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Atypical reversible posterior leukoencephalopathy syndrome (RPLS) induced by cediranib in a patient with metastatic rectal cancer

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Summary

Background Reversible posterior leukoenecphalopathy syndrome (RPLS) is a rare clinicoradiologic syndrome characterized by neurologic symptoms such as seizures, headaches, visual abnormalities, confusion and encephalopathy, accompanied by vasogenic edema of posterior white matter seen on neuroimaging. It has been reported in association with many anti-angiogenic therapies, including bevacizumab, sunitinib, sorafenib, pazopanib and regorafenib. Cediranib is a potent, orally available small molecule tyrosine kinase inhibitor with anti-angiogenic activity, which has been shown to have activity against various solid tumors. Case report We present a case of a 65 year old male with metastatic adenocarcinoma of the rectum who received cediranib as part of a phase I clinical trial. He developed confusion and fluctuations in his level of consciousness. MRI of the brain revealed diffuse low level T2 signal abnormality in the cerebral peduncles, pons, and medulla and patchy T2 signal in both thalami, consistent with RPLS. With conservative management, including tight blood pressure control, his symptoms improved and MRI findings resolved. Conclusion RPLS is a rare, but serious, clinicoradiologic syndrome which has been described as an adverse effect of many anti-angiogenic agents and should also be considered in patients on cediranib who present with neurologic symptoms along with vasogenic edema seen on MRI. If RPLS is suspected, cediranib should be discontinued and blood pressure should be aggressively controlled.

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References

  1. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A et al (1996) A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334(8):494–500

    Article  CAS  PubMed  Google Scholar 

  2. Casey SO, Sampaio RC, Michel E, Truwit CL (2000) Posterior reversible encephalopathy syndrome: utility of fluid-attenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions. AJNR Am J Neuroradiol 21(7):1199–1206

    CAS  PubMed  Google Scholar 

  3. Arrillaga-Romany IC, Dietrich J (2012) Imaging findings in cancer therapy-associated neurotoxicity. Semin Neurol 32(4):476–486

    Article  PubMed  Google Scholar 

  4. Marinella MA, Markert RJ (2009) Reversible posterior leucoencephalopathy syndrome associated with anticancer drugs. Intern Med J 39(12):826–834

    Article  CAS  PubMed  Google Scholar 

  5. Seet RC, Rabinstein AA (2012) Clinical features and outcomes of posterior reversible encephalopathy syndrome following bevacizumab treatment. QJM 105(1):69–75

    Article  CAS  PubMed  Google Scholar 

  6. Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA (2010) Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc 85(5):427–432

    Article  PubMed Central  PubMed  Google Scholar 

  7. Lee VH, Wijdicks EF, Manno EM, Rabinstein AA (2008) Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol 65(2):205–210

    Article  PubMed  Google Scholar 

  8. Lee EQ, Arrillaga-Romany IC, Wen PY (2012) Neurologic complications of cancer drug therapies. Continuum (Minneap Minn) 18(2):355–365

    Google Scholar 

  9. Ahn KJ, You WJ, Jeong SL, Lee JW, Kim BS, Lee JH et al (2004) Atypical manifestations of reversible posterior leukoencephalopathy syndrome: findings on diffusion imaging and ADC mapping. Neuroradiology 46(12):978–983

    Article  CAS  PubMed  Google Scholar 

  10. Tormoehlen LM (2013) Toxic leukoencephalopathies. Psychiatr Clin North Am 36(2):277–292

    Article  PubMed  Google Scholar 

  11. Chikarmane SA, Khurana B, Krajewski KM, Shinagare AB, Howard S, Sodickson A et al (2012) What the emergency radiologist needs to know about treatment-related complications from conventional chemotherapy and newer molecular targeted agents. Emerg Radiol 19(6):535–546

    Article  PubMed  Google Scholar 

  12. Burki F, Badie K, Bartoli P, Bernard P, Montastruc JL, Bagheri H (2008) Reversible posterior leukoencephalopathy syndrome associated with bevacizumab/doxorubicin regimen. Br J Clin Pharmacol 65(5):793–794

