Irinotecan: Summary and Future Directions

The quest for new, active chemotherapyregimens for lung cancer is an ongoing, dynamic process that has become morechallenging in the past 10 years due to the increased number of"active" agents.

Investigators were convened to discuss the status of one ofthese agents, irinotecan (Camptosar, CPT-11), at a seminar held during the IASLC9th World Congress, September 13, 2000, in Tokyo, Japan. The proceedings of thisseminar have been provided in this supplement to ONCOLOGY. For scientificcompleteness, the articles by Drs. John Murren and Caio Max Rocha Lima have beenadded, though they were not presented during the seminar.

Drs. Fukuoka, Tamura, and Sandler have provided a succinctoverview of the current state of affairs in the management of small-cell lungcancer. On average, these patients survive no more than 9 to 10 months if theypresent with extensive-stage disease, and just 20 to 24 months withlimited-stage disease. Of note, these rather unimpressive figures apply only tothose patients well enough to undergo intensive therapy and are derived fromstudies that often exclude poor performance status and elderly patients.

Irinotecan in Small-Cell Lung Cancer

Fortunately, it appears that newer agents may enhance survivalin small-cell lung cancer. One agent that has offered a possible survivalbenefit is irinotecan, a topoisomerase I poison that was developed and firststudied in Japan.[1,2] Only recently has irinotecan caught the attention ofNorth 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 isreasonably well tolerated in patients with small-cell lung cancer, and, in arecently completed randomized trial, proved to be superior to cisplatin plusetoposide[3]—the most commonly used regimen in the United States and Canada.Both overall response rate and survival were better with cisplatin plusirinotecan (see Table 1). Based on thesepromising results, a validation study is underway in the United States. Assumingthese results are confirmed, cisplatin plus irinotecan may well become the newstandard regimen for small-cell lung cancer.

Irinotecan in Non-Small-Cell Lung Cancer

Japanese investigators also led the effort to study irinotecanin non-small-cell lung cancer.[4,5] Single-agent activity is comparable toother "active" agents, and in combination with cisplatin, irinotecanis capable of effecting high objective response rates and median survivalscomparable to most commonly used cisplatin-based regimens.[6-8] For example,cisplatin plus irinotecan yields an overall response rate of around 35% and amedian survival of approximately 35 weeks in non-small-cell lung cancerpatients with advanced disease. These results are virtually identical to thatachieved in recently completed US cooperative group phase III trials withregimens such as cisplatin plus vinorelbine (Navelbine), cisplatin pluspaclitaxel (Taxol), carboplatin (Paraplatin) plus paclitaxel, or cisplatin plusgemcitabine (Gemzar).[9,10] All but the carboplatin and paclitaxel regimen areapproved by the US Food and Drug Administration for use in non-small-cell lungcancer in the United States. As discussed by Drs. Masuda and Langer, one couldmake a compelling argument for including the combination of cisplatin plusirinotecan as initial therapy in advanced non-small-cell lung cancer as well.

Nonplatinum Regimens

Although the aforementioned data are encouraging, there seems tobe a movement away from cisplatin-based therapies, at least in Europe and theUnited States. In fact, many lung cancer experts feel cisplatin is simply tootoxic given its modest level of activity. As noted by Dr. Murren, theavailability of other active agents of lesser toxicity provides an impetus tostudy non-platinum-containing combination regimens that may well possesscomparable levels of activity with far less toxicity.

Accordingly, the hunt for rationally designed new combinationsis underway, as illustrated by the work of Dr. Rocha Lima and colleagues. Theseinvestigators initiated a phase I study in which docetaxel (Taxotere) iscombined with gemcitabine and irinotecan. The timing of drug administration isbased on work conducted in preclinical tumor models and takes advantage ofpotentially synergistic interactions that could lead to greater cytotoxicity.

Combined-Modality Treatment

The combined use of chemotherapy and radiotherapy is nowconsidered standard treatment for patients with locally advanced non-small-celllung cancer.[11] However, even though survival is improved withcombined-modality treatment, local and distant relapses remain problematic.Thus, efforts to enhance local control and to reduce distant metastases areongoing. Drs. Choy and Langer have been leaders in this field. Their work isdesigned to help elucidate the means by which irinotecan can best be integratedinto our treatment armamentarium. It appears that irinotecan can be administeredsafely in conjunction with irradiation if given using a weekly administrationschedule. Preliminary results from their trials suggest the combination is atleast as effective as other commonly used regimens.

Future Directions

Finally, where are we headed? There is little doubt that thelung cancer treatment arena will become even more crowded in the near future asagents with unique mechanisms of action come into clinical use. For example, thetyrosine kinase inhibitors are promising agents that may well revolutionize hownon-small-cell lung cancer is treated.[12] Similarly, drugs that modulate BCL2(a regulator of cellular apoptosis) or the tyrosine kinase c-kit, oragents such as farnesyl transferase inhibitors that interfere with rassignaling, may play a major role in the management of small-cell lungcancer.[13-15] However, it seems unlikely these drugs will supplant traditionalchemotherapy or radiotherapy but rather will prove complementary to theseapproaches.

References:

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

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

3. Noda K, Nishiwaki Y, Kawahara M, et al: Randomized phase IIIstudy of irinotecan and cisplatin versus etoposide and cisplatin inextensive-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 weeklyintravenous infusions of CPT-11, a new derivative of camptothecin, in thetreatment of advanced non-small-cell lung cancer. J Natl Cancer Inst83:1164-1168, 1991.

5. Masuda N, Fukuoka M, Takada M, et al: CPT-11 in combinationwith cisplatin for advanced non-small-cell lung cancer. J Clin Oncol10:1775-1780, 1992.

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

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

8. DeVore RF, Johnson DH, Crawford J, et al: Phase II study ofirinotecan 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 trialcomparing cisplatin with cisplatin plus vinorelbine in the treatment of advancednon-small-cell lung cancer: A Southwest Oncology Group study. J Clin Oncol16:2459-2465, 1998.

10. Schiller JH, Harrington D, Sandler A, et al: A randomizedtrial 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 phaseIII trial in regionally advanced unresectable non-small cell lung cancer. Chest117:358-364, 2000.

12. Kris M, Ranson M, Ferry D, et al: Phase I study of oralZD1839 (Iressa), a novel inhibitor of epidermal growth factor tyrosine kinase(EGFR-TK): Evidence of good tolerability and activity. Clin Cancer Res5(suppl):3749S, 1999.

13. Ziegler A, Luedke GH, Fabbro D, et al: Induction ofapoptosis in small-cell lung cancer cells by an antisense oligodeoxynucleotidetargeting the bcl-2 coding sequence [see comments]. J Natl Cancer Inst89:1027-1036, 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 Cancer78:1035-1042, 1998.

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