- Email: [email protected]
Sustained remission of Parkinson disease associated melanoma with immunotherapy
Parkinsonism and Related Disorders 20 (2014) 1027e1029
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Sustained remission of Parkinson disease associated melanoma with immunotherapy Keywords: Tremor Parkinson disease Dopa-responsive dystonia
Parkinson disease (PD) is associated with a melanoma risk 3e21 times higher than the general population [1]. Ipilimumab is a T-cell activating agent (monoclonal antibody to cytotoxic T-lymphocyte antigen-4) recently approved for stage IV melanoma, with central nervous system (CNS) activity [2]. This mechanism raises potential safety concerns, given that neuroinflammation is a common histopathological feature of PD [3], and immune-related adverse events are common with ipilimumab [4]. We describe tolerability and outcome (including course of PD motor symptoms) in the first case (to our knowledge) of a PD patient treated with ipilimumab and whole brain radiotherapy for metastatic melanoma. Our male patient developed PD at age 50, melanoma T3 N0 M0, stage IIA at age 52, with progression to metastatic disease with brain and lung metastases at age 58. Given the limited options available for CNS metastatic disease, and concerns about tolerability in PD, we agreed to proceed with ipilimumab under close monitoring by neurology and oncology providers. The dose of antiparkinsonian drugs was optimized 5 weeks prior to initiation of ipilimumab. Our patient underwent a course of ipilimumab and whole brain radiation treatments with serial brain MRI and medical examinations. Adverse events and UPDRS-III motor scores were documented at each visit (Table 1) Unified Parkinson Disease Rating Scale-motor (UPDRS-III) “ON” score was 19 and levodopa equivalent daily dose (LEED) was 750 at baseline. Progression of brain and lung metastases was noted on restaging scans 12 weeks after initiation of ipilimumab (Fig. 1A and B). Whole brain radiation therapy was delivered weeks 12e15, with a complete response and no discernible residual tumor at the week 20 MRI scan (Fig. 1C and D). Transient symptoms of diarrhea, nausea, increased depression, and severe fatigue occurred following radiation. However; UPDRS-III score improved to 12, allowing LEED reduction to 450, at week 33. The week 44 scan showed no evidence of residual disease (Fig. 1E and F). UPDRS-III score returned to 17 and LEED to 700 at week 47. Constitutional symptoms improved after several weeks, motor symptoms progressed back to baseline, and the patient resumed his prior doses of antiparkinsonian drugs. http://dx.doi.org/10.1016/j.parkreldis.2014.05.017 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
There have been reports of immune related neurological complications including chronic inflammatory demyelinating polyradiculoneuropathy, transverse myelitis, and myositis with ipilimumab [5]. Therefore, close monitoring of neurological comorbidities may be indicated with this therapy. To our knowledge, considerations about melanoma treatment in the setting of comorbid Parkinson disease have not been studied. Our initial experience shows that ipilimumab could be tolerated, and may not worsen PD motor symptoms. However, transient improvement in motor symptoms in our patient (attributable to brain edema) following radiotherapy could have masked any symptom exacerbation. Future melanoma treatment studies should explore safety, tolerability, and efficacy in the setting of comorbid Parkinson disease and other neurological disorders.
Funding sources None. Table 1 Unified Parkinson Disease Rating Scale-motor scores at each follow up visit show transient improvement at week 33, 18 weeks after whole brain radiation. Week
0
2
22
33
47
Speech Facial expression Rest tremor-face Right upper limb Left upper limb Right lower limb Left lower limb Action tremor e right hand Action tremor e left hand Rigidity e neck Right upper limb Left upper limb Right lower limb Left lower limb Finger taps e right Finger taps e left Hand movements e right Hand movements e left Rapidly alternating movements e right Rapidly alternating movements e left Leg agility e right Leg agility e left Arising from a chair Posture Gait Postural stability Body bradykinesia UPDRS III total
2 1 0 0 2 0 0 0 0 0 0 1 1 1 1 1 0 0 1 1 1 1 0 1 1 1 2 19
1 1 0 1 2 0 0 0 1 0 0 1 0 0 0 2 1 1 1 1 1 1 0 1 1 0 0 17
1 2 0 1 2 0 0 1 0 1 0 0 0 0 0 1 0 0 2 2 0 0 0 0 1 0 2 16
1 1 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 0 0 0 1 0 2 12
1 1 0 0 3 0 0 0 0 1 1 1 1 1 0 0 0 1 1 2 0 0 0 0 1 0 2 17
1028
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1027e1029
Fig. 1. Brain magnetic resonance imaging shows brain metastases 12 weeks after ipilimumab (A and B); reduction in lesion volume at week 20 after completion of whole brain radiation (C and D); and absence of residual disease by week 44 (E and F). Images A, C, and E are T1 gadolinium enhanced MRI sequences and images B, D, and F are FLAIR MRI sequences.
