Novel Insights from Clinical Practice Oncol Res Treat 2014;37:757–760 DOI: 10.1159/000368316
Received: March 31, 2014 Accepted: August 18, 2014 Published online: October 30, 2014
Late-Onset Paraplegia after Complete Response to Two Cycles of Ipilimumab for Metastatic Melanoma Grainne M. O’Kanea Tomas G. Lyonsa Gabrielle C. Colleranb Marzuki Wan Ahmadb Scheryll Alkena Eoin C. Kavanaghc David Fitzpatrickd Brian Murrayb Catherine M. Kellya a
Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland Department of Neurology, Mater Misericordiae University Hospital, Dublin, Ireland c Department of Radiology, Mater Misericordiae University Hospital, Dublin, Ireland d St Luke‘s Hospital, Dublin, Ireland b
Established Facts • Ipilimumab is effective in metastatic melanoma. • Immunological side effects including colitis are common.
Novel Insights • Radiation in the setting of ipilimumab can result in dramatic responses (abscopal effect); in this case, a complete response. • Spinal cord oedema with consequent paraplegia is a potential complication of ipilimumab. • If the additive effect of radiation and immunotherapy results in greater response rates, it may also result in greater toxicities.
Summary Background: Ipilimumab has been shown to improve overall survival in patients with metastatic melanoma; however, complete responses (CRs) are uncommon. Immune-related side effects usually involve the skin or gastrointestinal tract. Neurologic events occur less frequently but are well described. Case Report: We report the case of a 58-year-old man with metastatic melanoma who commenced ipilimumab post spinal decompression and radiation. He developed a colitis post cycle 2 and ipilimumab was discontinued. Imaging, however, documented a radiological CR. 8 weeks later, he developed paraplegia and a myelitis despite an ongoing radiologi-
© 2014 S. Karger GmbH, Freiburg 2296-5270/14/3712-0757$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
cal CR. Steroid use resulted in some improvement radiologically, without clinical improvement. Conclusion: We report myelitis with consequent paraplegia as a potential neurological immune-related side effect of ipilimumab. We further describe a patient with a CR after 2 cycles of ipilimumab in the setting of radiation.
Introduction Ipilimumab has been shown to improve overall survival in patients with metastatic melanoma; however, complete responses (CRs) are uncommon. Immune-related side effects usually involve the skin or gastrointestinal tract. Neurologic
Dr. Catherine M. Kelly Department of Medical Oncology Mater Misericordiae University Hospital Eccles Street, Dublin 7, Ireland [email protected]
Downloaded by: NYU Medical Center Library 128.122.253.212 - 5/23/2015 4:52:01 PM
Keywords Immunotherapy · Melanoma · Side effects
Fig. 1. Sites of FDG-avid metastatic disease. (a) Right femur, (b) right lung base, (c) left rib, (d) right supraclavicular area.
DEFG
Fig. 2. PET images showing a radiological CR without evidence of FDG-active disease.
events occur less frequently but are well described. We report the case of a 58-year-old man with metastatic melanoma who commenced ipilimumab post spinal decompression and radiation.
D E F
Case Report
758
Oncol Res Treat 2014;37:757–760
Fig. 3. Spinal cord oedema (a) extending to level T7 at first presentation, (b) 4 weeks post steroids, (c) 7 months post onset of neurological signs.
