
Radiation oncology the most exposed 2 cm3 of the organs at risk. A Cox regression model was used to study the potential associations
Radiotherapy between clinical and dosimetric factors with survival endpoints and fistula formation.
Results and statistical analysis. A total of 81 patients were identified. All patients received pelvic+/− para-
aortic radiotherapy, 45 Gy in 25 fractions +/− boost to gross lymph nodes. Concomitant platinum-based chemo-
therapy was administered in 93.8% of cases. The median D90 CTVHR dose was 75.5 GyEQD2 (SD: 10.39 GyEQD2) and
median CTVHR volume was 47.6 cm3 (SD: 27.9 cm3). Median bladder and rectal D2cm3 dose were 75.04 GyEQD2
(SD: 8.72 GyEQD2) and 64.07 GyEQD2 (SD: 6.68 GyEQD2). After a median follow-up of 27.62 ± 25.10 months, recur-
rence was found in 34/81 patients (42%). Metastatic failure was the most common pattern of relapse (n = 25).
Use of a combined interstitial/intracavitary technique and D90 CTVHR ≥ 75.1 GyEQD2 were prognostic factors for
OS in univariate analysis (HR = 0.24, 95%IC: 0.057–1, p = 0.023; HR = 0.2, 95%IC: 0.059–0.68, p = 0.0025, re-
spectively). In multivariate analysis, a D90 CTVHR ≥ 75.1 GyEQD2 was significant for OS (HR = 0.23; 95%IC: 0.07,
0.78, p = 0.018). The occurrence of vesicovaginal fistula (VVF) was the most frequent pattern of local recurrence
(HR = 4.6, 95%CI: 1.5–14, p = 0.01).

⁎ Corresponding author at: Department of Radiation Oncology, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, 94800 Villejuif, France.
E-mail address: cyrus.chargari@gustaveroussy.fr (C. Chargari).

https://doi.org/10.1016/j.ygyno.2022.11.002
0090-8258/© 2022 Elsevier Inc. All rights reserved.

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K. KA, A. Laville, E. Rassy et al.
Conclusion. Advances in brachytherapy modalities improved local control and survival while reducing toxic-
ities. Enhancing local control through dose escalation and combined intracavitary/interstitial brachytherapy
techniques is a major factor in patients cure probability, together with systemic intensification to better control
distant events.
1. Introduction
Cervical cancer is the second most common cancer in women world-
wide in terms of incidence and mortality with a high prevalence in de-
veloping countries, where tumors are frequently diagnosed at an
advanced stage. The standard treatment for locally advanced cervical
cancer (LACC) consists of concomitant cisplatin-containing radioche-
motherapy followed by a brachytherapy boost [1,2]. This regimen
allows dose-escalation and increases the odds of curing patients [3]. In
the past years, the advances in brachytherapy techniques (e.g. integra-
tion of 3D image guidance, development of modern applicators)
translated into higher local control and progression-free survival prob-
abilities, in parallel with a decrease in the incidence of severe normal
tissue complications [3–7].
According to the 2018 International Federation of Gynecology and Ob-
stetrics (FIGO) classification, Stage Iva or T4 cervical cancers are defined
primary cervical tumors involving the bladder and/or the rectum, what-
ever the nodal status [8]. This presentation is quite rare in countries
with robust economies, accounting for approximately 2–3% of all cervi-
cal cancer cases, but more frequent in countries with limited access to
screening strategies. The management of stage T4 cervical cancer is
challenging, given the high incidence of fistula and technical difficulties
to achieve dose escalation in very advanced tumors [5]. In addition, data
on the feasibility and efficacy of brachytherapy in stage T4 are very lim-
ited [9–11]. It has been shown that patients with tumor spread to adja-
cent pelvic organs were less likely to receive brachytherapy boost,
correlating with a higher probability of local relapse, and yielding to
poor 5-year overall survival (approximately 20%) [12;13].
We report our experience of image-guided adaptive (IGABT) for the
treatment of patients with cervical cancer extending to adjacent pelvic
organs (bladder and/or rectum), with a focus on disease control and
functional outcome.
