10 oktober 2020: JAMA september 2020

Uit de resultaten van een zogeheten retrospectieve studie bij totaal 3112 patiënten met hersenuitzaaiingen blijkt dat wanneer bij deze patiënten de primaire tumor eerst volledig is weggehaald en daarna immuuntherapie wordt gecombineerd met radiotherapie / bestraling de overall overleving beduidend beter is in vergelijking met geen immuuntherapie.  De combinatie van immuuntherapie met alleen chemotherapie na complete operatie van de primaire tumor liet echter geen betere overall overleving zien. De studie is uitgevoerd door wetenschappers met hulp van de National Cancer Database.

Het studierapport is een groot retrospectief overzicht van 3112 patiënten met hersenuitzaaiingen (BM) van verschillende primaire tumortypen (waaronder niet-kleincellige longkanker , melanoom, darmkanker en nierkanker) waarvan een klein gedeelte is behandeld met immuuntherapie met anti-PD medicijnen (ICI) en operatieve verwijdering van de primaire tumor. De onderzoeksperiode liep van 2010 tot 2016, en de studie tracht primair het effect op de algehele overleving (OS) te identificeren wanneer er zoveel mogelijk tumorweefsel wordt weggehaald en pas daarna immuuntherapie wordt toegepast.

De belangrijkste overweging om deze analyse uit te voeren, gebaseerd op het al dan niet uitvoeren van resectie van de primaire tumor, was de eigen ervaring in hun ziekenhuis bij meer dan 75.000 patiënten met verbeterde overleving bij patiënten die een dergelijke resectie van de primaire tumor hadden ondergaan (Mediane overall overleving  verschilde enorm: 20 maanden versus 9 maanden).

De veronderstelde gedachte voor dit overlevingsverschil is dat het verwijderen van de primaire tumor de tumorbelasting aanzienlijk zal verminderen, en dat immuuntherapie beter kan werken in een lichaam waar het grootste deel van de tumormassa zoveel mogelijk is verminderd.

(redactie: Zonder arrogant te zijn maar ik roep dat al jaren. Immuuntherapie werkt gewoon het beste met zo weinig mogelijk tumorload). 

De 3112 patiënten werden gegroepeerd in een van de vier behandelingscategorieën:

  • groep 1) elke vorm van behandeling plus wel of geen immuuntherapie met anti-PD medicijnen ( ICI);
  • groep 2) chemotherapie plus wel of geen immuuntherapie met anti-PD medicijnen ( ICI);
  • groep 3) radiotherapie (RT) plus wel of geen immuuntherapie met anti-PD medicijnen ( ICI);
  • groep 4) chemoradiotherapie combinatie (RT) plus wel of geen immuuntherapie met anti-PD medicijnen ( ICI);

Om de effectiviteit van de immuuntherapie te evalueren, werd een Cox proportional hazards regressieanalyse gebruikt, waarbij werd gecorrigeerd voor leeftijd bij diagnose, ras, geslacht, woonplaats, inkomen, opleiding, type behandelingsinstelling, type primaire tumor en jaar van diagnose.

Slechts een kleine minderheid van de 3112 patiënten kreeg immuuntherapie (ICI) te weten 183 patiënten [5,88%]); Hiervan kregen 22 patiënten (6,47% van de hele studiegroep) chemotherapie plus immuuntherapie met anti-PD medicijnen (ICI), 72 patiënten (8,37%) kregen radiotherapie - bestraling (RT) plus ICI en 76 patiënten (5,17%) kregen chemoRT plus ICI.

Hoewel de algemene conclusie in de multivariabele analyse was dat patiënten die immuuntherapie met anti-PD-medicijnen (ICI) hadden gekregen een statistisch significant betere overall overleving (OS) hadden vergeleken met geen immuuntherapie (ICI) (HR, 0,62; 95% BI, 0,51-0,76; P <0,001), waren de zeer grote verschillen in aantallen tussen de twee onderlinge groepen, en de zeer kleine aantallen in de immuuntherapiegroep (ICI), zo groot dat de resultaten gemakkelijk zouden kunnen worden vertekend door onvoldoende beoordeelde variabelen en daarom op zijn best kan worden gezien als te verwachten resultaten (hypothesegenererend).