cord extending from T7 to L1, consistent with extensive oedema without evidence of metastatic disease or cord compression (fig. 3a). The MRI brain was normal and PET/CT confirmed a continued complete radiological remission. The differential diagnosis at this point included a paraneoplastic syndrome, radiation myelitis, transverse myelitis post spinal decompression, aseptic meningitis, leptomeningeal disease, an arteriovascular malformation, vascular myelopathy and ipilimumab-induced myelitis. Several investigations were performed. 2 lumbar punctures revealed mildly elevated protein levels (500–576 mg/l) and normal glucose levels (3.4–3.6 mmol/l). Each cerebrospinal fluid (CSF) sample contained minimal numbers of lymphocytes (maximum 16/μl). No malignant cells were identified. Bacterial cultures and a full viral screen for human immunodeficiency virus (HIV), hepatitis B and C virus, herpes simplex virus 1 and 2, varicella zoster virus and enterovirus were negative. The autoimmune screen was normal and the initial screen for paraneoplastic antibodies (Abs) including anti-Ri, -Hu, -Yo and -aquaporin was also negative. A more extensive paraneoplastic panel on serum conducted at the Mayo Clinic, Rochester, USA, for antinuclear neuronal Ab (ANNA)-1 (antiHu), ANNA-2 (anti-Ri), Purkinje cell Ab (PCA)-1 (anti-Yo), PCA-2,
O’Kane/Lyons/Colleran/Wan Ahmad/Alken/ Kavanagh/Fitzpatrick/Murray/Kelly
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A 58-year-old man was referred to medical oncology post resection of an ulcerated nodular malignant melanoma from the left leg. The Breslow thickness was 5.5 mm, and 2 of 17 inguinal lymph nodes were positive for disease. Initial staging scans using computed tomography (CT) of the thorax, abdomen and pelvis were negative for metastatic disease. The patient, however, complained of persistent back pain, and further imaging with positron emission tomography (PET)/CT scan showed diffuse, abnormally increased 18F-fluorodeoxyglucose (FDG) uptake within the 7th thoracic vertebral body (T7) without any other evidence of disease. A bone biopsy of T7 confirmed metastatic melanoma. The patient subsequently received a single palliative fraction of radiotherapy (8 cGray/1 fraction) for pain relief. Despite this, his symptoms persisted and subsequent magnetic resonance imaging (MRI) of the spine revealed retropulsion of T7 with impending cord compression. He underwent emergency spinal decompression and postoperatively received radiotherapy from T6 to T8 at a dose of 22.5 cGray in 9 fractions. Radiotherapy was completed in April 2012. A restaging PET/CT scan in May 2012 revealed multiple new sites of metastatic disease involving the right femur, the right lung base, the left posterior rib and the right supraclavicular region (fig. 1a–d). As genotyping was negative for the BRAF V600E mutation, ipilimumab was initiated in June 2012 at a dose of 3 mg/kg administered every 3 weeks. On day 16 post completion of cycle 2, the patient was admitted with grade 3 colitis requiring aggressive rehydration, steroids and antibiotics. He made a full recovery and ipilumumab was discontinued. A further PET/CT scan in August 2012, 5 weeks after his last cycle of treatment, documented a radiological complete response (CR) with no evidence of disease (fig. 2a–d). The patient remained well until November 2012, when he presented to the emergency department complaining of a 1-week history of unsteadiness, weakness of the left leg, constipation and difficulty passing urine. On clinical examination there was 4/5 power in the left leg and a sensory level evident at T10. Reflexes were brisk and plantars upgoing. Sensation was normal in the upper and lower limbs. An urgent MRI spine was performed, revealing an abnormal T2 hyperintense signal within the spinal
PCA-Tr, ANNA-3, collapsin response mediator protein 5 (CRMP5) immunoglobulin G (IgG), anti-glial/neuronal nuclear Ab type 1 (AGNA-1) IgG, amphiphysin IgG, voltage-gated potassium channel (VGKC) complex IgG, calcium channel Abs, glutamic acid decarboxylase 65 (GAD65) Ab, N-methyl-d-aspartate (NMDA)/į-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA)/gamma-aminobutyric acid (GABA)B receptor Abs and acetylcholine receptor Abs (alpha 1 and alpha 3) was also negative. Radiation doses and fields were extensively reviewed; however, given the distribution of cord oedema and the number of fractions administered, radiation myelitis was determined unlikely at a national neuro-oncology multidisciplinary meeting. Dynamic plain films of the spine confirmed satisfactory placement of metal rods inserted during decompression 8 months earlier. A CT myelogram was normal. The patient received pulsed weekly methylprednisone for 4 weeks with tapering prednisone between dosing. Initial treatment also included broad-spectrum antibiotics and intravenous aciclovir. The patient received 5 days of intravenous Ig and completed an intensive physiotherapy regimen. There was little clinical improvement; however, repeat imaging with MRI spine at 2 and 4 weeks (fig. 3b) following admission confirmed a reduction in the T2 signal along the spinal cord. Upon discharge, the patient required a walking frame and a urinary catheter. He was readmitted 8 weeks later having completed tapering steroids, with deterioration in power to 2/5 in the lower limbs; he was hyperreflexic with evident spasticity. An MRI spine showed progressive cord oedema extending proximally to the level of the C4/5 disc space and distally to the cauda equina. A PET/CT documented 2 small foci of FDGavid disease at S3 and L2. Further high-dose steroids resulted in slight improvement in the cord oedema radiologically, but no clinical improvement in symptoms. Temozolamide was commenced to treat the new bone metastases. A repeat MRI 7 months after the initial development of myelitis and paraplegia revealed marked regression in oedema but progression of disease in the lumbar spine after 3 cycles of temozolamide (fig. 3c).
