Increased genitourinary fistula rate after bevacizumab in recurrent cervical cancer patients initially treated with definitive radiochemotherapy and image-guided adaptive brachytherapy

A total of 35 patients were included in this study. Patients’ and treatment characteristics are shown in Table 1. There were no fistulae at the time of relapse diagnostic. CHT was received by 25 patients and 10 patients received CHT+BEV. Patient characteristics and treatment modalities in the both groups were similar. All 10 patients in the CHT +BEV group had undergone interstitial IGABT as opposed to 21/25 in the CHT group (p = 0.18).

Table 2 provides treatment details of the therapy at first diagnosis and the number of events analysed according to the type of treatment at recurrence. No statistically significant difference in radiation dose (90.4 Gy vs. 89.4 Gy, p = 0.353) or number of CHT cycles at RecCC (5.1 vs. 6.4, p = 0.403) was observed between treatment groups.

A total of six fistulae were recorded (patient tumour and treatment details in Table 3: P1-6). In the CHT+BEV group, a significantly higher rate of fistula formation (4/10 patients, 40%) was observed compared to the CHT only group (2/25 patients, 8%; p = 0.043).

GU fistula formation was noticed only in the CHT+BEV group (3/10 patients), of which two were grade 2 and one was grade 3 requiring surgical intervention [16]. Additionally, a grade 3 rectovaginal fistula was documented in this group (P2). In the CHT only group, both events were rectovaginal fistula grade 3. For all patients with G3 rectovaginal fistula a functional colostomy was performed. For the G3 GU fistula, an ileal conduit was necessary.

At the time of recurrence, 2 patients had persistent local disease (incomplete remission), 1 patient had local recurrence (which was treated with palliative re-irradiation) and 3 patients had systemic recurrence (Table 3).

All 6 patients with fistula formation had undergone an invasive procedure or palliative pelvic radiation prior to or during the systemic palliative treatment (Table 3). In the CHT group the events occurred subsequent to a posterior vaginal wall biopsy (P5) and after pelvic re-irradiation (P3). In this group, a further 10 of the remaining 23 patients had undergone an invasive procedure but did not develop fistula (Table 1). In the CHT+BEV group, 4/4 patients with events (100%) had undergone at least a minimally invasive procedure (i. e. ureter stenting) and only 1/6 patients (17%) did not develop an event after an invasive procedure.

We found no association between radiation dose to the target or the reported DVH parameters for OARs and the rate of fistula (Table 4).

In this study, patients receiving a combination of CHT and BEV for the treatment of RecCC had a significantly higher risk for fistula formation than patients receiving CHT alone (40 vs. 8%). We observed a notably higher rate of GU fistula in patients treated with CHT+BEV (30% vs. none). The rate of rectovaginal fistula was similar in the two groups (10 vs. 8%).

Previously published studies reported an overall fistula (>grade 2) formation rate of 8.6% (GI vaginal) and 3.2% GI perforation in 218 patients with preliminary metastatic or recurrent cervical cancer treated in the CHT+BEV arm [17] of the GOG 240 study (first data freeze). Furthermore, the rate of fistula (any grade) formation was even higher (12.6%) during CHT+BEV treatment if only patients with prior radiochemotherapy were considered [11]. Overall, GOG 240 reported an increased incidence of 6% of fistula formation (second data freeze) [9]. It is not clear how many patients had received definitive radiochemotherapy including IGABT in the GOG 240 cohort. In our cohort, only patients who received definite IGABT plus radiochemotherapy as initial treatment were included. Therefore, our cohort is the first one comparing CHT and CHT+BEV in LACC patients previously treated with definitive radiochemotherapy and IGABT.

