Table Info

Table 1.

Patient characteristics

Variable	Unadjusted population					PSM-adjusted population
Variable	All patients (N = 258)	No-BZD cohort (N = 150)	BZD cohort (N = 108)	P value	SMD	All patients (N = 216)	No-BZD cohort (N = 108)	BZD cohort (N = 108)	P value	SMD
Age
- Mean (SD), years	70.0 (8.4)	70.0 (7.9)	69.5 (9.0)	0.332	-	70.0 (8.43)	70.0 (7.77)	69.5 (9.04)	0.457	-
- ≥ 70 years	136 (52.7%)	82 (54.7%)	54 (50.0%)	0.459	0.046	111 (51.4%)	57 (52.8%)	54 (50.0%)	0.685	0.027
Sex
- Female	78 (30.2%)	40 (26.7%)	38 (35.2%)	0.207	0.093	74 (34.3%)	36 (33.3%)	38 (35.2%)	0.776	0.018
- Male	180 (69.8%)	110 (73.3%)	70 (64.8%)	0.207	0.093	142 (65.7%)	72 (66.7%)	70 (64.8%)	0.776	0.018
ECOG PS
- 0 or 1	208 (80.6%)	120 (80.0%)	88 (81.5%)	0.766	0.014	175 (81.0%)	87 (80.6%)	88 (81.5%)	0.863	0.009
- 2	50 (19.4%)	30 (20.0%)	20 (18.5%)	0.766	0.014	41 (19.0%)	21 (19.4%)	20 (18.5%)	0.863	0.009
Histologic subtype
- Nonsquamous	202 (78.3%)	118 (78.7%)	84 (77.8%)	0.864	< 0.001	167 (77.3%)	83 (76.9%)	84 (77.8%)	0.872	0.009
- Squamous	56 (21.7%)	32 (21.3%)	24 (22.2%)	0.864	< 0.001	49 (22.7%)	25 (23.1%)	24 (22.2%)	0.872	0.009
No. of metastatic sites
- ≤ 2	138 (53.5%)	79 (52.7%)	59 (54.6%)	0.755	0.019	120 (55.6%)	61 (56.5%)	59 (54.6%)	0.785	0.067
- > 2	120 (46.5%)	71 (47.3%)	49 (45.4%)	0.755	0.019	96 (44.4%)	47 (43.5%)	49 (45.4%)	0.785	0.067
Bone metastasis	53 (20.5%)	30 (19.1%)	23 (21.3%)	0.799	< 0.001	44 (20.4%)	21 (19.4%)	23 (21.3%)	0.737	0.055
Brain metastasis	58 (22.5%)	30 (20.0%)	28 (25.9%)	0.261	< 0.001	55 (25.5%)	27 (25.0%)	28 (25.9%)	0.877	0.059
Liver metastasis	28 (10.9%)	19 (12.7%)	9 (8.3%)	0.270	0.043	20 (9.3%)	11 (10.2%)	9 (8.3%)	0.641	0.039
PD-L1 TPS
- < 1%	80 (31.0%)	45 (30.0%)	35 (32.4%)	0.066	0.326	71 (32.9%)	36 (33.3%)	35 (32.4%)	0.663	0.083
- ≥ 1% and ≤ 49%	22 (8.5%)	8 (5.3%)	14 (13.0%)			22 (10.2%)	8 (7.4%)	14 (13.0%)
- ≥ 50%	156 (60.5%)	97 (64.7%)	59 (54.6%)			123 (56.9%)	64 (59.3%)	59 (54.6%)
BMI
- Mean (SD), kg/m²	25.1 (4.80)	24.8 (5.0)	25.6 (4.5)	0.635	< 0.001	25.9 (4.87)	26.0 (5.15)	25.6 (4.55)	0.233	-
- ≥ 25	130 (50.4%)	73 (48.7%)	57 (52.8%)	0.515	< 0.001	114 (52.8%)	57 (52.8%)	57 (52.8%)	0.999	< 0.001
Smoking habits
- Never	23 (8.9%)	14 (9.3%)	9 (8.3%)	0.781	< 0.001	20 (9.3%)	11 (10.2%)	9 (8.3%)	0.641	< 0.001
- Ever	235 (91.1%)	136 (90.7%)	99 (91.7%)	0.781	< 0.001	196 (90.7%)	97 (89.8%)	99 (91.7%)	0.641	< 0.001
Previous thoracic RT	35 (13.6%)	16 (10.7%)	19 (17.6%)	0.109	< 0.001	28 (13.0%)	9 (8.3%)	19 (17.6%)	0.043	< 0.001
LIPI score
- 0	100 (38.8%)	60 (40.0%)	40 (37.0%)	0.740	< 0.001	84 (38.9%)	44 (40.7%)	40 (37.0%)	0.742	< 0.001
- 1	88 (34.1%)	52 (34.7%)	36 (33.3%)			68 (31.5%)	32 (29.6%)	36 (33.3%)
- 2	70 (27.1%)	38 (25.3%)	32 (29.7%)			64 (29.6%)	32 (29.6%)	32 (29.6%)
First-line therapy
- Only pembrolizumab	156 (60.5%)	96 (64.0%)	60 (55.6%)	0.377	< 0.001	124 (57.4%)	64 (59.3%)	60 (55.6%)	0.596	< 0.001
- Pemetrexed-based	84 (32.6%)	45 (30.0%)	39 (36.1%)			75 (34.7%)	36 (33.3%)	39 (36.1%)
- Paclitaxel-based	18 (7.0%)	9 (6.0%)	9 (8.3%)			17 (7.9%)	8 (7.4%)	9 (8.3%)
Corticosteroids^a	103 (39.9%)	54 (36.0%)	49 (45.4%)	0.129	< 0.001	94 (43.5%)	45 (41.7%)	49 (45.4%)	0.585	< 0.001
APAP^b	101 (39.1%)	67 (44.7%)	34 (31.5%)	0.032	0.131	62 (28.7%)	28 (25.9%)	34 (31.5%)	0.369	< 0.001
Systemic antibiotics^c	58 (22.5%)	38 (25.3%)	20 (18.5%)	0.196	0.068	40 (18.5%)	20 (18.5%)	20 (18.5%)	0.999	< 0.001
PPI^d	88 (34.1%)	59 (39.3%)	29 (26.9%)	0.036	0.124	58 (26.9%)	29 (26.9%)	29 (26.9%)	0.999	< 0.001
Specific BZD intake
- N-substituted^e	57 (22.1%)	-	57 (52.8%)	-	-	57 (26.4%)	-	57 (52.8%)	-	-
- N-unsubstituted^f	51 (19.7%)	-	51 (47.2%)	-	-	51 (23.6%)	-	51 (47.2%)	-	-