Discussion Metastatic melanoma is an aggressive disease and its incidence is increasing globally [1]. Treatment options for metastatic melanoma have increased since the recent approval of new agents associated with improvement in overall survival [2–5]. Despite new therapies, the prognosis for individuals with metastatic melanoma remains poor. In patients treated with ipilimumab, a humanised monoclonal Ab targeting cytotoxic T cell lymphocyte antigen-4 (CTLA-4), the overall response rates were less than 10% [2]. Full appreciation of the adverse effects of new immune-potentiating agents alone and in combination with other treatment modalities outside of the clinical trial setting is at an early stage. CTLA-4 responds to an immune stimulus by suppressing the T cell response; ipilimumab binds CTLA-4, resulting in a persistent immune response affecting both malignant and nor-
mal tissue. Radiation-induced cell death resulting in the release of tumour antigens could theoretically enhance autoimmunity and therefore potential responses to ipilimumab. Colitis, which developed in our patient, is a known frequent complication of ipilimumab [6–10], and some studies report improved outcomes in patients developing such immune-related side effects [9, 11–14]. CRs to ipilimumab, however, are relatively infrequent and occur in only 2% of patients [2]. Objective responses with 1 CR in the context of radiotherapy demonstrating the ‘abscopal’ effect [15, 16] have been described and resulted in regression of metastatic lesions outside the radiation field, as evident in our case. The additive effect of radiation and ipilimumab is being investigated in clinical trials [17]. Neurological adverse events associated with ipiliumumab include inflammatory myopathy [18], Guillain-Barré syndrome [19], aseptic meningitis [20], posterior reversible encephalopathy syndrome [21], enteric neuropathy [22], meningo-radiculo-neuritis [23], myasthenia gravis [24] and transverse myelitis [25]. Our patient developed myelitis with paraplegia months after spinal decompression and radiation followed by ipilimumab therapy; similar toxicity has not been reported in the literature. We excluded most causes of a spinal myelitis, and although a spinal angiogram was not performed, a vascular complication would not ordinarily follow such a course. We consider ipilimumab-induced neurotoxicity post radiotherapy as a plausible explanation for this adverse event. This is further supported by the spontaneous regression of oedema on MRI over time. Persistent immune activation within the cord may have resulted in the radiological appearances and clinical manifestation of paraplegia. Elucidating the clinical effects of a new drug from the effects of the disease itself and those of other treatment modalities such as surgery and radiation is challenging. We would like to draw attention to potential neurotoxicity associated with ipilimumab therapy after radiation.
Acknowledgement We would like to thank Andrew McKeon MD, Neuroimmunology Laboratory, Mayo Clinic, Rochester, USA for his help with this case.
Disclosure Statement There are no potential conflicts of interest for any of the authors.
1 Lens MB, Dawes M: Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 2004;150:179–185.
Ipilimumab and Radiation in Metastatic Melanoma
2 Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–723.
3 Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–2516.
Oncol Res Treat 2014;37:757–760
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References
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11 Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, Kammula US, Topalian SL, Sherry RM, Kleiner D, et al.: Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 2006;24:2283–2289. 12 Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE, Kammula US, Hughes MS, Allen TE, Levy CL, et al.: Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 2007;13(22 Pt 1):6681–6688. 13 Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, Chapman PB, Schwartz GK, Allison JP, Wolchok JD: Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 2010;116:1767–1775. 14 Seregard S, Lundell G, Svedberg H, Kivelä T: Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis. Ophthalmology 2004;111:1228–1232. 15 Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, et al.: Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012;366:925–931. 16 Hiniker SM, Chen DS, Reddy S, Chang DT, Jones JC, Mollick JA, Swetter SM, Knox SJ: A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol 2012;5:404–407. 17 www.clinicaltrials.gov.