    Article  PubMed Central  PubMed  Google Scholar 

  13. Feske SK (2011) Posterior reversible encephalopathy syndrome: a review. Semin Neurol 31(2):202–215

    Article  PubMed  Google Scholar 

  14. Vaughn C, Zhang L, Schiff D (2008) Reversible posterior leukoencephalopathy syndrome in cancer. Curr Oncol Rep 10(1):86–91

    Article  PubMed  Google Scholar 

  15. Martin G, Bellido L, Cruz JJ (2007) Reversible posterior leukoencephalopathy syndrome induced by sunitinib. J Clin Oncol 25(23):3559

    Article  PubMed  Google Scholar 

  16. Ito T, Sakai T, Inagawa S, Utsu M, Bun T (1995) MR angiography of cerebral vasospasm in preeclampsia. Am J Neuroradiol 16(6):1344–1346

    CAS  PubMed  Google Scholar 

  17. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  18. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407(6801):249–257

    Article  CAS  PubMed  Google Scholar 

  19. Keefe D, Bowen J, Gibson R, Tan T, Okera M, Stringer A (2011) Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. Oncologist 16(4):432–444

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Thachil J (2011) Nitric oxide and adverse events of vascular endothelial growth factor inhibitors. Curr Med Res Opin 27(8):1503–1507

    Article  CAS  PubMed  Google Scholar 

  21. Armstrong TS, Wen PY, Gilbert MR, Schiff D (2012) Management of treatment-associated toxicites of anti-angiogenic therapy in patients with brain tumors. Neuro Oncol 14(10):1203–1214

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Allen JA, Adlakha A, Bergethon PR (2006) Reversible posterior leukoencephalopathy syndrome after bevacizumab/FOLFIRI regimen for metastatic colon cancer. Arch Neurol 63(10):1475–1478

    Article  PubMed  Google Scholar 

  23. Peter S, Hausmann N, Schuster A, Boehm HF (2008) Reversible posterior leukoencephalopathy syndrome and intravenous bevacizumab. Clin Experiment Ophthalmol 36(1):94–96

    Article  PubMed  Google Scholar 

  24. Lazarus M, Amundson S, Belani R (2012) An Association between Bevacizumab and Recurrent Posterior Reversible Encephalopathy Syndrome in a Patient Presenting with Deep Vein Thrombosis: A Case Report and Review of the Literature. Case Rep Oncol Med 2012:819546

    PubMed Central  PubMed  Google Scholar 

  25. Dogan E, Aksoy S, Arslan C, Dede DS, Altundag K (2010) Probable sorafenib-induced reversible encephalopathy in a patient with hepatocellular carcinoma. Med Oncol 27(4):1436–1437

    Article  PubMed  Google Scholar 

  26. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A et al (2012) OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 30(17):2039–2045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X et al (2013) Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 14(10):933–942

    Article  CAS  PubMed  Google Scholar 

  28. Dersch R, Stich O, Goller K, Meckel S, Dechent F, Doostkam S et al (2013) Atypical posterior reversible encephalopathy syndrome associated with chemotherapy with Bevacizumab Gemcitabine and Cisplatin. J Neurol 260(5):1406–1407

    Article  CAS  PubMed  Google Scholar 

  29. Sawaya R, Hammoud S (2012) Posterior reversible encephalopathy associated with bevacizumab therapy in metastatic ovarian cancer. European Journal of Neurology 19(S1):763

    Google Scholar 

  30. Sclafani F, Giuseppe G, Mezynksi J, Collins C, Crown J (2012) Reversible posterior leukoencephalopathy syndrome and bevacizumab in breast cancer. J Clin Oncol 30(26):e257–9

    Article  PubMed  Google Scholar 

  31. Lau PC, Paunipagar B (2011) Posterior reversible encephalopathy syndrome with bevacizumab. Hong Kong Med J 17(1):80–81

    CAS  PubMed  Google Scholar 

  32. Lou E, Turner S, Sumrall A, Reardon DA, Desjardins A, Peters KB et al (2011) Bevacizumab-induced reversible posterior leukoencephalopathy syndrome and successful retreatment in a patient with glioblastoma. J Clin Oncol 29(28):e739–42

    Article  PubMed  Google Scholar 

  33. Chang Y, Mbeo G, Littman SJ (2012) Reversible posterior leukoencephalopathy syndrome associated with concurrent bevacizumab, gemcitabine, and oxaliplatin for cholangiocarcinoma. J Gastrointest Cancer 43(3):505–507

