Neurologic complications of cancer treatment with biologic agents
- Eudocia Quant Lee, MD, MPH
Eudocia Quant Lee, MD, MPH
- Assistant Professor of Neurology
- Harvard Medical School
- Patrick Y Wen, MD
Patrick Y Wen, MD
- Section Editor — Neurooncology
- Professor of Neurology
- Harvard Medical School
Neurologic complications of anticancer therapy may result from direct toxic effects on the nervous system, or indirectly from drug-induced metabolic derangements or cerebrovascular disorders, or, in the case of ipilimumab, autoimmune disorders. Their recognition is important because of potential confusion with metastatic disease, paraneoplastic syndromes or comorbid neurologic disorders that do not require dose reduction or discontinuation. If the neurologic disorder is caused by the chemotherapy, discontinuation of the offending agent may prevent irreversible injury.
Here we discuss the neurologic complications associated with biologic agents, including both biological response modifiers and monoclonal antibodies. The neurological complications associated with cytotoxic chemotherapy agents are discussed elsewhere. (See "Overview of neurologic complications of non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy".)
BIOLOGICAL RESPONSE MODIFIERS
In more recent years there has been increasing interest in the use of biological response modifiers in cancer treatment. Frequently, they are used in combination with conventional chemotherapeutic agents (biochemotherapy).
Interferon — Interferon alpha (IFN-a) is useful for a number of cancers including hairy cell leukemia, Kaposi's sarcoma, melanoma, multiple myeloma, chronic myeloid leukemia (CML), and low-grade lymphoma. However, IFN-a is associated with a variety of substantial toxicities, which may limit the ability to deliver a full course of therapy . Frequent systemic toxicities include flu-like symptoms (myalgias, nausea, vomiting, arthralgias, fever, chills, and headache) and depression. The flu-like symptoms tend to be worse at the onset of therapy and usually improve with time.
Neurotoxicity tends to be dose-related. It is generally mild when low doses of IFN-a are used, as in the adjuvant setting for patients with malignant melanoma. In a detailed evaluation of 37 such patients treated with IFN, the most frequent neurotoxicity was tremor, observed in eight cases (22 percent) . (See "Adjuvant immunotherapy for melanoma", section on 'Interferon'.)
- Hauschild A, Gogas H, Tarhini A, et al. Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion. Cancer 2008; 112:982.
- Caraceni A, Gangeri L, Martini C, et al. Neurotoxicity of interferon-alpha in melanoma therapy: results from a randomized controlled trial. Cancer 1998; 83:482.
- Rohatiner AZ, Prior PF, Burton AC, et al. Central nervous system toxicity of interferon. Br J Cancer 1983; 47:419.
- Meyers CA, Scheibel RS, Forman AD. Persistent neurotoxicity of systemically administered interferon-alpha. Neurology 1991; 41:672.
- Lerner DM, Stoudemire A, Rosenstein DL. Neuropsychiatric toxicity associated with cytokine therapies. Psychosomatics 1999; 40:428.
- Pavol MA, Meyers CA, Rexer JL, et al. Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia. Neurology 1995; 45:947.
- Schachter J, Brenner B, Fenig E, et al. Toxicity of adjuvant high-dose interferon-alpha-2b in patients with cutaneous melanoma at high risk of recurrence. Oncol Rep 1999; 6:1389.
- Dickinson MD, Barr CD, Hiscock M, Meyers CA. Cognitive effects of pegylated interferon in individuals with primary brain tumors. J Neurooncol 2009; 95:231.
- Rutkove SB. An unusual axonal polyneuropathy induced by low-dose interferon alfa-2a. Arch Neurol 1997; 54:907.
- Bora I, Karli N, Bakar M, et al. Myasthenia gravis following IFN-alpha-2a treatment. Eur Neurol 1997; 38:68.
- Nishihori T, Abdo-Matkiwsky M, Fleishman SB, Blum RH. Severe action tremor related to interferon-alpha 2b therapy for malignant melanoma. Am J Clin Oncol 2005; 28:526.
- Delattre J, Vega F, Chen Q. Neurologic complications of immunotherapy. In: Neurologic complications of cancer, Wiley RG (Ed), Marcel Dekker, New York 1995. p.267.
- Lipton JH, Khoroshko N, Golenkov A, et al. Phase II, randomized, multicenter, comparative study of peginterferon-alpha-2a (40 kD) (Pegasys) versus interferon alpha-2a (Roferon-A) in patients with treatment-naïve, chronic-phase chronic myelogenous leukemia. Leuk Lymphoma 2007; 48:497.
- Hensley ML, Peterson B, Silver RT, et al. Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer and Leukemia Group B 9013. J Clin Oncol 2000; 18:1301.
- Michallet M, Maloisel F, Delain M, et al. Pegylated recombinant interferon alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase chronic myelogenous leukemia: a phase III study. Leukemia 2004; 18:309.
- Meyers CA, Obbens EA, Scheibel RS, Moser RP. Neurotoxicity of intraventricularly administered alpha-interferon for leptomeningeal disease. Cancer 1991; 68:88.
- Bradley JD, Scott CB, Paris KJ, et al. A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non-small-cell lung cancer (RTOG 93-04). Int J Radiat Oncol Biol Phys 2002; 52:1173.
- Alberts DS, Marth C, Alvarez RD, et al. Randomized phase 3 trial of interferon gamma-1b plus standard carboplatin/paclitaxel versus carboplatin/paclitaxel alone for first-line treatment of advanced ovarian and primary peritoneal carcinomas: results from a prospectively designed analysis of progression-free survival. Gynecol Oncol 2008; 109:174.
