Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 1069e1072

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Taiwanese Journal of Obstetrics & Gynecology

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Case Report

Fatal rectovaginal fistula in post-radiotherapy locally advanced

cervical cancer patients
Chang-Yu Wu a, 1, Li-Ming Tseng b, 1, Hui-Hua Chen c, Chen-Hsi Hsieh d, e,
Sheng-Mou Hsiao c, f, g, *
a
Department of Family Medicine, Far Eastern Memorial Hospital, Banqiao, New Taipei City, Taiwan
b
Department of Surgery, Far Eastern Memorial Hospital, Banqiao, New Taipei City, Taiwan
c
Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, Banqiao, New Taipei City, Taiwan
d
Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, Banqiao, New Taipei City, Taiwan
e
Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
f
Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
g
Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan, Taiwan

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

Article history: Objective: To present the detailed history of three cervical cancer patients with rectovaginal fistula, who
Accepted 11 January 2022 had undergone radiotherapy.
Cases report: A 74-year-old patient with end-stage renal disease undergoing hemodialysis had radio-
Keywords: therapy for her advanced cervical cancer. Colonoscopic biopsy showed radiation sigmoid colitis and
Bevacizumab ulcers. Laparotomy revealed colon perforation and rectovaginal fistula. The second case is a 54-year-old
Chronic kidney failure
cervical cancer patient, who had received concurrent chemoradiation therapy and further systemic
Radiotherapy
therapy with cisplatin, paclitaxel, and bevacizumab. She suffered from bloody stool and abdominal pain.
Rectovaginal fistula
Uterine cervical neoplasms
Rectovaginal fistula was found during exploratory laparotomy. The third case is a 35-year-old cervical
cancer patient, who had received concurrent chemoradiation therapy. Systemic therapy was then pre-
scribed with platinum, paclitaxel, and bevacizumab for her lung metastasis, and a rectovaginal fistula
was found later. All three patients did not survive later.
Conclusions: Fatal rectovaginal fistula may occur in post-radiation advanced cervical cancer patients.
Unnecessary colonoscopic biopsy may cause significant sequelae. In patients with high risk for rec-
tovaginal fistulas, chemotherapy without adding bevacizumab might be suggested in patients with low
risk of poor response to chemotherapy. In addition, three-dimensional conformal radiation therapy or
intensity-modulated radiation therapy should be used for patients with high risk for fistulas.
© 2022 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an
open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Introduction Pelvic radiotherapy is considered a primary cause of rectovaginal

For women with locally advanced cervical cancer, concur-
rent chemoradiation therapy was the standard treatment [1].
The incidence of rectovaginal fistula in post-radiation cervical
cancer patients is not common nowadays, but it can be fatal
and distressing. The rate of rectovaginal fistula formation is
around 3e13% in cervical cancer patients treated by radio-
therapy [2,3].
* Corresponding author. Department of Obstetrics and Gynecology, Far Eastern
Memorial Hospital, No. 21, Sec. 2, Nanya S. Rd., Banqiao Dist., New Taipei City,
Taiwan. Fax: þ886 2 8966-5567.
E-mail address: smhsiao2@gmail.com (S.-M. Hsiao).
1
Chang-Yu Wu and Lin-Ming Tseng contributed equally to this work.
fistula formation. Late radiation-induced skin damage includes all
layers of the skin, epidermis, dermis, subcutaneous tissue, and
vessels. Small arteries develop vascular sclerosis; resulting in arte-
riole narrowing or obliteration, which then leads to poor tissue
perfusion and chronic ischemia. The irradiated dermis and subcu-
taneous tissues are gradually replaced by dense and inelastic fibrotic
tissue [1e3]. Following radiation therapy, the patient may develop
proctitis followed by anterior rectal wall ulceration, then progress to
fistula.
However, rectovaginal fistula is not so common nowadays under
the technique of modern radiotherapy. Herein, we report the
detailed history of three fatal cases of rectovaginal fistula, who had
undergone pelvic radiotherapy for advanced cervical cancer. We
also discuss the probable contributing factors for the rectovaginal
fistulas.

