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Impact of Use of Gastric-Acid Suppressants and Oral Anti-Cancer Agents on Survival Outcomes: a Systematic Review and Meta-Analysis

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Impact of Use of Gastric-Acid Suppressants and Oral Anti-Cancer Agents on Survival Outcomes: a Systematic Review and Meta-Analysis cancers Review Impact of Use of Gastric-Acid Suppressants and Oral Anti-Cancer Agents on Survival Outcomes: A Systematic Review and Meta-Analysis Alice Indini 1 , Fausto Petrelli 2, Gianluca Tomasello 3, Erika Rijavec 1, Antonio Facciorusso 4 , Francesco Grossi 1 and Michele Ghidini 1,* 1 Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; [email protected] (A.I.); [email protected] (E.R.); [email protected] (F.G.) 2 Oncology Unit, ASST Bergamo Ovest, 24047 Treviglio (BG), Italy; [email protected] 3 Oncology Unit, Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20121 Milan, Italy; [email protected] 4 Gastroenterology Unit, Università Degli Studi di Foggia, 71122 Foggia, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-02-5503-2660; Fax: +39-02-5503-2659 Received: 29 March 2020; Accepted: 14 April 2020; Published: 18 April 2020 Abstract: We performed a systematic review and meta-analysis to evaluate the role of gastric acid suppressant use on outcomes of tyrosine kinase inhibitors (TKIs) and oral chemotherapy. We identified all research evaluating the effect of GAS (gastric acid suppressants) use on patients receiving oral chemotherapy or TKIs for solid tumors. The pooled hazard ratios (HRs) and 95% confidence interval (95%CI) for overall survival (OS) and progression-free survival (PFS) were calculated with a fixed-effects or a random effects model. The study population included n = 16 retrospective studies and 372,418 patients. The series concerned gastrointestinal tract tumors (n = 5 studies), renal cell carcinomas (RCC, n = 3 studies), non-small cell lung cancers (NSCLC, n = 5 studies), and soft tissue sarcomas or mixed histologies solid tumors in n = 3 studies. The pooled HRs for OS and PFS were 1.31 (95%CI: 1.20–1.43; p < 0.01) and 1.3 (95%CI 1.07–1.57; p < 0.01) for GAS and no GAS users, respectively. Only studies of EGFR (epidermal growth factor receptor) mutated NSCLC patients receiving TKIs and those with colorectal cancer receiving oral chemotherapy showed a significant correlation between GAS and poor survival. Our study supports the evidence of a possible negative impact of concomitant GAS therapy on survival outcomes of patients receiving oral anti-cancer drugs. Keywords: gastric acid suppressant; chemotherapy; tyrosine kinase inhibitors; proton pump inhibitors 1. Introduction Oral chemotherapy has historically been part of therapeutic regimens for the treatment of cancer [1–3]. Over the last years, new oral anti-cancer agents acting as multi-tyrosine kinase inhibitors (TKIs) have dramatically changed patient prognosis and thereby have become standard treatments for several types of tumors [4–9]. TKIs targeting the epidermal growth factor receptor (EGFR) (e.g., gefitinib, erlotinib, afatinib, osimertinib) are currently approved for treatment of EGFR mutant non-small cell lung carcinoma (NSCLC), and multi-targeted TKIs (e.g., sunitinib, axitinib, sorafenib, pazopanib) for the treatment of renal cell carcinoma (RCC). Moreover, several new TKIs are currently being tested in clinical trials in several types of solid tumors. The use of oral drugs has a positive impact on patient quality of life for the convenience of self-administration; however, there is a significant risk of drug–drug interactions. The diffusion of these drugs often parallels that of gastric acid suppressants (GAS), such as proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA). GAS commonly represent part of the complex drug regimen of an average oncologic patient, with an Cancers 2020, 12, 998; doi:10.3390/cancers12040998 www.mdpi.com/journal/cancers Cancers 2020, 12, x 2 of 15 Cancersantagonists2020, 12, 998 (H2RA). GAS commonly represent part of the complex drug regimen of an 2average of 14 oncologic patient, with an estimated rate of 50% inappropriate PPIs prescriptions, both in hospital estimatedand ambulatory rate of 50% settings inappropriate [10]. Because PPIs prescriptions, of the oral administration both in hospital and and pH-dependent ambulatory settings solubility [10]. of Becausechemotherapy of the oral and administration TKIs, concerns and pH-dependenthave been raised solubility over the of chemotherapy possible effect and of TKIs,co-administering concerns havedrugs been which raised raise over gastric the possible pH] [11,12]. effect of Chronic co-administering acid suppression drugs which can reduce raise gastric the effectiveness pH] [11,12]. of Chronicdrugs acidthat suppressionrequire an canacidic reduce pH for the their effectiveness absorption of drugs[13]. thatRetrospective