Irinotecan Highly Active in Lung Cancer

TOKYO, Japan—“I remain convinced that irinotecan is one of the most active agents for the treatment of lung cancer, both non–small-cell and small-cell,” stated David H. Johnson, MD, professor of medicine and director of medical oncology at Vanderbilt University Medical Center, Nashville. Dr. Johnson was leadoff speaker at a seminar titled ‘‘Current Status of Irinotecan in Lung Cancer’’ held in conjunction with the 9th World Conference on Lung Cancer. The meeting was supported by an educational grant from Pharmacia Oncology, Yakult Honsha Co., Ltd., Daiichi Pharmaceutical Co., Ltd., and Aventis Pharma S.A.

Dr. Johnson recalled being impressed with irinotecan (Camptosar) about a decade ago while visiting the National Cancer Institute in Tokyo, where irinotecan was undergoing initial studies. This drug ‘‘was extremely active,” Dr. Johnson said, “in fact more so than any that I had witnessed in my previous experience in the United States.’’

More recently, he was impressed by the complete remissions achieved by 2 out of 20 patients with stage IV non–small-cell lung cancer enrolled in a trial of irinotecan and cisplatin (Platinol) at Vanderbilt. “Actually those were the first two and until recently the only two complete remissions I’d ever seen in my experience with stage IV disease,” he noted.

Developed in Japan, irinotecan is “a semisynthesized derivative of camptothecin, which was originally isolated from the Chinese plant Camptotheca acuminata,” explained Masahiro Fukuoka, MD, professor of the 4th Department of Internal Medicine, Kinki University School of Medicine, Osaka. Originally synthesized in 1983, irinotecan was first approved in Japan in 1994 for small-cell lung cancer and hematologic malignancies, he reported. This was followed by approvals in France in 1995 and in the United States in 1996, he said. Clinical trials, he noted, have shown irinotecan is active not only in lung cancer and hematologic malignancies but also in colorectal, gastric, ovarian, and cervical cancers.

“Irinotecan is transformed to the active metabolite SN-38 by carboxylesterase, primarily in the liver,” Dr. Fukuoka said. A potent inhibitor of topoisomerase I, irinotecan affects some DNA replication processes, he noted. “Fecal excretion is the dominant route of elimination,” he explained, passing more than 60% of the dose. Urinary excretion, he added, accounts for about 30%.

Emerging Standard

Noriyuki Masuda, MD, PhD, chief, 2nd Department of Internal Medicine, Osaka Prefectural Habikino Hospital, Osaka, reported that his group has been studying irinotecan, also known as CPT-11, alone or in combination with other cytotoxic agents for more than 10 years in non–small-cell lung cancer. In particular, he noted, “the combination of CPT-11 and cisplatin has been studied as the emerging standard for the treatment of lung cancer in Japan.”

Two phase III trials, reported Dr. Masuda, have compared the irinotecan/cisplatin combination with vindesine/cisplatin regimens. In one, no differences in response rates or median survival were seen when a regimen of cisplatin 80 mg/m² on day 1 and vindesine 3 mg/m² on days 1, 8, and 15 was compared with treatment with the same dose of cisplatin plus irinotecan 60 mg/m² on days 1, 8, and 15. The median survival in both arms of the study was about 45 weeks.

The other study, however, showed significant survival differences in stage IV disease, reported Dr. Masuda, with a median survival of 50 weeks for cisplatin/irinotecan vs 36.4 weeks for cisplatin/vindesine. The dosage schedules for these drugs were the same as in the other phase III trial. This trial also included a third arm in which irinotecan was administered alone at a dose of 100 mg/m² on days 1, 8, and 15. Overall 1-year survival rates were 47% for cisplatin/irinotecan, 38% for cisplatin/vindesine, and 42% for irinotecan alone.

“Further studies are needed,” said Dr. Masuda, “to demonstrate whether CPT-11 plus cisplatin is superior in survival to other new drug combination regimens for advanced non–small-cell lung cancer and to evaluate the role of CPT-11 in combination therapy with other promising new agents for advanced non–small-cell lung cancer.”

Weekly Approach

Corey J. Langer, MD, codirector of thoracic oncology, Fox Chase Cancer Center, Philadelphia, reported that Fox Chase and Vanderbilt University have joined forces for a trial in which both irinotecan and cisplatin are given weekly to patients with advanced non–small-cell lung cancer. The weekly dose of irinotecan is 65 mg/m² and that of cisplatin is 30 mg/m². Both drugs are given for 4 weeks and cycles are repeated every 6 weeks.

