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Spontaneous rectovaginal fistula during bevacizumab therapy for ovarian cancer: a case report

      Recent studies have demonstrated efficacy of bevacizumab for recurrent ovarian cancer, but few data on its use and gastrointestinal potential complications when administered as adjuvant chemotherapy after cytoreductive surgery are available. In this study, we report the first case of a rectovaginal fistula in this indication.

      Key words

      Bevacizumab is a monoclonal antibody that targets the vascular endothelial growth factor receptor. It has been reported to improve overall survival in metastatic colorectal cancer.
      • Presta L.G.
      • Chen H.
      • O'Connor S.J.
      • et al.
      Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.
      • Hurwitz H.
      • Fehrenbacher L.
      • Novotny W.
      • et al.
      Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
      Two recent phase II studies have reported that bevacizumab is active in patients with recurrent ovarian cancer.
      • Garcia A.A.
      • Hirte H.
      • Fleming G.
      • et al.
      Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia.
      • Cannistra S.A.
      • Matulonis U.A.
      • Penson R.T.
      • et al.
      Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer.
      However, bevacizumab is associated with some side effects. Gastrointestinal or spontaneous bowel perforations and delayed postoperative fistulae have been described for metastatic colorectal cancer.
      • Gordon M.S.
      • Cunningham D.
      Managing patients treated with bevacizumab combination therapy.
      Few data are available on its use as an adjuvant treatment for ovarian cancer. No cases of fistulae have been described with the use of bevacizumab for ovarian cancer.
      Here we report the first case of a rectovaginal fistula occurring 2 months after debulking surgery with colorectal resection in which bevacizumab may have contributed to the fistula formation.

      Case Report

      A 45-year-old woman was referred under suspicion of ovarian cancer. Apart from a conservative hysterectomy, she had an unremarkable medical history. Physical examination, sonography, and a computed tomography (CT) scan showed an ovarian tumor with voluminous ascites and peritoneal carcinomatosis. The CA-125 serum level was 7000 U/L. The patient underwent initial laparoscopy, which confirmed the possibility for optimal cytoreductive surgery. We performed a posterior pelvectomy with terminoterminal anastomosis, bilateral salpingo-oophorectomy, appendectomy, omentectomy, right diaphragmatic peritoneal stripping, bilateral pelvic and paraaortic lymphadenectomy, cholecystectomy, and small bowel resection. During the course of the surgery, a cuff vaginal resection was carried out. At the end of the surgery, the patient had no residual disease.
      Histology showed a stage IIIC ovarian cancer with metastatic involvement in 10 of the 43 nodes removed.
      The oncological committee recommended adjuvant chemotherapy with bevacizumab.
      The first course of chemotherapy was administered 35 days after surgery and the second at 50 days. After 2 cycles of bevacizumab, the patient complained of passing flatus and feces per vagina. Clinical exam and CT scan revealed an obvious rectovaginal fistula (Figure). There was no evidence of local recurrence. The third course of chemotherapy was done without bevacizumab. The rectovaginal fistula healed spontaneously.
      Figure thumbnail gr1
      FIGURERectovaginal fistula on CT scan
      Air pocket in the vagina (white arrow).
      Chéreau. Spontaneous rectovaginal fistula during bevacizumab therapy for ovarian cancer. Am J Obstet Gynecol 2009.