2. Materials/methods
2.1. Patient selection
Clinical and treatment data of patients with histologically confirmed
LACC extending to the bladder and/or rectum and referred to our insti-
tution for an image-guided brachytherapy boost from 2006 to 2020
were collected in a retrospective study. Patients were included if they
had radiological evidence of bladder and/or rectal at magnetic reso-
nance imaging (MRI) or following cystoscopy and/or rectoscopy, even
without histological confirmation of mucosal involvement. As bladder
and/or rectal biopsies can potentially increase the risk of fistula without
impact on treatment modalities, those are usually not systematically
performed in our center. The most recent update of FIGO classification
system recommends that the bladder and rectum should be evaluated
by cystoscopy and sigmoidoscopy only if the patient is clinically symp-
tomatic. In addition, it allows using various imaging modalities to sup-
plement clinical findings with respect to tumor size and extent, in all
stages [8]. Patients also had a 18-fluorodeoxyglucose positrons emission
tomography/computed tomography (18-FDG PET/CT) as part of their
primary staging. Patients without para-aortic lymph node uptake
could undergo a para-aortic lymph node dissection to guide radiother-
apy volumes. This retrospective study was conducted in accordance
33
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Gynecologic Oncology 168 (2023) 32–38
© 2022 Elsevier Inc. All rights reserved.
with the ethical standards of the 1964 Declaration of Helsinki and its
amendments and was approved by a local ethics committee (registra-
tion code: 2022–145).
2.2. Radiochemotherapy
Patients were treated with pelvic external beam radiotherapy
(EBRT). The para-aortic area was included in patients with radiological
signs or histological evidence of para-aortic lymph node metastases.
EBRT was delivered through daily fractions of 1.8 to 2 Gy. EBRT modality
was either conformal radiotherapy or intensity-modulated radiother-
apy. Concomitant chemotherapy based on weekly cisplatin 40 mg/m2
was delivered unless renal contraindication in which case carboplatin
AUC2 was preferred. Macroscopic lymph nodes (pelvic or para-aortic)
were boosted to a total dose of 60 Gy, taking into account the contribu-
tion of brachytherapy. Patients with symptoms of vesicovaginal and/or
recto-vaginal fistulas underwent urinary and/or digestive diversion
prior to radiochemotherapy.
2.3. Brachytherapy indication
After external radiation therapy, the feasibility of brachytherapy was
discussed according to findings from clinical examination and an MRI
performed at a total dose of 40–45 Gy. If deemed technically feasible,
patients received an intracavitary uterovaginal brachytherapy boost
[4;5]. Brachytherapy was not considered in patients with persistence
of major symptoms of fistula despite urinary and/or digestive diversion.
In this situation of non-feasibility, it was discussed an EBRT boost or an-
terior pelvectomy, depending on operability and the possibility to
achieve histologically complete resection.
2.4. Brachytherapy technique
Procedures for catheterization were performed under general anes-
thesia and guided by transabdominal ultrasound. Intracavitary or com-
bined intracavitary/interstitial procedures were applied. Image-guided
adaptive brachytherapy (IGABT) was used, with a treatment planning
relying on an MRI performed with an applicator in place and through
continuous hourly pulses (PDR: pulse dose rate) were delivered
through Iridium-192 stepping source. Target volumes and organs at
risk (OARs) were delineated on T2-weighted MRI (preferred) or CT, tak-
ing into account data from a recent MRI performed without the applica-
tor. The high-risk clinical target volume (CTVHR) included the cervix and
residual disease at the time of brachytherapy. Parts of the bladder and/
or rectum could be included in the CTVHR if involved on the treatment
planning MRI. The intermediate-risk clinical target volume (CTVIR)
was defined as an anatomical expansion from the CTVHR by adding a
3D margin of 5–15 mm, to take into account the microscopic residuum,
and initial tumor extents, including parts of the bladder and/or rectum
that were initially involved [9]. Doses were converted into radiobiologi-
cally equivalent doses of 2 Gy/fraction (EQD2), using the linear-quadratic
model for calculation (half-time of repair: 1.5 h, α/β ratio = 10 Gy) and
3 Gy for target volumes and OARs, respectively [6]. The planning aim
was to deliver at least 60 GyEQD2 at 95% of the CTVIR, without exceeding
dose constraints of 75 GyEQD2, 75 GyEQD2 and 85 GyEQD2 at the most
irradiated 2cm3 (D2cm3) of the rectum, sigmoid colon and bladder,
K. KA, A. Laville, E. Rassy et al. Gynecologic Oncology 168 (2023) 32–38

Fig. 1. Example of a patient with stage cervical cancer involving the bladder on sagittal T2 magnetic resonance imaging (MRI).