Among the first 49 patients, the majority of whom had stage IV disease, the overall response rate is 36%, median time to progression is 6.9 months, and 1-year survival rate is 46%. “The weekly approach appears to be more active and clearly looks better tolerated,” Dr. Langer said. Relative dose intensity was “well maintained for both agents,” he observed, with that for irinotecan being 89%. As a result, he indicated, “phase III studies are currently in development comparing this weekly approach to other more standard regimens.”

In an ongoing trial at Fox Chase, radical thoracic radiation at a dose of 63 Gy is being combined with a weekly irinotecan/cisplatin regimen, Dr. Langer reported. The starting dose of irinotecan is 30 mg/m² and the protocol calls for escalation by 10 mg/m² up to a maximum of 70 mg/m². The cisplatin dose is fixed at 25 mg/m².

So far, 10 patients have been enrolled and the median number of treatments is 6. The response rate is 77%, Dr. Langer revealed, and at a 10-month median follow-up, 8 of the 10 patients are free of disease progression. “Absolutely no grade- 3 esophagitis” has occurred, he said.

JCOG Clinical Trials

For the past decade, the Japan Cooperative Oncology Group (JCOG) has studied irinotecan in various chemotherapy regimens as well as in combination with radiotherapy for activity against small-cell lung cancer, recounted Tomohide Tamura, MD, head of internal medicine, National Cancer Center Hospital, Tokyo. “Irinotecan may be one of the most active agents against small-cell lung cancer,” Dr. Tamura noted.

A recent JCOG phase III study comparing an irinotecan/cisplatin regimen with the standard etoposide (VePesid)/cis-platin treatment of small-cell lung cancer showed clear differences in extensive disease, Dr. Tamura indicated. Stopped after an interim analysis revealed the superiority of the irinotecan/cisplatin regimen, the trial achieved median survivals of 13.5 months in the irinotecan/cisplatin arm and 9.3 months in the etoposide/cisplatin.

“Based on the results of this trial,” said Dr. Tamura, “irinotecan plus cisplatin is considered to be a standard treatment against extensive-stage small-cell lung cancer.” Under the protocol, irinotecan 60 mg/m² was given on days 1, 8, and 15 and cisplatin 60 mg/m² on day 1 in four 28-day cycles. The study’s other arm also repeated cycles four times, but the cycle length was 3 weeks, with etoposide 100 mg/m² administered on days 1 and 3 and cisplatin 80 mg/m² on day 1.

Currently, JCOG is investigating three-drug combinations of irinotecan, etoposide, and cisplatin in extensive small-cell lung cancer, Dr. Tamura revealed. In limited-stage disease, he added, a study is exploring the value of concurrent etoposide and cisplatin plus twice- daily radiotherapy followed by three courses of irinotecan/cisplatin.

More US Studies

In the United States, planning is under way for a study similar to the JCOG trial that showed an advantage for irinotecan/cisplatin in small-cell lung cancer, said Alan B. Sandler, associate professor of medicine, Vanderbilt University, Nashville. “The plan in the United States is for a confirmatory trial looking at the combination of cisplatin and irinotecan, using a day 1 and day 8 weekly regimen every 21 days with the comparison arm being cisplatin and etoposide,” he explained.

The 21-day cycle is being considered, he added, because with the 28-day schedule used in Japan, “approximately 40% to 50% of patients do not receive day-15 CPT-11 due to either hematologic or diarrheal complications.” The Southwest Oncology Group, he noted, is considering a phase III trial using the same dosing schedules as those used in the JCOG study.

Second-Line Therapy

The efficacy of irinotecan in second-line therapy for small-cell lung cancer, reported Dr. Sandler, was explored in a US trial led by his Vanderbilt colleague, Russell DeVore, MD. Of the 44 evaluable patients, 27 were considered refractory or resistant to therapy because they “either failed prior therapy or relapsed within 90 days of cessation of therapy,” Dr. Sandler noted.

The other 17 patients were categorized as “sensitive” because their relapses occurred more than 90 days after initial chemotherapy ended. Used as a single agent in this trial, irinotecan was given at a dose of 125 mg/m² each week in the first months of 6-week cycles.

“Only one patient in the refractory population responded to therapy, as opposed to 29% of patients in the sensitive group,” reported Dr. Sandler. The overall median survival was 4.8 months, 5.9 months for the sensitive group, and 3.7 months for the refractory cohort. Irinotecan, he observed, “appears to be well tolerated in patients with sensitive relapsed small-cell lung cancer.” In studies of a variety of agents as second-line therapy, he noted, response rates have ranged from approximately 10%-30%.

Further study of irinotecan is warranted in previously untreated patients with extensive disease, Dr. Sandler concluded.