DPYD genotyping and 5-fluoropyrimidine toxicity: An overview of systematic reviews protocol. / [Artículo traducido] Genotipado del gen DPYD y toxicidad de las 5-fluoropirimidinas: protocolo de un resumen de revisiones sistemáticas.

INTRODUCTION: The increased risk of severe and life-threatening toxicity in patients with dihydropyridine dehydrogenase deficiency, under treatment with fluoropyrimidines, has been widely studied. An up-to-date overview of systematic reviews summarizing existing literature can add value by highlighting most relevant information and supports decision-making regarding treatment in dihydropyridine dehydrogenase deficient patients. The main objective of this overview is to identify published systematic reviews on the association between germline variations in the DPYD gene and fluoropyrimidine toxicity. METHODS AND ANALYSIS: This protocol was developed following the Preferred Reported Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist, and the overview of systematic reviews will be reported in accordance with the PRISMA statement. PubMed, Embase, Scopus and the Cochrane Library will be searched from inception to 2023. Systematic reviews irrespective of study designs that analyze the association between germline variations in the DPYD and fluoropyrimidine toxicity will be considered. Methodological quality will be assessed using AMSTAR2 checklist (Measurement Tool to Assess Systematic Reviews 2). Two independent investigators will perform the study selection, quality assessment and data collection. Discrepancies will be solved by a third investigator.

Is ranitidine necessary as premedication for regimens containing paclitaxel? A non-inferiority study.

BACKGROUND: Histamine type-2-receptor antagonist drugs (H2-antagonists) have been used as standard treatment to prevent hypersensitivity reactions (HRs) in paclitaxel-containing regimens, however, their use has been strongly questioned. Ranitidine has been the most widely used H2-antagonist. Therefore, especially after its withdrawal from the market, the objective of this study is to determine the impact of its elimination from premedication on HR incidence. METHODS: A cohort, multicenter, observational, prospective, and non-inferiority study, including paclitaxel-naïve cancer patients, designed to determine the incidence of HRs of any grade associated with paclitaxel administration and analyze non-inferiority against the incidence estimated in the literature (20%), with 5% as the maximum difference (Δ). Patients with a solid neoplasm of any type/stage, who initiated treatment with paclitaxel without H2-antagonists in the premedication regimen were enrolled. RESULTS: A total of 441 patients were included, of whom 50 presented 54 HRs of any grade. The cumulative incidence was 11.3% (95%CI 8.5-14.7), thus fulfilling the hypothesis of non-inferiority. Of the overall HRs detected, 15 were grade ≥ 3 with a cumulative incidence of 3.4% (95%CI 1.9-5.5). CONCLUSIONS: This study demonstrates that the elimination of ranitidine from paclitaxel premedication schedules is non-inferior in the development of HRs of any grade compared to the administration of H2-antagonists.

Pericardial effusion with pembrolizumab.

INTRODUCTION: The treatment of non-small cell lung cancer (NSCLC) has profoundly changed on account of the arrival of new therapies, like immunotherapy. Within this group of drugs, those aimed at the programmed cell death-1 or programmed cell death ligand-1(PD1/PDL-1) are very relevant, for example, Pembrolizumab. Although its adverse reactions are generally mild and well tolerated, it has been associated with certain immune-related adverse events (IrAEs) than can be serious and affect any organ. CASE REPORT: A 62-year-old woman diagnosed with stage IV NSCLC with a single bone metastasis and PD-L1 expression of 60% started treatment with cisplatin-pemetrexed-pembrolizumab, and maintenance with pembrolizumab. MANAGEMENT AND OUTCOME: The patient attended the ER with pericardial effusion that was assumed to be a Pembrolizumab IrAE and was managed with corticosteroids. The patient fully recovered but immunotherapy was not reintroduced due to the severity of the AE. DISCUSSION: The cardiovascular system is among the least affected organs by immunotoxicity, with an incidence between 0.09-0.6%. However, some authors suspect the incidence is underestimated. Median time to onset is highly variable, ranging from 6 weeks since the first dose to 2 years after discontinuation of the treatment. There are not guidelines on the most effective management of the IrAEs, but according to the pharmaceutical reference, corticosteroids should be initiated followed by a progressive reduction. If no response is obtained, another immunosuppressive agent should be added. The determination to restart immunotherapy depends on the severity of the adverse reaction, the availability of other alternative treatments, and the cancer response.

Hypophysitis secondary to pembrolizumab: a case report and review of the literature.

Pembrolizumab is a mAb against the programmed cell death protein-1 (PD-1). It has been approved for the treatment of advanced melanoma (unresectable or metastatic) in adults. Side effects associated with the use of anti-PD-1 are usually considered well tolerated; nevertheless, there are immune-related adverse events that may require treatment discontinuation. A 79-year-old man diagnosed with stage IV right scapular melanoma experienced unspecific symptoms and alterations of the hypothalamus-hypophysis axis after six cycles with pembrolizumab. The case was compatible with immune-related hypophysitis. Autoimmune thyroiditis and primary hypophysitis were excluded and toxicity due to pembrolizumab was considered the cause of hypophysitis. Pembrolizumab was discontinued and toxicity was managed with corticosteroids and hormonal replacement therapy (HRT). After 7 months of follow-up, symptoms were controlled with HRT but thyrotropin and corticotropin hormones had not recovered. It was decided not to reintroduce immunotherapy. Although endocrine disorders are common with the use of anti-PD-1, hypophysitis is very rare. However, clinical signs and symptoms can be nonspecific, therefore, it has probably been underdiagnosed. Monitoring hormones before and during the treatment is important for an early diagnosis and also to replace the alterations with HRT to control the symptoms. Hormonal function does not always recover, but it does not mean immunotherapy cannot be restarted and it should be evaluated in every case.