    Article  CAS  PubMed  Google Scholar 

  34. Ozcan C, Wong SJ, Hari P (2006) Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 354(9):980–2

    Article  PubMed  Google Scholar 

  35. Glusker P, Recht L, Lane B (2006) Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 354(9):980–2

    Article  CAS  PubMed  Google Scholar 

  36. Koopman M, Muller EW, Punt CJ (2008) Reversible posterior leukoencephalopathy syndrome caused by bevacizumab: report of a case. Dis Colon Rectum 51(9):1425–1426

    Article  PubMed  Google Scholar 

  37. El Maalouf G, Mitry E, Lacout A, Lievre A, Rougier P (2008) Isolated brainstem involvement in posterior reversible leukoencephalopathy induced by bevacizumab. J Neurol 255(2):295–296

    Article  PubMed  Google Scholar 

  38. Chen A, Agarwal N (2009) Reversible posterior leucoencephalopathy syndrome associated with sunitinib. Intern Med J 39(5):341–342

    Article  CAS  PubMed  Google Scholar 

  39. Cumurciuc R, Martinez-Almoyna L, Henry C, Husson H, de Broucker T (2008) Posterior reversible encephalopathy syndrome during sunitinib therapy. Rev Neurol 164(6–7):605–607

    Article  CAS  PubMed  Google Scholar 

  40. Padhy BM, Shanmugam SP, Gupta YK, Goyal A (2011) Reversible posterior leucoencephalopathy syndrome in an elderly male on sunitinib therapy. Br J Clin Pharmacol 71(5):777–779

    Article  PubMed Central  PubMed  Google Scholar 

  41. Duchnowska R, Miciuk B, Bodnar L, Wasniewski L, Szczylik C (2013) Severe neurological symptoms in a patient with advanced renal cell carcinoma treated with sunitinib. J Oncol Pharm Pract 19(2):186–189

    Article  PubMed  Google Scholar 

  42. Asaithambi G, Peters BR, Hurliman E, Moran BP, Khan AS, Taylor RA (2013) Posterior reversible encephalopathy syndrome induced by pazopanib for renal cell carcinoma. J Clin Pharm Ther 38(2):175–176

    Article  CAS  PubMed  Google Scholar 

  43. Chelis L, Souftas V, Amarantidis K, Xenidis N, Chamalidou E, Dimopoulos P (2012) Reversible posterior leukoencephalopathy syndrome induced by pazopanib. BMC Cancer 12:489

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Foerster R, Welzel T, Debus J, Gruellich C, Jaeger D, Potthoff K (2013) Posterior reversible leukoencephalopathy syndrome associated with pazopanib. Case Rep Oncol 6(1):204–208

    Article  PubMed Central  PubMed  Google Scholar 

  45. Govindarajan R, Adusumilli J, Baxter DL, El-Khoueiry A, Harik SI (2006) Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43–9006. J Clin Oncol 24(28):e48

    Article  PubMed  Google Scholar 

  46. Myint ZW, Sen JM, Watts NL, Druzgal TJ, Nathan BR, Ward MD, et al. (2013) Reversible Posterior Leukoencephalopathy Syndrome During Regorafenib Treatment: A Case Report and Literature Review of Reversible Posterior Leukoencephalopathy Syndrome Associated With Multikinase Inhibitors. Clin Colorectal Cancer Dec 27

  47. Chen H, Modiano MR, Neal JW, Brahmer JR, Rigas JR, Jotte RM, et al. A phase II multicenter study of aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic nonsquamous non-small cell lung cancer. Journal of Clinical Oncology 2012;30 (15 supplement abstr 7541).

