A platinum-based drug that forms cross-linking adducts blocking DNA replication and transcription.
Contains a 1,2-diaminocyclohexane moiety differing from other platinum agents.
Oxaliplatin-trans-l-1,2-diaminocyclohexane Oxaliplatin (DACH).
DNA mismatch repair enzymes unable to recognize oxaliplatin-DNA adducts making it more effective at inhibiting DNA synthesis than cisplatin and carboplatin.
More cytotoxic than cisplatin or carboplatin and, in general, lacks cross-resistance to either.
In combination with fluorouracil and leucovorin (FOLFOX 4) in colorectal cancer has a response rate of 51% with a time to progression of 9 months and a median survival of 14.7-16.2 months.
As a single agent in pretreated patients with metastatic colon carcinoma there is a 10% partial response rate and a 24% response rate in patients not previously treated.
Response rates reportedly up to 53% in patients with colorectal cancer when used in combination with 5-FU and leucovorin.
Side effects include peripheral neuropathy, vomiting, diarrhea and mild bone marrow suppression.
A common toxicity is oral thermal hyperalgesia, a form of acute neuropathy caused by disruption of voltage gated sodium channels that leads to hyperexcitability of cold sensing, sensory nerves.
Dose limiting toxicity relates to peripheral neuropathy.
Peripheral sensory neuropathy reported in 92% of patients with 13% grade 3 toxicity in adjuvant studies, with 60%, 39% and 21% at day 28, 6 months and 18 months. after treatment completion.
Neurotoxic effects are almost always sensory.
Can cause both an acute, mainly cold triggered, neuropathy and a chronic neuropathy.
Acute neuropathy is characterized by paresthesia and dysesthesia of the hands and feet and reverses within a week, while chronic neuropathy mainly consists of hypoesthesia and is only partially reversible.
When used as adjuvant therapy in colon cancer the major toxicity is neurotoxicity with approximately 12.5% having grade three neuropathy with six months of treatment.
Two types of neuropathy: an acute, reversible sensory neuropathy with early onset within hours -1-2 days of treatment, with resolution within 14 days, and is likely to recur with retreatment.
Acute neuropathy occurs in 80-90% of patients treated and chronic neuropathy affects 30-60% of patients.
Acute sensory neuropathy precipitated or worsened by exposure to cold presenting as transient paresthesia, dysesthesias and hypoesthesia of hands, feet, perioral or throat areas, jaw spasm, abnormal tongue sensation orbital pain , chest pressure and dysarthria may occur.
The neuropathy often worsens for many months after cessation of the drug, and persists in a significant proportion of patients even 2 years after completing therapy.
Acute reversible pattern reported in up to 56% of patients treated, with individual cycles acute neurotoxicity observed in about 30% of patients.
Ice should be avoided during drug infusion as cold temperatures can exacerbate acute neurological symptoms.
Acute symptoms of pharyngolaryngeal dysesthesia can be seen in 1-2% of patients with dysphagia or dyspnea.
Acute form of disease may manifest as tingling, paresthesias, muscle cramps, limb stiffness, and jaw spasms.
Incidence of acute neuropathy from this agent ranges from 80-98% (Cersosimo, R).
Neuropathy is relevant for the elderly who have an increased risk of falling and impairing function and independence.
Persistent neuropathy associated with interference with writing, swallowing, buttoning and impaired walking occurs in about 48% of patients receiving the drug.
Long term morbidity from distal sensory neuropathy of a grade 3 criteria that occur in 10-15% of patients receiving 85 mg 2 m² on an every other week schedule for more than 4 months (Andre T).
Persistent neuropathy can occur without acute neuropathy and symptoms may improve in some patients after drug discontinuation.
Because of neuropathy guidelines do not support use in patients who need adjuvant chemotherapy over the age of 70 years.
Incidence of neuropathy increases with age, particularly after age 70 years.
Chronic neuropathy associated with higher cumulative doses.
Chronic neurotoxicity develops in about 10 to 20% of patients after a cumulative dose of 750-850 mg/m² and is manifested by numbness and tingling of the hands and feet.
The acute neuropathy that is most often dose-limiting is pharyngolaryngeal dysethesia with tingling, numbness, and sensation of having a lump in the throat.
Acute neurotoxicity not explained by morphological damage of the nerve.
Mechanism of neuropathy unexplained, but it is suggested that the oxalate molecule released during its metabolism may affect the neuronal voltage gated Na+ channels.
Carbamazine a Na+ channel blocker can ameliorate acute neurotoxicity without significant pharmokinetic interactions with Oxaliplatin.
Three Regimens of Eloxatin Evaluation (TREE-2 study) evaluated the safety and efficacy of three oxaliplatin and fluoropyrimidine regimens, with or without bevacizumab in metastatic colorectal cancer-indicating that the addition of bevacizumab was well tolerated without markedly changing overall toxicity.
The TREE-2 study compared Oxaliplatin with fluoropyrimidine given as a continuous infusion, bolus or oral treatments with or without bevacizumab: overall response rates, time to progression and overall survival were improved over the same treatments without bevacizumab.
TREE-2 study revealed a median overall survival of previously untreated patients with metastatic colorectal cancer and oxaliplatin and fluoropyrimidine and bevacizumab to have a median overall survival of approximately 2 years.