16 juli 2020: Bron: Cancer Immunology june 19th. 2020

Wanneer kankerpatiënten behandeld worden met immuuntherapie met een anti-PD medicijn blijkt het meten tijdens de behandeling van de veranderingen in de verhouding van de neutrofielen tot de lymfocyten ratio (NLR) in het bloed een eenvoudige manier om de effectiviteit te meten. 
De NLR = Neutrofiel/lymfocyt-ratio en PLR = trombocyt/lymfocyt-ratio zijn als basismeting sowieso bij vele vormen van kanker voorspellende factoren voor de overall overleving.
Maar uit een recente studie blijkt het meten van de verhouding van de neutrofielen tot de lymfocyten ratio (NLR) op enkele momenten tijdens de behandeling sterke aanwijzingen te geven voor het verloop van de ziekte. 

Uit deze bron: "De NLR wordt berekend door het aantal neutrofielen door het aantal lymfocyten te delen en wordt voor meerdere vormen van kanker als een mogelijke overlevingsmarker beschouwd. Trombocyten spelen een rol bij de metastase van kanker en de PLR wordt ook steeds vaker als een prognostische biomarker onderzocht."

In een retrospectieve studie uitgevoerd met gegevens van drie Franse ziekenhuizen, werden patiënten die werden behandeld met nivolumab voor niet-kleincellige longkanker (NSCLC) of uitgezaaide nierkanker (mRCC) geëvalueerd op basis van de verhouding tussen neutrofielen en lymfocyten ratio (NLR) en het verband tussen NLR scores met de effectiviteit van de behandeling.

Aan het onderzoek namen 161 patiënten deel, 75 longkankerpatiënten en 86 nierkankerpatiënten met uitgezaaide tumoren deel (28% gunstig risico; 53% gemiddeld risico; en 11% slecht risico), met een mediane progressievrije ziekte (PFS) en overall oveleving (OS) van respectievelijk 4,6 maanden en 24,7 maanden. NLR-variaties werden onderzocht vanaf de start van de studie - vóór eerste toediening - tot en met elke keer dat nivolumab weer werd gegeven tot de datum van de eerste CT - scan. (tussen week 8 en 12).

Voor de groep van nierkankerpatiënten waren de mediane progressievrije ziekte (PFS) en mediane overall overleving (OS) 13,6 maanden versus 3,6 maanden (P = .003) en PFS niet bereikt versus OS van 19,6 maanden (P = .008) voor patiënten met respectievelijk een NLR-afname versus een NLR-toename.

In een multivariabele analyse bleef elke NLR-toename in week 6 onafhankelijk geassocieerd met een slechtere progressievrije ziektetijd - PFS (HR, 2,2; P = .01) en overall overleving - OS (HR, 1,7; P = .09).

NLR score was bij de start significant hoger bij patiënten met progressieve ziekte in vergelijking met patiënten met stabiele ziekte of gedeeltelijke en volledige respons (P = .048).

Conclusie van de onderzoekers: 

Elke toename van het NLR in week 6 ging gepaard met slechtere PFS- en OS-resultaten. NLR-variatie is een goedkope en dynamische marker die gemakkelijk kan worden verkregen om de werkzaamheid van anti-PD-1 te controleren. Dus het meten van de neutrofielen tot de lymfocyten ratio (NLR) tijdens de behandeling is een goedkope en eenvoudige manier om de werkzaamheid van immuuntherapie met anti-PD medicijnen vroegtijdig te herkennen. 

Het studierapport Variation in neutrophil to lymphocyte ratio (NLR) as predictor of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (mNSCLC) patients treated with nivolumab is tegen betaling in te zien.

Hier het abstract van de studie plus referentielijst:

Variation in neutrophil to lymphocyte ratio (NLR) as predictor of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (mNSCLC) patients treated with nivolumab

Abstract

Background

An elevated pre-treatment neutrophil to lymphocytes ratio (NLR) is associated with poor prognosis in various malignancies. Optimal cut-off is highly variable across studies and could not be determined individually for a patient to inform his prognosis. We hypothesize that NLR variations could be more useful than baseline NLR to predict progression-free survival (PFS) and overall survival (OS) in patients (pts) receiving anti-PD1 treatment.

Patients and methods

All pts with metastatic renal cell carcinoma (mRCC) and metastatic non-small cell lung cancer (mNSCLC) who received anti-PD1 nivolumab monotherapy in second-line setting or later were included in this French multicentric retrospective study. NLR values were prospectively collected prior to each nivolumab administration. Clinical characteristics were recorded. Associations between baseline NLR, NLR variations and survival outcomes were determined using Kaplan–Meier’s method and multivariable Cox regression models.

Results

161 pts (86 mRCC and 75 mNSCLC) were included with a median follow-up of 18 months. On the whole cohort, any NLR increase at week 6 was significantly associated with worse outcomes compared to NLR decrease, with a median PFS of 11 months vs 3.7 months (< 0.0001), and a median OS of 28.5 months vs. 18 months (p = 0.013), respectively. In multivariate analysis, NLR increase was significantly associated with worse PFS (HR 2.2; p = 6.10−5) and OS (HR 2.1; p = 0.005). Consistent results were observed in each cohort when analyzed separately.

