Skip to main content
Top
Published in: Strahlentherapie und Onkologie 10/2022

Open Access 11-05-2022 | Metastasis | Original Article

Long-term neurocognitive function after whole-brain radiotherapy in patients with melanoma brain metastases in the era of immunotherapy

Authors: Martin Salzmann, Klaus Hess, Kristin Lang, Alexander H. Enk, Berit Jordan, Jessica C. Hassel

Published in: Strahlentherapie und Onkologie | Issue 10/2022

Login to get access

Abstract

Background

Whole-brain radiotherapy (WBRT) used to be standard of care for patients suffering from melanoma brain metastases (MBM) and may still be applicable in selected cases. Deterioration of neurocognitive function (NCF) is commonly seen during and after WBRT. Knowledge on long-term effects in melanoma patients is limited due to short survival rates. With the introduction of immune checkpoint inhibitors, patients may experience ongoing disease control, emphasizing the need for paying more attention to potential long-term adverse effects.

Methods

In this single-center study, we identified in a period of 11 years all long-term survivors of MBM who received WBRT at least 1 year prior to inclusion. NCF was assessed by Neuropsychological Assessment Battery (NAB) screening and detailed neurological exam; confounders were documented.

Results

Eight patients (median age 55 years) could be identified with a median follow-up of 5.4 years after WBRT. Six patients reported no subjective neurological impairment. NAB screening revealed an average-range score in 5/8 patients. In 3/8 patients a NAB score below average was obtained, correlating with subjective memory deficits in 2 patients. In these patients, limited performance shown in modalities like memory function, attention, and spatial abilities may be considerably attributed to metastasis localization itself. Six out of 8 patients were able to return to their previous work.

