Data on the clinical efficacy of oxaliplatin appear to have been extracted from a total of 21 studies. Data on at least 1,511 patients appear to have contributed to these studies.
The drug was used as a first-line therapy in 6 studies (961 participants). Of these, 2 studies (620 participants) reported on the use of oxaliplatin in combination with other drugs, 2 studies (278 participants) reported on chronomodulated oxaliplatin in combination with other drugs, and the remaining 2 studies (63 participants) reported on the use of oxaliplatin as a single agent.
Oxaliplatin was used in second-line chemotherapy in 14 non-randomised trials (550 participants). Four studies (147 participants) were of oxaliplatin as a single agent. The remaining 10 studies (403 participants) investigated combination chemotherapies. Of these 6 studies (201 participants) used a comparative design.
The review included reference to two papers by the same author pertaining to neo-adjuvant oxaliplatin chemotherapy of resectable liver metastases. However, there was insufficient information relating to the number of patients in this trial/these trials. The review also cited a conference report of a reanalysis of 9 trials (682 patients) that assessed adverse events.
Information on tolerability and adverse events was taken from 8 studies.
In fixed-dose combination first-line therapy, the interim results of the two large RCTs reviewed were similar. In both, the rate of objective responses among patients treated with oxaliplatin was approximately twice that of patients in the control group. However, the median duration of survival was similar for the patients of either arm in both studies.
Among the two studies involving patients treated with chronomodulated therapy, those patients who received chronomodulated therapy had significantly higher objective response rates than those treated with the same drugs in continuous infusion regimens. One study saw this translate into a significant increase in the median duration of survival (from 14.9 to 19 months), whereas the other study saw a non significant fall in the median duration of survival (from 16.9 to 15.9 months).
Two studies investigated oxaliplatin monotherapy at a dose of 130 mg, given every 3 weeks in a 2-hour infusion. The objective response rate was 24% in one study and 20% in the other; the other outcome measures were comparable. However, in neither study was the drug compared with any other drug regimen.
Again, in non-comparative studies, combination therapy using oxaliplatin and 5-fluorouracil in second-line therapy achieved objective response rates of 30 to 45%. The median duration of survival ranged from 10 to 17 months. These studies used a variety of doses, frequencies and durations of infusion.
A series of dose-finding studies were conducted to investigate doses of 85, 100 and 130 mg/m2 oxaliplatin. The patients treated with the 100 mg/m2 dose had the most favourable outcomes.
In a non-comparative study of a combination of oxaliplatin and irinotecan, 42% of the 36 patients had an objective response. The median time to disease progression was 7.5 months, but the median survival was not reported.
There were no responses to oxaliplatin therapy in one small study of 12 patients with 5-fluorouracil resistant disease, whereas a 10% response rate was seen in this patient group in three other non-comparative studies with 135 patients in total.
The response rates were reported to have varied markedly in patients who received oxaliplatin as a neo-adjuvant therapy prior to the resection of operable hepatic metastases. In one study reviewed, 16% of the patients treated with chronomodulated 5-fluorouracil and oxaliplatin experienced tumour down-sizing sufficient to allow resection. Of these, 37 patients proceeded to undergo major excision and 16 patients underwent minor resection. The 5-year survival rate was 40%.
Gastrointestinal, haematological and neurological adverse events have been reported for both monotherapy and combination therapies involving oxaliplatin. Neurological events were the most likely to be dose-limiting. Severe neurotoxicity was seen in 10% of the 682 patients after 6 cycles of 130 mg/m2 therapy, and in 50% of the patients after 9 cycles. Three per cent of the patients treated with oxaliplatin alone, and 19% of the patients treated with oxaliplatin in combination with other cytotoxics, experienced WHO grade 3 to 4 neurotoxic events. A transient laryngopharyngeal dysesthesia with dyspnoea and dysphagia was seen in 1 to 2% of the patients.
Patients managed with continuous infusions were at a markedly increased risk of developing high-grade toxicity than those managed with chronomodulated regimens: 76 versus 14% for stomatitis (p=0.0001) and 31 versus 16% for peripheral sensory neuropathy. The incidences of diarrhoea (35 versus 29%) and vomiting (25 versus 24%) were similar between the regimens.
Patients on chronomodulated therapy had a significantly lower rate of withdrawal owing to adverse events than those managed with continuous infusion therapy: 28 versus 51% (p=0.002). They also had a significantly lower rate of hospital admissions owing to grade 4 toxicities: 10 versus 31% (p=0.001).