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Title: Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy

Abstract

Purpose: To analyze immune-related adverse events (ir-AEs) in patients treated with radiation and immune checkpoint blockade. Methods and Materials: We retrospectively reviewed records from patients with metastatic non-small cell lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined using Common Terminology Criteria for Adverse Events version 4.0, were tabulated in relation to treatment variables, and associations with sequencing and timing were assessed. Results: We identified 133 patients, of whom 28 received a CTLA-4 inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six patients received radiation within 14 days of an immune checkpoint inhibitor. Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated andmore » specific ir-AEs. Conclusions: Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated. Although conclusions are limited by the heterogeneity of patients and treatments, and future confirmatory studies are needed, this information can help guide clinical practice for patients receiving immune checkpoint therapy who require palliative radiation therapy.« less

Authors:
 [1];  [2];  [3];  [4]; ; ; ; ;  [1];  [5];  [1];  [5];  [1]
  1. Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (United States)
  2. (Canada)
  3. Harvard Medical School, Boston, Massachusetts (United States)
  4. Harvard Radiation Oncology Program, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (United States)
  5. Department of Medical Oncology and Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (United States)
Publication Date:
OSTI Identifier:
22649931
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 98; Journal Issue: 2; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; COMBINED THERAPY; DOSE EQUIVALENTS; IMMUNOTHERAPY; PATIENTS; RADIOTHERAPY

Citation Formats

Bang, Andrew, Division of Radiation Oncology, University of Ottawa, Ottawa, Ontario, Wilhite, Tyler J., Pike, Luke R.G., Cagney, Daniel N., Aizer, Ayal A., Taylor, Allison, Spektor, Alexander, Krishnan, Monica, Ott, Patrick A., Balboni, Tracy A., Hodi, F. Stephen, and Schoenfeld, Jonathan D., E-mail: jdschoenfeld@partners.org. Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy. United States: N. p., 2017. Web. doi:10.1016/J.IJROBP.2017.02.003.
Bang, Andrew, Division of Radiation Oncology, University of Ottawa, Ottawa, Ontario, Wilhite, Tyler J., Pike, Luke R.G., Cagney, Daniel N., Aizer, Ayal A., Taylor, Allison, Spektor, Alexander, Krishnan, Monica, Ott, Patrick A., Balboni, Tracy A., Hodi, F. Stephen, & Schoenfeld, Jonathan D., E-mail: jdschoenfeld@partners.org. Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy. United States. doi:10.1016/J.IJROBP.2017.02.003.
Bang, Andrew, Division of Radiation Oncology, University of Ottawa, Ottawa, Ontario, Wilhite, Tyler J., Pike, Luke R.G., Cagney, Daniel N., Aizer, Ayal A., Taylor, Allison, Spektor, Alexander, Krishnan, Monica, Ott, Patrick A., Balboni, Tracy A., Hodi, F. Stephen, and Schoenfeld, Jonathan D., E-mail: jdschoenfeld@partners.org. 2017. "Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy". United States. doi:10.1016/J.IJROBP.2017.02.003.
@article{osti_22649931,
title = {Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy},
author = {Bang, Andrew and Division of Radiation Oncology, University of Ottawa, Ottawa, Ontario and Wilhite, Tyler J. and Pike, Luke R.G. and Cagney, Daniel N. and Aizer, Ayal A. and Taylor, Allison and Spektor, Alexander and Krishnan, Monica and Ott, Patrick A. and Balboni, Tracy A. and Hodi, F. Stephen and Schoenfeld, Jonathan D., E-mail: jdschoenfeld@partners.org},
abstractNote = {Purpose: To analyze immune-related adverse events (ir-AEs) in patients treated with radiation and immune checkpoint blockade. Methods and Materials: We retrospectively reviewed records from patients with metastatic non-small cell lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined using Common Terminology Criteria for Adverse Events version 4.0, were tabulated in relation to treatment variables, and associations with sequencing and timing were assessed. Results: We identified 133 patients, of whom 28 received a CTLA-4 inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six patients received radiation within 14 days of an immune checkpoint inhibitor. Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs. Conclusions: Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated. Although conclusions are limited by the heterogeneity of patients and treatments, and future confirmatory studies are needed, this information can help guide clinical practice for patients receiving immune checkpoint therapy who require palliative radiation therapy.},
doi = {10.1016/J.IJROBP.2017.02.003},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 2,
volume = 98,
place = {United States},
year = 2017,
month = 6
}
  • Purpose: To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma. Methods and Materials: All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m{sup 2} for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion ofmore » RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m{sup 2} for 5 days every 4 weeks and continuation of BV every 2 weeks. Results: For these 10 patients, toxicities were compiled until study discontinuation or up to {approx}40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or delayed neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed. Conclusion: The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.« less
  • Purpose: To assess, in a multicenter setting, the long-term outcomes of a brief course of high-dose methotrexate followed by radiotherapy for patients with primary central nervous system lymphoma (PCNSL). Methods and Materials: Forty-six patients were entered in a Phase II protocol consisting of methotrexate (1 g/m{sup 2} on Days 1 and 8), followed by whole-brain irradiation (45-50.4 Gy). The median follow-up time was 7 years, with a minimum follow-up of 5 years. Results: The 5-year survival estimate was 37% ({+-}14%, 95% confidence interval [CI]), with progression-free survival being 36% ({+-}15%, 95% CI), and median survival 36 months. Of the originalmore » 46 patients, 10 were alive, all without evidence of disease recurrence. A total of 11 patients have developed neurotoxicity, with the actuarial risk being 30% ({+-}18%, 95% CI) at 5 years but continuing to increase. For patients aged >60 years the risk of neurotoxicity at 7 years was 58% ({+-}30%, 95% CI). Conclusion: Combined-modality therapy, based on high-dose methotrexate, results in improved survival outcomes in PCNSL. The risk of neurotoxicity for patients aged >60 years is unacceptable with this regimen, although survival outcomes for patients aged >60 years were higher than in many other series.« less
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