require an data acidic suggest pH for that their TKI absorptionplasma [concentration13]. Retrospective is decreased data suggest in that patients TKI plasma receiving concentration concomitant is decreased GAS therapy in patients with receivingsubsequently concomitant poorer GAS oncologic therapy outc withomes subsequently [14,15], however poorer oncologicpooled an outcomesalyses of patients [14,15], howeverenrolled in pooledclinical analyses trials have of patients shown enrolled inconsistent in clinical results trials [16,17]. have shown inconsistent results [16,17]. TheThe aim aim of ourof our meta-analysis meta-analysis is tois defineto define whether whether concomitant concomitant use use of GASof GAS therapy therapy (either (either PPI PPI or H2RA)or H2RA) in patientsin patients receiving receiving treatment treatment with with oral oral anti-cancer anti-cancer agents agents (i.e., (i.e., chemotherapy chemotherapy or TKIs)or TKIs) is is associatedassociated with with survival survival outcomes. outcomes. 2. Results2. Results A totalA total of 353 of potentially 353 potentially eligible eligible records records were identified were identified in the electronic in the databases. electronic After databases. exclusion After of nexclusion= 337 not of pertinent n = 337 not papers, pertinentn = 16 papers, were selected n = 16 forwere inclusion selected in for quantitative inclusion in analysis quantitative (n = 372,418 analysis patients(n = 372,418 included, patients with 12% included, of patients with receiving 12% of concomitantpatients receiving GAS therapy) concomitant [16–31 GAS]. The therapy) search results [16–31]. andThe characteristics search results of theand included characteristics studies of are the presented included instudies Figure are1 and presented Tables1 inand Figure2. 1 and Tables 1 and Table 2. Figure 1. Flow diagram of included studies. Figure 1. Flow diagram of included studies. Cancers 2020, 12, 998 3 of 14 Table 1. Main characteristics of the included studies. Study Number of Patients’ Disease Oral Anti-cancer Type of Author Principal Institution(s) Involved Study Design Period Patients Characteristics Drug GAS Cross Cancer Institute, Department of Ha, 2014 [23] retrospective 2006–2013 383 mRCC Sunitinib PPI Oncology, Edmonton, Alberta, Canada Cross Cancer Institute, Department of Sun, 2016 [27] retrospective 2008–2012 298 Early stage CRC Capecitabine PPI Oncology, Edmonton, Alberta, Canada Cross Cancer Institute, Department of EGFR mutant Chu, 2015 [19] retrospective 2007–2012 507 Erlotinib PPI, H2RA Oncology, Edmonton, Alberta, Canada advanced NSCLC Department of Thoracic Oncology, EGFR mutant Gefitinib Zenke, 2016 [30] National Cancer Center Hospital East, retrospective 2008–2011 130 PPI, H2RA advanced NSCLC Erlotinib Kashiwa, Japan Department of Haematology-Oncology, Kumarakulasinghe, EGFR mutant Gefitinib National University Cancer Institute, retrospective 2008–2013 157 PPI, H2RA 2016 [24] advanced NSCLC Erlotinib Singapore Chang Gung Memorial Hospital-Kaohsiung Medical Center, EGFR mutant Chen, 2016 [18] retrospective 2010–2013 269 EGFR TKIs NOS PPI Chang Gung University College of advanced NSCLC Medicine, Kaohsiung, Taiwan Department of Oncology, Cancer Centre of Graham, 2016 [21] Southeastern Ontario, Queen’s University, retrospective 2005–2011 117 CRC NA PPI Kingston retrospective Cross Cancer Institute, Department of Chu, 2017 [20] analysis (phase III 2008–2012 545 GEJC Capecitabine PPI Oncology, Edmonton, Alberta, Canada trial) Guangdong Medical University Affiliated Zhang, 2017 [31] Longhua Central Hospital, Shenzhen, retrospective 2008–2016 125 CRC Capecitabine PPI China pooled analysis Sunitinib Department of Medical Oncology, Lalani, 2017 [16] (phase II/III 2003–2013 2188 mRCC Axitinib PPI Dana-Farber Cancer Institute, Boston, USA studies) Sorafenib McAlister, 2018 Vanderbilt-Ingram Cancer Center, retrospective 2010–2015 90 mRCC Pazopanib PPI, H2RA [25] Nashville, USA Cancers 2020, 12, 998 4 of 14 Table 1. Cont. Study Number of Patients’ Disease Oral Anti-cancer Type of Author Principal Institution(s) Involved Study Design Period Patients Characteristics Drug GAS Danish Cancer Society Research Center, Solid Tumors Tvingsholm, 2018 Copenhagen, Denmark (Danish Cancer retrospective 1995–2011 353,071 (Danish Cancer NA PPI [28] Registry) Registry) Cross Cancer Institute, Department of Wong, 2019 [29] retrospective 2004–2013 389 stage II-III CRC Capecitabine PPI Oncology, Edmonton, Alberta, Canada Chang Gung Memorial Hospital, Chiayi EGFR mutant Fang, 2019 [21] retrospective 1997–2013 1278 Gefitinib PPI Branch, Puzi City, Chiayi County, Taiwan advanced NSCLC Gustave Roussy, Sarcoma Group, Villejuif, 2005–2007 Mir, 2019 [17] retrospective 333 STS Pazopanib PPI, H2RA France 2008–2010 The University of Mississippi, Oxford, Solid Tumors Sharma, 2019 [26]
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