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Cited by 275Cancer Immunotherapy and BiomarkersFerroptosis and cancer prognosisCOVID-19 and healthcare impacts

The DOI matches its Crossref record; 57 of the 58 references it cites were found in a registry or an index.

Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice

Open access
Cortellini, Alessio, Tucci, Marco, Adamo, Vincenzo, Stucci, Luigia Stefania, Russo, Alessandro, Tanda, Enrica Teresa, Spagnolo, Francesco, Rastelli, Francesca, Bisonni, Renato, Santini, Daniele, Russano, Marco, Anesi, Cecilia, Giusti, Raffaele, Filetti, Marco, Marchetti, Paolo, Botticelli, Andrea, Gelibter, Alain, Occhipinti, Mario Alberto, Marconcini, Riccardo, Vitale, Maria Giuseppa, Nicolardi, Linda, Chiari, Rita, Bareggi, Claudia, Nigro, Olga, Tuzi, Alessandro, De Tursi, Michele, Petragnani, Nicola, Pala, Laura, Bracarda, Sergio, Macrini, Serena, Inno, Alessandro, Zoratto, Federica, Veltri, Enzo, Di Cocco, Barbara, Mallardo, Domenico, Vitale, Maria Grazia, Pinato, David James, Porzio, Giampiero, Ficorella, Corrado, Ascierto, Paolo Antonio·2020·Journal for ImmunoTherapy of Cancer
DOI 10.1136/jitc-2020-001361PMC PMC7646355
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Abstract

Background: Concomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors. Methods: We conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, β-blockers, metformin and other oral antidiabetics, opioids. Results: From June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death. Conclusion: We confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.

