Current Oncology Reports

, Volume 14, Issue 4, pp 277–284

Incidence and Management of Gastrointestinal Perforation from Bevacizumab in Advanced Cancers

  • Taher Abu-Hejleh
  • James J. Mezhir
  • Michael J. Goodheart
  • Thorvardur R. Halfdanarson
Palliative Medicine (A Jatoi, Section Editor)

Abstract

Bevacizumab (Avastin™, Genentech) is a monoclonal antibody that deactivates the vascular endothelial growth factor leading to disruption of vital cancer signaling pathways and inhibition of angiogenesis which results in its anti-tumor activity. The use of bevacizumab in treating cancers has steadily increased since it was initially approved by the Food and Drug Administration for metastatic colorectal cancer. Clinical trials have revealed that bevacizumab has serious side effects, including spontaneous bowel perforation, which can occur in patients who have no involvement of the gastrointestinal tract by cancer. Although risk factors for bevacizumab-associated bowel perforation have been identified, it is still unclear which patients are specifically at risk for this complication. The management of bevacizumab-induced bowel perforation depends on the clinical presentation and the goals of care set by the treating physicians and the patient.

Keywords

Bevacizumab Avastin Cancer Bowel perforation Metastasis Colorectal cancer Ovarian cancer Breast cancer Non-small cell lung cancer Glioma Renal cell carcinoma 