- Brown TD, Koeller J, Beougher K, et al. A phase I clinical trial of recombinant DNA gamma interferon. J Clin Oncol 1987; 5:790.
- Denicoff KD, Rubinow DR, Papa MZ, et al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1987; 107:293.
- Buzaid AC, Atkins M. Practical guidelines for the management of biochemotherapy-related toxicity in melanoma. Clin Cancer Res 2001; 7:2611.
- Petrella T, Quirt I, Verma S, et al. Single-agent interleukin-2 in the treatment of metastatic melanoma: a systematic review. Cancer Treat Rev 2007; 33:484.
- Bernard JT, Ameriso S, Kempf RA, et al. Transient focal neurologic deficits complicating interleukin-2 therapy. Neurology 1990; 40:154.
- Esteva-Lorenzo FJ, Janik JE, Fenton RG, et al. Myositis associated with interleukin-2 therapy in a patient with metastatic renal cell carcinoma. Cancer 1995; 76:1219.
- Fraenkel PG, Rutkove SB, Matheson JK, et al. Induction of myasthenia gravis, myositis, and insulin-dependent diabetes mellitus by high-dose interleukin-2 in a patient with renal cell cancer. J Immunother 2002; 25:373.
- Loh FL, Herskovitz S, Berger AR, Swerdlow ML. Brachial plexopathy associated with interleukin-2 therapy. Neurology 1992; 42:462.
- Barba D, Saris SC, Holder C, et al. Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg 1989; 70:175.
- Hayes RL, Koslow M, Hiesiger EM, et al. Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer 1995; 76:840.
- Hotton KM, Khorsand M, Hank JA, et al. A phase Ib/II trial of granulocyte-macrophage-colony stimulating factor and interleukin-2 for renal cell carcinoma patients with pulmonary metastases: a case of fatal central nervous system thrombosis. Cancer 2000; 88:1892.
- Correale P, Campoccia G, Tsang KY, et al. Recruitment of dendritic cells and enhanced antigen-specific immune reactivity in cancer patients treated with hr-GM-CSF (Molgramostim) and hr-IL-2. results from a phase Ib clinical trial. Eur J Cancer 2001; 37:892.
- Westermann J, Reich G, Kopp J, et al. Granulocyte/macrophage-colony-stimulating-factor plus interleukin-2 plus interferon alpha in the treatment of metastatic renal cell carcinoma: a pilot study. Cancer Immunol Immunother 2001; 49:613.
- Paleologos N. Complications of chemotherapy. In: Iatrogenic Neurology, Biller J (Ed), Butterworth-Heinemann, Boston 1998. p.439.
- Drory VE, Lev D, Groozman GB, et al. Neurotoxicity of isolated limb perfusion with tumor necrosis factor. J Neurol Sci 1998; 158:1.
- Maloney DG, Grillo-López AJ, Bodkin DJ, et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 1997; 15:3266.
- Maloney DG, Press OW. Newer treatments for non-Hodgkin's lymphoma: monoclonal antibodies. Oncology (Williston Park) 1998; 12:63.
- Foran JM, Rohatiner AZ, Cunningham D, et al. European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 2000; 18:317.
- Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009; 113:4834.
- Mavragani CP, Vlachoyiannopoulos PG, Kosmas N, et al. A case of reversible posterior leucoencephalopathy syndrome after rituximab infusion. Rheumatology (Oxford) 2004; 43:1450.
- Rubenstein JL, Fridlyand J, Abrey L, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 2007; 25:1350.
- Bromberg JE, Doorduijn JK, Baars JW, et al. Acute painful lumbosacral paresthesia after intrathecal rituximab. J Neurol 2012; 259:559.
- Piccinni C, Sacripanti C, Poluzzi E, et al. Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents. Eur J Clin Pharmacol 2010; 66:199.
- Kaminski MS, Estes J, Zasadny KR, et al. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 2000; 96:1259.
- Vose JM, Wahl RL, Saleh M, et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol 2000; 18:1316.
- Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17:2639.
- FDA-approved prescribing information available online at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf?et_cid=31141095&et_rid=463638624&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2013%2f125427lbl.pdf (Accessed on February 25, 2013).
- Sherman JH, Aregawi DG, Lai A, et al. Optic neuropathy in patients with glioblastoma receiving bevacizumab. Neurology 2009; 73:1924.
- Pfeiffer P, Nielsen D, Yilmaz M, et al. Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. Acta Oncol 2007; 46:697.
- Baselga J, Pfister D, Cooper MR, et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 2000; 18:904.
- Feinstein TM, Gibson MK, Argiris A. Cetuximab-induced aseptic meningitis. Ann Oncol 2009; 20:1609.
- Nagovskiy N, Agarwal M, Allerton J. Cetuximab-induced aseptic meningitis. J Thorac Oncol 2010; 5:751.
- Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 2010; 363:1812.
- Shustov AR, Advani R, Brice P, et al. Complete remissions with brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large cell lymphoma (abstract 961). Blood 2010; 116:423.
- Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 2012; 30:2190.
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm287710.htm?source=govdelivery (Accessed on January 13, 2012).
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125557lbl.pdf?et_cid=34995040&et_rid=931330620&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2014%2f125557lbl.pdf (Accessed on December 17, 2014).
- Topp MS, Gökbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol 2014; 32:4134.
- BIOLOGICAL RESPONSE MODIFIERS
- - Interferon alfa-2a (Roferon, Pegasys)
- - Interferon alfa-2b (Intron, PEG-Intron)
- - Intrathecal interferon
- Beta and gamma interferon
- Tumor necrosis factor
- MONOCLONAL ANTIBODIES
- Tositumomab radioconjugate
- - Ado-trastuzumab emtansine