title: Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma.
abstract: Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma patients at four cancer centers in Germany and Switzerland were analyzed. Patients received either ipilimumab (n = 82) or ipilimumab and additional LPT (n = 45) if indicated for local tumor control. The addition of LPT to ipilimumab significantly prolonged overall survival (OS; median OS 93 vs. 42 weeks, unadjusted HR, 0.46; P = 0.0028). Adverse immune-related events were not increased by the combination treatment, and LPT-induced local toxicities were in most cases mild. In a multivariable Cox regression analysis, we show that the effect of added LPT on OS remained statistically significant after adjusting for BRAF status, tumor stage, tumor burden, and central nervous system metastases (adjusted HR, 0.56; 95% confidence interval, 0.31-1.01, P = 0.05). Our data suggest that the addition of LPT to ipilimumab is safe and effective in patients with metastatic melanoma irrespective of clinical disease characteristics and known risk factors. Induction of antitumor immune responses is most likely the underlying mechanism and warrants prospective validation. Cancer Immunol Res; 4(9); 744-54. ©2016 AACR.
authors.affiliation: Department I of Internal Medicine, Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany. Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Germany. Max-Planck-Institute for Metabolism Research, Cologne, Germany. Radio-Immuno-Oncology (RIO) Initiative, University Hospital of Cologne, Cologne, Germany. sebastian.theurich@uk-koeln.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Theurich
authors.affiliation: Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Germany. University Hospital Basel, Department of Internal Medicine, Medical Oncology, Basel, Switzerland.
authors.forename: Sacha I
authors.initials: SI
authors.lastname: Rothschild
authors.affiliation: Department of Dermatology/Venereology and Skin-Cancer-Center at the CIO, University Hospital of Cologne, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Department of Dermatology/Venereology and Skin-Cancer-Center at the CIO, University Hospital of Cologne, Cologne, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Fabri
authors.affiliation: Department of Dermatology/Venereology and Skin-Cancer-Center at the CIO, University Hospital of Cologne, Cologne, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sommer
authors.affiliation: Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Garcia-Marquez
authors.affiliation: Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Thelen
authors.affiliation: Division of Hematology/Oncology, Cantonal Hospital of Aarau, Aarau, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schill
authors.affiliation: Division of Hematology/Oncology, Cantonal Hospital of Aarau, Aarau, Switzerland.
authors.forename: Ramona
authors.initials: R
authors.lastname: Merki
authors.affiliation: Medical Oncology, St. Claraspital, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmid
authors.affiliation: Medical Oncology, St. Claraspital, Basel, Switzerland.
authors.forename: Dieter
authors.initials: D
authors.lastname: Koeberle
authors.affiliation: University Hospital Basel, Department of Internal Medicine, Medical Oncology, Basel, Switzerland.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
authors.affiliation: Radio-Immuno-Oncology (RIO) Initiative, University Hospital of Cologne, Cologne, Germany. Department of Radiation Therapy, University Hospital of Cologne, Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Baues
authors.affiliation: Department of Dermatology/Venereology and Skin-Cancer-Center at the CIO, University Hospital of Cologne, Cologne, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.affiliation: Helios-Klinik St. Elisabeth, Department of Dermatology, Oberhausen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Tigges
authors.affiliation: Helios-Klinik St. Elisabeth, Department of Dermatology, Oberhausen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kreuter
authors.affiliation: Institute for Diagnostic and Interventional Radiology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Borggrefe
authors.affiliation: Department I of Internal Medicine, Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany. Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital of Cologne, Germany. Radio-Immuno-Oncology (RIO) Initiative, University Hospital of Cologne, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: von Bergwelt-Baildon
authors.affiliation: Radio-Immuno-Oncology (RIO) Initiative, University Hospital of Cologne, Cologne, Germany. Department of Dermatology/Venereology and Skin-Cancer-Center at the CIO, University Hospital of Cologne, Cologne, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Schlaak
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D000074324:Ipilimumab / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000074322:Antineoplastic Agents, Immunological; D000074324:Ipilimumab; D048493:Proto-Oncogene Proteins B-raf