Background: Reduction in chemotherapy relative dose intensity (RDI) is a common outcome of hematologic toxicity during cancer chemotherapy and can affect treatment efficacy and, consequently, survival time. Several published studies have reported associations between RDI and overall survival, as well as the cumulative incidence of hematologic toxicities. A systematic literature review and meta-analysis of these results can elucidate opportunities to improve overall survival by managing hematologic toxicity.
Methods: PubMed, Embase, and Web of Science databases were searched from 2013 through 2019 to identify studies reporting the associations of chemotherapy RDI with survival in adult solid-tumor cancer patients. Titles and abstracts of articles were reviewed and after excluding irrelevant studies, two independent reviewers assessed the de-duplicated, full-text articles and abstracted relevant studies into an extraction database. Endpoints included overall and progression-free survival by RDI and the cumulative incidence of grade 3 or higher hematologic adverse events. Eligible publications included observational studies and clinical trials published in English from peer-reviewed journals and conference abstracts. Random-effects meta-analyses were conducted to quantify the association between RDI levels and overall survival using studies reporting a hazard ratio (HR) for overall survival by tumor type, chemotherapy regimen, and RDI threshold of 80% or 85%. The results of included outcomes were summarized across available studies, weighting studies by the inverse of their variance. Study heterogeneity was evaluated using Cochran's Q and I2 statistical tests. Summary HR and 95% confidence intervals (CI) were represented using forest plots.
Results: After reviewing 914 articles resulting from the literature searches, a total of 41 studies were included in the extraction database. Overall, two major categories of studies were identified: platinum-based regimens for breast, non-small cell lung cancer, or ovarian cancer; and 5-fluorouracil-based regimens (e.g. FOLFOX, FOLFIRI) for colorectal or pancreatic cancer. Meta-analysis of the five platinum-based studies (HR 1.17; 95% CI: 1.07-1.27) and four 5-fluorouracil-based studies (HR 1.39; 95% CI: 1.03-1.89) demonstrated significantly shorter survival time at RDI levels <80/85% vs. RDI levels ≥80/85% (Figure 1). Grade 3 or higher hematologic toxicities were reported by nine studies (two with age stratification). The cumulative incidence estimates of grade 3+ hematologic adverse events were higher for platinum-based regimens (14-22% for thrombocytopenia; 15-19% for anemia; and 24-58% for neutropenia) than 5-fluorouracil regimens (1-4% for thrombocytopenia; 5-19% for anemia; and 19-47% for neutropenia). In each study, neutropenia incidence was higher (0-58% across studies) than anemia (5-28%) and thrombocytopenia (1-22%) (Figure 2). Thrombocytopenia and anemia incidence were higher with paclitaxel in pancreas and ovarian cancers than other therapies. Hematologic toxicities were not reported separately by RDI in these studies.
Conclusions: Recent publications demonstrated longer survival with RDI ≥80/85% than with lower RDI for solid tumor cancer patients on platinum-based and 5-fluorouracil-based chemotherapy regimens. Grade 3+ hematologic toxicities commonly occurred in studies of platinum-based regimens and some 5-fluorouracil studies. Managing such toxicities may contribute to maintenance of higher RDI and ultimately benefit overall survival.
Bylsma:EpidStrategies: Current Employment. Nielson:Amgen Inc: Current Employment. Fryzek:EpidStrategies: Current Employment. Saad:Amgen Inc: Current Employment.
