The Centers for Disease Control and Prevention recently reported that the annual mortality for lung cancer in the United States is 154,000.[1] Small-cell lung cancer accounts for approximately 15% of these tumors. Over the past 2 decades, combination chemotherapy has become the standard of care for patients who present with extensive disease. Regimens such as EP (etoposide, cisplatin(Drug information on cisplatin) [Platinol]), CAV (cyclophosphamide [Cytoxan, Neosar], doxorubicin(Drug information on doxorubicin) [Adriamycin], vincristine), and EC (etoposide, carboplatin(Drug information on carboplatin) [Paraplatin]) can produce response rates as high as 80%. Nevertheless, for patients with extensive-stage disease, the median survival is just 7 to 11 months and few patients are alive 2 years from diagnosis. Even in limited-stage disease, combined modality treatment with concurrent chemotherapy and radiation produces long-term survival in only 15% of patients.
As a result, evaluation of newer agents in treatment of small-cell lung cancer is of critical importance. Newer agents that are active in small-cell lung cancer include irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), docetaxel (Taxotere), gemcitabine(Drug information on gemcitabine) (Gemzar), ifosfamide(Drug information on ifosfamide) (Ifex), paclitaxel(Drug information on paclitaxel), topotecan(Drug information on topotecan) (Hycamtin), and vinorelbine (Navelbine).[2] In this article, we will focus on progress in the development of camptothecin/taxane combinations in the management of small-cell lung cancer.
Role of Camptothecin Derivatives in Small-Cell Lung Cancer
The mechanism of action of camptothecin analogs involves their interaction with topoisomerase I. As a result, the DNA/topoisomerase complex is bound and normal DNA replication is disrupted, leading to double-stranded DNA breaks and cell death. Semisynthetic compounds in this class include topotecan and irinotecan.
Irinotecan has shown activity against a broad range of animal and human malignancies, including lung cancer. In chemotherapy-naive small-cell lung cancer patients, Negoro et al reported a 50% response rate to single-agent irinotecan in a small series.[3] In previously treated small-cell lung cancer patients, response rates of 16% to 47% have been reported.[4] More recently, a Japan Clinical Oncology Group phase III trial of 152 extensive-stage small-cell lung cancer patients showed superiority of irinotecan/cisplatin over etoposide(Drug information on etoposide)/cisplatin in terms of median survival (411 vs 282 days, P = .0021), overall response rate (83% vs 68%), and 2-year survival rate (19% vs 7%).[5] Two North American phase III trials are under way to further define the role of irinotecan/cisplatin combinations in small-cell lung cancer.
Topotecan is the other approved semisynthetic camptothecin. Schiller et al treated 48 newly diagnosed extensive-stage patients with topotecan at 2 mg/m²/d for 5 days every 3 weeks. The response rate was 40% and median survival was 10 months.[6] Pooled data of 168 patients with sensitive relapse (defined as relapse occurring more than 3 months after previous chemotherapy) showed that 18% responded to topotecan with a median survival of 30 weeks and a 1-year survival rate of 21%.[7] A randomized trial comparing topotecan with CAV in patients with sensitive relapse demonstrated comparable response rates and survival times for the two regimens. In that study, topotecan was more effective in controlling disease-related symptoms.[8] In a recent Eastern Cooperative Oncology Group (ECOG) study of 223 patients with extensive-stage small-cell lung cancer, topotecan given after four cycles of EP improved progression-free survival by 1.3 months when compared to observation. However, overall survival and quality of life were not statistically different in the two arms.[9]
Role of Taxanes in Small-Cell Lung Cancer
The taxanes promote microtubular assembly but prevent their disassembly, thus interfering with normal tubulin polymerization and cell division. Both the Pacific yew-derived paclitaxel and the semisynthetic compound docetaxel(Drug information on docetaxel) show promise in the treatment of small-cell lung cancer.
