COLORECTAL CANCER

Cancers of the colon and rectum (colorectal cancers) are the fourth most commonly diagnosed cancers and rank second among cancer deaths in the U.S. About 150,000 new cases of these cancers occur annually. Over a lifetime, affects about one in 18 people, resulting in 56,000 deaths in the U.S. each year.

Just recently, oxaliplatin, in injection form (Eloxatin®, Sanofi-Synthelabo) was approved by the Food and Drug Administration (FDA) for use in combination with infusions of 5-fluo-rouracil (5-FU) and leucovorin (LV). The combination is used for the treatment of patients with metastatic carcinoma of the colon or rectum when symptoms have recurred or worsened during initial therapy or within six months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan (Camptosar®, Pharmacia).

Oxaliplatin belongs to a new class of platinum agents. It contains a platinum atom complex with oxalate and diaminocyclo-hexane (DACH). The bulky DACH is thought to contribute greater cytotoxicity than that contributed by cisplatin (Plati-nol®, Bristol-Myers Squibb) and carboplatin (Paraplatin®, Bristol-Myers Squibb). The exact mechanism of action of oxali-platin is not known. Oxaliplatin undergoes nonenzymatic conversion in physiological solutions to active derivatives via displacement of the active oxalate ligand. Oxaliplatin forms reactive platinum complexes that are believed to inhibit synthesis of de-oxyribonucleic acid (DNA) by forming inter-strand and intra-strand cross-linking of DNA molecules. These cross-links inhibit DNA replication and transcription.

Oxaliplatin is not generally cross-resistant to cisplatin or car-boplatin, possibly because of the DACH group and resistance to DNA mismatch repair. Preclinical studies have shown that oxaliplatin is synergistic with FU and SN-38, the active metabolite of irinotecan. Oxaliplatin is a radiation-sensitizing agent and is cell cycle-phase-nonspecific.

In the pivotal clinical trial, oxaliplatin for injection in combination with infusions of 5-FU/LV demonstrated a statistically significant (P < .05) response rate compared with infusions of 5-FU/LV alone. The response rate was defined as a 30% or greater reduction in overall tumor size, maintained for four weeks or more. The effects of the combination on survival are not yet known. Oxaliplatin is not intended for patients with newly diagnosed colorectal cancer.

Oxaliplatin for injection should not be administered to patients with a history of known allergy to oxaliplatin or to other platinum compounds. Women of childbearing age should be advised not to become pregnant while undergoing treatment with oxaliplatin. As with other platinum compounds, hypersen-sitivity and anaphylactic or anaphylactoid reactions have been reported. Oxaliplatin is associated with potentially fatal pulmonary toxicity and two distinct types of primarily peripheral sensory neuropathies: an acute, reversible type of early onset and a persistent type (lasting longer than 14 days). An acute syndrome of pharyngolaryngeal dysesthesia, observed in 1% to 2% of patients, was characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm. Both 5-FU and oxaliplatin are associated with gastrointestinal and hematological adverse events.

The most frequently reported adverse events with oxaliplatin in combination with infusional 5-FU/LV were acute peripheral neuropathy in 56%, persistent neuropathy in 48%, fatigue in 68%, diarrhea in 67%, nausea in 65%, and vomiting in 40%. Changes in hematology parameters were also seen, for example, anemia in 81%, leukopenia in 76%, neutropenia in 73%, and thrombocy-topenia in 64%. The diarrhea and myelosuppression normally associated with 5-FU/LV were accentuated by oxaliplatin. Most of the neurotoxic events were reversible. Neutropenia was the major hematological toxicity.

Oxaliplatin for injection is intended for use by physicians who have experience in administering anticancer agents. The labeling for oxaliplatin includes a “black box” warning detailing this use and highlighting anaphylactic-like reactions associated with the product. This drug can have a toxic effect on nerve endings and may cause either an acute or a cumulative pattern of side effects. The result can be a feeling of numbness or tingling, which generally improves after the treatment is completed. An injection is scheduled every two weeks as follows: Day one. Oxaliplatin 85 mg/m2 IV infusion and leucovorin 200 mg/m2 IV are administered over two hours at the same time in separate bags, followed by a 5-FU 400-mg/m2 IV bolus given over two to four minutes, followed by a 5-FU 600 mg/m2 IV given as a 22-hour continuous infusion. discount drugs canda

Day two. A leucovorin 200-mg/m2 IV infusion is administered over two hours, followed by a 5-FU 400-mg/m2 IV bolus given over two to four minutes, followed by 5-FU 600 mg/m2 IV given as a 22-hour continuous infusion.

Premedication with antiemetics, including 5-hydroxytripamine (5-HT3) blockers, with or without dexamethasone, is recommended.