Oncol Res Treat 2014;37:757–760
18 Hunter G, Voll C, Robinson CA: Autoimmune inflammatory myopathy after treatment with ipilimumab. Can J Neurol Sci 2009;36:518–520. 19 Wilgenhof S, Neyns B: Anti-CTLA-4 antibody-induced Guillain-Barré syndrome in a melanoma patient. Ann Oncol 2011;22:991–993. 20 Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, Suri KB, Levy C, Allen T, Mavroukakis S, et al.: Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 2007;30:825–830. 21 Maur M, Tomasello C, Frassoldati A, Dieci MV, Barbieri E, Conte P: Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma. J Clin Oncol 2012;30:e76–e78. 22 Bhatia S, Huber BR, Upton MP, Thompson JA: Inflammatory enteric neuropathy with severe constipation after ipilimumab treatment for melanoma: a case report. J Immunother 2009;32:203–205. 23 Bompaire F, Mateus C, Taillia H, De Greslan T, Lahutte M, Sallansonnet-Froment M, Ouologuem M, Renard JL, Gorochov G, Robert C, et al.: Severe meningo-radiculo-neuritis associated with ipilimumab. Invest New Drugs 2012;30:2407–2410. 24 Johnson DB, Saranga-Perry V, Lavin PJ, Burnette WB, Clark SW, Uskavitch DR, Wallace DE, Dickson MA, Kudchadkar RR, Sosman JA: Myasthenia gravis induced by ipilimumab in patients with metastatic melanoma. J Clin Oncol 2014, in press. 25 Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S: Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro Oncol 2014;16:589–593.
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4 Robert C, Thomas L, Bondarenko I, O’Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517–2526. 5 Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, et al.: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107–114. 6 Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, Ridolfi R, Assi H, Maraveyas A, Berman D, et al.: A randomized, double-blind, placebocontrolled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 2009;15:5591–5598. 7 O’Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, et al.: Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol 2010;21: 1712–1717. 8 Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T, et al.: Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155–164. 9 Weber JS, O’Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E: Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 2008;26:5950–5956. 10 Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, et al.: Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005;23:6043–6053.
Received: March 31, 2014 Accepted: August 18, 2014 Published online: October 30, 2014
Late-Onset Paraplegia after Complete Response to Two Cycles of Ipilimumab for Metastatic Melanoma Grainne M. O’Kanea Tomas G. Lyonsa Gabrielle C. Colleranb Marzuki Wan Ahmadb Scheryll Alkena Eoin C. Kavanaghc David Fitzpatrickd Brian Murrayb Catherine M. Kellya a
Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland Department of Neurology, Mater Misericordiae University Hospital, Dublin, Ireland c Department of Radiology, Mater Misericordiae University Hospital, Dublin, Ireland d St Luke‘s Hospital, Dublin, Ireland b
Established Facts • Ipilimumab is effective in metastatic melanoma. • Immunological side effects including colitis are common.
Novel Insights • Radiation in the setting of ipilimumab can result in dramatic responses (abscopal effect); in this case, a complete response. • Spinal cord oedema with consequent paraplegia is a potential complication of ipilimumab. • If the additive effect of radiation and immunotherapy results in greater response rates, it may also result in greater toxicities.
Summary Background: Ipilimumab has been shown to improve overall survival in patients with metastatic melanoma; however, complete responses (CRs) are uncommon. Immune-related side effects usually involve the skin or gastrointestinal tract. Neurologic events occur less frequently but are well described. Case Report: We report the case of a 58-year-old man with metastatic melanoma who commenced ipilimumab post spinal decompression and radiation. He developed a colitis post cycle 2 and ipilimumab was discontinued. Imaging, however, documented a radiological CR. 8 weeks later, he developed paraplegia and a myelitis despite an ongoing radiologi-
© 2014 S. Karger GmbH, Freiburg 2296-5270/14/3712-0757$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
cal CR. Steroid use resulted in some improvement radiologically, without clinical improvement. Conclusion: We report myelitis with consequent paraplegia as a potential neurological immune-related side effect of ipilimumab. We further describe a patient with a CR after 2 cycles of ipilimumab in the setting of radiation.
Introduction Ipilimumab has been shown to improve overall survival in patients with metastatic melanoma; however, complete responses (CRs) are uncommon. Immune-related side effects usually involve the skin or gastrointestinal tract. Neurologic
Dr. Catherine M. Kelly Department of Medical Oncology Mater Misericordiae University Hospital Eccles Street, Dublin 7, Ireland [email protected]
Downloaded by: NYU Medical Center Library 128.122.253.212 - 5/23/2015 4:52:01 PM
Keywords Immunotherapy · Melanoma · Side effects
Fig. 1. Sites of FDG-avid metastatic disease. (a) Right femur, (b) right lung base, (c) left rib, (d) right supraclavicular area.
DEFG
Fig. 2. PET images showing a radiological CR without evidence of FDG-active disease.
events occur less frequently but are well described. We report the case of a 58-year-old man with metastatic melanoma who commenced ipilimumab post spinal decompression and radiation.
