Relative Dose Intensity of Chemotherapy and Survival in Patients with Advanced Stage Solid Tumor Cancer: A Systematic Review and Meta-Analysis

Abstract

Background. Chemotherapy-induced toxicities lead to therapy dose reduction or delay affecting patient outcomes. This systematic review and meta-analysis evaluated the impact of relative dose intensity (RDI) on survival in adult solid-tumor cancer patients on nonadjuvant-based chemotherapy regimens. Methods. PubMed, Embase, and Web of Science databases were searched for peer-reviewed English journal articles or congress abstracts evaluating association between RDI and survival; observational studies, case series of ≥20 patients, and clinical trials published between 2013─2020 were eligible. Meta-analyses were conducted to quantify the association between RDI levels and overall survival (OS) among studies reporting a hazard ratio (HR) for OS by similar tumor types, regimens, and RDI. Forest plots represented summary HR and 95% confidence interval (CI); Cochran's Q and I 2 tests evaluated study heterogeneity.Results. Overall, 914 articles were reviewed and 37 included; seven were eligible for meta-analysis. Significantly shorter OS at RDI <80 vs ≥80% and <85% vs ≥85% was observed upon meta-analysis of four carboplatin-based studies for breast, non-small cell lung, or ovarian cancer (HR 1.17; 95% CI: 1.07-1.27), and three FOLFOX-/FOLFIRI/ FOLFIRINOX-based studies for colorectal or pancreatic cancer (HR 1.39; 95% CI: 1.03-1.89). Grade 3 or higher hematologic toxicities were higher for carboplatin-based regimens (thrombocytopenia: 14-22%; anemia: 15-19%; neutropenia: 24-58%) than FOLFOX-/FOLFIRI/FOLFIRINOX-based regimens (thrombocytopenia: 1-4%; anemia: 5-19%; neutropenia: 19-47%). Conclusion.The results suggested longer OS with RDI ≥80 or ≥85% for both regimens, indicating that management of toxicities across treatment modalities may contribute to maintenance of higher RDI and benefit survival for patients with advanced solid tumors. The Oncologist ;9999:• • Implications for Practice: Chemotherapy-induced toxicities lead to dose reduction and/or treatment delay , thus affecting patient outcomes. Results of this systematic review and meta-analysis, evaluating the impact of relative dose intensity (RDI) on survival in solid tumor cancer patients on nonadjuvant-based chemotherapy regimens, demonstrate a longer overall survival with RDI levels of at least 80% for solid tumor cancer patients on carboplatin-based and FOLFOX-/FOLFIRI/FOLFIRINOXbased chemotherapy regimens, suggesting a protective effect of maintaining RDI ≥80 or ≥85%. While grade 3 or higher hematologic toxicities occurred more in carboplatin-based studies, managing toxicities across treatment regimens may contribute to maintenance of higher RDI and ultimately benefit overall survival.

Folic Acid Treatment Directly Influences the Genetic and Epigenetic Regulation along with the Associated Cellular Maintenance Processes of HT-29 and SW480 Colorectal Cancer Cell Lines

“…However, great care is required, as folate can promote the progression of established neoplasms, while the low intake has an exactly opposite effect [ 41 , 42 ]. FA is commonly used in CRC care as an adjunctive medication to promote the efficacy of chemotherapy medications [ 16 , 17 ]. However, its individual effect on FA-related cellular maintenance activities, along with the genetic and epigenetic regulation, has not been evaluated comprehensively.…”

“…Nevertheless, drugs interfering with folate metabolism, such as 5-fluorouracil (5-FU), are generally used in CRC treatment [ 16 ]. Chemotherapeutic regimens, such as FOLFIRI or FOLFOX, include a folate derivate, namely leucovorin, to increase the effect of 5-FU [ 17 ].…”

Chemotherapy dose per kilogram lean body mass increased dose-limiting toxicity event in male head and neck cancer with taxane and platinum-based induction therapy

“…In our study, HNC patients with signi cant toxicities during induction chemotherapy were not associated with better response rates (58.8% in patients without toxicity event vs 50% in patients with toxicity event, P = 0.389; Supplementary table 5). The bene t of the toxicity event, a proxy of adequate chemotherapy dose per cycle might be offset by insu cient relative dose intensity (RDI) [9]. Using our risk score, prophylactic protocol, like granulocytecolony stimulating factor injection, or intensive care could be applied for the high-risk group in order to prevent DLT events and achieve acceptable RDI.…”

“…Treatment-related toxicities, such as severe mucositis, febrile neutropenia (FN), acute kidney injury (AKI), and hyponatremia, are also increasingly being reported [7,8]. Dose-limiting toxicity (DLT) event could lead to therapy dose reduction or delay and resulted in worse outcomes in turn [9]. Besides traditional factors, like comorbidities, performance status, and impaired renal or hepatic function, body composition factors, and related variables, such as chemotherapy per kilogram lean body mass (LBM) were reported to be associated with DLT [10,11].…”

“…In order to achieve adequate relative dose intensity ( > = 80% at least) in chemotherapy, the rst step was to identify high-risk population for DLT and launch prevention protocols, like prophylactic G-CSF injection, more intensive care or close follow-up [9,15]. We aimed to perform a comprehensive analysis, consisting of chemotherapy dose per kilogram LBM, body composition factors, patients' characteristics and tumor factors, laboratory data, and etc.…”