Conclusion

Any NLR increase at week 6 was associated with worse PFS and OS outcomes. NLR variation is an inexpensive and dynamic marker easily obtained to monitor anti-PD1 efficacy.

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Data availability

Not applicable.

References

  1. 1.

    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30. https://doi.org/10.3322/caac.21442

    Article PubMed Google Scholar 

  2. 2.

    Abe H, Kamai T (2013) Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol Off J Jpn Urol Assoc 20(10):944–955. https://doi.org/10.1111/iju.12187

    CAS Article Google Scholar 

  3. 3.

    Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab vs docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639. https://doi.org/10.1056/NEJMoa1507643

    CAS Article PubMed PubMed Central Google Scholar 

  4. 4.

    Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab vs docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135. https://doi.org/10.1056/NEJMoa1504627

    CAS Article PubMed PubMed Central Google Scholar 

  5. 5.

    Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab vs everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813. https://doi.org/10.1056/NEJMoa1510665

    CAS Article PubMed PubMed Central Google Scholar 

  6. 6.

    Reck M, Rodríguez-Abreu D, Robinson AG et al (2016) Pembrolizumab vs chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833. https://doi.org/10.1056/NEJMoa1606774

    CAS Article PubMed Google Scholar 

  7. 7.

    Hammers HJ, Plimack ER, Infante JR et al (2017) Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol Off J Am Soc Clin Oncol 35(34):3851–3858. https://doi.org/10.1200/JCO.2016.72.1985

    CAS Article Google Scholar 

  8. 8.

    Hellmann MD, Ciuleanu T-E, Pluzanski A et al (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. https://doi.org/10.1056/NEJMoa1801946

    Article PubMed PubMed Central Google Scholar 

  9. 9.

    Michot JM, Bigenwald C, Champiat S et al (1990) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer Oxf Engl 2016(54):139–148. https://doi.org/10.1016/j.ejca.2015.11.016

    CAS Article Google Scholar 

  10. 10.

    Boutros C, Tarhini A, Routier E et al (2016) Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 13(8):473. https://doi.org/10.1038/nrclinonc.2016.58

    CAS Article PubMed PubMed Central Google Scholar 

  11. 11.

    Hallmarks of Cancer: The next generation: cell. https://www.cell.com/cell/fulltext/S0092-8674(11)00127-9?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867411001279%3Fshowall%3Dtrue. Published September 3, 2017. Accessed 3 Sep 2017.

  12. 12.

    Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899. https://doi.org/10.1016/j.cell.2010.01.025

    CAS Article PubMed PubMed Central Google Scholar 

  13. 13.

    Bui JD, Schreiber RD (2007) Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Curr Opin Immunol 19(2):203–208. https://doi.org/10.1016/j.coi.2007.02.001

    CAS Article PubMed Google Scholar 

  14. 14.

    Galdiero MR, Bonavita E, Barajon I, Garlanda C, Mantovani A, Jaillon S (2013) Tumor associated macrophages and neutrophils in cancer. Immunobiology 218(11):1402–1410. https://doi.org/10.1016/j.imbio.2013.06.003

    CAS Article PubMed Google Scholar 

  15. 15.

    Templeton AJ, McNamara MG, Eruga B et al (2014) Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. JNCI J Natl Cancer Inst 106(6):dju124. https://doi.org/10.1093/jnci/dju124

    CAS Article PubMed Google Scholar 

  16. 16.

    Marchioni M, Primiceri G, Ingrosso M et al (2016) The clinical use of the neutrophil to lymphocyte ratio (NLR) in urothelial cancer: a systematic review. Clin Genitourin Cancer 14(6):473–484. https://doi.org/10.1016/j.clgc.2016.04.008

    Article PubMed Google Scholar 

  17. 17.

    Bar-Ad V, Palmer J, Li L et al (2016) Neutrophil to lymphocyte ratio associated with prognosis of lung cancer. Clin Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mex. https://doi.org/10.1007/s12094-016-1593-y

    Article Google Scholar 

  18. 18.

    Vano Y-A, Oudard S, By M-A et al (2018) Optimal cut-off for neutrophil-to-lymphocyte ratio: fact or fantasy? A prospective cohort study in metastatic cancer patients. PLoS ONE. https://doi.org/10.1371/journal.pone.0195042

    Article PubMed PubMed Central Google Scholar 

  19. 19.

    Lalani A-KA, Xie W, Martini DJ et al (2018) Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunother Cancer 6(1):5. https://doi.org/10.1186/s40425-018-0315-0

    Article PubMed PubMed Central Google Scholar 

  20. 20.

    Khunger M, Patil PD, Khunger A et al (2018) Post-treatment changes in hematological parameters predict response to nivolumab monotherapy in non-small cell lung cancer patients. PLoS ONE. https://doi.org/10.1371/journal.pone.0197743

    Article PubMed PubMed Central Google Scholar 

  21. 21.

