Immunotherapy and Radiotherapy Combination

Abstract

Immunotherapy is a treatment proven to be effective in terms of response, duration of response and survival in many types of cancer by strengthening the immune system. The response rates are 20%, and new treatments that produce synergistic effect with immunotherapy are needed in resistant patients. Antigenic stimulation released from tumor cells with radiotherapy can complement immunotherapy by making the tumor more easily recognized by the immune system. The systemic effect of radiotherapy on metastases other than the irradiated target is defined as “abscopal” effect and the main purpose of immuno-radiotherapy is to evoke the “abscopal” effect. The significant contribution of immuno-radiotherapy to response and survival has been shown primarily in malignant melanoma and lung cancers, and is seen as a promising treatment method in other solit tumors as well.

Keywords

• immunotherapy
• radiotherapy
• combined modality therapy

İmmunoterapi ve Radyoterapi Kombinasyonu

Abstract

İmmunoterapi, bağışıklık sisteminin güçlendirilmesi ile birçok kanser türünde yanıt, yanıt süresi ve sağkalım açısından etkinliği kanıtlanmış bir tedavidir. Yanıt oranları %20 olup dirençli hastalarda immunoterapi ile sinerjik etki yaratan yeni tedavilere gereksinim vardır. Radyoterapi ile tümör hücrelerinden salınan antijenik uyarı tümörün bağışıklık sistemi tarafından daha kolay tanınmasını sağlayarak immunoterapinin tamamlayıcısı olabilir. Radyoterapinin, ışınlanan hedef dışındaki metastazlar üzerindeki sistemik etkisi “abscopal” etki olarak tanımlanmış olup immuno-radyoterapinin temel amacı “abscopal” etkiyi uyandırmaktır. İmmuno-radyoterapinin yanıt ve sağkalıma anlamlı katkısı öncelikle malign melanom ve akciğer kanserlerinde gösterilmiş olup diğer solid tümörlerde de gelecek vaat eden önemli bir tedavi yöntemi olarak görülmektedir.

Keywords

• immunoterapi
• radyoterapi
• kombine model tedavi

References

1. 1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature, 2011; 480 (7378): 480-9.
2. 2. Li Z, Song W, Rubinstein M, Liu D. Recent updates in cancer immunotherapy: a comprehensive review and perspective of the 2018 China Cancer Immunotherapy Workshop in Beijing. J Hematol Oncol. 2018, 21;11(1):142.
3. 3. Kang SP, Gergich K, Lubiniecki GM, et al. Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic. Ann Oncol, 2017; 28(6): 1388-1398.
4. 4. Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol, 2002; 20 (8): 2045-52.
5. 5. Hamid O, Robert C, Daud A, et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol, 2019; 30 (4): 582-588.
6. 6. Ascierto PA, Long GV, Robert C, et al. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol, 2019; 5 (2): 187-194.
7. 7. www.nccn.org
8. 8. Garon EB, Hellman MD, Rizvi NA, et al. Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J Clin Oncol, 2019; 37 (28): 2518-2527.

