Notfälle in der Medikamentösen Tumortherapie

Zusammenfassung

Hintergrund Immunmodulatorische Therapien gewinnen immer größere Bedeutung in der Uro-Onkologie. Aus diesem Grund werden wir vermutlich immer häufiger mit Nebenwirkungen konfrontiert werden. Hinzu kommt eine immer größere Zahl an Kombinationen mit anderen Wirkmechanismen. Als Folge dieser Therapie können immun-vermittelte Nebenwirkungen auftreten. Diese unterscheiden sich von den Nebenwirkungen einer Chemotherapie und anderen zielgerichteten Therapien und erfordern daher andere Behandlungsstrategien.

Ziel der Arbeit Anhand der aktuellen Literatur werden die Daten zur Graduierung und stadienabhängigen Management dargelegt sowie mit Beispielen aus der Praxis anschaulich dargestellt.

Material und Methoden Literaturrecherche zur Detektion und Therapiemanagement von im Rahmen der immunonkologischen Therapie vermittelten Nebenwirkungen.

Ergebnisse Die behandlungsbezogenen Ereignisse können prinzipiell alle Organsystem betreffen, häufig sehen finden sich Toxizitäten im Bereich der Haut, wie Ausschlag oder Pruritus, Hypo- oder Hyperthyreosen, Arthritiden, Muskelschmerzen und gastrointestinale Symptome. In der Häufigkeit sind die meisten Nebenwirkungen Grad 1 bis 2 zuzuordnen, jedoch auch Grad 3 bis 4 Toxizitäten sind grundsätzlich gut zu therapieren, sofern sie frühzeitig erkannt werden. Seltene Komplikationen wie neurologische Toxizitäten, Pneumonitis oder auch Karditis können bei zu später Diagnose einen fulminanten Verlauf entwickeln.

Diskussion Selbst Notfälle sind gut zu managen, wenn wir die wichtigsten Nebenwirkungen und therapeutischen Optionen kennen. Dabei kommt den immunvermittelten Nebenwirkungen ein besonderer Stellenwert zu, weil sie grundsätzlich jedes Organsystem betreffen können. So lange wir jedoch bei Patienten, die Symptome zeigen, an die Möglichkeit einer Toxizität durch Checkpointinhibitoren denken, sind die meisten Nebenwirkungen gut zu therapieren und daher kontrollierbar.

Abstract

Background Immunomodulatory therapies are becoming increasingly important in uro-oncology. For this reason, we will probably be increasingly confronted with side effects. In addition, there is an increasing number of combinations with other mechanisms of action. Immune-mediated side effects may occur as a consequence of this therapy. These are different from the side effects of chemotherapy and other targeted therapies and therefore require different treatment strategies.

Aim Based on the current literature, the data on graduation and stage-dependent management will be presented as well as illustrated with examples from practice.

Materials and methods Literature review on the detection and therapeutic management of adverse events mediated in the setting of immuno-oncologic therapy.

Results Treatment-related events can in principle affect all organ systems. Toxicities in the area of the skin, such as rash or pruritus, hypo- or hyperthyreosis, arthritis, muscle pain and gastrointestinal symptoms are frequently seen. In terms of frequency, most side effects are grade 1 to 2, but grade 3 to 4 toxicities are also generally well treatable if detected early. Rare complications such as neurological toxicities, pneumonitis or carditis can develop a fulminant course if diagnosed too late.

Conclusions Even emergencies are manageable if we know the most important side effects and the therapeutic options. Immune-mediated side effects are of particular importance because they can affect any organ system. However, as long as we consider the possibility of toxicity from checkpoint inhibitors when the patient presents with symptoms, most side effects are easy to treat and therefore manageable.