https://doi.org/10.1016/j.tjog.2022.01.007
1028-4559/© 2022 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
C.-Y. Wu, L.-M. Tseng, H.-H. Chen et al.
Case presentation
Case 1
A 74-year-old woman, gravida 2, parity 2, had a history of hy-
pertension, chronic kidney disease. She was diagnosed with cer-
vical cancer, squamous cell carcinoma, cT3bN0M0, FIGO stage IIIB
in March 2019. Bladder cancer, non-invasive papillary urothelial
carcinoma, low-grade, cT1N0M0 was also diagnosed simulta-
neously and treated with transurethral tumor resection. This
woman underwent whole pelvic radiotherapy 50.4 Gy in 28 frac-
tions, followed by brachytherapy 30 Gy in 5 fractions and
completed in May 2019. Due to chronic kidney disease with uremic
symptoms, she started hemodialysis since September 2019. Owing
to bloody stool, colonoscopy and biopsy was performed in
September 2019. Abdomen computed tomography showed radia-
tion sigmoid colitis with concealed perforation. Antibiotics were
prescribed; however, the bloody stool became worse in December
2019. Colonoscopy revealed a suspicious advanced colon tumor,
and a biopsy (total 14 pieces) was performed and the histopa-
thology revealed only ulcerative tissue without cancer cells. After
that, she suffered from persistent fever with leukocytosis and
vaginal bleeding. Repeated abdomen computed tomography
revealed suspicious sigmoid colon rupture with pelvic abscess
formation (Fig. 1). Exploratory laparotomy found a 5 cm sigmoid
perforation, a necrotic ileum with two small perforations, a necrotic
rectum, a necrotic uterus, and a rectovaginal fistula. Radical proc-
tectomy, Hartmann procedure, partial ileum resection with anas-
tomosis, and total hysterectomy were performed. Final
histopathology did not reveal any malignant cells. The post-
operative condition deteriorated, and she passed away on the 37th
day after the surgery.
Fig. 1. The computed tomography showed suspicious sigmoid colon rupture with
pelvic abscess formation.
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Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 1069e1072
Case 2
A 54-year-old woman, gravida 3, parity 2, was diagnosed with
cervical cancer, cT3bN1M1, FIGO stage IVB with bone metastasis in
May 2018. The patient received concurrent chemoradiation therapy
with cisplatin (40 mg/m2) for six cycles, 45 Gy pelvic and paraaortic
radiotherapy, 20 Gy cervix tumor external beam boost radiotherapy
and 30 Gy radiotherapy for right clavicular metastasis, and 10 Gy
intracavitary brachytherapy. Moreover, systemic chemotherapy
with paclitaxel (175 mg/m2), cisplatin (50 mg/m2), and bev-
acizumab (15 mg/kg) were prescribed for nine cycles. The last cycle
of chemotherapy plus bevacizumab was prescribed on March 26,
2019. On April 13, 2019, she was admitted to our hospital due to
intermittent fever, abdominal pain, and bloody stool. Abdomen
computed tomography revealed hollow organ perforation (Fig. 2A)
and a rectovaginal fistula (Fig. 2B). Pelvic examination showed a
2 cm rectovaginal fistula. Intravenous antibiotics and parenteral
nutrition support were prescribed. Owing to persistent bloody stool
and deteriorated abdominal pain, an exploratory laparotomy was
arranged. During the operation, a 4*3 cm rectovaginal fistula with
local abscess formation was found. Transverse colostomy, pelvic
abscess drainage, enterolysis, and total hysterectomy were then
performed. Histopathological reports disclosed extensive necrosis
of the cervix and endometrium and tiny residual adenocarcinoma
over the endometrium. Poor abdominal wound healing with
ventral hernia was noted, and she underwent abdominal wound
debridement and fascia repair on the 22nd postoperative day.
However, the patient's condition deteriorated, and intra-abdominal
infection progressed. This patient received hospice palliative care
later, and she passed away on the 64th day after transverse
colonostomy.
Case 3
A 35-year-old woman, gravida 3, parity 3, was diagnosed with
cervical cancer, squamous cell carcinoma, cT3bN1M0, FIGO stage
IIICr in April 2020. The patient received concurrent chemoradiation
therapy with cisplatin (40 mg/m2) for six cycles, 59.4 Gy external
beam radiotherapy, and 30 Gy intracavitary brachytherapy. More-
over, multiple pulmonary metastasis and local recurrence were
found in September 2020, and this woman received laparoscopic
hysterectomy for pelvic pain and systemic chemotherapy with
paclitaxel (175 mg/m2), cisplatin (50 mg/m2) or carboplatin
(AUC ¼ 5) and bevacizumab (15 mg/kg) for four cycles thereafter.
The last cycle of chemotherapy was prescribed on February 4, 2021.
However, she was admitted to our hospital on February 18, 2021
due to stool passage from the vagina for 10 days (i.e., the fistula
occurred on the fourth day after the last chemotherapy). Abdomen
computed tomography revealed ileus and a rectovaginal fistula
(Fig. 3A and B). Pelvic examination showed a 2 cm rectovaginal
fistula. Loop transverse colostomy was performed initially but the
ileus persisted; then ileocolic anastomosis was performed to solve
her ileus. However, the patient's condition deteriorated, and intra-
abdominal infection progressed. She passed away in July 2021 (i.e.,
the 100th day after ileocolic anastomosis).
Discussion
In our patients, rectal ulcers with necroinflammatory exudates,
necrotic debris, fibrosis tissue, and uterine necrosis with granulo-
matous tissue were noted, which were compatible with late
radiation-induced damage. In addition to radiotherapy, the
contributing factor for the development of rectovaginal fistula is
unknown. However, end-stage renal disease and colonoscopic bi-
opsy in the first patient, and the use of bevacizumab in the second
C.-Y. Wu, L.-M. Tseng, H.-H. Chen et al. Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 1069e1072

