The quest for new, active chemotherapy
regimens for lung cancer is an ongoing, dynamic process that has become more
challenging in the past 10 years due to the increased number of
Investigators were convened to discuss the status of one of
these agents, irinotecan (Camptosar, CPT-11), at a seminar held during the IASLC
9th World Congress, September 13, 2000, in Tokyo, Japan. The proceedings of this
seminar have been provided in this supplement to ONCOLOGY. For scientific
completeness, the articles by Drs. John Murren and Caio Max Rocha Lima have been
added, though they were not presented during the seminar.
Drs. Fukuoka, Tamura, and Sandler have provided a succinct
overview of the current state of affairs in the management of small-cell lung
cancer. On average, these patients survive no more than 9 to 10 months if they
present with extensive-stage disease, and just 20 to 24 months with
limited-stage disease. Of note, these rather unimpressive figures apply only to
those patients well enough to undergo intensive therapy and are derived from
studies that often exclude poor performance status and elderly patients.
Irinotecan in Small-Cell Lung Cancer
Fortunately, it appears that newer agents may enhance survival
in small-cell lung cancer. One agent that has offered a possible survival
benefit is irinotecan, a topoisomerase I poison that was developed and first
studied in Japan.[1,2] Only recently has irinotecan caught the attention of
North American and European investigators. However, as reviewed by Dr. Tamura,
irinotecan has been fairly extensively studied in Japan.
The combination of cisplatin (Platinol) and irinotecan is
reasonably well tolerated in patients with small-cell lung cancer, and, in a
recently completed randomized trial, proved to be superior to cisplatin plus
etoposidethe most commonly used regimen in the United States and Canada.
Both overall response rate and survival were better with cisplatin plus
irinotecan (see Table 1). Based on these
promising results, a validation study is underway in the United States. Assuming
these results are confirmed, cisplatin plus irinotecan may well become the new
standard regimen for small-cell lung cancer.
Irinotecan in Non-Small-Cell Lung Cancer
Japanese investigators also led the effort to study irinotecan
in non-small-cell lung cancer.[4,5] Single-agent activity is comparable to
other "active" agents, and in combination with cisplatin, irinotecan
is capable of effecting high objective response rates and median survivals
comparable to most commonly used cisplatin-based regimens.[6-8] For example,
cisplatin plus irinotecan yields an overall response rate of around 35% and a
median survival of approximately 35 weeks in non-small-cell lung cancer
patients with advanced disease. These results are virtually identical to that
achieved in recently completed US cooperative group phase III trials with
regimens such as cisplatin plus vinorelbine (Navelbine), cisplatin plus
paclitaxel (Taxol), carboplatin (Paraplatin) plus paclitaxel, or cisplatin plus
gemcitabine (Gemzar).[9,10] All but the carboplatin and paclitaxel regimen are
approved by the US Food and Drug Administration for use in non-small-cell lung
cancer in the United States. As discussed by Drs. Masuda and Langer, one could
make a compelling argument for including the combination of cisplatin plus
irinotecan as initial therapy in advanced non-small-cell lung cancer as well.
Although the aforementioned data are encouraging, there seems to
be a movement away from cisplatin-based therapies, at least in Europe and the
United States. In fact, many lung cancer experts feel cisplatin is simply too
toxic given its modest level of activity. As noted by Dr. Murren, the
availability of other active agents of lesser toxicity provides an impetus to
study non-platinum-containing combination regimens that may well possess
comparable levels of activity with far less toxicity.
Accordingly, the hunt for rationally designed new combinations
is underway, as illustrated by the work of Dr. Rocha Lima and colleagues. These
investigators initiated a phase I study in which docetaxel (Taxotere) is
combined with gemcitabine and irinotecan. The timing of drug administration is
based on work conducted in preclinical tumor models and takes advantage of
potentially synergistic interactions that could lead to greater cytotoxicity.
The combined use of chemotherapy and radiotherapy is now
considered standard treatment for patients with locally advanced non-small-cell
lung cancer. However, even though survival is improved with
combined-modality treatment, local and distant relapses remain problematic.
Thus, efforts to enhance local control and to reduce distant metastases are
ongoing. Drs. Choy and Langer have been leaders in this field. Their work is
designed to help elucidate the means by which irinotecan can best be integrated
into our treatment armamentarium. It appears that irinotecan can be administered
safely in conjunction with irradiation if given using a weekly administration
schedule. Preliminary results from their trials suggest the combination is at
least as effective as other commonly used regimens.
Finally, where are we headed? There is little doubt that the
lung cancer treatment arena will become even more crowded in the near future as
agents with unique mechanisms of action come into clinical use. For example, the
tyrosine kinase inhibitors are promising agents that may well revolutionize how
non-small-cell lung cancer is treated. Similarly, drugs that modulate BCL2
(a regulator of cellular apoptosis) or the tyrosine kinase c-kit, or
agents such as farnesyl transferase inhibitors that interfere with ras
signaling, may play a major role in the management of small-cell lung
cancer.[13-15] However, it seems unlikely these drugs will supplant traditional
chemotherapy or radiotherapy but rather will prove complementary to these
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