Conclusion

Five of 8 long-term survivors with MBM after WBRT experienced little to no restriction in everyday activities. In 3 out of 8 patients, cognitive decline was primarily explained by localization of the metastases in functionally relevant areas of the brain. The results of our small patient cohort do not support general avoidance of WBRT for treatment of brain metastases. However, long-term studies including pretreatment NCF tests are needed to fully analyze the long-term neurocognitive effects of WBRT
Appendix
Available only for authorised users
Literature
1.
go back to reference Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ et al (2018) Combined nivolumab and Ipilimumab in melanoma metastatic to the brain. N Engl J Med 379(8):722–730PubMedPubMedCentralCrossRef Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ et al (2018) Combined nivolumab and Ipilimumab in melanoma metastatic to the brain. N Engl J Med 379(8):722–730PubMedPubMedCentralCrossRef
2.
go back to reference Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP et al (2018) Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 19(5):672–681PubMedCrossRef Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP et al (2018) Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 19(5):672–681PubMedCrossRef
3.
go back to reference Schmidberger H, Rapp M, Ebersberger A, Hey-Koch S, Loquai C, Grabbe S et al (2018) Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: sequence matters. Strahlenther Onkol 194(12):1144–1151PubMedPubMedCentralCrossRef Schmidberger H, Rapp M, Ebersberger A, Hey-Koch S, Loquai C, Grabbe S et al (2018) Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: sequence matters. Strahlenther Onkol 194(12):1144–1151PubMedPubMedCentralCrossRef
4.
go back to reference Davies MA, Liu P, McIntyre S, Kim KB, Papadopoulos N, Hwu WJ et al (2011) Prognostic factors for survival in melanoma patients with brain metastases. Cancer 117(8):1687–1696PubMedCrossRef Davies MA, Liu P, McIntyre S, Kim KB, Papadopoulos N, Hwu WJ et al (2011) Prognostic factors for survival in melanoma patients with brain metastases. Cancer 117(8):1687–1696PubMedCrossRef
5.
go back to reference Sampson JH, Carter JH Jr., Friedman AH, Seigler HF (1998) Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. JNS 88(1):11–20CrossRef Sampson JH, Carter JH Jr., Friedman AH, Seigler HF (1998) Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. JNS 88(1):11–20CrossRef
6.
go back to reference Rishi A, Yu HM (2020) Current treatment of melanoma brain metastasis. Curr Treat Options in Oncol 21(6):45CrossRef Rishi A, Yu HM (2020) Current treatment of melanoma brain metastasis. Curr Treat Options in Oncol 21(6):45CrossRef
7.
go back to reference Gutzmer R, Vordermark D, Hassel JC, Krex D, Wendl C, Schadendorf D et al (2020) Melanoma brain metastases—Interdisciplinary management recommendations 2020. Cancer Treat Rev 89:102083PubMedCrossRef Gutzmer R, Vordermark D, Hassel JC, Krex D, Wendl C, Schadendorf D et al (2020) Melanoma brain metastases—Interdisciplinary management recommendations 2020. Cancer Treat Rev 89:102083PubMedCrossRef
8.
go back to reference Coit DG, Thompson JA, Albertini MR, Barker C, Carson WE, Contreras C et al (2019) Cutaneous melanoma, version 2.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 17(4):367–402PubMedCrossRef Coit DG, Thompson JA, Albertini MR, Barker C, Carson WE, Contreras C et al (2019) Cutaneous melanoma, version 2.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 17(4):367–402PubMedCrossRef
9.
go back to reference Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft DK, AWMF). Diagnostik, Therapie und Nachsorge des Melanoms, Langversion 3.2, 2019, AWMF Registernummer: 032/024OL. Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft DK, AWMF). Diagnostik, Therapie und Nachsorge des Melanoms, Langversion 3.2, 2019, AWMF Registernummer: 032/024OL.
10.
go back to reference Liermann J, Winkler JK, Syed M, Neuberger U, Reuss D, Harrabi S et al (2020) Stereotactic radiosurgery with concurrent immunotherapy in melanoma brain metastases is feasible and effective. Front Oncol 10:592796PubMedPubMedCentralCrossRef Liermann J, Winkler JK, Syed M, Neuberger U, Reuss D, Harrabi S et al (2020) Stereotactic radiosurgery with concurrent immunotherapy in melanoma brain metastases is feasible and effective. Front Oncol 10:592796PubMedPubMedCentralCrossRef
11.
go back to reference Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK et al (2016) Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA 316(4):401–409PubMedPubMedCentralCrossRef Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK et al (2016) Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA 316(4):401–409PubMedPubMedCentralCrossRef
12.
go back to reference Hong AM, Fogarty GB, Dolven-Jacobsen K, Burmeister BH, Lo SN, Haydu LE et al (2019) Adjuvant whole-brain radiation therapy compared with observation after local treatment of melanoma brain metastases: a multicenter, randomized phase III trial. J Clin Oncol 37(33):3132–3141PubMedCrossRef Hong AM, Fogarty GB, Dolven-Jacobsen K, Burmeister BH, Lo SN, Haydu LE et al (2019) Adjuvant whole-brain radiation therapy compared with observation after local treatment of melanoma brain metastases: a multicenter, randomized phase III trial. J Clin Oncol 37(33):3132–3141PubMedCrossRef
13.