Verder concludeerden de auteurs dat radiotherapie - bestraling (RT) plus immuuntherapie met anti-PD medicijnen (ICI) geassocieerd was met statistisch significant verbeterde overall overleving (OS) vergeleken met radiotherapie - bestraling alleen (HR 0,59; 95% BI 0,42-0,84; P = 0,003).

Echter chemotherapie plus immuuntherapie (ICI) of chemoRT plus ICI werd niet geassocieerd met een verbeterde overall overleving (OS). immuuntherpaie met anti-PD medicijnen gecombineerd met radiotherapie verbeterde de overall overleving met 10 maanden vergeleken met alleen radiotherpaie - bestraling. Wat een heel groot verschil is voor deze groep van patiënten waarbij de mediane overall overleving vaak slechts maanden is en zeker geen jaren. 

Het volledige studierapport: Association of Immunotherapy With Survival Among Patients With Brain Metastases Whose Cancer Was Managed With Definitive Surgery of the Primary Tumor is gratis in te zien.

JAMA Netw Open. 2020;3(9):e2015444. doi:10.1001/jamanetworkopen.2020.15444
Key Points Español  中文 (Chinese)

Question  Is combining immunotherapy with other cancer treatments associated with improved overall survival in patients with brain metastases?

Findings  In this comparative effectiveness study of 3112 adult patients who received definitive surgery of the primary cancer site, those who received any treatment plus immunotherapy had better overall survival than those who received no immunotherapy. Results varied with other combined therapies; immunotherapy plus radiation therapy was associated with improved overall survival compared with radiation therapy alone, but immunotherapy plus chemotherapy was not associated with improved overall survival compared with chemotherapy alone.

Meaning  In this study, immunotherapy plus radiotherapy was associated with improved overall survival compared with radiotherapy alone.

Abstract

Importance  Immunotherapy has shown significant control of intracranial metastases in patients with melanoma. However, the association of immunotherapy combined with other cancer treatments and overall survival (OS) of patients with brain metastases, regardless of primary tumor site, is unknown.

Objective  To explore the association of immunotherapy with OS in patients with cancer and brain metastases who received definitive surgery of the primary site.

Design, Setting, and Participants  This comparative effectiveness study included 3112 adult patients in the National Cancer Database from 2010 to 2016 with non–small cell lung cancer, breast cancer, melanoma, colorectal cancer, or kidney cancer and brain metastases at the time of diagnosis and who received definitive surgery of the primary site. Data analysis was conducted from March to April 2020.

Exposures  Treatment groups were stratified as follows: (1) any treatment with or without immunotherapy, (2) chemotherapy with or without immunotherapy, (3) radiotherapy (RT) with or without immunotherapy, and (4) chemoradiation with or without immunotherapy.

Main Outcomes and Measures  The association of immunotherapy with OS was assessed with Cox proportional hazards regression, adjusted for age at diagnosis, race, sex, place of living, income, education, treatment facility type, primary tumor type, and year of diagnosis.

Results  Of 3112 patients, 1436 (46.14%) were men, 2714 (87.72%) were White individuals, 257 (8.31%) were Black individuals, and 123 (3.98%) belonged to other racial and ethnic groups. The median (range) age at diagnosis was 61 (19-90) years. Overall, 183 (5.88%) received immunotherapy, 318 (10.22%) received chemotherapy alone, 788 (25.32%) received RT alone, and 1393 (44.76%) received chemoradiation alone; 22 (6.47%) received chemotherapy plus immunotherapy, 72 (8.37%) received RT plus immunotherapy, and 76 (5.17%) received chemoradiation plus immunotherapy. In the multivariable analysis, patients who received immunotherapy had significantly improved OS compared with no immunotherapy (hazard ratio, 0.62; 95% CI, 0.51-0.76; P < .001). Treatment with RT plus immunotherapy was associated with significantly improved OS compared with RT alone (hazard ratio, 0.59; 95% CI, 0.42-0.84; P = .003). Chemotherapy plus immunotherapy or chemoradiation plus immunotherapy were not associated with improved OS in the multivariable analysis.