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25(33):5180–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2006;355(24):2542–50.PubMedCrossRefGoogle Scholar
  3. 3.
    Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666–76.PubMedCrossRefGoogle Scholar
  4. 4.
    Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26(33):5422–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231–7.PubMedCrossRefGoogle Scholar
  6. 6.
    •• Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients. JAMA. 2011;305(5):487–494. Ranpura and colleagues completed an excellent systematic review and meta-analysis and concluded that adding bevacizumab to chemotherapy increases the risk of treatment related mortality. This paper gives an insight into the type and incidence of bevacizumab induced serious adverse events in various cancers.PubMedCrossRefGoogle Scholar
  7. 7.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539–44.PubMedCrossRefGoogle Scholar
  9. 9.
    Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21(1):60–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Nogué M, Salud A, Vicente P, et al. Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging–defined poor-prognosis locally advanced rectal cancer: the AVACROSS study. Oncologist. 2011;16(5):614–20.PubMedCrossRefGoogle Scholar
  12. 12.
    Velenik V, Ocvirk J, Music M, et al. Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study. Radiat Oncol. 2011;6(1):105.PubMedCrossRefGoogle Scholar
  13. 13.
    Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009;20(11):1842–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008;26(21):3523–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23(16):3697–705.PubMedCrossRefGoogle Scholar
  16. 16.
    •• Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet oncol. 2009;10(6):559–568. The meta-analysis by Hapani and colleagues studies in depth the gastrointestinal perforation as a complication from bevacizumab treatment. This meta-analysis provides very useful information when counseling patients about gastrointestinal perforation as an adverse effect of bevacizumab. It also gives a perspective to the treating physicians on the incidence of bowel perforation from bevacizumab use in various cancers.PubMedCrossRefGoogle Scholar
  17. 17.
    Saif MW, Elfiky A, Salem RR. Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol. 2007;14(6):1860–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Lordick F, Geinitz H, Theisen J, Sendler A, Sarbia M. Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases. Int J Radiat Oncol Biol Phys. 2006;64(5):1295–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Badgwell B, Camp E, Feig B, et al. Management of bevacizumab-associated bowel perforation: a case series and review of the literature. Ann Oncol. 2008;19(3):577–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Sugrue M, Kozloff M, Hainsworth J, et al. Risk factors for gastrointestinal perforations in patients with metastatic colorectal cancer receiving bevacizumab plus chemotherapy. J Clin Oncol. 2006;24(18 suppl):3535.Google Scholar
  21. 21.
    Abbrederis K, Kremer M, Schuhmacher C. Ischemic anastomotic bowel perforation during treatment with bevacizumab 10 months after surgery. Chirurg. 2008;79(4):351–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol. 2005;91(3):173–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484–96.PubMedCrossRefGoogle Scholar
  24. 24.
    Monk BJ, Choi DC, Pugmire G, Burger RA. Activity of bevacizumab (rhuMAB VEGF) in advanced refractory epithelial ovarian cancer. Gynecol Oncol. 2005;96(3):902–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Garcia AA, 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. J Clin Oncol. 2008;26(1):76–82.PubMedCrossRefGoogle Scholar
  26. 26.
    Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(33):5165–71.PubMedCrossRefGoogle Scholar
  27. 27.
    Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83.PubMedCrossRefGoogle Scholar
  28. 28.
    Byrne AT, Ross L, Holash J, et al. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res. 2003;9(15):5721–8.PubMedGoogle Scholar
  29. 29.
    Yoneda J, Kuniyasu H, Price JE, Bucana CD, Fidler IJ, Crispens MA. Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J Natl Cancer Inst. 1998;90(6):447–54.PubMedCrossRefGoogle Scholar
  30. 30.
    Kobold S, Hegewisch-Becker S, Oechsle K, Jordan K, Bokemeyer C, Atanackovic D. Intraperitoneal VEGF inhibition using bevacizumab: a potential approach for the symptomatic treatment of malignant ascites? Oncologist. 2009;14(12):1242–51.PubMedCrossRefGoogle Scholar
  31. 31.
    Han ES, Monk BJ. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol. 2007;105(1):3–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Nimeiri HS, Oza AM, Morgan RJ, et al. Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: a trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol. 2008;110(1):49–55.PubMedCrossRefGoogle Scholar
  33. 33.
    Konner JA, Grabon DM, Gerst SR, et al. Phase II study of intraperitoneal paclitaxel plus cisplatin and intravenous paclitaxel plus bevacizumab as adjuvant treatment of optimal stage II/III epithelial ovarian cancer. J Clin Oncol. 2011;29(35):4662–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Simpkins F, Belinson JL, Rose PG. Avoiding bevacizumab related gastrointestinal toxicity for recurrent ovarian cancer by careful patient screening. Gynecol Oncol. 2007;107(1):118–23.PubMedCrossRefGoogle Scholar
  35. 35.