On the left: MRI at diagnosis, showing massive infiltration of posterior bladder wall, histologically confirmed as squamous cell carcinoma.
On the middle, MRI at time of brachytherapy showing good partial response. A combined intracavitary/interstitial technique was used.
On the right: MRI after 8 months follow-up showing complete local remission and no symptom of fistula.

respectively [10]. Dose escalation to the CTVHR was assumed without
exceeding OARs dose constraints. An example of treatment is shown
in Fig. 1.
2.5. Follow-up and statistical analysis
Follow-up was performed at 6–8 weeks after brachytherapy, then
every 3 months for 2 years, then every 6 months until the 5th year,
then annually thereafter. MRI scans were routinely performed 6–8
weeks after brachytherapy and then every 6 months for two years,
then every year for three additional years. Additional imaging proce-
dures (18-FDG PET/CT) were conducted if clinically indicated. Failures
were classified into local (relapse in the cervix, uterine corpus, vagina,
parametrium, bladder or rectum), regional (relapse in the pelvic
lymph nodes) or distant (relapse in the para-aortic nodes or distant
sites) failures. All relapses were considered, not only first events. Local
control (LC) rate (absence of local relapse), progression-free survival
(PFS), and overall survival (OS) were calculated using the Kaplan-
Meier method and Cox proportional hazards survival estimates. Factors
for local control and fistula formation were examined. Wilcoxon and
Fisher's tests were used for comparisons between variables. For analy-
ses of continuous variables, the median was used to separate patients
into two groups. Follow-up and survival times were calculated from
the date of histopathologic diagnosis. P values were estimated using 2-
tailed tests. A threshold of <0.05 was defined for significance. No redun-
dant variables with P values <0.1 were included in the multivariate
analyses. Statistical analyses were performed using R version 3.3.2
[11] (http://www.R-project.org) and the R-package “survival” (version
2.40–1 [12]).
3. Results
3.1. Patients and tumors characteristics
A total of 84 patients referred for IGABT boost for a stage T4 cervical
cancer were identified. Three patients were contra-indicated for
brachytherapy. Two among them had vesicovaginal fistula measuring
6 cm3 and 9 cm2 in area with symptoms despite urinary diversion and
were treated with anterior pelvetomy following EBRT. The third patient
had catheterization failure and was treated with EBRT boost.
Brachytherapy could be performed in 81/84 (97%) patients who
were, therefore, eligible for study inclusion. The median age was 54.6
years. Seventy (86%) had bladder involvement only, five (6%) had rectal
involvement only, and six (7%) had both bladder and rectal involve-
ment. Among them, 17 patients (21%) had endoscopic confirmation of
organ extension and the remaining patients had involvement of adja-
cent organs at MRI. A total of 56 (69%) patients had lymph node exten-
sion. The most cranial site of lymph node extension was pelvic in 27
patients and para-aortic in 29 patients. Patients and tumors characteris-
tics are detailed in Table 1.
3.2. EBRT characteristics
EBRT characteristics are summarized in Table 2. All 81 patients un-
derwent external beam radiotherapy with a total dose of 45 Gy in
1.8 Gy per fraction. Among the 81 patients, 25 (31%) had their whole
treatment delivered in our department and 56 (69%) were referred for
brachytherapy boost after receiving EBRT in other centers. Ten patients
(13%) primary treated in other institutes had induction chemotherapy
because of the fear that upfront radiotherapy would favor fistula forma-
tion. All patients primarily treated in our center were treated with up-
front radiotherapy. Concomitant chemotherapy was delivered in 76
patients (94%). Among them, the median number of chemotherapy cy-
cles was 5 (range: 3–6). Thirty patients (37%) had a ureteral catheter
placed prior to EBRT because of hydronephrosis and nine patients had
urinary diversion (pyelostomy).