Acknowledgments
References
The authors thank the patient and his family for participation in this work, and Keenan Gannon for his assistance in manuscript preparation.
[1] Constantinescu R, Elm J, Auinger P, Sharma S, Augustine EF, Khadim L, et al. Malignant melanoma in early-treated Parkinson's disease: the NET-PD trial. Mov Disord 2014;29(2):263e5 [Epub 2013/12/11]. [2] Acharya UH, Jeter JM. Use of ipilimumab in the treatment of melanoma. Clin Pharmacol 2013;5(Suppl. 1):21e7 [Epub 2013/10/12].
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1027e1029 [3] Hirsch EC, Jenner P, Przedborski S. Pathogenesis of Parkinson's disease. Mov Disord 2013;28(1):24e30 [Epub 2012/08/29]. [4] Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012;30(21): 2691e7 [Epub 2012/05/23]. [5] Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neurooncology 2014;16(4):589e93 [Epub 2014/02/01].
David R. Shprecher* Department of Neurology, University of Utah, 729 Arapeen Drive, Salt Lake City, UT 84108, United States
1029
Kenneth F. Grossmann Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States Jonathan D. Tward Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States *
Corresponding author. Tel.: þ1 801 585 1311. E-mail addresses: [email protected], [email protected] (D.R. Shprecher). 18 March 2014
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Sustained remission of Parkinson disease associated melanoma with immunotherapy Keywords: Tremor Parkinson disease Dopa-responsive dystonia
Parkinson disease (PD) is associated with a melanoma risk 3e21 times higher than the general population [1]. Ipilimumab is a T-cell activating agent (monoclonal antibody to cytotoxic T-lymphocyte antigen-4) recently approved for stage IV melanoma, with central nervous system (CNS) activity [2]. This mechanism raises potential safety concerns, given that neuroinflammation is a common histopathological feature of PD [3], and immune-related adverse events are common with ipilimumab [4]. We describe tolerability and outcome (including course of PD motor symptoms) in the first case (to our knowledge) of a PD patient treated with ipilimumab and whole brain radiotherapy for metastatic melanoma. Our male patient developed PD at age 50, melanoma T3 N0 M0, stage IIA at age 52, with progression to metastatic disease with brain and lung metastases at age 58. Given the limited options available for CNS metastatic disease, and concerns about tolerability in PD, we agreed to proceed with ipilimumab under close monitoring by neurology and oncology providers. The dose of antiparkinsonian drugs was optimized 5 weeks prior to initiation of ipilimumab. Our patient underwent a course of ipilimumab and whole brain radiation treatments with serial brain MRI and medical examinations. Adverse events and UPDRS-III motor scores were documented at each visit (Table 1) Unified Parkinson Disease Rating Scale-motor (UPDRS-III) “ON” score was 19 and levodopa equivalent daily dose (LEED) was 750 at baseline. Progression of brain and lung metastases was noted on restaging scans 12 weeks after initiation of ipilimumab (Fig. 1A and B). Whole brain radiation therapy was delivered weeks 12e15, with a complete response and no discernible residual tumor at the week 20 MRI scan (Fig. 1C and D). Transient symptoms of diarrhea, nausea, increased depression, and severe fatigue occurred following radiation. However; UPDRS-III score improved to 12, allowing LEED reduction to 450, at week 33. The week 44 scan showed no evidence of residual disease (Fig. 1E and F). UPDRS-III score returned to 17 and LEED to 700 at week 47. Constitutional symptoms improved after several weeks, motor symptoms progressed back to baseline, and the patient resumed his prior doses of antiparkinsonian drugs. http://dx.doi.org/10.1016/j.parkreldis.2014.05.017 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
There have been reports of immune related neurological complications including chronic inflammatory demyelinating polyradiculoneuropathy, transverse myelitis, and myositis with ipilimumab [5]. Therefore, close monitoring of neurological comorbidities may be indicated with this therapy. To our knowledge, considerations about melanoma treatment in the setting of comorbid Parkinson disease have not been studied. Our initial experience shows that ipilimumab could be tolerated, and may not worsen PD motor symptoms. However, transient improvement in motor symptoms in our patient (attributable to brain edema) following radiotherapy could have masked any symptom exacerbation. Future melanoma treatment studies should explore safety, tolerability, and efficacy in the setting of comorbid Parkinson disease and other neurological disorders.