Conclusions and Relevance  In this study, the addition of immunotherapy to RT was associated with improved OS compared with radiotherapy alone in patients with brain metastases who received definitive surgery of the primary tumor site.

References
1.
Langer  CJ, Mehta  MP.  Current management of brain metastases, with a focus on systemic options.   J Clin Oncol. 2005;23(25):6207-6219. doi:10.1200/JCO.2005.03.145PubMedGoogle ScholarCrossref
2.
Villano  JL, Durbin  EB, Normandeau  C, Thakkar  JP, Moirangthem  V, Davis  FG.  Incidence of brain metastasis at initial presentation of lung cancer.   Neuro Oncol. 2015;17(1):122-128. doi:10.1093/neuonc/nou099PubMedGoogle ScholarCrossref
3.
Feng  W, Zhang  P, Zheng  X, Chen  M, Mao  WM.  Incidence and treatment of brain metastasis in patients with esophageal carcinoma.   World J Gastroenterol. 2015;21(19):5805-5812. doi:10.3748/wjg.v21.i19.5805PubMedGoogle ScholarCrossref
4.
Davis  FG, Dolecek  TA, McCarthy  BJ, Villano  JL.  Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data.   Neuro Oncol. 2012;14(9):1171-1177. doi:10.1093/neuonc/nos152PubMedGoogle ScholarCrossref
5.
Nayak  L, Lee  EQ, Wen  PY.  Epidemiology of brain metastases.   Curr Oncol Rep. 2012;14(1):48-54. doi:10.1007/s11912-011-0203-yPubMedGoogle ScholarCrossref
6.
Achrol  AS, Rennert  RC, Anders  C,  et al.  Brain metastases.   Nat Rev Dis Primers. 2019;5(1):6. doi:10.1038/s41572-019-0061-8PubMedGoogle ScholarCrossref
7.
Nolan  C, Deangelis  LM.  Overview of metastatic disease of the central nervous system.   Handb Clin Neurol. 2018;149:3-23. doi:10.1016/B978-0-12-811161-1.00001-3PubMedGoogle ScholarCrossref
8.
Michl  M, Thurmaier  J, Schubert-Fritschle  G,  et al.  Brain metastasis in colorectal cancer patients: survival and analysis of prognostic factors.   Clin Colorectal Cancer. 2015;14(4):281-290. doi:10.1016/j.clcc.2015.05.009PubMedGoogle ScholarCrossref
9.
Fabi  A, Felici  A, Metro  G,  et al.  Brain metastases from solid tumors: disease outcome according to type of treatment and therapeutic resources of the treating center.   J Exp Clin Cancer Res. 2011;30(1):10. doi:10.1186/1756-9966-30-10PubMedGoogle ScholarCrossref
10.
Esmaeilzadeh  M, Majlesara  A, Faridar  A,  et al.  Brain metastasis from gastrointestinal cancers: a systematic review.   Int J Clin Pract. 2014;68(7):890-899. doi:10.1111/ijcp.12395PubMedGoogle ScholarCrossref
11.
Cohen  JV, Kluger  HM.  Systemic immunotherapy for the treatment of brain metastases.   Front Oncol. 2016;6:49. doi:10.3389/fonc.2016.00049PubMedGoogle ScholarCrossref
12.
Kocher  M, Soffietti  R, Abacioglu  U,  et al.  Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study.   J Clin Oncol. 2011;29(2):134-141. doi:10.1200/JCO.2010.30.1655PubMedGoogle ScholarCrossref
13.
Soffietti  R, Kocher  M, Abacioglu  UM,  et al.  A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results.   J Clin Oncol. 2013;31(1):65-72. doi:10.1200/JCO.2011.41.0639PubMedGoogle ScholarCrossref
14.
Lauko  A, Thapa  B, Venur  VA, Ahluwalia  MS.  Management of brain metastases in the new era of checkpoint inhibition.   Curr Neurol Neurosci Rep. 2018;18(10):70. doi:10.1007/s11910-018-0877-8PubMedGoogle ScholarCrossref
15.