All patients who developed fistulae in our cohort had undergone a minor intervention (5/6, 83%; repeated ureter stenting, biopsy or pelvic re-irradiation) or a major pelvic surgery (1/6, 17%). This is in accordance with the observation of Feddock el al. [19], who associated pelvic radiation and invasive procedures with 8.2% fistula formation, even in the absence of CHT ± BEV. In the CHT group, 43% (10/23) of the non-event patients had undergone an intervention, while in the CHT+BEV only group, 17% (1/6) had undergone an invasive pelvic procedure and did not develop a fistula. This may suggest that BEV in the presence of an invasive pelvic procedure may trigger GU fistula formation. There are case reports in literature suggesting that a combination of perioperative BEV administration and an invasive procedure could result in fistula formation. Aortooesophageal fistula rupture or colovesical fistula during treatment including BEV due to metastatic colorectal cancer have been reported in case studies [25]. One other report describes two late-onset pulmonary fistulae after resection of pulmonary metastasis from colorectal cancer following perioperative CHT with BEV [26]. An increased risk of bowel perforation or fistula formation for patients with recurrent epithelial ovarian cancer treated with BEV has been observed [24, 27, 28].

Although not statistically significant due to the limited number of patients and events, one may observe the fact that 3/6 patients with fistulae had a local recurrence (2 patients never achieved complete local remission and 1 had a local recurrence).

We could not detect any association between comorbidities, radiation dose, performance status or previously performed bowel surgery prior to the diagnosis of RecCC and a higher rate of fistula formation. Our findings are in accordance with previously published reports [20]. In a study including 30 patients with FIGO stage IVA (with bladder or/and rectal infiltration) undergoing radiochemotherapy, the 5‑year fistula-free survival rate was 64%, but no prognostic variables were identified. Although all the patients in the CHT +BEV group underwent interstitial IGABT as opposed to 84% in the CHT group, the use of interstitial implants is not statistically correlated to the occurrence of fistula when BEV is added to the treatment of RecCC (p = 0.18). Moreover, recent literature shows that primarily use of advanced IGABT, especially interstitial implants, does not increase late toxicity when compared to intracavitary therapy only [18].

Recent studies suggest that only intermediate- and high-risk RecCC patients show a survival benefit when receiving CHT+BEV [21]. These patients have 2–3 (intermediate-) and 4–5 (high-risk) risk factors from: black race, performance status 1, pelvic disease, prior cisplatin and progression-free interval <365 days. Hence, patient selection is crucial with respect to side effects and complications. Several approaches were performed to identify biomarkers to predict the effect of BEV on an individual basis [22]. However, no predictive biomarker has been established thus far.

CHT+BEV is administered to RecCC patients without curative intent. The quality of life in this palliative setting is of particular importance and should have a substantial influence on the selection of therapy. Interestingly, while GOG 240 reported an increased rate of fistula in the CHT+BEV group, the quality of life was not decreased in this group. Other reports show that fistula formation leads to a substantial reduction in quality of life [23]. Therefore, patient-reported outcomes, as used in GOG 240, might not be appropriate to determine the detrimental effect of fistula formation on quality of life.

Based on our observations, we suggest that when facing persistent disease or local recurrence, with or without systemic disease, caution should be used in prescribing CHT+BEV. This combination should be offered only after thoroughly informing the patients about the high probability of developing fistula, especially GU fistula. Prudence should also be used when facing ureteral stent change or other pelvic interventions, which are common in patients with RecCC.

Admittedly, the shortcomings of this study have to be considered. This was a retrospective data analysis of a small patient cohort from a single institution. The limited number of patients included in this report impaired statistical analysis and multivariate models were not feasible. However, given the lack of published data and increasing number of patients who are possibly candidates for this treatment, we want to raise awareness about the potential risks of using BEV in addition to CHT in the setting of pelvic RecCC and related interventions.

Until larger studies are available, based on our observations in this small cohort, and given the overall survival benefit [9], CHT+BEV should probably be offered mainly to patients with local control and systemic recurrences. Future clinical studies are required to identify predictive and prognostic factors for fistula formation, in order to improve patient selection for CHT+BEV in the setting of RecCC.