3.3. Brachytherapy characteristics
All patients had an intracavitary procedure and among them 25
(31%) were treated with a combined intracavitary/interstitial tech-
nique. Among patients treated with a combined intracavitary/intersti-
tial technique, the median number of interstitial catheters per patient
was 6 (range: 2–12). The median of the minimal dose delivered to
90% of the CTVHR (D90 CTVHR) was 75.5 GyEQD2 (SD: 10.39 GyEQD2) and
median CTVHR volume was 47.65 cm3 (SD: 27.9 cm3). The median
minimal dose delivered to 90% of the CTVIR (D90 CTVIR) was 64 GyEQD2
(SD: 7 GyEQD2). Median bladder D2cm3 was 75.04EQD2 (SD: 8.72
GyEQD2). Median rectal D2cm3 was 64.07EQD2 (SD: 6.68 GyEQD2).
When comparing patients treated with BT in 2006–2014 (n = 29) and
those treated in 2015–2020 (n = 52), a combined interstitial/intracavi-
tary technique was more frequently used in the recent treatment period
of treatment: 4/29 (14%) in 2006–2014 versus 21/52 (41%) in
2014–2020 (p = 0.01). As a consequence, mean D90 CTVHR increased

34

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Table 1 Table 2
Characteristics of the 81 patients treated with IGABT. Characteristics of treatment.

Characteristics No. of patients (%) Characteristics No. of patients (%) /

median (SD)
N 81
Age (years) Mean ± SD 54.6 ± 13.17 Neoadjuvant CT 10 (12.3)
PS 0 37 (45.7) Concurrent chemotherapy use 76 (93.8)
1 32 (39.5) Number of concurrent chemotherapy cycles 4.08 ± 1.51
2 10 (12.3) Pelvic radiotherapy dose Mean ± SD 45.11 ± 0.59
3 2 (2.5) Sequential radiation boost Pelvic nodes 53.73 ± 2.99
BMI Mean ± SD 23.97 ± 5.67 Para-aortic 54.27 ± 6.69
Follow-up time (months) Mean ± SD 27.62 ± 25.10 nodes
Invasion of bladder 76 (93.8) Groins 55 ± NA
Invasion of rectum 11 (13.6) Brachytherapy PDR 81 (100)
Rectoscopy 3 (3.7) Combined IC/IS technique Yes 25 (30.9)
Vaginal invasion Yes 67 (82.7) No 56 (69.1)
Lower third 14 (17.3) Number of interstitial needles Mean ± SD 6.24 ± 3.54
involvement OTT (from the start of RT to the end of Mean ± SD 58.12 ± 16.33
Transversal dimension (mm) mean ± SD 57.77 ± 16.6 BT)
Antero-posterior dimension (mm) mean ± SD 46.79 ± 12.6 Median TRAK(cGy.h−1.m−1) 1.60 ± 0.63
Hydronephrosis Unilateral 30 (37.0) Median CTVHR D90(Gyα/β10) dose 75.49 ± 10.19
Bilateral 15 (18.5) Median CTVIR D90(Gyα/β10) dose 64.55 ± 7.17
No 50 (61.7) Bladder D2cm3 (Gyα/β3) 75.04 ± 8.72
TNM T4a N0 M0 25 (30.9) ICRU (Gyα/β3) 69.69 ± 11.84
T4a N1 M0 29 (35.8) Rectum D2cm3 (Gyα/β3) 64.07 ± 6.68
T4a N2 M0 27 (33.3) ICRU (Gyα/β3) 58.23 ± 6.31
Nodal involvement at 18-FDG PET/CT Yes 50 (61.7) Sigmoid D2cm3 (Gyα/β3) 56.13 ± 11.14
Pelvic nodes 10 (12.3)
BT: brachytherapy; TRAK: total reference air kerma; HR-CTV: high-risk clinical target vol-
unilateral
ume; IC/IS: intracavitary/interstitial; ICRU: international commission on radiation units;
Pelvic nodes 16 (19.8)
IR: intermediate-risk clinical target volume: OTT: overall treatment time; PDR: pulse
bilateral
dose rate; RT: radiation therapy; SD: standard deviation.
Para-aortic nodes 19 (23.5)
Histology Squamous cell 71 (87.7)
carcinoma
Adenocarcinoma 9 (11.1)
Other 1 (1.2)
without local failure: 1/ moderately to poorly differentiated grade
Differentiation Low 23 (28.4) (HR = 0.26, 95%CI: 0.057–1.2, p = 0.044); 2/ a D90 CTVIR dose <63.5
Moderate 24 (29.6) GyEQD2 (HR = 0.07, 95%CI: 0.01–0.64, p = 0.017, respectively); 3/ a
High 32 (39.5) vesico-vaginal fistula formation (HR = 4.6, 95%CI: 1.5–14, p = 0.01).