Fig. 2. The computed tomography showed (A) suspicious hollow organ perforation and (B) rectovaginal fistula.

Fig. 3. The computed tomography showed (A) rectovaginal fistula and (B) abscess formation at the vaginal stump.

and third patient might contribute to the development of rec-
tovaginal fistulas.
In the first patient, a rectovaginal fistula developed in a woman
with end-stage renal disease. Similarly, Kao et al. reported that a
vesicovaginorectal fistula was found in an end-stage renal disease
patient with recurrent cervical cancer [4]. Ischemia might play a
role in the development of colon perforation in patients with
chronic renal insufficiency [5].
In addition, the rectovaginal fistula developed after colonoscopic
biopsy in the first patient. Feddock et al. also reported that per-
forming a biopsy in an irradiated field is associated with a relatively
low yield and significantly contributes to the risk for fistula devel-
opment [6]. Poor renal function has long been known to affect
wound healing [7]. Thus, colonoscopic biopsy in patients who have
a history of pelvic radiotherapy and end-stage renal disease, might
be prohibited except having a strictly clinical indication.
In our second and third patients, the use of bevacizumab might
contribute to the development of rectovaginal fistulas. To our
knowledge, there were only 9 cases of rectovaginal fistulas [8e11]
and 18 cases of gastrointestinal (GI) fistulas [12] developed after
bevacizumab treatment in women with cervical cancer. Suzuki
et al. reported a case of grade 2 rectovaginal fistula, who underwent