Schlüsselwörter

Immuntherapie - Uroonkologie - Notfälle

Keywords

Immunotherapy - uroonkology - emergencies

Publikationsverlauf

Eingereicht: 12. Mai 2023

Angenommen nach Revision: 12. Juli 2023

Artikel online veröffentlicht:
22. August 2023

• Literatur

• 1 Zander H, Müller-Egert S, Zwiewka M. et al. Checkpoint inhibitors for cancer therapy. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020; 63: 1322-1330
• 2 S3-Leitlinie Diagnostik, Therapie und Nachsorge des Nierenzellkarzinoms Leitlinie (Langversion).
• 3 Powles T, Plimack ER, Soulières D. et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 2020; 21: 1563-1573
• 4 Motzer RJ, Penkov K, Haanen J. et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2019; 380: 1103-1115
• 5 Choueiri TK, Powles T, Burotto M. et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2021; 384: 829-841
• 6 Motzer R, Alekseev B, Rha S-Y. et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. New England Journal of Medicine 2021; 384: 1289-1300
• 7 Escudier B, Sharma P, McDermott DF. et al. CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma. Eur Urol 2017; 72: 962-971
• 8 Bajorin DF, Witjes JA, Gschwend JE. et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. New England Journal of Medicine 2021; 384: 2102-2114
• 9 Balar AV, Castellano D, O’Donnell PH. et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18: 1483-1492
• 10 Powles T, Csőszi T, Özgüroğlu M. et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22: 931-945
• 11 Balar AV, Galsky MD, Rosenberg JE. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. The Lancet 2017; 389: 67-76
• 12 Galsky MD, Arija JÁA, Bamias A. et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. The Lancet 2020; 395: 1547-1557
• 13 Kamta J, Chaar M, Ande A. et al. Advancing Cancer Therapy with Present and Emerging Immuno-Oncology Approaches. Front Oncol 2017; 7
• 14 Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480: 480-489
• 15 Boutros C, Tarhini A, Routier E. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016; 13: 473-486
• 16 Syn NL, Teng MWL, Mok TSK. et al. De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol 2017; 18: e731-e741
• 17 Haanen JBAG, Carbonnel F, Robert C. et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28: iv119-iv142
• 18 June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy?. Nat Med 2017; 23: 540-547
• 19 Dow ER, Yung M, Tsui E. Immune Checkpoint Inhibitor-associated Uveitis: Review of Treatments and Outcomes. Ocul Immunol Inflamm 2021; 29: 203-211
• 20 Velasco R, Villagrán M, Jové M. et al. Encephalitis Induced by Immune Checkpoint Inhibitors: A Systematic Review. JAMA Neurol 2021; 78: 864-873
• 21 Jia XH, Geng LY, Jiang PP. et al. The biomarkers related to immune related adverse events caused by immune checkpoint inhibitors. Journal of Experimental & Clinical Cancer Research 2020; 39: 1-17
• 22 National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 2017
• 23 Hassel JC, Heinzerling L, Aberle J. et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Cancer Treat Rev 2017; 57: 36-49
• 24 Eigentler TK, Hassel JC, Berking C. et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev 2016; 45: 7-18
• 25 George S, Rini BI, Hammers HJ. Emerging Role of Combination Immunotherapy in the First-line Treatment of Advanced Renal Cell Carcinoma: A Review. JAMA Oncol 2019; 5: 411-421
• 26 Weber JS, Hodi FS, Wolchok JD. et al. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol 2017; 35: 785-792
• 27 Patrinely JR, Johnson R, Lawless AR. et al. Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma. JAMA Oncol 2021; 7: 744-748
• 28 Balaji A, Zhang J, Wills B. et al. Immune-related adverse events requiring hospitalization: Spectrum of toxicity, treatment, and outcomes. J Oncol Pract 2019; 15: E825-E834
• 29 Wang L, Hricak H, Kattan MW. et al. Prediction of seminal vesicle invasion in prostate cancer: incremental value of adding endorectal MR imaging to the Kattan nomogram. Radiology 2007; 242: 182-188
• 30 Belum VR, Benhuri B, Postow MA. et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016; 60: 12-25
• 31 Sibaud V, Meyer N, Lamant L. et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016; 28: 254-263
• 32 Haanen J, Obeid M, Spain L. et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology 2022; 33: 1217-1238
• 33 Beck KE, Blansfield JA, Tran KQ. et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 2006; 24: 2283-2289
• 34 Naidoo J, Wang X, Woo KM. et al. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol 2017; 35: 709-717
• 35 De Martin E, Michot JM, Papouin B. et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol 2018; 68: 1181-1190
• 36 Grünwald V, Voss MH, Rini BI. et al. Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events. Br J Cancer 2020; 123: 898-904
• 37 Sangro B, Chan SL, Meyer T. et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020; 72: 320-341
• 38 Johnson DB, Balko JM, Compton ML. et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016; 375: 1749-1755
• 39 Heinzerling L, Ott PA, Hodi FS. et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer 2016; 4
• 40 Michel L, Rassaf T, Totzeck M. Biomarkers for the detection of apparent and subclinical cancer therapy-related cardiotoxicity. J Thorac Dis 2018; 10: S4282-S4295
• 41 National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. US DEPARTMENT OF HEALTH AND HUMAN SERVICE. 2017
• 42 Mehta A, Gupta A, Hannallah F. et al. Myocarditis as an immune-related adverse event with ipilimumab/nivolumab combination therapy for metastatic melanoma. Melanoma Res 2016; 26: 319-320
• 43 Kushnir I, Wolf I. Nivolumab-Induced Pericardial Tamponade: A Case Report and Discussion. Cardiology 2017; 136: 49-51
• 44 Geisler BP, Raad RA, Esaian D. et al. Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome. J Immunother Cancer 2015; 3
• 45 Yun S, Vincelette ND, Mansour I. et al. Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication. Case Rep Oncol Med 2015; 2015: 1-5
• 46 Wolchok JD, Hoos A, O’Day S. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria. Clinical Cancer Research 2009; 15: 7412-7420
• 47 Carpenter KJ, Murtagh RD, Lilienfeld H. et al. Ipilimumab-Induced Hypophysitis: MR Imaging Findings. American Journal of Neuroradiology 2009; 30: 1751-1753
• 48 Hassel JC, Heinzerling L, Aberle J. et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Cancer Treat Rev 2017; 57: 36-49
• 49 Hofmann L, Forschner A, Loquai C. et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 2016; 60: 190-209
• 50 Scott ES, Long GV, Guminski A. et al. The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma. Eur J Endocrinol 2018; 178: 173-180
• 51 Brahmer JR, Lacchetti C, Schneider BJ. et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36: 1714-1768
• 52 Marini A, Bernardini A, Gigli GL. et al. Neurologic Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review. Neurology 2021; 96: 754-766
• 53 Wang J, Zheng Q, Chen J. Immune checkpoint inhibitor-induced autoimmune encephalitis in metastatic squamous cell lung cancer. Immunotherapy 2023; 15: 409-416
• 54 Chung M, Jaffer M, Verma N. et al. Immune checkpoint inhibitor induced anti-glutamic acid decarboxylase 65 (Anti-GAD 65) limbic encephalitis responsive to intravenous immunoglobulin and plasma exchange. J Neurol. 2020; 267: 1023-1025
• 55 Williams TJ, Benavides DR, Patrice KA. et al. Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor Treatment for Metastatic Cancer. JAMA Neurol. 2016; 73: 928-933
• 56 Velasco R, Villagrán M, Jové M. et al. Encephalitis Induced by Immune Checkpoint Inhibitors: A Systematic Review. JAMA Neurol. 2021; 78: 864-873