    Brufsky AM, Hurvitz S, Perez E, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011;29(32):4286–93.PubMedCrossRefGoogle Scholar
  36. 36.
    Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2–negative metastatic breast cancer. J Clin Oncol. 2010;28(20):3239–47.PubMedCrossRefGoogle Scholar
  37. 37.
    Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2–negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29(10):1252–60.PubMedCrossRefGoogle Scholar
  38. 38.
    U.S. Food and Drug Administration. FDA Commissioner Removes Breast Cancer Indication from Avastin Label. 2011.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279485.htm. Accessed 16 April 2012.
  39. 39.
    Smith I, Pierga JY, Biganzoli L, et al. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2251 patients. Ann Oncol. 2011;22(3):595–602.PubMedCrossRefGoogle Scholar
  40. 40.
    Cortés J, Caralt M, Delaloge S, et al. Safety of bevacizumab in metastatic breast cancer patients undergoing surgery. Eur J Cancer. 2012;48(4):475–81.Google Scholar
  41. 41.
    Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer: AVAil. J Clin Oncol. 2009;27(8):1227–34.PubMedCrossRefGoogle Scholar
  42. 42.
    Reck M, Von Pawel J, Zatloukal P, et al. Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010;21(9):1804–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22(11):2184–91.PubMedCrossRefGoogle Scholar
  44. 44.
    Gray J, Murren J, Sharma A, Kelley S, Detterbeck F, Bepler G. Perforated viscus in a patient with non-small cell lung cancer receiving bevacizumab. J Thorac Oncol. 2007;2(6):571–3.PubMedCrossRefGoogle Scholar
  45. 45.
    Schellhaas E, Loddenkemper C, Schmittel A, Buhr HJ, Pohlen U. Bowel perforation in non-small cell lung cancer after bevacizumab therapy. Invest New Drugs. 2009;27(2):184–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Herbst RS, O'Neill VJ, Fehrenbacher L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non–small-cell lung cancer. J Clin Oncol. 2007;25(30):4743–50.PubMedCrossRefGoogle Scholar
  47. 47.
    Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol. 2010;28(1):43–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Genentech Inc. Avastin prescribing information. December 2011. Genentech, San Francisco, CA, USA.Google Scholar
  49. 49.
    Vredenburgh JJ, Desjardins A, Herndon JE, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25(30):4722–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. World Federation of Neuro-Oncology Meeting 2005:91.Google Scholar
  51. 51.
    Bokstein F, Shpigel S, Blumenthal DT. Treatment with bevacizumab and irinotecan for recurrent high–grade glial tumors. Cancer. 2008;112(10):2267–73.PubMedCrossRefGoogle Scholar
  52. 52.
    Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733–40.PubMedCrossRefGoogle Scholar
  54. 54.
    Desjardins A, Reardon DA, Herndon II JE, et al. Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas. Clin Cancer Res. 2008;14(21):7068–73.PubMedCrossRefGoogle Scholar
  55. 55.
    Reardon DA, Desjardins A, Peters K, et al. Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J Neurooncol. 2011;103(2):1–9.CrossRefGoogle Scholar
  56. 56.
    Gutin PH, Iwamoto FM, Beal K, et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. 2009;75(1):156–63.PubMedCrossRefGoogle Scholar
  57. 57.
    Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28(13):2144–50.PubMedCrossRefGoogle Scholar
  58. 58.
    Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2008;370(9605):2103–11.CrossRefGoogle Scholar
  59. 59.
    Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28(13):2137–43.PubMedCrossRefGoogle Scholar
  60. 60.
    Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24.PubMedCrossRefGoogle Scholar
  61. 61.
    Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–81.PubMedCrossRefGoogle Scholar
  62. 62.
    Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–56.PubMedCrossRefGoogle Scholar
  63. 63.
    Dias OM, Barbosa CCL, Teixeira LR, Vargas FS. Gastropleural fistula from gastric perforation due to renal cell carcinoma after bevacizumab chemotherapy: a case report. Clinics. 2011;66(8):1495–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Smith FO, Goff SL, Klapper JA, et al. Risk of bowel perforation in patients receiving interleukin-2 after therapy with anti-CTLA 4 monoclonal antibody. J Immunother. 2007;30(1):130.PubMedCrossRefGoogle Scholar
  65. 65.
    Heimann DM, Schwartzentruber DJ. Gastrointestinal perforations associated with interleukin-2 administration. J Immunother. 2004;27(3):254–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Ganapathi AM, Westmoreland T, Tyler D, Mantyh CR. Bevacizumab-associated fistula formation in postoperative colorectal cancer patients. J Am Coll Surg. 2012;214(4):582–8.Google Scholar
  67. 67.
    Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti–vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349(5):427–34.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Taher Abu-Hejleh
    • 1
  • James J. Mezhir
    • 2
  • Michael J. Goodheart
    • 3
  • Thorvardur R. Halfdanarson
    • 1
  1. 1.Department of Internal Medicine, Division of Hematology, Oncology, and Bone Marrow TransplantationThe University of Iowa Hospitals and ClinicsIowa CityUSA
  2. 2.Department of Surgery, Division of Surgical Oncology and Endocrine SurgeryThe University of Iowa Hospitals and ClinicsIowa CityUSA
  3. 3.Department of Gynecology and Obstetrics, Division of Gynecologic OncologyThe University of Iowa Hospitals and ClinicsIowa CityUSA

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