Funding sources None. Table 1 Unified Parkinson Disease Rating Scale-motor scores at each follow up visit show transient improvement at week 33, 18 weeks after whole brain radiation. Week
0
2
22
33
47
Speech Facial expression Rest tremor-face Right upper limb Left upper limb Right lower limb Left lower limb Action tremor e right hand Action tremor e left hand Rigidity e neck Right upper limb Left upper limb Right lower limb Left lower limb Finger taps e right Finger taps e left Hand movements e right Hand movements e left Rapidly alternating movements e right Rapidly alternating movements e left Leg agility e right Leg agility e left Arising from a chair Posture Gait Postural stability Body bradykinesia UPDRS III total
2 1 0 0 2 0 0 0 0 0 0 1 1 1 1 1 0 0 1 1 1 1 0 1 1 1 2 19
1 1 0 1 2 0 0 0 1 0 0 1 0 0 0 2 1 1 1 1 1 1 0 1 1 0 0 17
1 2 0 1 2 0 0 1 0 1 0 0 0 0 0 1 0 0 2 2 0 0 0 0 1 0 2 16
1 1 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 0 0 0 1 0 2 12
1 1 0 0 3 0 0 0 0 1 1 1 1 1 0 0 0 1 1 2 0 0 0 0 1 0 2 17
1028
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1027e1029
Fig. 1. Brain magnetic resonance imaging shows brain metastases 12 weeks after ipilimumab (A and B); reduction in lesion volume at week 20 after completion of whole brain radiation (C and D); and absence of residual disease by week 44 (E and F). Images A, C, and E are T1 gadolinium enhanced MRI sequences and images B, D, and F are FLAIR MRI sequences.
Acknowledgments
References
The authors thank the patient and his family for participation in this work, and Keenan Gannon for his assistance in manuscript preparation.
[1] Constantinescu R, Elm J, Auinger P, Sharma S, Augustine EF, Khadim L, et al. Malignant melanoma in early-treated Parkinson's disease: the NET-PD trial. Mov Disord 2014;29(2):263e5 [Epub 2013/12/11]. [2] Acharya UH, Jeter JM. Use of ipilimumab in the treatment of melanoma. Clin Pharmacol 2013;5(Suppl. 1):21e7 [Epub 2013/10/12].
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1027e1029 [3] Hirsch EC, Jenner P, Przedborski S. Pathogenesis of Parkinson's disease. Mov Disord 2013;28(1):24e30 [Epub 2012/08/29]. [4] Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012;30(21): 2691e7 [Epub 2012/05/23]. [5] Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neurooncology 2014;16(4):589e93 [Epub 2014/02/01].
David R. Shprecher* Department of Neurology, University of Utah, 729 Arapeen Drive, Salt Lake City, UT 84108, United States
1029
Kenneth F. Grossmann Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States Jonathan D. Tward Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States *
Corresponding author. Tel.: þ1 801 585 1311. E-mail addresses: [email protected], [email protected] (D.R. Shprecher). 18 March 2014