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Figures

Figure 1 Kaplan-Meier survival estimates. Progression-free survival; (A) Steroids. No: 13.5 months (95% CI 10.8 to 15.4; 472 events); non-cancer indications: 10.0 months (95% CI 7.2 to 18.3; 36 events); cancer indications: 4.9 months (95% CI 3.6 to 6.5; 247 events); (B) Systemic antibiotics. No: 10.5 months (95% CI 9.2 to 11.9, 622 events); prophylaxis: 2.8 months (95% CI 2.1 to 6.7, 25 events); infections: 10.9 months (95% CI 6.4 to 37.5, 34 events); (C) Gastric acid suppressants. No: 13.5 months (95% CI 10.5 to 18.2, 288 events); gastritis/GERD: 11.2 months (95% CI 7.9 to 17.3, 60 events); prophylaxis: 8.2 months (95% CI 6.9 to 9.9, 333 events). Overall survival; (D) Steroids. No: 30.8 months (95% CI 24.4 to 36.3; 432 censored); non-cancer indications: 44.6 months (95% CI 12.0 to 44.6; 30 censored); cancer indications: 7.8 months (95% CI 5.4 to 9.8; 58 censored); (E) Systemic antibiotics. No: 22.8 months (95% CI 18.9 to 27.4, 494 censored); prophylaxis: 4.9 months (95% CI 3.5 to 11.0, 8 censored); infections: 15.2 months (95% CI 9.8 to 18.1, 18 censored); (F) Gastric acid suppressants. No: 29.4 months (95% CI 22.8 to 39.8, 266 censored); gastritis/GERD: 23.2 months (95% CI 13.4 to 30.8, 59 censored); prophylaxis: 14.8 months (95% CI 12.3 to 52.3, 195 censored). GERD, gastroesophageal reflux disease.
Figure 1 Kaplan-Meier survival estimates. Progression-free survival; (A) Steroids. No: 13.5 months (95% CI 10.8 to 15.4; 472 events); non-cancer indications: 10.0 months (95% CI 7.2 to 18.3; 36 events); cancer indications: 4.9 months (95% CI 3.6 to 6.5; 247 events); (B) Systemic antibiotics. No: 10.5 months (95% CI 9.2 to 11.9, 622 events); prophylaxis: 2.8 months (95% CI 2.1 to 6.7, 25 events); infections: 10.9 months (95% CI 6.4 to 37.5, 34 events); (C) Gastric acid suppressants. No: 13.5 months (95% CI 10.5 to 18.2, 288 events); gastritis/GERD: 11.2 months (95% CI 7.9 to 17.3, 60 events); prophylaxis: 8.2 months (95% CI 6.9 to 9.9, 333 events). Overall survival; (D) Steroids. No: 30.8 months (95% CI 24.4 to 36.3; 432 censored); non-cancer indications: 44.6 months (95% CI 12.0 to 44.6; 30 censored); cancer indications: 7.8 months (95% CI 5.4 to 9.8; 58 censored); (E) Systemic antibiotics. No: 22.8 months (95% CI 18.9 to 27.4, 494 censored); prophylaxis: 4.9 months (95% CI 3.5 to 11.0, 8 censored); infections: 15.2 months (95% CI 9.8 to 18.1, 18 censored); (F) Gastric acid suppressants. No: 29.4 months (95% CI 22.8 to 39.8, 266 censored); gastritis/GERD: 23.2 months (95% CI 13.4 to 30.8, 59 censored); prophylaxis: 14.8 months (95% CI 12.3 to 52.3, 195 censored). GERD, gastroesophageal reflux disease.CC BY-NC · PubMed Central
Figure 2 Kaplan-Meier survival estimates. Progression-free survival; (A) Gastric acid suppressants. No: 13.5 months (95% CI 10.5 to 18.2, 288 events); H2 antagonists: 10.3 months (95% CI 3.8 to 13.9; 40 events); proton pump inhibitors: 8.4 months (95% CI 7.5 to 10.0; 353 events); (B) Anticoagulants. No: 10.9 months (95% CI 9.9 to 13.0, 573 events); yes: 6.3 months (95% CI 3.9 to 9.2, 108 events); (C) Opioids. No: 11.0 months (95% CI 10.0 to 13.5, 564 events); yes: 3.8 months (95% CI 2.9 to 6.4, 56 events). Overall survival (D) Gastric acid suppressants. No: 29.4 months (95% CI 22.8 to 39.8, 266 censored); H2 antagonists: 21.1 months (95% CI 6.1 to 25.0; 28 censored); proton pump inhibitors: 15.4 months (95% CI 12.5 to 18.1; 226 censored); (E) Anticoagulants. No: 23.9 months (95% CI 18.9 to 28.6, 460 censored); yes: 12.4 months (95% CI 7.8 to 15.1; 60 censored); (F) Opioids No: 23.2 months (95% CI 18.9 to 28.8, 452 censored); yes: 8.6 months (95% CI 4.7 to 12.7; 22 censored).
Figure 2 Kaplan-Meier survival estimates. Progression-free survival; (A) Gastric acid suppressants. No: 13.5 months (95% CI 10.5 to 18.2, 288 events); H2 antagonists: 10.3 months (95% CI 3.8 to 13.9; 40 events); proton pump inhibitors: 8.4 months (95% CI 7.5 to 10.0; 353 events); (B) Anticoagulants. No: 10.9 months (95% CI 9.9 to 13.0, 573 events); yes: 6.3 months (95% CI 3.9 to 9.2, 108 events); (C) Opioids. No: 11.0 months (95% CI 10.0 to 13.5, 564 events); yes: 3.8 months (95% CI 2.9 to 6.4, 56 events). Overall survival (D) Gastric acid suppressants. No: 29.4 months (95% CI 22.8 to 39.8, 266 censored); H2 antagonists: 21.1 months (95% CI 6.1 to 25.0; 28 censored); proton pump inhibitors: 15.4 months (95% CI 12.5 to 18.1; 226 censored); (E) Anticoagulants. No: 23.9 months (95% CI 18.9 to 28.6, 460 censored); yes: 12.4 months (95% CI 7.8 to 15.1; 60 censored); (F) Opioids No: 23.2 months (95% CI 18.9 to 28.8, 452 censored); yes: 8.6 months (95% CI 4.7 to 12.7; 22 censored).CC BY-NC · PubMed Central

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Research works printed but not linked: 2

