Current Status of Irinotecan in Lung Cancer

January 1, 2001

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]

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

Irinotecan is a semisynthetic analog of the quinoline-basedalkaloid camptothecin, which was originally from the native Chinese/Tibetanornamental tree Camptotheca acuminata, known by Chinese and Tibetans as xi shu("happy tree"). Irinotecan is a prodrug that is transformed to itsactive metabolite SN-38 (7-ethyl-10-hydroxycamptothecin) by a carboxylesterase,which occurs mainly in the liver, bowel mucosa, and tumor tissue (see Figure1).SN-38 is 100- to 1,000-fold more cytotoxic than irinotecan, and it is a potentinhibitor of the nuclear enzyme topoisomerase I, which is involved in such keynuclear processes as DNA replication.

The conjugation of SN-38 glucuronide (SN-38G) to SN-38 bybeta-glucuronidase, produced by intestinal flora, may contribute toenterohepatic 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 ofabout 30%.

Irinotecan was first discovered and synthesized in Japan byYakult Honsha Co, Ltd, in 1983. It initially demonstrated strong activityagainst a broad variety of experimental tumors.[2] Subsequently, clinical phaseI studies were initiated in Japan in 1986, in Europe in 1990, and in the UnitedStates in 1991. In 1994, irinotecan was first approved in Japan for treatment ofnon-small-cell lung cancer, small-cell lung cancer, and gynecologicmalignancies. In 1995, France approved irinotecan as second-line treatment ofcolorectal cancer, and a year later the agent was also approved for second-linetreatment of colorectal cancer in the United States (see Table1).

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

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

References:

1. Cancer Facts and Figures 2000. Atlanta, American CancerSociety, 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, anovel water-soluble derivative of camptothecin, against murine tumors. CancerRes 47:5944-5947, 1987.