New Clinical Strategies in Non–Small-Cell Lung Cancer

Introduction

Newer chemotherapy agents have improved the survival and quality of life for patients with non–small-cell lung cancer (eg, paclitaxel(Drug information on paclitaxel) [Taxol], docetaxel [Taxotere], gemcitabine(Drug information on gemcitabine) [Gemzar], vinorelbine [Navelbine], topotecan [Hycamtin], and irinotecan(Drug information on irinotecan) [CPT-11; Camptosar]).[1,2] We are only beginning to appreciate the advantages of these drugs. There are several clinical strategies to pursue in evaluating these agents in an attempt to further improve the quality of life and prognosis for patients with this disease.

Certainly, an understanding of basic mechanisms is critical, and several mechanistic-based therapies may be applied successfully in the near future. We do not yet, however, have any new practical or efficacious therapies applicable for patients today arising from basic research. We do have a number of new chemotherapeutic agents, several of which show good activity in non–small-cell lung cancer.

Several pragmatic clinical strategies are currently being investigated at our center and by others, and three of these will be discussed in this article.

Paclitaxel Over a 1-Hour Infusion and a Weekly Schedule

Our group was the first to shorten the infusion of paclitaxel to 1 hour.[3] We initiated a study soon after the 3-hour infusion schedule proved to be safe and less myelosuppressive than a 24-hour schedule. We have amply documented, and this has been confirmed by others, that a 1-hour infusion schedule is safe, is not associated with a high incidence of hypersensitivity reactions, and has comparable activity to longer infusions for many paclitaxel-sensitive tumors. We have subsequently performed many trials using paclitaxel over a 1-hour infusion in combination with other drugs. Others have also studied combination chemotherapy in various settings.

Although there are no randomized comparisons to definitively prove equivalence, it does appear from multiple comparisons of phase II trials that 1-hour paclitaxel infusions are very similar to 3-hour infusions in reference to efficacy in lung cancer, breast cancer, ovarian cancer, and several other malignancies. There is no apparent difference in toxicity. There are many advantages of a 1-hour infusion, including less time in the outpatient area or clinic and office, less expense, ease of use when combining with other drugs, and patient convenience. Pharmacologically, the maximum plasma concentration is higher with a 1-hour infusion. However, in all other respects, the pharmacokinetics are very similar to the 3-hour infusion. Despite a considerable volume of clinical data now available, 3-hour infusion has remained more popular.

It seems that this is mainly a reflection of historical precedence, and certainly there is no major disadvantage of a 3-hour infusion other than two additional hours of administration. Other than important practical issues allowing for more efficient treatment with less expense, this may not be viewed as a major difference.

Recently, the use of paclitaxel in a weekly schedule has been explored. Several single-agent studies are now complete and combination programs are in progress. Weekly administration of paclitaxel has a very acceptable toxicity profile. Doses as high as 175 mg/m²/week have been given without severe myelosuppression becoming the dose-limiting toxicity. However, neuropathy becomes quite serious (grade 3/4) if patients continue treatment at these higher dose levels. At 100 mg/m² or below, patients often tolerate many weeks of paclitaxel without any serious neuropathy or myelosuppression. Weekly paclitaxel has often been administered as a 1-hour infusion. Early results suggest that there is single-agent activity in lung, breast, and ovarian cancers.

Several combination studies are ongoing. At the Sarah Cannon–Minnie Pearl Cancer Center, weekly evaluations of paclitaxel in several settings are being performed, as described in Table 1. These studies are underway and it is too early to present any results. It is expected that paclitaxel in effective doses, particularly with the dose-dense weekly regimen, can be given safely with several combinations of other drugs. Hopefully, this strategy will improve the overall cytotoxic efficacy of the combination in sensitive tumor types, such as small-cell lung cancer, non–small-cell lung cancer, and breast cancer.

Development of New Triple-Drug Combination Chemotherapy

The combination of paclitaxel and carboplatin(Drug information on carboplatin) (Paraplatin) has become extremely popular. This combination has been evaluated in phase II trials, and phase III randomized prospective studies are currently in progress. The combination is relatively well tolerated, and produces less thrombocytopenia than expected from carboplatin alone at a similar dose. In addition, the activity in non–small-cell lung cancer is notable and most studies show a 1-year survival rate of about 40%. A 2-year survival rate of 20% has been observed in at least one study.[4] Most of these studies are not yet mature enough to report long-term survival rates.