go back to reference Michielin O, van Akkooi ACJ, Ascierto PA, Dummer R, Keilholz U (2019) Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up††Approved by the ESMO Guidelines Committee: February 2002, last update September 2019. Ann Oncol 30(12):1884–1901PubMedCrossRef Michielin O, van Akkooi ACJ, Ascierto PA, Dummer R, Keilholz U (2019) Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up††Approved by the ESMO Guidelines Committee: February 2002, last update September 2019. Ann Oncol 30(12):1884–1901PubMedCrossRef
14.
go back to reference Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG et al (2009) Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10(11):1037–1044PubMedCrossRef Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG et al (2009) Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10(11):1037–1044PubMedCrossRef
15.
go back to reference Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC et al (2017) Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 18(8):1049–1060PubMedPubMedCentralCrossRef Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC et al (2017) Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 18(8):1049–1060PubMedPubMedCentralCrossRef
16.
go back to reference Jordan B, Margulies A, Cardoso F, Cavaletti G, Haugnes HS, Jahn P et al (2020) Systemic anticancer therapy-induced peripheral and central neurotoxicity: ESMO-EONS-EANO Clinical Practice Guidelines for diagnosis, prevention, treatment and follow-up. Ann Oncol 31(10):1306–1319PubMedCrossRef Jordan B, Margulies A, Cardoso F, Cavaletti G, Haugnes HS, Jahn P et al (2020) Systemic anticancer therapy-induced peripheral and central neurotoxicity: ESMO-EONS-EANO Clinical Practice Guidelines for diagnosis, prevention, treatment and follow-up. Ann Oncol 31(10):1306–1319PubMedCrossRef
17.
go back to reference Petermann F, Jäncke L (2016) Neuropsychological Assessment Battery (NAB) – Aussagekraft und Anwendungen der deutschsprachigen Adaptation. Hogrefe AGCrossRef Petermann F, Jäncke L (2016) Neuropsychological Assessment Battery (NAB) – Aussagekraft und Anwendungen der deutschsprachigen Adaptation. Hogrefe AGCrossRef
18.
go back to reference Giuseppe ZR, Silvia C, Eleonora F, Gabriella M, Marica F, Silvia C et al (2020) Hippocampal-sparing radiotherapy and neurocognitive impairment: a systematic literature review. J Can Res Ther 16(6):1215–1222 Giuseppe ZR, Silvia C, Eleonora F, Gabriella M, Marica F, Silvia C et al (2020) Hippocampal-sparing radiotherapy and neurocognitive impairment: a systematic literature review. J Can Res Ther 16(6):1215–1222
19.
go back to reference Kondziolka D, Niranjan A, Flickinger JC, Lunsford LD (2005) Radiosurgery with or without whole-brain radiotherapy for brain metastases: the patients’ perspective regarding complications. Am J Clin Oncol 28(2):173–179PubMedCrossRef Kondziolka D, Niranjan A, Flickinger JC, Lunsford LD (2005) Radiosurgery with or without whole-brain radiotherapy for brain metastases: the patients’ perspective regarding complications. Am J Clin Oncol 28(2):173–179PubMedCrossRef
20.
go back to reference Zivelonghi C, Zekeridou A (2021) Neurological complications of immune checkpoint inhibitor cancer immunotherapy. J Neurol Sci 424:117424PubMedCrossRef Zivelonghi C, Zekeridou A (2021) Neurological complications of immune checkpoint inhibitor cancer immunotherapy. J Neurol Sci 424:117424PubMedCrossRef
22.
go back to reference Hwang SY, Kim K, Ha B, Lee D, Kim S, Ryu S et al (2021) Neurocognitive effects of chemotherapy for colorectal cancer: a systematic review and a meta-analysis of 11 studies. Cancer Res Treat 53(4):1134–1147PubMedPubMedCentralCrossRef Hwang SY, Kim K, Ha B, Lee D, Kim S, Ryu S et al (2021) Neurocognitive effects of chemotherapy for colorectal cancer: a systematic review and a meta-analysis of 11 studies. Cancer Res Treat 53(4):1134–1147PubMedPubMedCentralCrossRef
23.
go back to reference Weller J, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Hau P et al (2019) Health-related quality of life and neurocognitive functioning with lomustine-temozolomide versus temozolomide in patients with newly diagnosed, MGMT-methylated glioblastoma (CeTeG/NOA-09): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 20(10):1444–1453PubMedCrossRef Weller J, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Hau P et al (2019) Health-related quality of life and neurocognitive functioning with lomustine-temozolomide versus temozolomide in patients with newly diagnosed, MGMT-methylated glioblastoma (CeTeG/NOA-09): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 20(10):1444–1453PubMedCrossRef
24.
go back to reference Reijneveld JC, Taphoorn MJB, Coens C, Bromberg JEC, Mason WP, Hoang-Xuan K et al (2016) Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 17(11):1533–1542PubMedCrossRef Reijneveld JC, Taphoorn MJB, Coens C, Bromberg JEC, Mason WP, Hoang-Xuan K et al (2016) Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 17(11):1533–1542PubMedCrossRef
25.
go back to reference Deng X, Zheng Z, Lin B, Su H, Chen H, Fei S et al (2017) The efficacy and roles of combining temozolomide with whole brain radiotherapy in protection neurocognitive function and improvement quality of life of non-small-cell lung cancer patients with brain metastases. BMC Cancer 17(1):42PubMedPubMedCentralCrossRef Deng X, Zheng Z, Lin B, Su H, Chen H, Fei S et al (2017) The efficacy and roles of combining temozolomide with whole brain radiotherapy in protection neurocognitive function and improvement quality of life of non-small-cell lung cancer patients with brain metastases. BMC Cancer 17(1):42PubMedPubMedCentralCrossRef
27.
