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Current Status of Irinotecan in Lung Cancer

Current Status of Irinotecan in Lung Cancer

ABSTRACT: Survival in lung cancer patients has not improved over the past 2 decades. Irinotecan (Camptosar, CPT-11), a semisynthetic analog of the quinoline-based alkaloid camptothecin, is one of several new drugs that have demonstrated promising activity in the treatment of lung cancer in recent years. This article gives a brief overview of the mechanism, development history, and current uses of this agent. [ONCOLOGY 15(Suppl 1):6-7, 2001]

Introduction

Lung cancer is the leading cause of cancer death in Japan, the United States, and most of the other developed countries worldwide.[1] Locally advanced or metastatic disease is present in more than 75% of lung cancer patients at time of diagnosis. This factor, as well as the need for more effective treatment, is the prominent reason why survival in lung cancer patients has not improved over the past 2 decades. In recent years, however, several new agents have demonstrated promising activity in the treatment of lung cancer. Among these is irinotecan (Camptosar, CPT-11).

Irinotecan is a semisynthetic analog of the quinoline-based alkaloid camptothecin, which was originally from the native Chinese/Tibetan ornamental tree Camptotheca acuminata, known by Chinese and Tibetans as xi shu ("happy tree"). Irinotecan is a prodrug that is transformed to its active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin) by a carboxylesterase, which occurs mainly in the liver, bowel mucosa, and tumor tissue (see Figure 1). SN-38 is 100- to 1,000-fold more cytotoxic than irinotecan, and it is a potent inhibitor of the nuclear enzyme topoisomerase I, which is involved in such key nuclear processes as DNA replication.

The conjugation of SN-38 glucuronide (SN-38G) to SN-38 by beta-glucuronidase, produced by intestinal flora, may contribute to enterohepatic recirculation of SN-38, leading to the onset of delayed diarrhea. The dominant route of elimination of the SN-38 metabolite is fecal excretion, accounting for 62% of the administered dose, compared with urinary excretion of about 30%.

Irinotecan was first discovered and synthesized in Japan by Yakult Honsha Co, Ltd, in 1983. It initially demonstrated strong activity against a broad variety of experimental tumors.[2] Subsequently, clinical phase I studies were initiated in Japan in 1986, in Europe in 1990, and in the United States in 1991. In 1994, irinotecan was first approved in Japan for treatment of non-small-cell lung cancer, small-cell lung cancer, and gynecologic malignancies. In 1995, France approved irinotecan as second-line treatment of colorectal cancer, and a year later the agent was also approved for second-line treatment of colorectal cancer in the United States (see Table 1).

Irinotecan was approved in the United States in 2000 for use in combination with fluorouracil and leucovorin in first-line treatment of metastatic colorectal cancer. In Japan, phase III trials of irinotecan in small-cell lung cancer are ongoing.

Results of several phase III studies in non-small-cell and small-cell lung cancer have been reported at meetings of the American Society of Clinical Oncology and other oncology organizations in 1999 and 2000. The use of irinotecan in lung cancer is discussed further in other articles in this supplement.

References

1. Cancer Facts and Figures 2000. Atlanta, American Cancer Society, 2000. Also available at http://www.cancer.org (accessed October 16, 2000).

2. Kunimoto T, Nitta K, Tanaka T, et al: Antitumor activity of 7-ethyl-10-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 47:5944-5947, 1987.

 
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