Based upon the activity of paclitaxel and carboplatin, we have studied several three-drug combinations in phase I/II trials adding gemcitabine, vinorelbine, and topotecan(Drug information on topotecan), respectively, to a paclitaxel and carboplatin combination. The study is complete for the three-drug combination of paclitaxel, carboplatin, and gemcitabine. Paclitaxel has been administered as a 1-hour infusion in all of these studies. Table 2 illustrates the maximum tolerated dose recommended without growth factor support, of all three agents as determined from these phase I trials.

Paclitaxel and Carboplatin Plus Gemcitabine

The first triple-drug combination with the addition of gemcitabine was tested in a phase II trial by the Minnie Pearl Research Network, a community oncology clinical research network. In this study, 69 previously untreated patients with stage IIIB or IV non–small-cell lung cancer were treated. These patients had no central nervous system metastasis, a performance status of 0 to 2, and measurable disease with adequate bone marrow, kidney, and liver function. All patients gave an informed consent. The median age was 60 years (range 26 to 80 years), and there were 46 men and 23 women. Of these, 51 patients (74%) had stage IV disease, and of the 63 evaluable patients, 30 had objective responses (48%), including one complete response and 29 partial responses. An additional 29 patients (33%) had minor responses or stable disease. Follow-up is very short, however; 69% of the patients remain alive after a median follow-up of 5 months. Toxicity primarily was myelosuppression.

Grade 3 or 4 leukopenia was seen in 51% of the patients, but in only 26% of the courses, and grade 3 or 4 thrombocytopenia was seen in 43% of the patients, but in only 17% of the courses. Eleven patients were hospitalized with neutropenia and fever, and eight patients (12%) required platelet transfusions. Other grade 3/4 toxicity was unusual, except fatigue, which was seen in 12% of the patients. There were no treatment-related deaths.

The preliminary results of this study suggest that this triple-drug combination is highly active and well tolerated in the treatment of advanced non–small-cell lung cancer and may be superior to the combination of paclitaxel and carboplatin. Further studies, including randomized trials, may be necessary to document this possibility.

Paclitaxel and Carboplatin Plus Vinorelbine

The second triple-drug combination added vinorelbine to the paclitaxel and carboplatin combination. A phase I study in patients with lung cancer has been completed and a phase II study is now in progress. In the phase I study, the doses of paclitaxel and carboplatin were initially fixed at 200 mg/m² and an area under the concentration-time curve of 6.0 (AUC in mg/mL · min), respectively, both given over a 1-hour infusion. Vinorelbine was initially scheduled on days 1 and 8 with doses escalated in sequential cohorts of patients at 17.5 mg/m², 20 mg/m², and 22.5 mg/m². No cytokines were planned prophylactically. Patients with previously untreated stage IIIB and IV non–small-cell lung were eligible, and the entry criteria were otherwise identical to the triplet combination study using gemcitabine.

Twenty patients were entered in this study and received a median of five courses of chemotherapy. The dosing of vinorelbine on days 1 and 8 resulted in held or reduced doses on day 8 in 40% of patients. This schedule was modified to allow vinorelbine to be given on either day 8 or 15, depending on the blood counts. This subsequently allowed us to more effectively deliver 22.5 mg on day 1 and then on either day 8 or 15. At this dose level, the percentages of planned doses of paclitaxel, carboplatin, and vinorelbine actually administered were 91%, 91%, and 73%, respectively, during the first two courses. The dose-limiting toxicity was leukopenia. When utilizing the day 8 or 15 vinorelbine dosing, grade IV leukopenia did not occur in any patients at 20 mg/m2, and occurred in 33% of the patients at 22.5 mg/m².

Of the 98 courses administered, eight (8%) were associated with neutropenic fever. Grade 3/4 nonhematologic toxicity was unusual, but did include fatigue in eight patients, emesis in two patients, and neuropathy in one patient. There were no treatment-related deaths in the phase I study. It was notable that of 19 evaluable patients, 13 (68%) had partial responses. The three-drug regimen was feasible and relatively well tolerated. A phase II study is now in progress utilizing paclitaxel at 200 mg/m², carboplatin at an AUC of 6.0, and vinorelbine at 22.5 mg/m² given on day 1 and either day 8 or 15.