Unknown 2 (2.5)
Performance status was significant for OS. A D90 CTVHR dose ≥75.1
Preexisting vesico-vaginal and/or 12 (14.8)
rectal fistula GyEQD2 was significant for OS (HR = 0.2, 95%CI: 0.059–0.68, 0.0025).
Median D90CTVHR dose was 66.5 GyEQD2 among patients with local
BMI: body mass index; PS: performance status according to the World Health Organiza-
tion; SD: standard deviation;TNM: tumor node metastasis staging system; 18-FDG PET/ relapse, versus 75 GyEQD2 among patients without local relapse (p =
CT: 18 fluorooxyglucose positons emission tomography. 0.03). Use of a combined intracavitary/interstitial technique was
significant for OS (HR = 0.2, 95%CI: 0.059–0.68, p = 0.04).
In multivariate analysis, performance status was significant for OS
over time: 69 GyEQD2 prior in 2006–2014 versus 79 GyEQD2 in 2015–2020 (HR = 3.08, 95%CI: 1.13–8.36, p = 0.026) and a D90 CTVHR ≥ 75.1
(p = 0.02). The difference in terms of D90CTVIR did not reach significance GyEQD2 was significant for OS, (HR = 3.08, 95%CI: 1.13–8.36, p =
(61.5 GyEQD2 versus 69.5 GyEQD2, p = 0.2). There was no significant 0.026). PFS was not significant in performance status, use of interstitial
difference in terms of bladder and rectum D2cm3 doses between needles (HR = 2.06, 95%CI: 0.91–4.62, p = 0.08 and HR = 0.52, 95%CI:
patients treated in 2006–2014 and those treated in 2015–2020. 0.20–1.34, p = 0.05, respectively).
The brachytherapy course was concomitant with an additional che-
motherapy course in 13/81 (16%) patients. The median overall treat-
ment time, calculated from the start of external radiation therapy to 3.6. Fistula formation
the end of brachytherapy was 55 days (range: 38–108 days).
A total of 12 patients presented clinical symptoms of fistulas, two of
which had symptoms occurring before any treatment. Among the 65
3.4. Disease control patients without clinical fistula before treatment, 10/65 (12.3%) devel-
oped a fistula during post-treatment follow-up, including eight patients
With a median follow-up of 27.62 ± 25.10 months, 34/81 patients with vesicovaginal fistula, one patient with recto-vaginal fistula, and
(42.0%) had tumor recurrence. Distant metastatic relapse was the
one patient with both vesicovaginal and recto-vaginal fistula. Among
most frequent pattern of recurrence, observed in 25 patients (31%). these 10 patients, 7/10 had fistula in the context of local relapse and
Lymph node relapse within the pelvis and/or para-aortic area was
three patients had fistulas occurring without sign of local relapse, and
reported in 17 patients (21%). Local recurrence was reported in 13 were therefore considered as complications of treatment. Treatment
patients (16%). The 5-year estimated probability of OS was 53%
of vesicovaginal fistulae was surgical in all 10 patients: five had anterior
(95% CI: 39–73%) and 5-year PFS was 35% (95% CI: 24–52%). Local pelvectomy and skin ureteroileostomy, three had ureteroileostomy, one
control (LC) probability at two and five years was 75% (95% CI:
had ileocolonic urinary reservoir, and one had surgical repair.
64–88%). Survival curves are shown in Fig. 2. A transverse tumor dimension >55 mm was predictive of fistula
during external radiotherapy (HR = 0.15, 95%IC:0.018–1, p = 0.027).
3.5. Prognostic factors A CTVHR volume > 39 cm3 was predictive of fistula formation after
brachytherapy (p = 0.0011). Bladder D2cc was not significant for
Results of univariate analyses are shown in Table 3. In univariate fistula formation. No treatment-related factor for recto-vaginal fistula
analysis, the following factors were associated with poorer survival formation was identified.

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K. KA, A. Laville, E. Rassy et al.
Fig. 2. Kaplan-Meier estimated survival curves.