The ECOG performed a phase II study of single-agent paclitaxel in previously untreated extensive-stage small-cell lung cancer patients. Paclitaxel at 250 mg/m² infused over 24 hours produced a response rate of 34%, but 56% of patients had grade 4 leukopenia.[10] The North Central Cancer Treatment Group used a similar paclitaxel schedule with the addition of granulocyte colony stimulating factor (G-CSF [Neupogen]) support and reported a 53% response rate and a reduction to 14% in the rate of grade 4 leukopenia.[11] In a small trial involving pretreated patients with early relapses, paclitaxel was associated with a 29% response rate.[12] When paclitaxel was combined with cisplatin, Nair et al reported impressive response rates of 71% to 89% in extensive-stage small-cell lung cancer patients.[13]
Docetaxel has also been studied for the treatment of small-cell lung cancer. In a phase II trial of chemotherapy-naive small-cell lung cancer patients conducted by the Southwest Oncology Group (SWOG), docetaxel at 100 mg/m² produced a response rate of 25% and a median survival of 9 months.[14] The European Organization for Research and Treatment of Cancer (EORTC) reported a response rate of 25% with single-agent docetaxel at a dose of 60 mg/m² in previously treated patients.[15]
Combinations of Docetaxel and Irinotecan
In animal and human cell lines, the combination of taxanes and camptothecins can be additive or synergistic, but results have been conflicting. Chou et al showed synergism between paclitaxel and topotecan in human teratocarcinoma cell line,[16] but Kaufman et al actually showed antagonism when this combination was used in a human lung cancer cell line.[17] In vitro studies of the combination of docetaxel and irinotecan showed notable activity in many models. There was the suggestion that their activity in combination may be dependent on dosing, sequencing, and cell type.
Couteau et al showed in a phase I study that when docetaxel was given prior to irinotecan, no relevant drug interaction was detected and the pharmacokinetics were consistent with the behavior of each drug given individually.[18] Takeda et al gave the irinotecan prior to docetaxel and reported a mild increase in docetaxel clearance.[19] The bulk of evidence suggests no clinically significant interaction between these two drugs with respect to pharmacokinetics.[18-21]
In terms of dosing schedule, initial studies administered the medications on an every 3-week cycle. However, high rates of neutropenia and late diarrhea were reported in such studies (see Table 1). Couteau et al reported 85% with grade 4 leukopenia lasting a median of 5 days (and 22.5% with febrile neutropenia).[18] Adjei et al reported 94% with grade 3/4 leukopenia and 17% with febrile neutropenia.[22] Masuda et al reported grade 3 or 4 neutropenia in only 19% with only 6% having febrile neutropenia, but this study employed lower dose intensity. Most phase II trials of docetaxel/irinotecan also report neutropenia as the most frequent toxicity.
When given with equivalent dose intensity, docetaxel on a weekly schedule has a lower incidence of neutropenia compared to a 3-week schedule. Additionally, more frequent administration allows the option of withholding doses when neutrophil counts are borderline. Additionally, irinotecan displays a more favorable toxicity profile when given on a weekly basis. Major toxicities of irinotecan when given on an every-3-week schedule tend to be granulocytopenia, febrile neutropenia, and/or late diarrhea. When given on a weekly schedule, irinotecan has lower incidences of severe neutropenia and diarrhea. Thus giving docetaxel/irinotecan combinations on a weekly schedule should be considered as a means of increasing the safety of administration.
At the Yale Cancer Center, we have conducted a phase I study evaluating weekly docetaxel/irinotecan. We originally delivered the medications weekly for 4 weeks on an every-6-week cycle, but due to frequent treatment delays at day 21 due to neutropenia, we amended the dosing guidelines. We found that the combination was better tolerated when docetaxel at 35 mg/m² and irinotecan at 60 mg/m² were given on days 1 and 8 of an every-3-week cycle. In 44 patients studied, preliminary data show grade 3 or 4 neutropenia in 25% and only 1 patient had dose-limiting febrile neutropenia (2.3%). Diarrhea became the dose-limiting toxicity, but first-cycle grade 3 or 4 diarrhea was only present in 11.3%. Font et al, Vernejoux et al, and Seneviratne et al also reported reduced complications of neutropenia in weekly docetaxel/irinotecan regimens and various gastrointestinal toxicities then became dose-limiting toxicities.[21,23,24] Thus, weekly combinations appear to allow safer administration of docetaxel/irinotecan.
Phase II studies of docetaxel/irinotecan have been reported at least in abstract form for non-small-cell lung cancer, ovarian cancer, gastric cancer, pancreatic cancer, and mesothelioma.[25-29] Unfortunately, progress in the evaluation of small-cell lung cancer has been slower. Possible reasons include lower incidence of small-cell lung cancer patients compared to non-small-cell lung cancer, and preferential enrollment in standard regimen or other clinical trials (such as phase III studies of cisplatin/irinotecan). Nevertheless, studies of this promising combination should be pursued for patients with extensive disease.
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