Ahluwalia  MS, Vogelbaum  MV, Chao  ST, Mehta  MM.  Brain metastasis and treatment.   F1000Prime Rep. 2014;6:114. doi:10.12703/P6-114PubMedGoogle ScholarCrossref
16.
Puhalla  S, Elmquist  W, Freyer  D,  et al.  Unsanctifying the sanctuary: challenges and opportunities with brain metastases.   Neuro Oncol. 2015;17(5):639-651. doi:10.1093/neuonc/nov023PubMedGoogle ScholarCrossref
17.
Krop  IE, Lin  NU, Blackwell  K,  et al.  Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA.   Ann Oncol. 2015;26(1):113-119. doi:10.1093/annonc/mdu486PubMedGoogle ScholarCrossref
18.
Fan  Y, Huang  Z, Fang  L,  et al.  Chemotherapy and EGFR tyrosine kinase inhibitors for treatment of brain metastases from non-small-cell lung cancer: survival analysis in 210 patients.   Onco Targets Ther. 2013;6:1789-1803.PubMedGoogle Scholar
19.
Cochran  DC, Chan  MD, Aklilu  M,  et al.  The effect of targeted agents on outcomes in patients with brain metastases from renal cell carcinoma treated with Gamma Knife surgery.   J Neurosurg. 2012;116(5):978-983. doi:10.3171/2012.2.JNS111353PubMedGoogle ScholarCrossref
20.
Knisely  JP, Yu  JB, Flanigan  J, Sznol  M, Kluger  HM, Chiang  VL.  Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival.   J Neurosurg. 2012;117(2):227-233. doi:10.3171/2012.5.JNS111929PubMedGoogle ScholarCrossref
21.
Ahluwalia  MS, Winkler  F.  Targeted and immunotherapeutic approaches in brain metastases.   Am Soc Clin Oncol Educ Book. 2015;67-74. doi:10.14694/EdBook_AM.2015.35.67PubMedGoogle Scholar
22.
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. doi:10.1016/S1470-2045(16)30053-5PubMedGoogle ScholarCrossref
23.
Tawbi  HA, Forsyth  PA, Algazi  A,  et al.  Combined nivolumab and ipilimumab in melanoma metastatic to the brain.   N Engl J Med. 2018;379(8):722-730. doi:10.1056/NEJMoa1805453PubMedGoogle ScholarCrossref
24.
Kiess  AP, Wolchok  JD, Barker  CA,  et al.  Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment.   Int J Radiat Oncol Biol Phys. 2015;92(2):368-375. doi:10.1016/j.ijrobp.2015.01.004PubMedGoogle ScholarCrossref
25.
Skrepnik  T, Sundararajan  S, Cui  H, Stea  B.  Improved time to disease progression in the brain in patients with melanoma brain metastases treated with concurrent delivery of radiosurgery and ipilimumab.   Oncoimmunology. 2017;6(3):e1283461. doi:10.1080/2162402X.2017.1283461PubMedGoogle Scholar
26.
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 stereotactic radiosurgery.   Cancer. 2016;122(19):3051-3058. doi:10.1002/cncr.30138PubMedGoogle ScholarCrossref
27.
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. doi:10.1016/S1470-2045(18)30139-6PubMedGoogle ScholarCrossref
28.
Robert  C, Thomas  L, Bondarenko  I,  et al.  Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.   N Engl J Med. 2011;364(26):2517-2526. doi:10.1056/NEJMoa1104621PubMedGoogle ScholarCrossref
29.
Diao  K, Bian  SX, Routman  DM,  et al.  Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity.   J Neurooncol. 2018;139(2):421-429. doi:10.1007/s11060-018-2880-yPubMedGoogle ScholarCrossref
30.
Tazi  K, Hathaway  A, Chiuzan  C, Shirai  K.  Survival of melanoma patients with brain metastases treated with ipilimumab and stereotactic radiosurgery.   Cancer Med. 2015;4(1):1-6. doi:10.1002/cam4.315PubMedGoogle ScholarCrossref