      Comment

      In a review of the literature on late bowel complications with treatment with bevacizumab (Table), perforations or fistulae have been reported for colorectal cancer but not for ovarian cancer. In the 7 published cases of late gastrointestinal complications, 2 risk factors were identified: progressive local disease
      • August D.A.
      • Serrano D.
      • Poplin E.
      “Spontaneous” delayed colon and rectal anastomotic complications associated with Bevacizumab therapy.
      • Wolf I.
      • Urban D.
      • Pfeffer R.
      • Catane R.
      • Aderka D.
      High incidence of fistula formation during bevacizumab treatment in rectal cancer patients.
      • Adenis A.
      • Vanseymortier L.
      • Foissey D.
      • Colombel J.F.
      Bevacizumab and postponed suture leakages after surgery for ulceration cancer.
      • Ley E.J.
      • Vukasin P.
      • Kaiser A.M.
      • Ault G.
      • Beart R.W.
      Delayed rectovaginal fistula: a potential complication of bevacizumab (Avastin).
      and radiotherapy. A review article
      • Han E.S.
      • Monk B.J.
      What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer?.
      reports 16 perforations in 298 ovarian cancer patients. As observed for colon cancer, all the patients had progressive disease. Perforations may be caused by necrosis of the tumor with weakening of the intestinal wall.
      TABLEClinical characteristics of patients with delayed anastomotic complications under treatment with bevacizumab
      ReferenceCancer typeSurgeryRadiotherapyEvolutive diseaseLocal recurrenceAnastomotic fistulaInterval between surgery and complication (mo)Duration of bevacizumab (wk)
      August et al
      • August D.A.
      • Serrano D.
      • Poplin E.
      “Spontaneous” delayed colon and rectal anastomotic complications associated with Bevacizumab therapy.
       Case 1RectumYes, anastomotic leakYesYesYesYes266
       Case 2RectumYesYesYesNoYes3320
       Case 3RectumYesNoYesNoYes514
      Wolf et al
      • Wolf I.
      • Urban D.
      • Pfeffer R.
      • Catane R.
      • Aderka D.
      High incidence of fistula formation during bevacizumab treatment in rectal cancer patients.
       Case 1RectumYesYesYesYesYes3.56
       Case 2RectumYesYesYesYesYes4.52
      Adenis et al
      • Adenis A.
      • Vanseymortier L.
      • Foissey D.
      • Colombel J.F.
      Bevacizumab and postponed suture leakages after surgery for ulceration cancer.
      RectumYes, anastomotic leakYesYesNoYes303
      Ley et al
      • Ley E.J.
      • Vukasin P.
      • Kaiser A.M.
      • Ault G.
      • Beart R.W.
      Delayed rectovaginal fistula: a potential complication of bevacizumab (Avastin).
      RectumYes, posterior vaginectomyYesYesNoYes3224
      Present caseOvaryYes, posterior vaginectomyNoNoNoYes, spontaneous healing24
      Chéreau. Spontaneous rectovaginal fistula during bevacizumab therapy for ovarian cancer. Am J Obstet Gynecol 2009.
      Two particular aspects of our case report deserve special mention. First, there was no evidence of local active disease. Second, the patient did not receive radiotherapy. Therefore, the fistula could not be related to the risk factors reported in colon carcinoma. The only risk factor of rectovaginal fistulae was the opening of the vagina during surgery. However, postoperative anastomotic leakage usually occurs soon after surgery; the largest series to study rectosigmoid resection for ovarian cancer
      • Richardson D.L.
      • Mariani A.
      • Cliby W.A.
      Risk factors for anastomotic leak after recto-sigmoid resection for ovarian cancer.
      reported that the mean interval was 19 days (range, 4-32).
      Some authors recommend a free interval of at least 30 days between surgery and bevacizumab treatment.
      • Gordon M.S.
      • Cunningham D.
      Managing patients treated with bevacizumab combination therapy.
      Our patient received the first course at 35 days, and there was no rectovaginal fistula when chemotherapy was initiated. Therefore, the use of bevacizumab seemed to be the most evident risk factor.
      In light of this complication, some precautions should be proposed: first, the initiation of bevacizumab treatment should be delayed until the second cycle of chemotherapy, as is recommended in some clinical trials. Second, an ileostomy may be proposed for dysfunction of the distal colorectal anastomosis, as has been suggested by Richardson et al
      • Richardson D.L.
      • Mariani A.
      • Cliby W.A.
      Risk factors for anastomotic leak after recto-sigmoid resection for ovarian cancer.
      for selected patients after rectosigmoid resection for ovarian cancer.
      In conclusion, this case report raises the issue of the specific risk of chemotherapy with bevacizumab for ovarian cancer patients with bowel resection.

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