D E F
Case Report
758
Oncol Res Treat 2014;37:757–760
Fig. 3. Spinal cord oedema (a) extending to level T7 at first presentation, (b) 4 weeks post steroids, (c) 7 months post onset of neurological signs.
cord extending from T7 to L1, consistent with extensive oedema without evidence of metastatic disease or cord compression (fig. 3a). The MRI brain was normal and PET/CT confirmed a continued complete radiological remission. The differential diagnosis at this point included a paraneoplastic syndrome, radiation myelitis, transverse myelitis post spinal decompression, aseptic meningitis, leptomeningeal disease, an arteriovascular malformation, vascular myelopathy and ipilimumab-induced myelitis. Several investigations were performed. 2 lumbar punctures revealed mildly elevated protein levels (500–576 mg/l) and normal glucose levels (3.4–3.6 mmol/l). Each cerebrospinal fluid (CSF) sample contained minimal numbers of lymphocytes (maximum 16/μl). No malignant cells were identified. Bacterial cultures and a full viral screen for human immunodeficiency virus (HIV), hepatitis B and C virus, herpes simplex virus 1 and 2, varicella zoster virus and enterovirus were negative. The autoimmune screen was normal and the initial screen for paraneoplastic antibodies (Abs) including anti-Ri, -Hu, -Yo and -aquaporin was also negative. A more extensive paraneoplastic panel on serum conducted at the Mayo Clinic, Rochester, USA, for antinuclear neuronal Ab (ANNA)-1 (antiHu), ANNA-2 (anti-Ri), Purkinje cell Ab (PCA)-1 (anti-Yo), PCA-2,
O’Kane/Lyons/Colleran/Wan Ahmad/Alken/ Kavanagh/Fitzpatrick/Murray/Kelly
Downloaded by: NYU Medical Center Library 128.122.253.212 - 5/23/2015 4:52:01 PM
A 58-year-old man was referred to medical oncology post resection of an ulcerated nodular malignant melanoma from the left leg. The Breslow thickness was 5.5 mm, and 2 of 17 inguinal lymph nodes were positive for disease. Initial staging scans using computed tomography (CT) of the thorax, abdomen and pelvis were negative for metastatic disease. The patient, however, complained of persistent back pain, and further imaging with positron emission tomography (PET)/CT scan showed diffuse, abnormally increased 18F-fluorodeoxyglucose (FDG) uptake within the 7th thoracic vertebral body (T7) without any other evidence of disease. A bone biopsy of T7 confirmed metastatic melanoma. The patient subsequently received a single palliative fraction of radiotherapy (8 cGray/1 fraction) for pain relief. Despite this, his symptoms persisted and subsequent magnetic resonance imaging (MRI) of the spine revealed retropulsion of T7 with impending cord compression. He underwent emergency spinal decompression and postoperatively received radiotherapy from T6 to T8 at a dose of 22.5 cGray in 9 fractions. Radiotherapy was completed in April 2012. A restaging PET/CT scan in May 2012 revealed multiple new sites of metastatic disease involving the right femur, the right lung base, the left posterior rib and the right supraclavicular region (fig. 1a–d). As genotyping was negative for the BRAF V600E mutation, ipilimumab was initiated in June 2012 at a dose of 3 mg/kg administered every 3 weeks. On day 16 post completion of cycle 2, the patient was admitted with grade 3 colitis requiring aggressive rehydration, steroids and antibiotics. He made a full recovery and ipilumumab was discontinued. A further PET/CT scan in August 2012, 5 weeks after his last cycle of treatment, documented a radiological complete response (CR) with no evidence of disease (fig. 2a–d). The patient remained well until November 2012, when he presented to the emergency department complaining of a 1-week history of unsteadiness, weakness of the left leg, constipation and difficulty passing urine. On clinical examination there was 4/5 power in the left leg and a sensory level evident at T10. Reflexes were brisk and plantars upgoing. Sensation was normal in the upper and lower limbs. An urgent MRI spine was performed, revealing an abnormal T2 hyperintense signal within the spinal
PCA-Tr, ANNA-3, collapsin response mediator protein 5 (CRMP5) immunoglobulin G (IgG), anti-glial/neuronal nuclear Ab type 1 (AGNA-1) IgG, amphiphysin IgG, voltage-gated potassium channel (VGKC) complex IgG, calcium channel Abs, glutamic acid decarboxylase 65 (GAD65) Ab, N-methyl-d-aspartate (NMDA)/į-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA)/gamma-aminobutyric acid (GABA)B receptor Abs and acetylcholine receptor Abs (alpha 1 and alpha 3) was also negative. Radiation doses and fields were extensively reviewed; however, given the distribution of cord oedema and the number of fractions administered, radiation myelitis was determined unlikely at a national neuro-oncology multidisciplinary meeting. Dynamic plain films of the spine confirmed satisfactory placement of metal rods inserted during decompression 8 months