Oxaliplatin-Related Thrombocytopenia

D. L. Jardim; C. A. Rodrigues; Y. A. S. Novis; V. G. Rocha; P. M. Hoff

Disclosures

Ann Oncol. 2012;23(8):1937-1942. 

In This Article

Abstract and Introduction

Abstract

Oxaliplatin is a third generation platinum compound that inhibits DNA synthesis, mainly through intrastrandal cross-links in DNA. Most of the experience with the clinical use of this drug is derived from colorectal cancer but it is also used in other tumor types such as ovary, breast, liver and non-Hodgkin's lymphoma. Thrombocytopenia is a frequent toxicity seen during oxaliplatin treatment, occurring at any grade in up to 70 % of patients and leading to delays or even discontinuation of the chemotherapy. Although myelossupression is recognized as the main cause of oxaliplatin-related thrombocytopenia, new mechanisms for this side-effect have emerged, including splenic sequestration of platelets related to oxaliplatin-induced liver damage and immune thrombocytopenia. These new pathophysiology pathways have different clinical presentations and evolution and may need specific therapeutic maneuvers. This article attempts to review this topic and provides useful clinical information for the management of oxaliplatin-related thrombocytopenia.

Introduction

Oxaliplatin is a third generation platinum analog that binds to DNA forming cross-links which inhibit DNA replication and transcription, resulting in cell death. Since its approval by the USA Food and Drug Administration (FDA) for use in metastatic colorectal cancer (CRC) in 2002, this drug has been widely used to treat this malignancy and a wide range of other tumors. Several studies have demonstrated that oxaliplatin combined with 5-fluorouracil (5-FU) and folinic acid, in a regimen commonly known as FOLFOX, increases survival in the metastatic setting and reduces the risk of disease recurrence when used as a treatment of stage III CRC.[1–3] In these major trials, the incidence of thrombocytopenia of all grade was >70 %, which is substantially superior than the rate observed when 5-FU and folinic acid are used without oxaliplatin.[1,2] In a review of chemotherapy-induced thrombocytopenia including >47 000 patients with solid tumors, CRC was associated with the highest prevalence of thrombocytopenia by cancer type, and most patients had received a platinum-based chemotherapy regimen.[4] Although grades 3–4 thrombocytopenia are noted in only 3%–4% of patients exposed to oxaliplatin, this toxicity is of significant concern since the majority of patients with CRC will receive this drug in a given moment of their treatment and the incidence of this toxicity tends to increase during repeated exposures.

Even though the major dose-limiting side-effect of oxaliplatin is neurotoxicity, with the widespread use of this drug several groups have also shown the need to discontinue oxaliplatin due to thrombocytopenia.[5] The presence of significant thrombocytopenia could possibly limit the benefits of oxaliplatin by preventing appropriate administration of it at the optimal doses and schedule. Particularly in the adjuvant setting, where it is used with curative intent, this issue is a major concern. In addition, oxaliplatin-based chemotherapy has also been increasingly used to permit resection of hepatic metastases and thrombocytopenia, in this context, may increase bleeding risks, postsurgical morbidity, the need for blood transfusions and the duration of hospitalization.

Mild bone marrow suppression similar to that of other platinum-based compounds is the main cause of oxaliplatin-induced thrombocytopenia. However, novel mechanisms of oxaliplatin-induced thrombocytopenia have emerged and may be associated with different clinical presentation and may even need different approaches.[6,7] These novel mechanisms include an immune-dependent mechanism and splenic sequestration of platelets due to portal hypertension related to sinusoidal injury. In Figure 1, we present a schematic representation of these mechanisms involved in oxaliplatin-related thrombocytopenia, while Table 1 summarizes the main features related to them.

Figure 1.

Schematic representation of the mechanisms involved in oxaliplatin-related thrombocytopenia.

In the light of these new mechanisms, this review will provide a clinical overview of them and management recommendations for patients presenting a low-platelet count during treatment with oxaliplatin, including issues related to myelossupresion.

processing....