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Clinical Use of Camptosar (CPT-11)

Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021-6007

Camptosar is the first new agent approved by the Food and Drug Administration for the treatment of advanced colorectal cancer in 40 years. The drug, previously known as CPT-11, is a derivative of camptothecin, a chemical isolated from the stem wood of the Chinese tree camptotheca acuminata. Camptothecin was shown in early clinical trials to have antitumor activity, but also to have severe and unpredictable toxicities. In the mid 1980s, camptothecin was shown to be a potent inhibitor of the nuclear enzyme topoisomerase I (topo I).This understanding of the unique mechanism of action led to a flurry of investigations aimed at identifying water-soluble derivatives of camptothecin which would retain or improve upon its clinical activity and which would have more manageable and predictable toxicities. Two such derivatives have now reached the market: topotecan (Hycamtin) and irinotecan (CPT-11, or Camptosar).

It is important to recognize that these camptothecin derivatives do not necessarily share the same spectrum of activity. Topotecan, which is approved for use in cisplatin-refractory ovarian carcinoma, is essentially inactive in colorectal cancer. Irinotecan, or Camptosar, on the other hand, is highly active in colorectal cancer. In one study done by our group at Memorial Sloan-Kettering Cancer Center, 32% of colorectal patients with no prior chemotherapy achieved a major (>50%) reduction in tumor size. Perhaps as importantly, roughly 20% achieved a more modest tumor regression and another roughly 20% achieved a stabilization of disease, with only about a quarter of the patients treated showing overt progression of disease. In a trial published from the University of Texas, San Antonio, a 23% major objective response rate was reported in patients whose disease had progressed through 5-FU-based therapy. This antitumor activity in previously treated patients has led to Camptosar’s current approved clinical indication.

The standard treatment regimen for Camptosar in North America involves 90 minute intravenous infusions of 125 mg/m² weekly for four consecutive weeks followed by a two-week rest. More rapid intravenous infusions at this dose may lead to acute cholinergic reactions resulting in early-onset diarrhea. This type of cholinergic reaction, involving diarrhea and/or diaphoresis in the period during or within 12 hours of drug administration, is self-limiting, can be controlled or prevented with atropine, and does not require specific antidiarrheal agents for treatment. Decadron 10-20 mg i.v. is adequate antiemesis treatment for the majority of patients, but approximately one-fourth of patients will require Zofran or Kytril in addition. Compazine should be avoided within 24 hours of Camptosar administration since the combination has been reported to cause jitteriness and agitation.

The two major side effects of Camptosar are neutropenia and diarrhea. The drug is relatively platelet-sparing. The key to management of diarrhea is early recognition and aggressive therapy. Patients must be instructed to begin loperamide (Imodium) therapy at the very first sign of diarrhea (increase in stool frequency, soft or liquid stools). If a watery stool is experienced, patient should take loperamide 2 mg (one tablet) every two hours until they have gone twelve hours without a liquid stool. All too often, despite specific instructions to the contrary, patients may follow the directions on the box of loperamide, which limits the dose to four tablets daily. It must be emphasized to your patients that they are taking this over-the-counter medication according to your specific directions, and not according to the directions on the box.

The most important factor influencing clinical results with Camptosar is appropriate patient selection. Patients with a good performance status, good caloric intake, and ability and desire to cooperate with complex instructions, are good candidates for treatment with Camptosar. Patients who are severely debilitated, with ECOG 3-4 performance status, and/or patients with poor gut function and poor p.o. intake, appear to tolerate Camptosar poorly, are less likely to benefit from treatment, and should be seriously considered for supportive care rather than aggressive chemotherapy. Proper patient selection can greatly increase the likelihood of success, and decrease the risk of severe or life-threatening complications.

Issues under active investigation include the use of Camptosar as a first-line agent, combination regimens of Camptosar plus 5-FU and leucovorin, and Camptosar plus radiation therapy. Camptosar will be entereing clinical trials in the adjuvant treatment of locally advanced colon cancer as well.

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