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Irinotecan: Summary and Future Directions

Irinotecan: Summary and Future Directions

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 "active" agents.

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 etoposide[3]—the 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.

Nonplatinum Regimens

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.

Combined-Modality Treatment

The combined use of chemotherapy and radiotherapy is now considered standard treatment for patients with locally advanced non-small-cell lung cancer.[11] 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.

Future Directions

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.[12] 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 approaches.

References

1. Negoro S, Fukuoka M, Niitani H, et al: Phase II study of CPT-11, new camptothecin derivative, in small cell lung cancer. Proc Am Soc Clin Oncol 10:241, 1991.

2. Masuda N, Fukuoka M, Kununoki Y, et al: CPT-11: A new derivative of camptothecin for the treatment of refractory or relapsed small cell lung cancer. J Clin Oncol 10:1225-1229, 1992.

3. Noda K, Nishiwaki Y, Kawahara M, et al: Randomized phase III study of irinotecan and cisplatin versus etoposide and cisplatin in extensive-disease small cell lung cancer: Japan Clinical Oncology Group Study (JCOG9511). Proc Am Soc Clin Oncol 19:483a, 2000.

4. Negoro S, Fukuoka M, Masuda N, et al: Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst 83:1164-1168, 1991.

5. Masuda N, Fukuoka M, Takada M, et al: CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer. J Clin Oncol 10:1775-1780, 1992.

6. Masuda N, Fukuoka M, Kudoh S, et al: Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer. Br J Cancer 68:777-782, 1993.

7. Fukuoka M, Masuda N: Clinical studies of irinotecan alone and in combination with cisplatin. Cancer Chemother Pharmacol 34(suppl):S105-S111, 1994.

8. DeVore RF, Johnson DH, Crawford J, et al: Phase II study of irinotecan plus cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 17:2710-2720, 1999.

9. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: A Southwest Oncology Group study. J Clin Oncol 16:2459-2465, 1998.

10. Schiller JH, Harrington D, Sandler A, et al: A randomized trial of four chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 19:1a, 2000.

11. Sause W, Kolesar P, Taylor S, et al: Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer. Chest 117:358-364, 2000.

12. Kris M, Ranson M, Ferry D, et al: Phase I study of oral ZD1839 (Iressa), a novel inhibitor of epidermal growth factor tyrosine kinase (EGFR-TK): Evidence of good tolerability and activity. Clin Cancer Res 5(suppl):3749S, 1999.

13. Ziegler A, Luedke GH, Fabbro D, et al: Induction of apoptosis in small-cell lung cancer cells by an antisense oligodeoxynucleotide targeting the bcl-2 coding sequence [see comments]. J Natl Cancer Inst 89:1027-1036, 1997.

14. Zangemeister-Wittke U, Schenker T, Luedke GH, et al: Synergistic cytotoxicity of bcl-2 antisense oligodeoxynucleotides and etoposide, doxorubicin and cisplatin on small-cell lung cancer cell lines. Br J Cancer 78:1035-1042, 1998.

15. Du W, Lebowitz PF, Prendergast GC: Cell growth inhibition by farnesyl transferase inhibitors is mediated by gain of geranylgeranylated RhoB. Mol Cell Biol 19:1831-1840, 1999.

 
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