Irinotecan in Lung and Other Malignancies

July 1, 2001

The purpose of the annual workshops sponsored by The Universityof Texas M. D. Anderson

The purpose of the annual workshops sponsored by The Universityof Texas M. D. AndersonCancer Center is to review the latest data on new agents, with a particularfocus on the broadlyused agent irinotecan (CPT-11, Camptosar). Investigators from around the worldare invited to present current research. The forums are highly interactive andfrank, 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 wereheld, covering

colorectal carcinoma;

lung carcinoma;

breast carcinoma;

miscellaneous tumors including lymphomas; and

novel uses of topoisomerases, including enhancement ofradiation-induced cytotoxicity.

In addition to stimulating research, these workshops also aim todevelop enduring material for wider distribution to those who did not attendthis workshop. Three publications are intended as a result of this most recentworkshop. This final volume is devoted to novel agents in lung and othermalignancies, and includes discussions on topoisomerase I inhibitors in lungcarcinoma, head and neck cancers, and lymphoma; combined-modality therapy; andangiogenesis inhibitors. Previous volumes were devoted to gastrointestinalmalignancies and breast malignancies and were publishedin March and May 2001, respectively.

Leading off this volume, Masahiro Fukuoka discusses the role oftopoisomerase I inhibitors in the treatment of small-cell lung cancer.Chemotherapy regimens (such as the combination of etoposide [VP-16, VePesid] andcisplatin [Platinol]) are currently the main treatment for all stages ofsmall-cell lung cancer, although therapeutic outcomes leave room forimprovement. A discussion of phase II studies of single-agent irinotecan andcombinations with cisplatin or etoposide is included, with a focus on theJapanese studies. Data from the Japan Clinical Oncology Group (JCOG) phase IIIstudy (JCOG 9511) of irinotecan and cisplatin vs etoposide and cisplatin(standard arm) in extensive-disease small-cell lung cancer demonstrated that theirinotecan-containing arm had significant advantages in response rate andsurvival at the second interim analysis. Toxicity in this arm was mild, andthere were no treatment-related deaths. This phase III study thus establishesirinotecan and cisplatin as an active new regimen for extensive-diseasesmall-cell lung cancer.

Corey Langer reviews the activity of irinotecan either alone orin combination with cisplatin and other agents (ie, taxanes, gemcitabine[Gemzar], and other platinums), and addresses its emerging role as a componentof radiosensitizing therapy in locally advanced non-small-cell lung cancer. Hecovers planned and ongoing phase III trials to establish the utility ofirinotecan in both non-small-cell lung cancer and small-cell lung cancer. In aJapanese phase III trial in non-small-cell lung cancer assessing irinotecan asa single agent or in combination with cisplatin vs vindesine (Eldisine) andcisplatin, significant survival advantage was reported in theirinotecan-containing arms. However, this advantage was not seen in a phase IIIstudy comparing vindesine and cisplatin vs irinotecan and cisplatin. Inextensive-disease small-cell lung cancer, North American phase III efforts willattempt to replicate and extend the results of the Japanese JCOG 9511 phase IIItrial.

Hak Choy provides a critical overview of the current status ofirinotecan used concurrently with radiotherapy in the treatment of a variety ofsolid tumors. In addition, he discusses the background and putative mechanismsof topoisomerase I inhibitors, such as camptothecins, and the mounting evidencethat irinotecan has definite radiosensitizing properties that may be useful inthe treatment of solid tumors. In this regard, data from a plethora of clinicaltrials 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 cancermanagement, 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 than—and have single-agent activity atleast comparable to—that of cisplatin. Moreover, combinations of platinums andnewer agents provide improved survival compared to single-agent cisplatin andfewer side effects, or both, compared to standard combinations such ascisplatin/vindesine or cisplatin/etoposide.

Myelosuppression is a major clinical problem in the managementof cancer patients receiving cytotoxic therapy. Saroj Vadhan-Raj presents datafrom three clinical trials to examine the safety and in vivo biological effectsof recombinant human thrombopoietin (rhTPO) in cancer patients receivingmyelosuppressive chemotherapy. The data indicate that rhTPO is well toleratedwithout constitutional symptoms, fluid retention, major organ toxicities, orenhanced incidence of thrombosis. An ongoing trial is examining the importanceof dose and schedule of rhTPO in achieving optimal biological effect.

Lee Ellis describes the concepts, mechanisms, characteristics ofspecific and nonspecific angiogenic factors, and their regulation by molecularsignaling pathways. Thus, targeting the mechanisms that drive tumor angiogenesismay lead to the development of therapies that may prolong survival with reducedtoxicity.

Barbara Murphy and coworkers report data from their phase IIstudy evaluating the efficacy and tolerability of irinotecan and othertopoisomerase I inhibitors in patients with metastatic or recurrent head andneck 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%, whileaminocamptothecin (9-AC) and topotecan (Hycamtin) failed to demonstratesubstantial clinical activity. They conclude that further investigation ofirinotecan in the treatment of squamous cell carcinoma of the head and neck isindicated, and that combinations with other active agents may capitalize on theefficacy of irinotecan while potentially avoiding the toxicity of the high-doseregimens.

Andreas Sarris and colleagues conclude the volume by discussingthe early results of a phase II trial of irinotecan in 22 patients with relapsedor refractory non-Hodgkin’s lymphoma (NHL), using a 3-week schedule ofadministration. The authors report promising activity (45% response) in patientswith relapsed aggressive NHL, and accrual is continuing in all treatment armsfor better determination of the response rate in the various NHL subcategories.

In conclusion, I believe that the data presented at TheUniversity of Texas M. D. Anderson Cancer Center Investigators’ Workshopprovide new insights about the trends and practices in various areas ofoncology. As with the two preceding volumes, I hope you, the reader, will findthe information in this volume relevant, stimulating, and useful in designingnew trials.