31.
Silk  AW, Bassetti  MF, West  BT, Tsien  CI, Lao  CD.  Ipilimumab and radiation therapy for melanoma brain metastases.   Cancer Med. 2013;2(6):899-906. doi:10.1002/cam4.140PubMedGoogle ScholarCrossref
32.
Di Giacomo  AM, Ascierto  PA, Pilla  L,  et al.  Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial.   Lancet Oncol. 2012;13(9):879-886. doi:10.1016/S1470-2045(12)70324-8PubMedGoogle ScholarCrossref
33.
Weber  JS, Amin  A, Minor  D, Siegel  J, Berman  D, O’Day  SJ.  Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial.   Melanoma Res. 2011;21(6):530-534. doi:10.1097/CMR.0b013e32834d3d88PubMedGoogle ScholarCrossref
34.
Kiess  AP, Wolchok  JD, Barker  CA,  et al.  Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment.   Int J Radiat Oncol Biol Phys. 2015;92(2):368-375. doi:10.1016/j.ijrobp.2015.01.004PubMedGoogle ScholarCrossref
35.
Shoukat  S, Marcus  DM, Rizzo  M,  et al  Outcome with stereotactic radiosurgery (SRS) and ipilimumab (ipi) for malignant melanoma brain metastases (mets).   J Clin Oncol. 2014;32(15):9076. doi:10.1200/jco.2014.32.15_suppl.9076Google ScholarCrossref
36.
Acharya  S, Mahmood  M, Mullen  D,  et al.  Distant intracranial failure in melanoma brain metastases treated with stereotactic radiosurgery in the era of immunotherapy and targeted agents.   Adv Radiat Oncol. 2017;2(4):572-580. doi:10.1016/j.adro.2017.07.003PubMedGoogle ScholarCrossref
37.
Murphy  B, Walker  J, Bassale  S,  et al.  Concurrent radiosurgery and immune checkpoint inhibition: Improving regional intracranial control for patients with metastatic melanoma.   Am J Clin Oncol. 2019;42(3):253-257. doi:10.1097/COC.0000000000000509PubMedGoogle ScholarCrossref
38.
Siva  S, MacManus  MP, Martin  RF, Martin  OA.  Abscopal effects of radiation therapy: a clinical review for the radiobiologist.   Cancer Lett. 2015;356(1):82-90. doi:10.1016/j.canlet.2013.09.018PubMedGoogle ScholarCrossref
39.
Barker  HE, Paget  JT, Khan  AA, Harrington  KJ.  The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence.   Nat Rev Cancer. 2015;15(7):409-425. doi:10.1038/nrc3958PubMedGoogle ScholarCrossref
40.
Vatner  RE, Cooper  BT, Vanpouille-Box  C, Demaria  S, Formenti  SC.  Combinations of immunotherapy and radiation in cancer therapy.   Front Oncol. 2014;4:325. doi:10.3389/fonc.2014.00325PubMedGoogle ScholarCrossref
41.
Mittal  D, Gubin  MM, Schreiber  RD, Smyth  MJ.  New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape.   Curr Opin Immunol. 2014;27:16-25. doi:10.1016/j.coi.2014.01.004PubMedGoogle ScholarCrossref
42.
Haynes  NM, van der Most  RG, Lake  RA, Smyth  MJ.  Immunogenic anti-cancer chemotherapy as an emerging concept.   Curr Opin Immunol. 2008;20(5):545-557. doi:10.1016/j.coi.2008.05.008PubMedGoogle ScholarCrossref
43.
Ma  Y, Conforti  R, Aymeric  L,  et al.  How to improve the immunogenicity of chemotherapy and radiotherapy.   Cancer Metastasis Rev. 2011;30(1):71-82. doi:10.1007/s10555-011-9283-2PubMedGoogle ScholarCrossref
44.
Germano  G, Lamba  S, Rospo  G,  et al.  Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth.   Nature. 2017;552(7683):116-120. doi:10.1038/nature24673PubMedGoogle ScholarCrossref

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