9. 9. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol, 2015; 16 (5): 522-30.
10. 10. Eggermont AMM, Chiarion-Sileni V, Grob JJ, Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer, 2019; 119: 1-10.
11. 11. Eggermont AMM, Blank CU, Mandala M, et al. Prognostic and predictive value of AJCC-8 staging in the phase III EORTC1325/KEYNOTE-054 trial of pembrolizumab vs placebo in resected high-risk stage III melanoma. Eur J Cancer, 2019; 116: 148-157.
12. 12. Weber J, Mandala M, del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Eng J Med, 2017; 377 (19): 1824-1835.
13. 13. Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol, 2003; 21 (10): 2004-10.
14. 14. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol, 2015; 16 (2): 187-99.
15. 15. Antonia SJ, Villegas A, Daniel D, et al. PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med, 2017; 377: 1919–1929.
16. 16. Bradley JD, Hu C, Komaki RR, et al. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. J Clin Oncol, 2020; 38 (7): 706-714.
17. 17. Meng X, Feng R, Yang L, et al. The Role of Radiation Oncology in Immuno-Oncology. Oncologist, 2019; 24 (Suppl1): S42-S52.
18. 18. Vanpouille-Box C, Formenti SC, Demaria S. Toward Precision Radiotherapy for Use with Immune Checkpoint Blockers. Clin Cancer Res, 2018; 24 (2): 259-265.
19. 19. Yang H, Jin T, Li M, et al. Synergistic effect of immunotherapy and radiotherapy in non-small cell lung cancer: current clinical trials and prospective challenges, Precision Clinical Medicine, 2019; 1–14
20. 20. Bath C. In Era of Immunotherapy, Radiation Therapy May Become Essential Component of Systemic Treatments of Cancer, February 25, 2019, www.ascopost.com/issues
21. 21. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: Changing strategies for cancer treatment. Blood 2009; 114:589–595.
22. 22. Wang X, Schoenhals JE, Li A, et al. Suppression of type I IFN signaling in tumors mediates resistance to anti-PD-1 treatment that can be overcome by radiotherapy. Cancer Res, 2017; 77:839–850.
23. 23. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res, 2014; 74:5458–5468.
24. 24. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest, 2014; 124:687–695.
25. 25. Weiss T, Weller M, Guckenberger M, et al. NKG2D-based CAR T cells and radiotherapy exert synergistic efficacy in glioblastoma. Cancer Res, 2018; 78:1031–1043.
26. 26. Silk AW, Bassetti MF, West BT, et al. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med, 2013; 2: 899–906.
27. 27. Tang C, Welsh JW, de Groot P, et al. Ipilimumab with stereotactic ablative radiation therapy: Phase I results and immunologic correlates from peripheral T cells. Clin Cancer Res, 2017; 23:1388–1396.
28. 28. Anderson ES, Postow MA, Wolchok JD, et al. Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. J Immunother Cancer, 2017; 5: 76.
29. 29. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: A secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol, 2017; 18: 895–903.
30. 30. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castrationresistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol, 2014; 15:700–712.
31. 31. Mathew M, Tam M, Ott PA, et al. Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res, 2013; 23:191–195.
32. 32. Patel KR, Shoukat S, Oliver DE, et al. Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases. Am J Clin Oncol, 2017; 40:444–450.
33. 33. O’Donnell JS, Smyth MJ, Teng MW. Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade? Genome Med, 2016; 8 (1): 111.
34. 34. Weichselbaum RR, Liang H, Deng L, et al. Radiotherapy and immunotherapy: A beneficial liaison? Nat Rev Clin Oncol, 2017; 14: 365–379.
35. 35. Koller KM, Mackley HB, Liu J, et al. Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Cancer Biol Ther, 2017; 18 (1): 36-42.
36. 36. Hiniker SM, Reddy SA, Maecker HT, et al. A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Int J Radiat Oncol Biol Phys, 2016; 96:578–588.
37. 37. Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA, 2014; 312 (17): 1744-53.
38. 38. Mole RH. Whole body irradiation; radiobiology or medicine? Br J Radiol, 1953; 26(305):234-41.
39. 39. By Jason Liu, BS; Heath B. Mackley MD, FACRO, Combining immunotherapy with radiation therapy to induce the abscopal response: What clinical and treatment variables matter?, March 2019, www.appliedradiationoncology.com, 13-19.
40. 40. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med, 2012; 366:925–931.
41. 41. Kropp LM, De Los Santos JF, McKee SB, Conry RM. Radiotherapy to Control Limited Melanoma Progression Following Ipilimumab. J Immunother, 2016; 39 (9): 373-378.