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C.-Y. Wu, L.-M. Tseng, H.-H. Chen et al.
prior pelvic irradiation and received paclitaxel, carboplatin, and
bevacizumab for the treatment of advanced/recurrent cervical
cancer [10]. Kim et al. also reported that bevacizumab adminis-
tration was significantly associated with fistula formation in the
multivariable analysis (hazard ratio ¼ 4.76, 95% confidence
interval ¼ 1.71 to 13.23); and a 10-month treatment interval be-
tween radiotherapy and the administration of bevacizumab was
suggested [11]. Similarly, the Gynecologic Oncology Group (GOG)
240 study reported that the addition of bevacizumab to chemo-
therapy was associated with increased overall survival (17.0
months vs. 13.3 months), but also associated with an increased risk
of GI fistula of grade 3 or higher (3% vs. 0%) [13]. In the final report of
GOG 240 study, there were significant GI fistulas in cervical cancer
patients receiving chemotherapy plus bevacizumab, compared
with chemotherapy only (i.e., grade 2 GI fistula, chemotherapy
alone versus chemotherapy plus bevacizumab: 1 (0.5%) versus 11
(5%), p ¼ 0.006); grade 3 GI fistula, chemotherapy alone versus
chemotherapy plus bevacizumab: 0 (0%) versus 7 (3%), p ¼ 0.02)
[12]. Contrary to our study (i.e., the second and third patients in this
study), none of the GI fistulas in the GOG 240 study required urgent
surgical interventional or resulted in sepsis or death [12]. However,
our current study could remind gynecologic oncologists about the
possibility of fatal rectovaginal fistulas after chemotherapy plus
bevacizumab in post-radiotherapy cervical cancer patients.
The Moore criteria is used to predict the response to cisplatin-
based chemotherapy in women with advanced cervical cancers and
included five prognostic factors (i.e., performance status >0, pelvic
disease, African-American ancestry, disease-free interval <1 year, and
prior platinum exposure) [14]. Those cervical cancer women with
0e1 factor were considered as low risk, 2e3 factors as mid-risk, and
4e5 factors as high risk of poor response to cisplatin-based chemo-
therapy [14]. Owing to the insignificant benefit (hazard ratio ¼ 0.96,
95% confidence interval ¼ 0.51e1.83, p ¼ 0.91) of adding bevacizumab
in the low risk group [15], chemotherapy without adding bev-
acizumab might be suggested for patients with low risk of poor
response to chemotherapy and high risk for rectovaginal fistulas.
Some studies revealed that there is a correlation between rectal
radiation dose and the risk of late rectal complications in cervical
cancer patients. In Cheng et al.’s study, patients with >110 Gy of a
total maximal proximal rectal biologic effective dose presented
with a significantly increased frequency of grade 2 or greater rectal
complications [16]. The maximal rectal biologic effective doses of
our first, second, and third patients were 90.8 Gy, 87.2 Gy, and
73.8 Gy, respectively. The rectal irradiation dose of the three pa-
tients did not exceed 110 Gy. Thus, the development of rectovaginal
fistulas in our three patients is less likely to be associated with
excessive irradiation dose.
In this study, all patients were treated with two-dimensional
conventional radiotherapy. Nowadays, the technique of three-
dimensional conformal radiation therapy and intensify-modulated
radiation therapy arises, it gives a more precise target to the tissue
and reduces comorbidities, compared with the two-dimensional
conventional radiotherapy [17]. Thus, in patients with high risk for
rectovaginal fistula, three-dimensional conformal radiation therapy
or intensity-modulated radiation therapy might be used instead.
Conclusions
Fatal rectovaginal fistula may occur in post-radiation advanced
cervical cancer patients. Unnecessary colonoscopic biopsy may
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Taiwanese Journal of Obstetrics & Gynecology 61 (2022) 1069e1072
cause significant sequelae. In patients with high risk for rec-
tovaginal fistulas, chemotherapy without adding bevacizumab
might be suggested in patients with low risk of poor response to
chemotherapy. In addition, three-dimensional conformal radiation
therapy or intensity-modulated radiation therapy should be used
for patients with high risk for fistulas.
Declaration of competing interest
There is no conflict of interest.
Acknowledgement
None.
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