earlier. A CT myelogram was normal. The patient received pulsed weekly methylprednisone for 4 weeks with tapering prednisone between dosing. Initial treatment also included broad-spectrum antibiotics and intravenous aciclovir. The patient received 5 days of intravenous Ig and completed an intensive physiotherapy regimen. There was little clinical improvement; however, repeat imaging with MRI spine at 2 and 4 weeks (fig. 3b) following admission confirmed a reduction in the T2 signal along the spinal cord. Upon discharge, the patient required a walking frame and a urinary catheter. He was readmitted 8 weeks later having completed tapering steroids, with deterioration in power to 2/5 in the lower limbs; he was hyperreflexic with evident spasticity. An MRI spine showed progressive cord oedema extending proximally to the level of the C4/5 disc space and distally to the cauda equina. A PET/CT documented 2 small foci of FDGavid disease at S3 and L2. Further high-dose steroids resulted in slight improvement in the cord oedema radiologically, but no clinical improvement in symptoms. Temozolamide was commenced to treat the new bone metastases. A repeat MRI 7 months after the initial development of myelitis and paraplegia revealed marked regression in oedema but progression of disease in the lumbar spine after 3 cycles of temozolamide (fig. 3c).
Discussion Metastatic melanoma is an aggressive disease and its incidence is increasing globally [1]. Treatment options for metastatic melanoma have increased since the recent approval of new agents associated with improvement in overall survival [2–5]. Despite new therapies, the prognosis for individuals with metastatic melanoma remains poor. In patients treated with ipilimumab, a humanised monoclonal Ab targeting cytotoxic T cell lymphocyte antigen-4 (CTLA-4), the overall response rates were less than 10% [2]. Full appreciation of the adverse effects of new immune-potentiating agents alone and in combination with other treatment modalities outside of the clinical trial setting is at an early stage. CTLA-4 responds to an immune stimulus by suppressing the T cell response; ipilimumab binds CTLA-4, resulting in a persistent immune response affecting both malignant and nor-
mal tissue. Radiation-induced cell death resulting in the release of tumour antigens could theoretically enhance autoimmunity and therefore potential responses to ipilimumab. Colitis, which developed in our patient, is a known frequent complication of ipilimumab [6–10], and some studies report improved outcomes in patients developing such immune-related side effects [9, 11–14]. CRs to ipilimumab, however, are relatively infrequent and occur in only 2% of patients [2]. Objective responses with 1 CR in the context of radiotherapy demonstrating the ‘abscopal’ effect [15, 16] have been described and resulted in regression of metastatic lesions outside the radiation field, as evident in our case. The additive effect of radiation and ipilimumab is being investigated in clinical trials [17]. Neurological adverse events associated with ipiliumumab include inflammatory myopathy [18], Guillain-Barré syndrome [19], aseptic meningitis [20], posterior reversible encephalopathy syndrome [21], enteric neuropathy [22], meningo-radiculo-neuritis [23], myasthenia gravis [24] and transverse myelitis [25]. Our patient developed myelitis with paraplegia months after spinal decompression and radiation followed by ipilimumab therapy; similar toxicity has not been reported in the literature. We excluded most causes of a spinal myelitis, and although a spinal angiogram was not performed, a vascular complication would not ordinarily follow such a course. We consider ipilimumab-induced neurotoxicity post radiotherapy as a plausible explanation for this adverse event. This is further supported by the spontaneous regression of oedema on MRI over time. Persistent immune activation within the cord may have resulted in the radiological appearances and clinical manifestation of paraplegia. Elucidating the clinical effects of a new drug from the effects of the disease itself and those of other treatment modalities such as surgery and radiation is challenging. We would like to draw attention to potential neurotoxicity associated with ipilimumab therapy after radiation.
Acknowledgement We would like to thank Andrew McKeon MD, Neuroimmunology Laboratory, Mayo Clinic, Rochester, USA for his help with this case.
Disclosure Statement There are no potential conflicts of interest for any of the authors.
1 Lens MB, Dawes M: Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 2004;150:179–185.
Ipilimumab and Radiation in Metastatic Melanoma
2 Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–723.
3 Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–2516.
Oncol Res Treat 2014;37:757–760
759
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