42. 42. Golden EB, Chhabra A, Chachoua A, et al. Local radiotherapy and granulocyte-macrophage colony stimulating factor to generate abscopal responses in patients with metastatic solid tumours: A proof of-principle trial. Lancet Oncol, 2015; 16:795–803.
43. 43. Chen D, Menon H, Verma V, et al. Response and outcomes after anti-CTLA4 versus anti-PD1 combined with stereotactic body radiation therapy for metastatic non-small cell lung cancer: retrospective analysis of two single-institution prospective trials. J Immunother Cancer, 2020; 8 (1): doi: 10.1136/jitc-2019-000492
44. 44. Demaria S, Formenti SC. Radiation as an immunological adjuvant: Current evidence on dose and fractionation. Front Oncol, 2012; 2:153.
45. 45. Verbrugge I, Hagekyriakou J, Sharp LL, et al. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res, 2012; 72:3163–3174.
46. 46. Filatenkov A, Baker J, Mueller AM, et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin Cancer Res, 2015; 21:3727–3739
47. 47. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody.Clin Cancer Res, 2009; 15:5379–5388.
48. 48. Marconi R, Strolin S, Bossi G, Strigari L. A meta-analysis of the abscopal effect in preclinical models: Is the biologically effective dose a relevant physical trigger? PLoS One, 2017; 12 (2): e0171559.
49. 49. Cushman TR, Caetano MS, Welsh JW, Verma V. Overview of ongoing clinical trials investigating combined radiotherapy and immunotherapy. Immunotherapy, 2018; 10 (10):851-60
50. 50. Brody JD, Ai WZ, Czerwinski DK, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: A phase I/II study. J Clin Oncol, 2010; 28:4324–4332.
51. 51. Teng F, Meng X, Kong L, et al. Tumor infiltrating lymphocytes, forkhead box P3, programmed death ligand-1, and cytotoxic T lymphocyte-associated antigen-4 expressions before and after neoadjuvant chemoradiation in rectal cancer. Transl Res, 2015; 166:721–732.e721
52. 52. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res, 2011; 17 (13): 4550-7.
53. 53. Bernstein MB, Krishnan S, Hodge JW, et al. Immunotherapy and stereotactic ablative radiotherapy (ISABR): A curative approach? Nat Rev Clin Oncol, 2016; 13:516–524.
54. 54. Huang AC, Postow MA, Orlowski RJ, et al. Tcell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature, 2017; 545:60–65.
55. 55. Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin, 2017; 67:65–85.
56. 56. Luke JJ, Lemons JM, Karrison TG, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol, 2018;36:1611–1618.
57. 57. Nakamura N, Kusunoki Y, Akiyama M. Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay. Radiat Res, 1990; 123(2):224-7.
58. 58. Aliru ML, Schoenhals JE, Venkatesulu BP, et al. Radiation therapy and immunotherapy: what is the optimal timing or sequencing? Immunotherapy, 2018; 10 (4): 299-316.
59. 59. Hiniker SM, Chen DS, Reddy S, et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol, 2012; 5:404–407.
60. 60. An Y, Jiang W, Kim BYS, et al. Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiother Oncol, 2017; 125:80–88.
61. 61. Ribeiro Gomes J, Schmerling RA, Haddad CK, et al. Analysis of the abscopal effect with anti-PD1 therapy in patients with metastatic solid tumors. J Immunother, 2016; 39:367–372.
62. 62. Grimaldi AM, Simeone E, Giannarelli D, et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology, 2014; 3: e28780.
63. 63. Fiorica F, Belluomini L, Stefanelli A, et al. Immun Checkpoint Inhibitor Nivolumab and Radiotherapy in Pretreated Lung Cancer Patients: Efficacy and Safety of Combination. Am J Clin Oncol, 2018; Jan 31. doi: 10.1097/COC.0000000000000428.
64. 64. Bersanelli M, Lattanzi E, D’Abbiero N, et al. Palliative radiotherapy in advanced cancer patients treated with immune-checkpoint inhibitors: The PRACTICE study. Biomed Rep, 2020; 12(2): 59-67.
65. 65. Levy A, Massard C, Soria JC, et al. Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. Eur J Cancer, 2016; 68:156–162.
66. 66. Liniker E, Menzies AM, Kong BY, et al. Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma. Oncoimmunology, 2016; 5:e1214788.
67. 67. Ahmed KA, Stallworth DG, Kim Y, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol, 2016; 27:434–441.
68. 68. Qian JM, Yu JB, Kluger HM, Chiang VL. Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to steriotactic radiosurgery. Cancer, 2016; 122 (19): 3051-8.
69. 69. Moravan MJ, Fecci PE, Anders CK, et al. Current multidisciplinary management of brain metastases. Cancer; 2020; 126 (7): 1390-1406.
70. 70. Iorgulescu JB, Harary M, Zogg CK, et al. Improved risk-adjusted for melanoma brain metastases in the era of checkpoint blockade immunotherapies: results from a National Cohort. Cancer Immunol Res, 2018; 6 (9): 1039-1045.
71. 71. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol, 2012; 13 (5):459–465.
