Oxaliplatin

Platinum Agent

 

Attributes

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Other Contra-Indication

This drug is contra-indicated in patients with a known allergy to it

 

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Oxaliplatin

Oxaliplatin is a platinum-based cancer chemotherapy drug.^[2] These drugs are usually classified as alkylating agents, although they are not capable of actually adding alkyl groups to DNA and simply work by a similar mechanism.Oxaliplatin is typically administered with fluorouracil and leucovorin in a combination known as FOLFOX for the treatment of colorectal cancer. Oxaliplatin is marketed by Sanofi-Aventis under the trademark Eloxatin or by Medac GmbH under the trademark Oxaliplatin Medac. There are generic equivalents on the market now ^[3]

History

Oxaliplatin was discovered in 1976 at Nagoya City University by Professor Yoshinori Kidani, who was granted U.S. Patent 4,169,846 over the drug in 1979. Oxaliplatin was subsequently in-licensed by Debiopharm and developed as an advanced colorectal cancer treatment. Debio licensed the drug to Sanofi-Aventis in 1994. Eloxatin gained European approval in 1996 (firstly in France) and approval by the U.S. Food and Drug Administration (FDA) in 2002.

Clinical use

Oxaliplatin has been compared with other platinum compounds (Cisplatin, Carboplatin) in advanced cancers (gastric, ovarian) and it has never proved more effective in terms of overall survival. Claims of a more favourable toxicity profile appear questionable to those who have seen the neurotoxic side effects of Oxaliplatin.

Advanced colorectal cancer

In clinical studies, Oxaliplatin by itself had no activity against advanced colorectal cancer. Despite this, it has been extensively studied in combination with Fluorouracil and Folinic Acid (a combination known as FolFOx). When compared with Fluorouracil and Folinic Acid administered according to the "De Gramont regimen" there was no significant increase in overall survival.

Adjuvant treatment of colorectal cancer

After the curative resection of colorectal cancer, chemotherapy based on Fluorouracil and folinic acid reduces the risk of relapse. The benefit is clinically relevant when cancer has spread to locoregional lymph nodes (stage III, Dukes C). The addition of Oxaliplatin improves relapse-free survival, but data on overall survival have not yet been published in extenso.
When cancer has not spread to the locoregional lymph nodes (stage II, Dukes B) the benefit of chemotherapy is marginal and the decision on whether to give adjuvant chemotherapy should be carefully evaluated by discussing with the patient the realistic benefits and the possible toxic side effects of treatment. This is even more relevant when the oncologist proposes treatment with Oxaliplatin.

Adverse effects

Side-effects of oxaliplatin treatment can potentially include:

• Neuropathy, (both an acute, reversible sensitivity to cold and numbness in the hands and feet and a chronic, possibly irreversible foot/leg, hand/arm numbness, often with deficits in proprioception)^[4]
• Fatigue
• Nausea, vomiting, and/or diarrhea
• Neutropenia
• Ototoxicity (hearing loss)
• Extravasation if Oxaliplatin leaks from the infusion vein it may cause severe damages to the connective tissue.

In addition, some patients may experience an allergic reaction to platinum-containing drugs.Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin.^[4]

Mechanism of action

In contrast to cisplatin and carboplatin, oxaliplatin features 1,2-diaminocyclohexane in place of the two ammonia ligands. It also features a bidentate oxalate group. Overall the drug consists of a square-planar platinum(II) center.Although the exact mechanism of oxaliplatin remains unclear, the cytotoxicity of platinum compounds is thought to result from inhibition of DNA synthesis.^[5] In vivo studies showed Oxaliplatin has anti-tumor activity against colon carcinoma through its (non-targeted) cytotoxic effects.

Patent information

Eloxatin is covered by patent numbers 5338874 (Expiry Apr 07,2013), 5420319 (Expiry Aug 08,2016), 5716988 (Expiry Aug 07,2015) and 5290961 (Expiry Jan 12, 2013) (see Electronic Orange Book patent info for Eloxatin).^[6] Exclusivity code I-441, which expired on Nov 04, 2007, is for use combination with infusional 5-FU/LV for adjuvant treatment stage III colon cancer patients who have undergone complete resection primary tumor-based on improvement in disease free survival with no demonstrated benefit overall survival after 4 years. Exclusivity code NCE, New Chemical Entity, expires on Aug 09, 2007.^[6]

References

1. ^ Ehrsson H, Wallin I, Yachnin J. Medical Oncology. 2002; 19:251-265.
2. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
3. ^ Generic Oxaliplatin Approved [1]
4. ^ ^{a b} Pasetto LM, D'Andrea MR, Rossi E, Monfardini S. Oxaliplatin-related neurotoxicity: how and why? Crit Rev Oncol Hematol. 2006 Aug;59(2):159-68. Pub. June 27, 2006. PMID 16806962.
5. ^ Micromedex, accessed 08.2008
6. ^ ^{a b} Orange Book. accessdata.fda.gov. URL: http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021759&Product_No=001&table1=OB_Rx. Accessed on: July 22, 2007.

Additional sources

• Graham J, Mushin M, Kirkpatrick P (2004). "Oxaliplatin." (PDF). Nat Rev Drug Discov 3 (1): 11–2. PMID 14756144. http://www.dresources.com/nature/ntr_0104.pdf. 

External links

• Oxaliplatin - Official web site of manufacturer.
• Oxaliplatin Prescribing Information - Official prescribing information.
• Virtual Cancer Centre: Oxaliplatin/Eloxatin
• NCI Drug Information Summary on Oxaliplatin