Irinotecan in Lung and Other Malignancies
Irinotecan in Lung and Other Malignancies
The purpose of the annual workshops sponsored by The University of Texas M. D. Anderson Cancer Center is to review the latest data on new agents, with a particular focus on the broadly used agent irinotecan (CPT-11, Camptosar). Investigators from around the world are invited to present current research. The forums are highly interactive and frank, thus allowing stimulation of new ideas and directions.
The 3rd Investigators’ Workshop was held on July 13-16, 2000, in St. Croix, US Virgin Islands. Five separate scientific sessions were held, covering
miscellaneous tumors including lymphomas; and
novel uses of topoisomerases, including enhancement of radiation-induced cytotoxicity.
In addition to stimulating research, these workshops also aim to develop enduring material for wider distribution to those who did not attend this workshop. Three publications are intended as a result of this most recent workshop. This final volume is devoted to novel agents in lung and other malignancies, and includes discussions on topoisomerase I inhibitors in lung carcinoma, head and neck cancers, and lymphoma; combined-modality therapy; and angiogenesis inhibitors. Previous volumes were devoted to gastrointestinal malignancies and breast malignancies and were published in March and May 2001, respectively.
Leading off this volume, Masahiro Fukuoka discusses the role of topoisomerase I inhibitors in the treatment of small-cell lung cancer. Chemotherapy regimens (such as the combination of etoposide [VP-16, VePesid] and cisplatin [Platinol]) are currently the main treatment for all stages of small-cell lung cancer, although therapeutic outcomes leave room for improvement. A discussion of phase II studies of single-agent irinotecan and combinations with cisplatin or etoposide is included, with a focus on the Japanese studies. Data from the Japan Clinical Oncology Group (JCOG) phase III study (JCOG 9511) of irinotecan and cisplatin vs etoposide and cisplatin (standard arm) in extensive-disease small-cell lung cancer demonstrated that the irinotecan-containing arm had significant advantages in response rate and survival at the second interim analysis. Toxicity in this arm was mild, and there were no treatment-related deaths. This phase III study thus establishes irinotecan and cisplatin as an active new regimen for extensive-disease small-cell lung cancer.
Corey Langer reviews the activity of irinotecan either alone or in combination with cisplatin and other agents (ie, taxanes, gemcitabine [Gemzar], and other platinums), and addresses its emerging role as a component of radiosensitizing therapy in locally advanced non-small-cell lung cancer. He covers planned and ongoing phase III trials to establish the utility of irinotecan in both non-small-cell lung cancer and small-cell lung cancer. In a Japanese phase III trial in non-small-cell lung cancer assessing irinotecan as a single agent or in combination with cisplatin vs vindesine (Eldisine) and cisplatin, significant survival advantage was reported in the irinotecan-containing arms. However, this advantage was not seen in a phase III study comparing vindesine and cisplatin vs irinotecan and cisplatin. In extensive-disease small-cell lung cancer, North American phase III efforts will attempt to replicate and extend the results of the Japanese JCOG 9511 phase III trial.
Hak Choy provides a critical overview of the current status of irinotecan used concurrently with radiotherapy in the treatment of a variety of solid tumors. In addition, he discusses the background and putative mechanisms of topoisomerase I inhibitors, such as camptothecins, and the mounting evidence that irinotecan has definite radiosensitizing properties that may be useful in the treatment of solid tumors. In this regard, data from a plethora of clinical trials in non-small-cell and small-cell lung, head and neck, gastrointestinal, and cervical cancers are discussed.
Continuing with the discussions of non-small-cell lung cancer management, John Murren describes the rationale for non-platinum chemotherapy. He notes that new agents such as taxanes, vinorelbine (Navelbine), gemcitabine, and irinotecan are better tolerated thanand have single-agent activity at least comparable tothat of cisplatin. Moreover, combinations of platinums and newer agents provide improved survival compared to single-agent cisplatin and fewer side effects, or both, compared to standard combinations such as cisplatin/vindesine or cisplatin/etoposide.
Myelosuppression is a major clinical problem in the management of cancer patients receiving cytotoxic therapy. Saroj Vadhan-Raj presents data from three clinical trials to examine the safety and in vivo biological effects of recombinant human thrombopoietin (rhTPO) in cancer patients receiving myelosuppressive chemotherapy. The data indicate that rhTPO is well tolerated without constitutional symptoms, fluid retention, major organ toxicities, or enhanced incidence of thrombosis. An ongoing trial is examining the importance of dose and schedule of rhTPO in achieving optimal biological effect.
Lee Ellis describes the concepts, mechanisms, characteristics of specific and nonspecific angiogenic factors, and their regulation by molecular signaling pathways. Thus, targeting the mechanisms that drive tumor angiogenesis may lead to the development of therapies that may prolong survival with reduced toxicity.
Barbara Murphy and coworkers report data from their phase II study evaluating the efficacy and tolerability of irinotecan and other topoisomerase I inhibitors in patients with metastatic or recurrent head and neck carcinoma. Irinotecan demonstrated a modest overall response rate of 21.2% with a median survival of 214 days and a 1-year survival rate of 30.2%, while aminocamptothecin (9-AC) and topotecan (Hycamtin) failed to demonstrate substantial clinical activity. They conclude that further investigation of irinotecan in the treatment of squamous cell carcinoma of the head and neck is indicated, and that combinations with other active agents may capitalize on the efficacy of irinotecan while potentially avoiding the toxicity of the high-dose regimens.
Andreas Sarris and colleagues conclude the volume by discussing the early results of a phase II trial of irinotecan in 22 patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL), using a 3-week schedule of administration. The authors report promising activity (45% response) in patients with relapsed aggressive NHL, and accrual is continuing in all treatment arms for better determination of the response rate in the various NHL subcategories.
In conclusion, I believe that the data presented at The University of Texas M. D. Anderson Cancer Center Investigators’ Workshop provide new insights about the trends and practices in various areas of oncology. As with the two preceding volumes, I hope you, the reader, will find the information in this volume relevant, stimulating, and useful in designing new trials.