72. 72. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol, 2016; 17 (7): 976-983.
73. 73. Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol, 2018; 19 (5): 672-681.
74. 74. Ahmed KA, Abuodeh YA, Echevarria MI, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol, 2016; 27 (12): 2288-2294.
75. 75. Lim SH, Lee JY, Lee MY, et al. A randomized phase III trial of steriotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metestases in non-small cell lung cancer. Ann Oncol, 2015; 26 (4): 762-8.
76. 76. Gandhi L, Rodriquez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Eng J Med, 2018; 378 (22): 2078-2092.
77. 77. Gadgeel SM, Lukas RV, Goldschmidt J, et al. Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study. Lung Cancer, 2019; 128: 105-112.
78. 78. ElJalby M, Pannullo SC, Schwartz TH, et al. Optimal Timing and Sequence of Immunotherapy When Combined with Stereotactic Radiosurgery in the Treatment of Brain Metastases. World Neurosurg, 2019; 127: 397-404.
79. 79. Cohen-Inbar O, Shih H-H, Xu Z, et al. The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab. J Neurosurg, 2017; 127:1007-1014.
80. 80. Chen L, Douglass J, Kleinberg L, et al. Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma. Int J Radiat Oncol Biol Phys, 2018; 100 (4): 916-925.
81. 81. Schapira E, Hubbeling H, Yeap BY, et al. Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1 Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With Brain Metastases. Int J Radiat Oncol Biol Phys, 2018; 101 (3): 624-629.
82. 82. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res, 2009; 15 (23): 7412-20.
83. 83. Akhoundova D, Hiltbrunner S, Mader C, et al. 18F-FET PET for Diagnosis of Pseudoprogression of Brain Metastases in Patients With Non-Small Cell Lung Cancer. Clin Nucl Med, 2020; 45 (2): 113-117.
84. 84. Galldiks N, Kocher M, Ceccon G, et al. Imaging challenges of immunotherapy and targeted therapy in patients with brain metastases: response, progression, and pseudoprogression. Neuro Oncol, 2020; 22 (1): 17-30.
85. 85. Martin AM, Cagney DN, Catalano PJ, et al. Immunotherapy and Symptomatic Radiation Necrosis in Patients With Brain Metastases Treated With Stereotactic Radiation. JAMA Oncol, 2018; 4 (8): 1123-1124.
86. 86. Minniti G, Scaringi C, Paolini S, et al. Single-Fraction Versus Multifraction (3 × 9 Gy) Stereotactic Radiosurgery for Large (>2 cm) Brain Metastases: A Comparative Analysis of Local Control and Risk of Radiation-Induced Brain Necrosis. Int J Radiat Oncol Phys, 2016; 95 (4): 1142-8.
87. 87. Minniti G, Anzellini D, Reverberi C, et al. Stereotactic radiosurgery combined with nivolumab or Ipilimumab for patients with melanoma brain metastases: evaluation of brain control and toxicity. J Immunother Cancer, 2019; 7 (1): 102.
88. 88. Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol, 2015; 16 (15): e534-e542.
89. 89. Li YD, Lamano JB, Kaur G, et al. Lymphopenia predicts response to stereotactic radiosurgery in lung cancer patients with brain metastases. J Neurooncol, 2019; 143 (2): 337-347.
90. 90. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PDL1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet, 2016; 387:1540–1550
91. 91. Bauml JM, Mick R, Ciunci C, et al. Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer: A Phase 2 Trial. JAMA Oncol, 2019; Jul 11: doi: 10.1001/jamaoncol.2019.1449.
92. 92. Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitör immunotherapy. Nat Rev Cancer, 2019; 19 (3): 133-150.
93. 93. Shibaki R, Akamatsu H, Fujimoto M, et al. Nivolumab induced radiation recall pneumonitis after two years of radiotherapy. Ann Oncol, 2017; 28:1404–1405.
94. 94. Peters S, Felip E, Dafni U, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial. Lung Cancer, 2019; 133: 88-87.
95. 95. Verma V, Cushman TR, Tang C, Welsh JW. Toxicity of radiation and immunotherapy combinations. Adv Radiat Oncol, 2018; 3 (4): 506-511.
96. 96. Kroeze SG, Fritz C, Hoyer M, et al. Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: A systematic review. Cancer Treat Rev, 2017; 53: 25-37.
97. 97. 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 (7): 785-792.
98. 98. Horvat TZ, Adel NG, Dang TO, et al. Immune-Related Adverse Event, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol, 2015; 33(28): 3193-8.
99. 99. Arbour KC, Mezqita L, Long N, et al. Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer. J Clin Oncol, 2018; 36 (28): 2872-2878.
100. 100. Scott SC, Pennell NA. Early Use of Systemic Corticosteroids in Patients with Advanced NSCLC Treated with Nivolumab. J Thorac Oncol, 2018; 13 (11): 1771-1775.
101. 101. www.clinicaltrials.gov