Drug-drug interactions with proton pump inhibitors in cancer patients: an underrecognized cause of treatment failure.

New concepts and drugs have revolutionized medical treatment for cancers. These drugs, which are very expensive and usually well tolerated, have dramatically improved cancer prognosis. We must use them wisely for patients to fully benefit. Gastric acid antisecretory drugs and particularly proton pump inhibitors (PPIs) revolutionized the treatment of gastroduodenal ulcers and severe gastroesophageal reflux, but are frequently overused for symptomatic treatment of epigastric pain or heartburn. Long-term acid suppression may alter the efficacy of many anticancer drugs, such as tyrosine kinase inhibitors (TKIs), cyclin-dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors (ICIs), by either decreasing gastric acid secretion and thus drug absorption, or by modifying the gut microbiome that modulates the response to ICIs. Oncologists thus need to pay particular attention to the concomitant use of PPIs and anticancer drugs. These interactions translate into major clinical impacts, with demonstrated loss of efficacy for some TKIs (erlotinib, gefitinib, pazopanib), and conflicting results with many other oral drugs, including capecitabine and CDK 4/6 inhibitors. Furthermore, the profound changes in the gut microbiome due to using PPIs have shown that the benefit of using ICIs may be suppressed in patients treated with PPIs. As the use of PPIs is not essential, we must apply the precautionary principle. The first sentence of a recent Comment in Nature was "Every day, millions of people are taking medications that will not help them". We fear that every day millions of cancer patients are taking medications that harm them. While this may well be only association and not causation, there is enough to make us pause until we reach a clear answer. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician

Long-Term Use of Proton Pump Inhibitors in Cancer Patients: An Opinion Paper.

Multikinase inhibitors (MKIs), and particularly tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs), are currently some of the major breakthroughs in cancer treatment. Proton pump inhibitors (PPIs) revolutionised the treatment of acid-related diseases, but are frequently overused for epigastric pain or heartburn. However, long-term acid suppression from using PPIs may lead to safety concerns, and could have a greater impact in cancer patients undergoing therapy, like bone fractures, renal toxicities, enteric infections, and micronutrient deficiencies (iron and magnesium). Moreover, acid suppression may also affect the pharmacokinetics of drugs (at least during acid suppression) and decrease the absorption of many molecularly-targeted anticancer therapies, which are mostly weak bases with pH-dependent absorption. This type of drug-drug interaction may have detrimental effects on efficacy, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including capecitabine. Furthermore, the long-term use of PPIs results in severe alterations to the gut microbiome and recent retrospective analyses have shown that the benefit of using CPIs was suppressed in patients treated with PPIs. These very expensive drugs are of great importance because of their efficacy. As the use of PPIs is not essential, we must apply the precautionary principle. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician

Patterns of care and outcomes of 417 patients with METAstatic SYNovial sarcoma (METASYN): real-life data from the French Sarcoma Group (FSG)

International audienceBackground: Synovial sarcoma (SS) occurs in both adult and pediatric patients. The primary aim of this study is to describe the outcomes, prognostic factors, and treatment of patients with metastatic SS within a nationwide cohort.Patients and methods: All pediatric and adult patients with metastatic SS are registered in the French Sarcoma Group database. Data were collected from the national database https://conticabase.sarcomabcb.org/ up to March 2020. Descriptive and comparative analyses were conducted using SAS 9.4 and Stata Special Edition 16.1 software.Results: Between January 1981 and December 2019, 417 patients with metastatic SS from 17 French sarcoma centers were included, including 64 (15.3%) under the age of 26 years. Median age was 42.5 years (range 9-87 years). The metastases were synchronous (cohort 1) or metachronous (cohort 2) in 18.9% (N = 79) and 81.1% (N = 338) patients, respectively. Median overall survival (OS) from the date of metastasis was 22.3 months (95% confidence interval 19.7-24.1 months). First-line chemotherapy without ifosfamide and/or doxorubicin was unfavorable for progression-free survival and OS (P 12 months, local therapy, and ifosfamide in the first metastatic line were independent favorable prognostic factors.Conclusions: The outcome of patients with metastatic SS is influenced by local treatment, management in reference centers, and cytotoxic treatments given in the perioperative and metastatic setting

Immunovirological status in people with perinatal and adult-acquired HIV-1 infection: a multi-cohort analysis from FranceResearch in context

Summary: Background: No study has compared the virological and immunological status of young people with perinatally-acquired HIV infection (P-HIV) with that of people with HIV adulthood (A-HIV) having a similar duration of infection. Methods: 5 French cohorts of P-HIV and A-HIV patients with a known date of HIV-infection and receiving antiretroviral treatment (ART), were used to compare the following proportions of: virological failure (VF) defined as plasma HIV RNA ≥ 50 copies/mL, CD4 cell percentages and CD4:CD8 ratios, at the time of the most recent visit since 2012. The analysis was stratified on time since infection, and multivariate models were adjusted for demographics and treatment history. Findings: 310 P-HIV were compared to 1515 A-HIV (median current ages 20.9 [IQR:14.4–25.5] and 45.9 [IQR:37.9–53.5] respectively). VF at the time of the most recent evaluation was significantly higher among P-HIV (22.6%, 69/306) than A-HIV (3.3%, 50/1514); p ≤ 0.0001. The risk of VF was particularly high among the youngest children (2–5 years), adolescents (13–17 years) and young adults (18–24 years), compared to A-HIV with a similar duration of infection: adjusted Odds-Ratio (aOR) 7.0 [95% CI: 1.7; 30.0], 11.4 [4.2; 31.2] and 3.3 [1.0; 10.8] respectively. The level of CD4 cell percentages did not differ between P-HIV and A-HIV. P-HIV aged 6–12 and 13–17 were more likely than A-HIV to have a CD4:CD8 ratio ≥ 1: 84.1% vs. 58.8% (aOR = 3.5 [1.5; 8.3]), and 60.9% vs. 54.7% (aOR = 1.9 [0.9; 4.2]) respectively. Interpretation: P-HIV were at a higher risk of VF than A-HIV with a similar duration of infection, even after adjusting for treatment history, whereas they were not at a higher risk of immunological impairment. Exposure to viral replication among young patients living with HIV since birth or a very early age, probably because of lower adherence, could have an impact on health, raising major concerns about the selection of resistance mutations and the risk of HIV transmission. Funding: Inserm - ANRS MIE