4. Discussion
There are few data in the literature to guide the treatment process
among patients with LACC involving adjacent organs. The prognosis of
patients is very poor, with a 5-year OS of approximately 20% in the liter-
ature, mainly based on retrospective series involving usually few
patients [13–20]. Even in large cohorts, such as the EMBRACE I prospec-
tive study, patients with stage T4 tumors accounted for only 34/1341
(2.5%) patients [21].
This retrospective study of 81 patients is to date the largest single-
center cohort evaluating clinical, therapeutic and prognostic outcomes
after IGABT in this selected population of patients with tumors spread-
ing to adjacent organs. In this study, we found a median relapse-free
survival of 48.1 months and a median PFS of 19.7 months. Almost 40%
of the patients had a tumor relapse, with distant failure being the
main cause of treatment failure. In a previous series, based on 71
36
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Gynecologic Oncology 168 (2023) 32–38
patients treated prior to 2015 (71 patients, including only 31 treated
with IGABT), we had reported a median OS and PFS of 27.3 and 15.8
months respectively. LC rate was 63.8% at 2 years [17]. In this updated
cohort including only patients treated with image-guided brachyther-
apy, we report significantly better results, with a 2-year LC of approxi-
mately 75.2%. This difference may be explained by the increasing use
of IGABT (48% in the previous cohort versus 100% in this series) and of
combined intracavitary/interstitial techniques (12% in the previous
publication versus 31% in the present study), leading to higher tumor
doses. Our observed risk of local failure (16%; 13/81) is much lower
than previously reported in the literature for similar tumor stages,
with local failure rates ranging from 39 to 44% in series without 3D
guided brachytherapy [13–19]. A D90CTVHR ≥ 75.1 GyEQD2 was an
important prognostic factor for OS. There is now a high level of
evidence that the dose escalation process in LACC translates into better
local control, with large series reporting a high probability of local con-
trol after IGABT [21–23]. The mean D90 CTVHR dose in our series was
lower than that reported in other series of patients treated with IGABT
for various tumor stages [17]. This may be due to the low use of com-
bined intracavitary/interstitial techniques in the first years following
IGABT implementation (prior to 2014), but also because all relapses
were examined, not just the first events. In addition, the presence of fre-
quent vaginal extensions in these advanced tumors should be high-
lighted, as vaginal involvement cannot be treated with the same doses
as cervical tumors because of a risk of necrosis. In the EMBRACE I cohort,
local control probability was also very high for all subgroups, including
stage T4 tumors (91%) [21]. Five-year OS was the same for patients with
a T4 tumor treated according to the EMBRACE I protocol or among our
subgroup of patients treated with IGABT (52–53%) [21]. The dismal
prognosis of patients with stage T4 cervical cancer, in addition to the in-
vasion of neighboring organs, is also related to other poor prognostic
factors, such as para-aortic lymph node extension or poor general
health status.
These data confirm that the integration of image guidance, together
with increasing use of combined intracavitary/interstitial technique was
associated with better outcomes in this poor prognosis subgroup. We
found an association between survival and the ability to perform dose
escalation. Indeed, the use of IGABT was associated with better out-
comes in numerous studies testing the integration of image-guidance
for LACC, all stages included [2;3;21].
One unexpected but important finding was that D90CTVIR was
associated with better local control, but D90CTVHR was not. This may
be explained by insufficient statistical power, but also by aspects
specific to this challenging situation of adjacent organs involvement.
Because of the presence of pre-fistula or fistula in the context of fre-
quent massive para-aortic lymph node extension, it was uncertain
whether dose escalation to the cervix and involved parts of bladder
would lead to a favorable therapeutic index, in terms of risk of compli-
cation versus survival benefit. Our objective was therefore in these
cases to achieve adequate coverage of initial tumor extent (at least 60
GyEQD2) in these very advanced tumors, while minimizing the risk of
fistula. Such strategy was in line with our historical French experience,
of dose prescription to the envelope isodose, from which was partially
derived the concept of CTVIR and that refers to the isodose covering
the initial tumor spread.
One major concern for patients receiving brachytherapy for stage T4
cervical cancer is the risk of fistulas (vesical-vaginal or recto-vaginal). In
our series, all but three patients could receive a brachytherapy boost.