PSM: propensity score matching; BZD: benzodiazepine; SMD: standardized mean difference; SD: standard deviation; ECOG PS: Eastern Cooperative Oncology Group Performance Status; PD-L1 TPS: programmed cell death ligand-1 tumor proportion score; BMI: body mass index; RT: radiotherapy; LIPI: lung immune prognostic index; APAP: acetaminophen; PPI: proton pump inhibitors. ^a Corticosteroids refer to the use of prednisone or an equivalent drug at a dose of at least 10 mg per day for at least 5 days within the 30 days before the start of treatment, excluding premedication for chemotherapy; ^b APAP refers to the use of at least 1,000 mg per day for more than 24 h during the 30 days before the start of treatment; ^c systemic antibiotics and ^d PPI refer to the use of these medications in the 30 days before the start of treatment; ^e N-substituted denoted intake of alprazolam, diazepam, bromazepam, or triazolam; ^f N-unsubstituted denoted intake of lorazepam, clonazepam, delorazepam, or lormetazepam

Supplementary materials

The supplementary material for this article is available at: https://www.explorationpub.com/uploads/Article/file/1002287_sup_1.pdf.

Declarations

Author contributions

F Nelli, AF, AV: Data curation. DG: Formal analysis. F Nelli, AF, AV, AR, F Natoni, GP, DR, MGC, CS: Investigation. F Nelli, DG, EMR: Methodology. F Nelli, EMR: Supervision. F Nelli, AF, EMR: Writing—original draft, Writing—review & editing. All authors worked on and approved the final manuscript.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the referring Ethics Committee “Comitato Etico Lazio 1” (Oss-R-281; protocol number: 855/CE Lazio1; date of approval September 27, 2022).

Consent to participate

Written consent was obtained from all patients involved in the study, granting permission for the intended treatment and the use of anonymized clinical information for research purposes.

Consent to publication

Non applicable.

Availability of data and materials

The raw data supporting the conclusions of this manuscript will be made available by the authors to any qualified researcher on reasonable request.

Funding

Non applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Hanahan D, Monje M. Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell. 2023;41:573–80. [DOI] [PubMed] [PMC]

Li TJ, Jiang J, Tang YL, Liang XH. Insights into the leveraging of GABAergic signaling in cancer therapy. Cancer Med. 2023;12:14498–510. [DOI] [PubMed] [PMC]

Yang Y, Ren L, Li W, Zhang Y, Zhang S, Ge B, et al. GABAergic signaling as a potential therapeutic target in cancers. Biomed Pharmacother. 2023;161:114410. [DOI] [PubMed]

Bhandage AK, Barragan A. GABAergic signaling by cells of the immune system: more the rule than the exception. Cell Mol Life Sci. 2021;78:5667–79. [DOI] [PubMed] [PMC]

