Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Camptosar (Pharmacia & Upjohn)
20 mg/mL in 2 mL and 5 mL glass vials
Indication: rectal or colonic cancer
The topoisomerases are enzymes involved in many cellular functions including the replication of DNA. Inhibitors of these enzymes have been studied in the treatment of cancer. For example, doxorubicin inhibits topoisomerase II. Irinotecan inhibits topoisomerase I, resulting in breaks in the strands of DNA.
This drug is a semisynthetic derivative of camptothecin which is a plant extract. Irinotecan has been investigated in phase II studies looking mainly at response rates rather than survival. It has been found to have some effect in solid tumours.
As colorectal tumours have higher concentrations of topoisomerase I, they may be more sensitive to enzyme inhibition than the normal cells of the mucosa.
The approval for marketing is mainly based on 3 phase II studies of 304 patients with metastatic colorectal cancer. The patients' cancers had either recurred or progressed after treatments including 5-fluorouracil. These patients were given irinotecan once a week for 4 weeks. They then had a two week rest period. The number of additional courses depended on the patients' responses and their tolerance of the drug.
Patients who were given the recommended starting dose (125 mg/m2) had an overall response rate of 15%. The median duration of this response was approximately 6 months.
The benefits of treatment are offset by the toxicity of irinotecan. Although only 4% of the patients discontinued treatment, 1.6% (5 people) died due to potentially drug-related causes. Nearly 90% of the patients develop diarrhoea. Nausea, vomiting and abdominal pain occur in the majority of patients. More than half the patients develop anaemia, leucopenia or neutropenia. Patients who have received radiotherapy are more likely to develop neutropenia. Other adverse effects include asthenia, fever and alopecia.
Irinotecan forms an active metabolite and liver metabolism seems to be the main route of excretion. However, the drug has not been evaluated in patients with hepatic dysfunction. As a life-threatening pulmonary syndrome was seen in early trials, there have also been few studies of patients with compromised pulmonary function or pleural effusions. Irinotecan has some cholinergic effects so extra caution is needed if it is given to patients with asthma or cardiovascular disease. Intravenous atropine may be needed in patients who develop diarrhoea within 24 hours of treatment.
Although irinotecan may offer some hope, the proportion of patients with metastatic disease who will benefit is unclear. Many will have complications such as ascites which may restrict the use of the drug in practice. As the median number of courses is 3, many of the patient's remaining weeks of life are going to be occupied with receiving and recovering from treatment.