  48. Powell MA, Sill MW, Goodfellow PJ, Jeske YW, Leslie KK, Lankes HA, et al. (2012) A phase II trial of brivanib in recurrent or persistent endometrial cancer: A gynecologic oncology group study. Int J Gynecol Cancer ; 22 (8); s3: E115 2012;22 (8) (s3):E115

  49. Schilder RJ, Sill MW, Lankes HA, Gold MA, Mannel RS, Modesitt SC et al (2013) A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: a Gynecologic Oncology Group study. Gynecol Oncol 129(1):86–91

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Heckman CA, Holopainen T, Wirzenius M, Keskitalo S, Jeltsch M, Yla-Herttuala S et al (2008) The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis. Cancer Res 68(12):4754–4762

    Article  CAS  PubMed  Google Scholar 

  51. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR et al (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65(10):4389–4400

    Article  CAS  PubMed  Google Scholar 

  52. Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U et al (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25(21):3045–3054

    Article  CAS  PubMed  Google Scholar 

  53. Mulders P, Hawkins R, Nathan P, de Jong I, Osanto S, Porfiri E et al (2012) Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study. Eur J Cancer 48(4):527–537

    Article  CAS  PubMed  Google Scholar 

  54. Goss GD, Arnold A, Shepherd FA, Dediu M, Ciuleanu TE, Fenton D et al (2010) Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. J Clin Oncol 28(1):49–55

    Article  CAS  PubMed  Google Scholar 

  55. Campbell NP, Kunnavakkam R, Leighl N, Vincent MD, Gandara DR, Koczywas M et al (2012) Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium. Lung Cancer 78(1):76–80

    Article  PubMed Central  PubMed  Google Scholar 

  56. Garland LL, Chansky K, Wozniak AJ, Tsao AS, Gadgeel SM, Verschraegen CF et al (2011) Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509. J Thorac Oncol 6(11):1938–1945

    Article  PubMed Central  PubMed  Google Scholar 

  57. Alberts SR, Fitch TR, Kim GP, Morlan BW, Dakhil SR, Gross HM et al (2012) Cediranib (AZD2171) in patients with advanced hepatocellular carcinoma: a phase II North Central Cancer Treatment Group Clinical Trial. Am J Clin Oncol 35(4):329–333

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Matulonis UA, Berlin S, Ivy P, Tyburski K, Krasner C, Zarwan C et al (2009) Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 27(33):5601–5606

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Kummar S, Allen D, Monks A, Polley EC, Hose CD, Ivy SP et al (2013) Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 31(18):2296–2302

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A et al (2013) Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31(26):3212–3218

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Laurie SA, Solomon BJ, Seymour L, Ellis PM, Goss GD, Shepherd FA et al (2014) Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29. Eur J Cancer 50(4):706–712

    Article  CAS  PubMed  Google Scholar 

  62. Cunningham D, Wong RP, D'Haens G, Douillard JY, Robertson J, Stone AM et al (2013) Cediranib with mFOLFOX6 vs bevacizumab with mFOLFOX6 in previously treated metastatic colorectal cancer. Br J Cancer 108(3):493–502

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW et al (2012) Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol 30(29):3596–3603

    Article  CAS  PubMed  Google Scholar 

  64. Schmoll HJ, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL et al (2012) Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol 30(29):3588–3595

    Article  CAS  PubMed  Google Scholar 

  65. Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R et al (2001) Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19(3):843–850

    CAS  PubMed  Google Scholar 

  66. Sclafani F, Giuseppe G, Mezynksi J, Collins C, Crown J (2012) Reversible posterior leukoencephalopathy syndrome and bevacizumab in breast cancer. J Clin Oncol 30(26):e257–9

    Article  PubMed  Google Scholar 

  67. Endo A, Fuchigami T, Hasegawa M, Hashimoto K, Fujita Y, Inamo Y et al (2012) Posterior reversible encephalopathy syndrome in childhood: report of four cases and review of the literature. Pediatr Emerg Care 28(2):153–157

    PubMed  Google Scholar 

  68. Sivrioglu AK, Incedayi M, Mutlu H, Meral C. (2013) sPosterior reversible encephalopathy syndrome in a child with Henoch-Schonlein purpura. BMJ Case Rep 2013 Aug 14:10.1136/bcr-2013-008900

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Acknowledgments

We acknowledge AstraZeneca, which conducted the phase I trial in which this patient was enrolled.

Conflict of Interest

Dr. Ron Hennig has stock in Roche and Pfizer. All other authors declare that they have no conflict of interest.

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Correspondence to Christina A. K. Kim.

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Kim, C.A.K., Price-Hiller, J., Chu, Q.S. et al. Atypical reversible posterior leukoencephalopathy syndrome (RPLS) induced by cediranib in a patient with metastatic rectal cancer. Invest New Drugs 32, 1036–1045 (2014). https://doi.org/10.1007/s10637-014-0113-6

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