The comprehensive review by Dr. Karen Kelly meticulously outlines the
rationale for the study of irinotecan in non-small-cell lung cancer (NSCLC),
summarizes results of trials of this agent as monotherapy and as a component of
doublet and triplet regimens in previously untreated NSCLC patients, and then
reviews its role in previously treated NSCLC patients.
Like the taxanes and gemcitabine, irinotecan is certainly an active drug in
NSCLC. Unfortunately, however, it appears a therapeutic plateau has been reached
in the treatment of advanced NSCLC with these newer active drugs in combination
with a platinum compound. Median survivals of approximately 8 months and 1-year
survival rates of approximately 35% are now widely reported in multiple phase
III trials from a variety of cooperative groups.[1,2]
Strategies for Using Irinotecan
Despite attempts at varying the active agents studied, their schedules of
administration, and sequences/doses of component agents, no recent trial has
suggested an appreciable move forward with any such approach. To that end, it is
difficult to foresee in what setting irinotecan might be routinely advantageous
when used in the untreated NSCLC population. However, a burgeoning understanding
of the molecular biology of common solid tumors may provide an opportunity for
irinotecan and other agents to be used more creatively in this disease.
One such strategy would be to study drug combinations for tumor types in
which the leading candidates for successful targeted therapies and irinotecan
both have activity. To date, the most promising classes of agents have been
either small molecules (eg, erlotinib [OSI-774, Tarceva], gefitinib [ZD1839,
Iressa]) or monoclonal antibodies targeting the HER family (trastuzumab [Herceptin],
cetuximab [IMC-C225, Erbitux]).
Given the frequency of perturbations in this signaling pathway in common
solid tumors and the activity profile of irinotecan, combination trials could be
envisioned in NSCLC as well as colorectal, ovarian, and cervical cancers.[3,4]
Moreover, preclinical data suggest that epidermal growth factor receptor (EGFR)-tyrosine
kinase (TK) inhibitors may be helpful in diseases that have little EGFR
expressionfor example, small-cell lung cancer (SCLC), in which irinotecan is
Design of Future Trials
1. Schiller JH, Harrington D, Belani CP, et al: Comparison of four
chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med
2. Kelly K, Crowley J, Bunn P, et al: A randomized phase III trial of
paclitaxel plus carboplatin (PC) vs vinorelbine plus cisplatin (VC) in untreated
advanced non-small cell lung cancer (NSCLC): A Southwest Oncology Group (SWOG)
trial (abstract 1777). Proc Am Soc Clin Oncol 18:461a, 1999.
3. Garcia-Carbonero R, Supko JG: Current perspectives on the clinical
experience, pharmacology, and continued development of the camptothecins. Clin
Cancer Res 8:641-661, 2002.
4. Arteaga C: The epidermal growth factor receptor: From mutant oncogene in
nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol
5. Sirotnak F, Zakowski M, Miller V, et al: Efficacy of cytotoxic agents
against human tumor xenografts is markedly enhanced by coadministration of
ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res
6. Albanell J, Rojo F, Averbuch S, et al: Pharmacodynamic studies of the EGF
receptor inhibitor ZD1839 (Iressa) in skin from cancer patients:
Histopathological and molecular consequences of receptor inhibition. J Clin
Oncol 20:110-124, 2001.
7. Lin ZP, Boller YC, Amser SM, et al: Prevention of brefeldin A-induced
resistance to teniposide by the proteasome inhibitor MG-132: Involvement of NF-kB
activation in drug resistance. Cancer Res 58:3059-3065, 1998.
8. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared
with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med