Oxaliplatin toxicity

The dose of capecitabine begins at 1250 mg/m2 twice a day when used by itself lower doses are used often when it is given in combination with irinotecan or oxaliplatin or in patients with renal insufficiency. The dose should be taken on a full stomach with breakfast and dinner. Capecitabine administered with warfarin can result in significant increases in the patient s INR and requires close monitoring to prevent bleeding. The convenience of oral administration and an improvement in toxicity make capecitabine a useful alternative to IV 5-FU both by itself and incorporated into other regimens used in colon cancer. 

Oxaliplatin has a mechanism similar to that of cisplatin but, unlike other platinums, is associated with minimal renal toxicity, hematologic toxicity, and nausea and vomiting. 

The second criteria, a different activity spectrum, is met by oxaliplatin (Figure 1.9A), the l isomer of [oxalatol f ra/rv-1,2-diaminocyclohexane)platinum (II)], oxaliplatin, [Pt(II)(oxalato)(DACH)]. This platinum agent is used for secondary treatment of metastatic colorectal cancer.77 Oxaliplatin, like carboplatin, has a kinetically slower leaving group, and is also less nephrotoxic than cisDDP. The limiting toxicity of oxaliplatin is peripheral sensory neuropathy, also seen with cisDDP. The neuropathy affects the extremities and increases in incidence and... 

Cetuximab has modest activity in relapsed colorectal cancer as a single agent but is more effective with irinotecan and possibly oxaliplatin based regimens where a doubling of the response rate has been observed. There is some evidence that cetuximab may reverse irinotecan resistance. Toxic effects of cetuximab include hypersensitivity reactions, malaise, nausea, headache and an acneiform rash. 

This benefit comes at a cost of significant toxicity, particularly neuropathic, and more mature data are necessary to demonstrate the ultimate benefit of adjuvant therapies on improved overall survival. So far irinotecan plus 5-FU based therapy has produced disappointing results in adjuvant treatment. Despite the present lack of data addressing overall survival benefit, oxaliplatin plus 5-FU/leucovorin is widely recommended as the gold standard adjuvant therapy for stage 3 disease. For those whose medical fitness or other contra-indications preclude oxaliplatin based therapy 5-FU/leucovorin on a weekly or monthly schedule is recommended. Oral capecitabine for 6 months has recently been reported to be at least equivalent to 5-FU/leucovorin. 

Colorectal cancer (CRC) is the third most common cause of cancer-related death in women and men in the United States. The current therapeutic options for patients with metastatic CRC (mCRC) are 5-fluorouracil (5-FU) based chemotherapy regimens with the addition of irinotecan (CPT-11) or oxaliplatin. It still remains a challenge for oncologists to evaluate the reasons for a wide variation in response and toxicity among patients undergoing systemic 5-FU based chemotherapy. Pharmacogenomics... 

Ciccolini J, Mercier C, Dahan L et al. Implication of DPD deficiency in severe or lethal toxicities after 5-fluorouracil and capecitabine-based chemotherapies. AACR Annual Meeting Proceedings 2004 46. Ciccolini J, Mercier C, Dahan L et al. Toxic death-case after capecitabine + oxaliplatin (XELOX) administration probable implication of dihydropyrimidine deshydrogenase deficiency. Cancer Chemother Pharmacol 2006 58 272-275. 

Oxaliplatin 130 mg/m2 IV every 3 weeks or 85 mg/m2 IV every 2 weeks Nausea and vomiting, laryngopharyngeal dysesthesias Peripheral sensory neuropathy, diarrhea, myelosuppression, and renal toxicity... 

Metzger, G., Massari, C., Etienne, M.C., Comisso, M., Brienza, S., Touitou, Y., Milano, G., Bastian, G., Misset, J.L., Levi, F. Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin relationship with mucosal toxicity in patients with cancer. Clin. Pharmacol. Ther. 1994, 56 190-201. 

Neurological toxicity. Patients receiving oxaliplatin must be questioned prior to each cycle of chemotherapy about neurological symptoms and doses should be adjusted according to severity of any functional impairment and duration of symptoms. Refer to the oxaliplatin Summary of Product Characteristics (2008). 

After intravenous administration of oxaliplatin, about 33% and 40% of the dose is bound to erythrocytes and plasma proteins. The half-life averages 26 days, which is in accordance with the normal life expectancy of erythrocytes (12-50 days). Oxaliplatin undergoes rapid non-enzymatic biotransformation to form a variety of reactive platinum intermediates, which bind rapidly and extensively to plasma proteins and erythrocytes. The antineoplastic and toxic properties appear to reside in the non-protein bound fraction, whereas platinum bound to plasma proteins or erythrocytes is considered to be pharmacologically inactive. Biotransformation produces DACH-platinum dichloride, 12-DACH-platinum dicysteinate, 1,2-DACH-platinum diglutathionate, 1,2-DACH-platinum mono-glutathionate, and 1,2-DACH-platinum methionine. The erythrocyte contains only thiol derivatives, whereas all derivatives can be recovered from the plasma. 

The platinum-containing metabolites of oxaliplatin are predominantly excreted in the urine (about 50% of the dose within 3 days), whereas drug excretion via the feces is of minor importance (about 5% of the dose after 11 days). The mean total platinum half-hfe averages 9 days after oxaliplatin administration (130 mg/m intravenously) (8,9). There is a strong negative correlation between the mean plasma concentration of unbound oxaliplatin and renal function however, moderate renal impairment does not increase the risk of acute toxicity associated with oxaliplatin (30). 

The further development of the third-generation platinum derivative tetraplatin (ormaplatin, trans-u, L-l,2-diaminocyclohexane tetrachloroplatinnm) has been abandoned, because drug-induced severe motor and sensory peripheral neuropathy occurred even at low cumulative doses. The high neurotoxic potential of tetraplatin may be associated with its pharmacokinetics it is rapidly metabolized to 1,2-DACH-platinnm dichloride, which was 3.8 times more nenro-toxic than oxaliplatin in a neurite ontgrowth assay (45). 

Persistent Lhermitte s sign (an electric-like sensation induced by flexion of the neck) suggestive of irreversible spinal cord toxicity has been reported in a patient taking cisplatin and etoposide (81). Of four patients with oxaliplatin neurotoxicity, two presented with Lhermitte s sign, one had urinary retention, and one had both (82). All had received cumulative doses of 1248-2040 mg/m, which is more than the generally accepted neurotoxic threshold for oxaliplatin (1000 mg/m ). 

In a pilot study in 15 patients, subcutaneous amifostine was given 20 minutes before oxaUplatin, in order to counteract oxaliplatin-induced peripheral neurosensory toxicity. In 10 patients, this regimen reduced the severity of cumulative neuropathy without compromising antitumor efficacy the amifostine was well tolerated (114). 

Oxaliplatin (130 mg/m2) every 2 weeks Previous CT patients (excluded neuro toxic CT) White European (77), Hispanic (14), African (5), Asian (ii) GSTPl Ilel05Val GSTM1 deletion GSTT1 deletion... 

---