RESUMO
The importance of the immune system in the response against cancer has always been a subject of intense investigation. The advent of immune checkpoint inhibitors has transformed the landscape of oncologic treatments, while expanding the understanding of this disease's pathophysiology. Consequently, many therapies are being investigated, with interventions directed at different steps and pathways of the immune response. Relevantly, immunotherapy sensitizers have arisen as approaches focused on the synergistic effects of immunotherapy combination, or the combination of immunotherapy and other treatment modalities, such as chemotherapy or radiation therapy. Concomitantly, novel immunotherapy modalities are also in development. Approaches focusing from the tumor intrinsic pathways to the tumor microenvironment and ex-vivo interventions, such as CAR-T cell therapies and tumor-infiltrating lymphocytes are important examples. Although many of those interventions were initially envisioned as standalone options, their combination has demonstrated promising results in early-phase in vitro studies and clinical trials. The possibility of coupling different immunotherapy modalities, as well as with other techniques, further strengthen the concept of sensitizers, allowing for deeper and more robust responses in cancer treatment. This review aims to present an overview of the concepts of these sensitizing mechanisms that are the basis for the synergistic effects of immunotherapy combination, or the combination of immunotherapy and a multitude of therapeutic strategies. Novel immunotherapy modalities are also presented, focusing on the potential of combining them with sensitizer interventions. Understanding the complexity underlying these principles may be the key for future breakthroughs and improved patient outcomes.
RESUMO
Background: Current guidelines recommend several direct oral anticoagulant agents (DOACs) equally for managing cancer-associated venous thromboembolism (VTE). Objectives: The aim of this study was to assess the efficacy and safety of DOACs in patients with active cancer. Methods: Literature searches were conducted in PubMed, Embase, and Cochrane Central in November 2022. Randomized controlled trials investigating anticoagulation strategies (vitamin K antagonists, parenteral anticoagulation [eg, low-molecular weight heparin], and DOACs) for VTE in patients with active cancer were identified for network meta-analysis. The outcomes included recurrent VTE, recurrent pulmonary embolism, recurrent deep venous thrombosis, major bleeding, clinically relevant nonmajor bleeding (CRNMB), and a composite outcome of major bleeding or CRNMB. Pooled HRs and 95% CIs were estimated using either the HR or relative risk provided from each study. Random-effects models were used for all the analyses. Results: Seventeen randomized controlled trials involving 6,623 patients with active cancer were included. No significant differences were found among the DOACs for efficacy outcomes (recurrent VTE, pulmonary embolism, and deep venous thrombosis). In terms of major bleeding, apixaban was similarly safe compared with dabigatran and rivaroxaban but was associated with a decreased risk compared with edoxaban (HR: 0.38; 95% CI: 0.15-0.93). Regarding CRNMB, edoxaban was similarly safe compared with apixaban but was associated with a decreased risk compared with rivaroxaban (HR: 0.31; 95% CI: 0.10-0.91). Compared with parenteral anticoagulation, apixaban was associated with a reduced risk for recurrent VTE (HR: 0.60; 95% CI: 0.38-0.93) without increasing bleeding, edoxaban was associated with an increased risk for major bleeding or CRNMB (HR: 1.35; 95% CI: 1.02-1.79), and rivaroxaban was associated with an increased risk for CRNMB (HR: 3.76; 95% CI: 1.43-9.88). Conclusions: DOACs demonstrate comparable efficacy but exhibit different safety profiles. Apixaban may confer an antithrombotic benefit without an increased risk for bleeding, distinguishing it from other contemporary anticoagulation strategies in patients with active cancer and VTE.