The 15% (10/65) rate of fistulas formation occurring during or after
brachytherapy seems acceptable, possibly because of image guidance
and careful dose optimization, with bladder D2cm3 doses that remained
below the usual dose threshold of 85 GyEQD2 [24–28]. Possibly the
benefit in local control afforded by brachytherapy contributed to
minimizing the risk of fistula, as most cases of fistula were secondary
to local relapse. In line with retrospective and prospective data
showing that larger tumors and more advanced stages require higher
K. KA, A. Laville, E. Rassy et al.
Table 3
Prognosis factors in univariate and multivariate analysis for overall survival, progression free survival and local control. Only factors with p value <0.1 in univariate analysis are shown.
Patient characteristics
Overall survival WHO performance status
Combined IC/IS technique
CTVHR D90 dose
PFS WHO performance status
interstitial needles
CTVHR D90 dose >75.1 Gy EQD2
Local control well differentiated grade
VVF formation
CTVIR D90 dose >63.5 Gy EQD2
CTVHR volume > 39 cm3
Transverse dimension at diagnosis >55 mm
VVF formation after BT CTVHR volume > 39 cm3
BT: brachytherapy; CTVHR: high-risk clinical target volume; CTVHR D90: minimal dose to 90% of the high-risk clinical target volume; CTVIR D90: minimal dose to 90% of the intermediate-risk
clinical target volume; HR: hazard ratio; IC/IS: intracavitary/interstitial; PFS: progression-free survival; VVF: vesico-vaginal fistula; WHO: World Health Organization.
doses to be cured, our data confirm the place of brachytherapy in these
advanced situations [21;23;24]. Prior to treatment, patients should
receive a comprehensive information on the risk of treatment-related
fistula, but also on the fact that the dose escalation process afforded by
brachytherapy is the best way to avoid tumor-related fistula. The lim-
ited efficacy of salvage surgery (especially for lateropelvic relapses)
should also be taken into account at time of treatment planning [29].
The main limitations of our study are its retrospective nature and a
lack of long-term follow-up, in part due to the poor prognosis of pa-
tients. Most patients 56/81 (69.1%) were referred for brachytherapy
only, so follow-up information was not always complete. In addition,
not all patients had histological confirmation of bladder and/or rectal in-
vasion. Nevertheless, our data provide a strong argument for the use of
IGABT in the management of stage T4 cervical cancer. Brachytherapy is
the best modality to increase the dose to the tumor while minimizing
toxicities. This is especially true since advances in imaging have greatly
contributed to its effectiveness in terms of both survival and LC. The
incidence of fistulas was acceptable, and the majority of surviving pa-
tients had no severe urinary symptoms at their last follow-up.
5. Conclusion
The prognosis of cervical cancers spreading to adjacent organs
remains poor, mainly because of distant events. Advances in primary
staging and brachytherapy modalities are however associated with bet-
ter local control and survival while reducing toxicities. Most fistulas are
caused by tumor progression. Improving local control through dose
escalation and combined intracavitary/interstitial brachytherapy
techniques is a major factor in patients cure probability.
Author contribution
Kanta KA: conception, data acquisition, data management, critical
analysis, drafting/final editing.
Adrien LAVILLE: data acquisition, critical analysis, drafting/final
editing.
Roger Sun: statistical analysis, critical analysis, drafting/final editing.
Elie RASSY, Radouane EL AYACHI, Patricia PAUTIER, Mouhamadou
Bachir BA, Sophie BOCKEL, Samir ACHKAR, Sophie ESPENEL, Amandine
MAULARD, Philippe MORICE, Sébastien GOUY, Christine HAIE-MEDER:
critical analysis, drafting/final editing.
Cyrus CHARGARI: conception, supervision, critical analysis, drafting/
final editing.
Declaration of Competing Interest
None related to this study.
The authors declare no conflict of interest.
37
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Gynecologic Oncology 168 (2023) 32–38
Univariate Multivariate
HR (95% CI) p HR (95% CI) p
0.0075 3.08 (1.13–8.36) 0.026
0.24 (0.057–1) 0.023
0.2 (0.059–0.68) 0.0025 0.23 (0.07, 0.78) 0.018
2.3 (1.1–4.7) 0.039
0.062
0.53 (0.27–1.1) 0.071
0.26 (0.057–1.2) 0.044
4.6 (1.5–14) 0.01
0.07 (0.01–0.64) 0.017
0.00042
0.15 (0.018–1) 0.027
0.0011
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