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.

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