Oxaliplatin-related thrombocytopenia

Oxaliplatin-related thrombocytopenia

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...........

paywalled: Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.

Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.:

Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.

Hepatogastroenterology. 2012 Jul-Aug

Abstract
Background/Aims:
We conducted a phase I trial of IP oxaliplatin and paclitaxel with IV paclitaxel and bevacizumab in patients with peritoneal carcinomatosis.

Methodology:
Patients received IV bevacizumab (2.5mg/kg) over 1 hour (day 1), then IV paclitaxel (110mg/m2) 24-hr-infusion (day 1) and IP oxaliplatin (25-40mg/m2) (day 2), and IP paclitaxel (30-60mg/m2) (day 8 from cycle 2 onwards). A '3+3' design was used.

Results:
Nineteen patients were treated (median age 60 years; 10 women, 9 men; median number of prior therapies 3). Primary tumors were colorectal (n=9), signet ring carcinoma (n=2), gastric (n=2), ovarian (n=2) and others (n=4). The maximum tolerated doses (MTD) of IP oxaliplatin and IP paclitaxel were 25mg/m2 and 60mg/ m2, respectively. Nine (47%) patients reported no toxicities >grade 2. Two patients receiving IP oxaliplatin 40mg/m2 and IP paclitaxel 60mg/m2 had dose limiting toxicities (DLT) of grade 3 diarrhea/dehydration and febrile neutropenia. Toxicities included abdominal pain (n=14), nausea (n=10) and constipation (n=7). Of 12 patients restaged at 2 months, 7 (58%) had stable disease (SD) including 2 (17%) who had SD for >4 months.

Conclusions: 
IP paclitaxel and IP oxaliplatin can be given safely at 60mg/m2 and 25mg/m2, respectively.

PMID: 22580643 [PubMed - in process]

open access: Oxaliplatin-related thrombocytopenia

Oxaliplatin-related thrombocytopenia

Abstract/Full Text:

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. 

conclusions

Oxaliplatin-related thrombocytopenia can prevent the administration of the optimal dose and schedule of this important chemotherapy agent and limit its benefits in the adjuvant or metastatic setting. Mild to moderate bone marrow suppression is the main cause of thrombocytopenia during and after treatment with oxaliplatin. In this setting, patients present thrombocytopenia concomitant to anemia and neutropenia usually 1–2 weeks after treatment. Therapeutic approaches will include dose delays or reduction and consideration of platelet-stimulating agents. However, novel mechanisms of oxaliplatin-related thrombocytopenia should promptly be recognized by physicians and include an immune-dependent mechanism, as well as portal hypertension related to sinusoidal injury yielding splenic sequestration of platelets.

OIIT usually presents a sudden and isolated drop in platelet counts minutes to hours after oxaliplatin administration, leading to acute hemorrhagic events. Female patients with advanced CRC and prior oxaliplatin exposure are more likely to develop this consequence. Prompt immunological testing documenting oxaliplatin-mediated platelet destruction leads to definitive diagnosis. Platelets counts will improve after discontinuation of treatment and transfusions may be necessary during the acute phase. Other measures such as corticoid or immunoglobulin administration are controversial and patients with documented OIIT should not be rechallenged with oxaliplatin.

Hepatic sinusoidal injury is a well-known complication of oxaliplatin treatment and can lead to portal hypertension and hypersplenism. Thrombocytopenia in this setting demonstrates a different natural history, with moderate but prolonged reductions in platelet counts. Splenomegaly and other complications of portal hypertension are recognized in these patients. Platelet recovery is slow and usually takes 2–3 years to be complete after treatment discontinuation. When a fast platelet recovery is wanted, splenic embolization might be considered as a therapeutic measure.

An improvement in the recognition of these mechanisms of oxaliplatin-related thrombocytopenia will permit a better documentation of them and help to understand possible risk factors associated with this complication in different settings. This information may help the development of new preventive and therapeutic approaches and allow for a more rational management of cancer patients treated with oxaliplatin that present thrombocytopenia.

The Oncologist: commentary + link to original paper - Calcium and Magnesium Prophylaxis for Oxaliplatin-Related (taxanes) Neurotoxicity: Is It a Trade-off Between Drug Efficacy and Toxicity?

 1)  link to commentary: 

 Calcium and Magnesium Prophylaxis for Oxaliplatin-Related Neurotoxicity: Is It a Trade-off Between Drug Efficacy and Toxicity?

"In this context, a large international academic trial involving several U.S. and European oncological centers—the Chemotherapy-Induced Peripheral Neuropathy Outcome Measures Standardization (CI-PERINOMS) study[16]—recently completed the enrollment of >280 patients with CIPN who were examined with an extended series of scales and questionnaires to assess their reliability and validity, a critical step in the search for the optimal method to detect and describe its features in daily practice and in clinical trials. In fact, until reliable, valid, reproducible, and responsive methods are used to properly assess CIPN, any effort to establish an effective neuroprotection treatment will be unrealistic."

2)  link to original paper:

Calcium and Magnesium Prophylaxis for Oxaliplatin-Related Neurotoxicity: Is It a Trade-off Between Drug Efficacy and Toxicity?

"......Furthermore, there is a lack of standardization in timing of assessment of neurotoxicity and inadequate assessment of long-term neurotoxicity related to oxaliplatin between studies investigating Ca/Mg prophylaxis. Also, because of the initial concerns raised by the IDMC examining the CONCePT trial, many of the major trials were terminated early and are thus underpowered. The NCCTG has initiated another prospective randomized, double-blinded trial aimed at addressing these issues."  (safety)

in research: Combinations of Resveratrol, Cisplatin and Oxaliplatin Applied to Human Ovarian Cancer Cells

Targeting Src in Mucinous Ovarian Carcinoma (dasatinib/oxaliplatin)

"Targeting src kinase with combination of dasatinib and oxaliplatin may be an attractive approach in this disease."

Hyperthermic intra-peritoneal chemotherapy using Oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma. Results of a phase II

CONCLUSION:
Using intra-peritoneal Oxaliplatin associated with hyperthermia as consolidation therapy for advanced ovarian cancer results in a high risk of grade 3 morbidities with only a small benefit on survival