Zhang B, Vogelzang A, Miyajima M, Sugiura Y, Wu Y, Chamoto K, et al. B cell-derived GABA elicits IL-10⁺macrophages to limit anti-tumour immunity. Nature. 2021;599:471–6. [DOI] [PubMed] [PMC]

Huang D, Wang Y, Thompson JW, Yin T, Alexander PB, Qin D, et al. Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression. Nat Cell Biol. 2022;24:230–41. [DOI] [PubMed] [PMC]

Möhler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002;300:2–8. [DOI] [PubMed]

Nausea and Vomiting Related to Cancer Treatment (PDQ^®)–Health Professional Version [Internet]. [Cited 2024 Sep 30]. Available from: https://www.cancer.gov/about-cancer/treatment/side-effects/nausea/nausea-hp-pdq

Yasuda S, Sugano K, Matsuda Y, Kako J, Takagi Y, Watanabe H, et al. Systematic review and meta-analysis of the efficacy of benzodiazepines for dyspnea in patients with cancer. Jpn J Clin Oncol. 2023;53:327–34. [DOI] [PubMed] [PMC]

10.

Olsen RW. GABA_Areceptor: Positive and negative allosteric modulators. Neuropharmacology. 2018;136:10–22. [DOI] [PubMed] [PMC]

11.

Betlazar C, Middleton RJ, Banati R, Liu GJ. The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes. Cells. 2020;9:512. [DOI] [PubMed] [PMC]

12.

Sparrow EL, James S, Hussain K, Beers SA, Cragg MS, Bogdanov YD. Activation of GABA(A) receptors inhibits T cell proliferation. PLoS One. 2021;16:e0251632. [DOI] [PubMed] [PMC]

13.

Falcón CR, Hurst NF, Vivinetto AL, López PHH, Zurita A, Gatti G, et al. Diazepam Impairs Innate and Adaptive Immune Responses and Ameliorates Experimental Autoimmune Encephalomyelitis. Front Immunol. 2021;12:682612. [DOI] [PubMed] [PMC]

14.

Obiora E, Hubbard R, Sanders RD, Myles PR. The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort. Thorax. 2013;68:163–70. [DOI] [PubMed]

15.

Oh TK, Park HY, Han JY, Song IA. Prior benzodiazepine use and mortality among adult patients with sepsis: A retrospective population-based cohort study in South Korea. Int J Clin Pract. 2021;75:e14517. [DOI] [PubMed]

16.

Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2022;185:576. [DOI] [PubMed]

17.

Lei Y, Li X, Huang Q, Zheng X, Liu M. Progress and Challenges of Predictive Biomarkers for Immune Checkpoint Blockade. Front Oncol. 2021;11:617335. [DOI] [PubMed] [PMC]

18.

Cornwell AC, Tisdale AA, Venkat S, Maraszek KE, Alahmari AA, George A, et al. Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer. Clin Cancer Res. 2023;29:3793–812. [DOI] [PubMed] [PMC]

19.

Registri farmaci sottoposti a monitoraggio [Internet]. Agenzia Italiana del Farmaco; c2024 [cited 2024 Sep 30]. Available from: https://www.aifa.gov.it/registri-farmaci-sottoposti-a-monitoraggio

20.

PD-L1 IHC 22C3 pharmDx [Internet]. Agilent Technologies, Inc; c2024 [cited 2024 Sep 30]. Available from: https://www.agilent.com/en/product/pharmdx/pd-l1-ihc-22c3-pharmdx

21.

Mezquita L, Auclin E, Ferrara R, Charrier M, Remon J, Planchard D, et al. Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non-Small Cell Lung Cancer. JAMA Oncol. 2018;4:351–7. [DOI] [PubMed] [PMC]

22.

Benzodiazepine derivatives [Internet]. PharmGKB; c2024 [cited 2024 Sep 30]. Available from: https://www.pharmgkb.org/chemical/PA10402

23.

Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al.; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18:e143–52. [DOI] [PubMed] [PMC]

24.

Wang X, Ji X. Sample Size Estimation in Clinical Research: From Randomized Controlled Trials to Observational Studies. Chest. 2020;158:S12–20. [DOI] [PubMed]

25.

Zhang Z, Kim HJ, Lonjon G, Zhu Y; written on behalf of AME Big-Data Clinical Trial Collaborative Group. Balance diagnostics after propensity score matching. Ann Transl Med. 2019;7:16. [DOI] [PubMed] [PMC]

26.

The R project for statistical computing [Internet]. The R Foundation; c2024 [cited 2024 Sep 30]. Available from: https://www.r-project.org

27.

Sherman RE, Anderson SA, Dal Pan GJ, Gray GW, Gross T, Hunter NL, et al. Real-World Evidence - What Is It and What Can It Tell Us? N Engl J Med. 2016;375:2293–7. [DOI] [PubMed]

28.

Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Stürmer T. Variable selection for propensity score models. Am J Epidemiol. 2006;163:1149–56. [DOI] [PubMed] [PMC]

29.

Pizzutilo EG, Romanò R, Roazzi L, Agostara AG, Oresti S, Zeppellini A, et al. Immune Checkpoint Inhibitors and the Exposome: Host-Extrinsic Factors Determine Response, Survival, and Toxicity. Cancer Res. 2023;83:2283–96. [DOI] [PubMed] [PMC]

30.

Chen J, Chen S, Luo H, Long S, Yang X, He W, et al. The negative effect of concomitant medications on immunotherapy in non-small cell lung cancer: An umbrella review. Int Immunopharmacol. 2023;124:110919. [DOI] [PubMed]

31.

Li H, Zhang L, Yang F, Zhao R, Li X, Li H. Impact of concomitant medications on the efficacy of immune checkpoint inhibitors: an umbrella review. Front Immunol. 2023;14:1218386. [DOI] [PubMed] [PMC]

32.

Oh MS, Guzner A, Wainwright DA, Mohindra NA, Chae YK, Behdad A, et al. The Impact of Beta Blockers on Survival Outcomes in Patients With Non-small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors. Clin Lung Cancer. 2021;22:e57–62. [DOI] [PubMed] [PMC]

33.

Montégut L, Derosa L, Messaoudene M, Chen H, Lambertucci F, Routy B, et al. Benzodiazepines compromise the outcome of cancer immunotherapy. Oncoimmunology. 2024;13:2413719. [DOI] [PubMed] [PMC]

34.

Wiley SZ, Sriram K, Salmerón C, Insel PA. GPR68: An Emerging Drug Target in Cancer. Int J Mol Sci. 2019;20:559. [DOI] [PubMed] [PMC]

35.

O’Hayre M, Degese MS, Gutkind JS. Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr Opin Cell Biol. 2014;27:126–35. [DOI] [PubMed] [PMC]

36.

Lynch JR, Wang JY. G Protein-Coupled Receptor Signaling in Stem Cells and Cancer. Int J Mol Sci. 2016;17:707. [DOI] [PubMed] [PMC]

37.

Xu J, Mathur J, Vessières E, Hammack S, Nonomura K, Favre J, et al. GPR68 Senses Flow and Is Essential for Vascular Physiology. Cell. 2018;173:762–75.e16. [DOI] [PubMed] [PMC]

38.

Cao L, Li W, Yang X, Zhang W, Li M, Zhang H, et al. Inhibition of host Ogr1 enhances effector CD8⁺T-cell function by modulating acidic microenvironment. Cancer Gene Ther. 2021;28:1213–24. [DOI] [PubMed] [PMC]

39.

Ye S, Zhu Y, Zhong D, Song X, Li J, Xiao F, et al. G protein-coupled receptor GPR68 inhibits lymphocyte infiltration and contributes to gender-dependent melanoma growth. Front Oncol. 2023;13:1202750. [DOI] [PubMed] [PMC]

40.

Naqash AR, McCallen JD, Mi E, Iivanainen S, Marie MA, Gramenitskaya D, et al. Increased interleukin-6/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non-small cell lung cancer. J Immunother Cancer. 2023;11:e007310. [DOI] [PubMed] [PMC]

41.

Huseni MA, Wang L, Klementowicz JE, Yuen K, Breart B, Orr C, et al. CD8⁺T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy. Cell Rep Med. 2023;4:100878. [DOI] [PubMed] [PMC]

42.

Hailemichael Y, Johnson DH, Abdel-Wahab N, Foo WC, Bentebibel SE, Daher M, et al. Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity. Cancer Cell. 2022;40:509–23.e6. [DOI] [PubMed] [PMC]

43.

Poth KJ, Guminski AD, Thomas GP, Leo PJ, Jabbar IA, Saunders NA. Cisplatin treatment induces a transient increase in tumorigenic potential associated with high interleukin-6 expression in head and neck squamous cell carcinoma. Mol Cancer Ther. 2010;9:2430–9. [DOI] [PubMed]

44.

Kiss E, Abdelwahab EHMM, Steib A, Papp E, Torok Z, Jakab L, et al. Cisplatin treatment induced interleukin 6 and 8 production alters lung adenocarcinoma cell migration in an oncogenic mutation dependent manner. Respir Res. 2020;21:120. [DOI] [PubMed] [PMC]

45.

Cao P, Wang Y. Effect of pemetrexed on the efficacy, toxic reaction, and survival rate of patients with EGFR-TKI resistant moderate and advanced lung cancer. Am J Transl Res. 2021;13:7857–65. [PubMed] [PMC]

46.

Pusztai L, Mendoza TR, Reuben JM, Martinez MM, Willey JS, Lara J, et al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine. 2004;25:94–102. [DOI] [PubMed]