go back to reference Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C et al (2013) Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol 15(10):1429–1437PubMedPubMedCentralCrossRef Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C et al (2013) Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol 15(10):1429–1437PubMedPubMedCentralCrossRef
28.
go back to reference Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A et al (2014) Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 32(34):3810–3816PubMedPubMedCentralCrossRef Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A et al (2014) Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 32(34):3810–3816PubMedPubMedCentralCrossRef
29.
go back to reference Oskan F, Ganswindt U, Schwarz SB, Manapov F, Belka C, Niyazi M (2014) Hippocampus sparing in whole-brain radiotherapy. A review. Strahlenther Onkol 190(4):337–341PubMedCrossRef Oskan F, Ganswindt U, Schwarz SB, Manapov F, Belka C, Niyazi M (2014) Hippocampus sparing in whole-brain radiotherapy. A review. Strahlenther Onkol 190(4):337–341PubMedCrossRef
30.
go back to reference Rodríguez de Dios N, Couñago F, Murcia-Mejía M, Rico-Oses M, Calvo-Crespo P, Samper P et al (2021) Randomized phase III trial of prophylactic cranial irradiation with or without hippocampal avoidance for small-cell lung cancer (PREMER): a GICOR-GOECP-SEOR study. J Clin Oncol 39(28):3118–3127PubMedCrossRef Rodríguez de Dios N, Couñago F, Murcia-Mejía M, Rico-Oses M, Calvo-Crespo P, Samper P et al (2021) Randomized phase III trial of prophylactic cranial irradiation with or without hippocampal avoidance for small-cell lung cancer (PREMER): a GICOR-GOECP-SEOR study. J Clin Oncol 39(28):3118–3127PubMedCrossRef
31.
go back to reference Jiang C, Kleber TJ, Switchenko JM, Khan MK (2021) Single institutional outcomes of whole brain radiotherapy for metastatic melanoma brain metastases. Radiat Oncol 16(1):31PubMedPubMedCentralCrossRef Jiang C, Kleber TJ, Switchenko JM, Khan MK (2021) Single institutional outcomes of whole brain radiotherapy for metastatic melanoma brain metastases. Radiat Oncol 16(1):31PubMedPubMedCentralCrossRef
33.
go back to reference Minniti G, Anzellini D, Reverberi C, Cappellini GCA, Marchetti L, Bianciardi F et al (2019) Stereotactic radiosurgery combined with nivolumab or Ipilimumab for patients with melanoma brain metastases: evaluation of brain control and toxicity. J Immunother Cancer 7(1):102PubMedPubMedCentralCrossRef Minniti G, Anzellini D, Reverberi C, Cappellini GCA, Marchetti L, Bianciardi F et al (2019) Stereotactic radiosurgery combined with nivolumab or Ipilimumab for patients with melanoma brain metastases: evaluation of brain control and toxicity. J Immunother Cancer 7(1):102PubMedPubMedCentralCrossRef
34.
go back to reference Li J, Ludmir EB, Wang Y, Guha-Thakurta N, McAleer MF, Settle SH et al (2020) Stereotactic radiosurgery versus whole-brain radiation therapy for patients with 4–15 brain metastases: a phase III randomized controlled trial. Int J Radiat Oncol Biol Phys 108(3 Supplement):S21–S22CrossRef Li J, Ludmir EB, Wang Y, Guha-Thakurta N, McAleer MF, Settle SH et al (2020) Stereotactic radiosurgery versus whole-brain radiation therapy for patients with 4–15 brain metastases: a phase III randomized controlled trial. Int J Radiat Oncol Biol Phys 108(3 Supplement):S21–S22CrossRef
35.
go back to reference Sahgal A, Ruschin M, Ma L, Verbakel W, Larson D, Brown PD (2017) Stereotactic radiosurgery alone for multiple brain metastases? A review of clinical and technical issues. Neuro Oncol 19(suppl_2):ii2–ii15PubMedPubMedCentralCrossRef Sahgal A, Ruschin M, Ma L, Verbakel W, Larson D, Brown PD (2017) Stereotactic radiosurgery alone for multiple brain metastases? A review of clinical and technical issues. Neuro Oncol 19(suppl_2):ii2–ii15PubMedPubMedCentralCrossRef
36.
go back to reference Lai J, Liu J, Zhao J, Li A, Liu S, Deng Z et al (2021) Effective method to reduce the normal brain dose in single-isocenter hypofractionated stereotactic radiotherapy for multiple brain metastases. Strahlenther Onkol 197(7):592–600PubMedCrossRef Lai J, Liu J, Zhao J, Li A, Liu S, Deng Z et al (2021) Effective method to reduce the normal brain dose in single-isocenter hypofractionated stereotactic radiotherapy for multiple brain metastases. Strahlenther Onkol 197(7):592–600PubMedCrossRef
37.
go back to reference Choi S, Hong A, Wang T, Lo S, Chen B, Silva I et al (2021) Risk of radiation necrosis after stereotactic radiosurgery for melanoma brain metastasis by anatomical location. Strahlenther Onkol 197(12):1104–1112PubMedCrossRef Choi S, Hong A, Wang T, Lo S, Chen B, Silva I et al (2021) Risk of radiation necrosis after stereotactic radiosurgery for melanoma brain metastasis by anatomical location. Strahlenther Onkol 197(12):1104–1112PubMedCrossRef
38.
go back to reference Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A et al (2020) ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol 31(11):1435–1448PubMedCrossRef Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A et al (2020) ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol 31(11):1435–1448PubMedCrossRef
Metadata
Title
Long-term neurocognitive function after whole-brain radiotherapy in patients with melanoma brain metastases in the era of immunotherapy
Authors
Martin Salzmann
Klaus Hess
Kristin Lang
Alexander H. Enk
Berit Jordan
Jessica C. Hassel
Publication date
11-05-2022
Publisher
Springer Berlin Heidelberg
Published in
Strahlentherapie und Onkologie / Issue 10/2022
Print ISSN: 0179-7158
Electronic ISSN: 1439-099X
DOI
https://doi.org/10.1007/s00066-022-01950-1

Other articles of this Issue 10/2022

Strahlentherapie und Onkologie 10/2022 Go to the issue