    Ameratunga M, Chénard-Poirier M, Moreno Candilejo I et al (1990) Neutrophil-lymphocyte ratio kinetics in patients with advanced solid tumours on phase I trials of PD-1/PD-L1 inhibitors. Eur J Cancer Oxf Engl 2018(89):56–63. https://doi.org/10.1016/j.ejca.2017.11.012

    CAS Article Google Scholar 

  22. 22.

    Bagley SJ, Kothari S, Aggarwal C et al (2017) Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer Amst Neth 106:1–7. https://doi.org/10.1016/j.lungcan.2017.01.013

    Article Google Scholar 

  23. 23.

    Kiriu T, Yamamoto M, Nagano T et al (2018) The time-series behavior of neutrophil-to-lymphocyte ratio is useful as a predictive marker in non-small cell lung cancer. PLoS ONE. https://doi.org/10.1371/journal.pone.0193018

    Article PubMed PubMed Central Google Scholar 

  24. 24.

    Diem S, Schmid S, Krapf M et al (2017) Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer Amst Neth 111:176–181. https://doi.org/10.1016/j.lungcan.2017.07.024

    Article Google Scholar 

  25. 25.

    Nakaya A, Kurata T, Yoshioka H et al (February 2018) Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab. Int J Clin Oncol. https://doi.org/10.1007/s10147-018-1250-2

    Article PubMed PubMed Central Google Scholar 

  26. 26.

    Shiroyama T, Suzuki H, Tamiya M et al (2018) Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non-small cell lung cancer. Cancer Med 7(1):13–20. https://doi.org/10.1002/cam4.1234

    CAS Article PubMed Google Scholar 

  27. 27.

    Becht E, Giraldo NA, Lacroix L et al (2016) Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol 17(1):218. https://doi.org/10.1186/s13059-016-1070-5

    CAS Article PubMed PubMed Central Google Scholar 

  28. 28.

    Yarchoan M, Hopkins A, Jaffee EM (2017) Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 377(25):2500–2501. https://doi.org/10.1056/NEJMc1713444

    Article PubMed PubMed Central Google Scholar 

  29. 29.

    Seymour L, Bogaerts J, Perrone A et al (2017) iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 18(3):e143–e152. https://doi.org/10.1016/S1470-2045(17)30074-8

    Article PubMed PubMed Central Google Scholar 

  30. 30.

    T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.—PubMed—NCBI. https://www.ncbi.nlm.nih.gov/pubmed/?term=T-cell+invigoration+to+tumour+burden+ratio+associated+with+anti-+PD-1+response. Accessed 22 June 2019.

  31. 31.

    Chiou VL, Burotto M (2015) Pseudoprogression and immune-related response in solid tumors. J Clin Oncol Off J Am Soc Clin Oncol 33(31):3541–3543. https://doi.org/10.1200/JCO.2015.61.6870

    CAS Article Google Scholar 

  32. 32.

    Escudier B, Motzer RJ, Sharma P et al (2017) Treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in CheckMate 025. Eur Urol 72(3):368–376. https://doi.org/10.1016/j.eururo.2017.03.037

    CAS Article PubMed Google Scholar 

  33. 33.

    Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30(7):1073–1081. https://doi.org/10.1093/carcin/bgp127

    CAS Article PubMed Google Scholar 

  34. 34.

    Kargl J, Busch SE, Yang GHY et al (2017) Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat Commun 8(1):1–11. https://doi.org/10.1038/ncomms14381

    CAS Article Google Scholar 

  35. 35.

    Dirican N, Karakaya YA, Gunes S, Daloglu FT, Dirican A (2017) Association of intra-tumoral tumour-infiltrating lymphocytes and neutrophil-to-lymphocyte ratio is an independent prognostic factor in non-small cell lung cancer. Clin Respir J 11(6):789–796. https://doi.org/10.1111/crj.12417

    CAS Article PubMed Google Scholar 

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Funding

The investigators AS, YA had access to the raw data. All authors approved the final manuscript. The corresponding author had full access to all the data, and takes final responsibility for the manuscript submitted for publication.

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Contributions

AS, RE, SO and YAV were involved in the study design and concept. AS, YAV, EF, VF, DB, JT, PB, CT were involved in the identification and selection of patients. AS and RE were involved in the statistical analysis. LF was involved in the radiographic evaluation. All authors were involved in the review and editing of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Y. A. Vano.

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Conflict of interest

YV, SO, CT and PB: consulting fees from BMS, MSD, Pfizer, Novartis, Ipsen, Roche, Astellas, Sanofi, Janssen. DB: funding to institution for clinical research, advisory role or travel accommodation: Bristol-Meyers Squibb, Pfizer, Roche, Ipsen, MSD, Astra-Zeneca. No potential conflicts of interest were disclosed by the other authors.

Ethics approval and consent to participate

The study was approved by the local institutional review board and was conducted with Good Clinical Practice Guidelines and the Declaration of Helsinki. All patients gave their oral consent. CNIL declaration No 2215794 v 0

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Simonaggio, A., Elaidi, R., Fournier, L. et al. Variation in neutrophil to lymphocyte ratio (NLR) as predictor of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (mNSCLC) patients treated with nivolumab. Cancer Immunol Immunother (2020). https://doi.org/10.1007/s00262-020-02637-1


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