  1. Woolley KK . How variables uncorrelated with the dependent variable can actually make excellent predictors: the important suppressor variable case. Southwest educational research association annual meeting proceedings, 1997. Available: https://eric.ed.gov/?id=ED407420 [Accessed 10 Jun 2020].
  2. Thompson, 1997, Examples of easily Explainable suppressor variables in multiple regression research, Multi Linear Regres Viewpoints, 24, 11

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Metadata

Authors
Cortellini, A., Tucci, M., Adamo, V., Stucci, L. S., Russo, A., Tanda, E. T., Spagnolo, F., Rastelli, F., Bisonni, R., Santini, D., Russano, M., Anesi, C., Giusti, R., Filetti, M., Marchetti, P., Botticelli, A., Gelibter, A., Occhipinti, M. A., Marconcini, R., Vitale, M. G., Nicolardi, L., Chiari, R., Bareggi, C., Nigro, O., Tuzi, A., De Tursi, M., Petragnani, N., Pala, L., Bracarda, S., Macrini, S., Inno, A., Zoratto, F., Veltri, E., Di Cocco, B., Mallardo, D., Vitale, M. G., Pinato, D. J., Porzio, G., Ficorella, C., & Ascierto, P. A.
Affiliations
  • University of L'Aquila (IT)
  • Istituto Tumori Bari (IT)
  • University of Messina (IT)
  • University of Bari Aldo Moro (IT)
  • Ospedale Policlinico San Martino (IT)
  • Medical Oncology, ASUR District Area 4 Fermo, Fermo, Italy
  • Università Campus Bio-Medico (IT)
  • Azienda Ospedaliera Sant'Andrea (IT)
  • Policlinico Umberto I (IT)
  • Sapienza University of Rome (IT)
  • Azienda Ospedaliera Universitaria Pisana (IT)
  • Azienda Ospedaliero-Universitaria di Modena (IT)
  • UOC Oncologia Padova Sud, Azienda ULSS 6 Euganea, Padova, Italy
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
  • Ospedale di Circolo e Fondazione Macchi (IT)
  • Department of Medical, Oral and Biotechnological Sciences, Gabriele d'Annunzio University of Chieti and Pescara, Chieti, Italy
  • University of Chieti-Pescara (IT)
  • European Institute of Oncology (IT)
  • Medical Oncology, Azienda Ospedaliera S. Maria, Terni, Italy
  • Azienda Ospedaliera S.Maria (IT)
  • Ospedale Sacro Cuore Don Calabria (IT)
  • Ospedale Santa Maria Goretti (IT)
  • Medical Oncology, Santa Maria Goretti Hospital, Latina, Italy
  • Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
  • Hammersmith Hospital (GB)
  • Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy
Corresponding author
Cortellini, Alessio
ORCID
Venue
Journal for ImmunoTherapy of Cancer
Publisher
BMJ
Published
2020-11
Volume
8
Issue
2
Pages
e001361
ISSN
2051-1426 (ISSN-L)
DOI
10.1136/jitc-2020-001361
PMC
PMC7646355
OpenAlex
W3097304584
Cited by
275
References
58
Citations by year
2026: 36 · 2025: 46 · 2024: 50 · 2023: 56 · 2022: 50 · 2021: 36 · 2020: 1
FWCI
12.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, cc-by-nc)
Funders
  • Institute for Translational Medicine and Therapeutics
  • Wellcome Trust (PS3416)
  • Cancer Research UK
  • National Institute for Health and Care Research
  • Imperial Experimental Cancer Medicine Centre
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Oncology › COVID-19 and healthcare impacts
Keywords
PD-1/PD-L1 inhibitors, immune checkpoint inhibitors, concomitant medications, drug-drug interactions, corticosteroids, proton pump inhibitors, statins, aspirin, beta-blockers, antibiotics, objective response rate, progression-free survival, overall survival, non-small cell lung cancer, melanoma, renal cell carcinoma, stage IV cancer, immunotherapy safety
MeSH terms
Immune Checkpoint Inhibitors, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Retrospective Studies, Young Adult

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