New Clinical Strategies in Non–Small-Cell Lung Cancer

In an attempt to further improve the quality of life and prognosis of patients with non–small-cell lung cancer, several clinical strategies exist to evaluate newer chemotherapy agents for this disease. Several of these pragmatic strategies are being investigated at our center and by others, and all of these represent rather classic empiric or semiempiric methods, primarily utilizing cytotoxic therapy. Three new clinical strategies are reviewed in this article: 1) the use of paclitaxel (Taxol) over a 1-hour infusion and a weekly schedule; 2) the development of triple-drug combination regimens utilizing new chemotherapeutic agents; and 3) the rationale, plans, and preliminary information regarding neoadjuvant and adjuvant therapy with the newer drug combinations. [ONCOLOGY 13(4):60-64, 1999] Introduction Newer chemotherapy agents have improved the survival and quality of life for patients with non–small-cell lung cancer (eg, paclitaxel [Taxol], docetaxel [Taxotere], gemcitabine [Gemzar], vinorelbine [Navelbine], topotecan [Hycamtin], and 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 (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, 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. Paclitaxel and Carboplatin Plus Topotecan The third three-drug regimen evaluated topotecan added to the combination of paclitaxel and carboplatin. Although topotecan probably has a little less single-agent activity in non–small-cell lung cancer than gemcitabine and vinorelbine, the available phase II trials show that the 1-year survival of these patients is quite comparable to the other newer drugs including paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan.[2] In addition, topotecan has substantial activity in small-cell lung cancer. The phase I trial of paclitaxel, carboplatin, and topotecan was performed in patients with a variety of solid tumors, but an attempt was made to treat several patients with progressive small-cell lung cancer. Certainly, this combination could also be applied to patients with non–small-cell lung cancer. A total of 18 patients were treated in the phase I trial. It was decided arbitrarily to use topotecan daily for 3 days rather than 5 days and to fix the dose of paclitaxel at 135 mg/m² and carboplatin at an AUC of 5.0, both on day 1. We started at a dose of topotecan of 1 mg/m²/day. Thrombocytopenia was dose-limiting at the initial topotecan dose of 1 mg/m². All five patients in this cohort experienced grade 3/4 thrombocytopenia with a median nadir of 26,000 (range 8,000 to 50,000). At 0.75 mg/m² on days one to three, seven patients were treated, four of which experienced at least one episode of grade 3/4 thrombocytopenia (five of 41 courses). This level of thrombocytopenia was considered acceptable. Subsequently, we added the cytokine growth factor (G-CSF) and increased the dose of paclitaxel to 175 mg/m² with an additional six patients enrolled. Grade 4 neutropenia was eliminated, although two of six patients (five of 10 courses) experienced grade 4 thrombocytopenia. In all patients, grade 4 neutropenia was only seen in eight of 67 courses, with one episode of febrile neutropenia. Only minimal nonhematologic toxicity was observed on this regimen (no grade 3/4 toxicity). Substantial activity was seen, with seven of 10 extensive small-cell lung cancer patients responding (six partial remissions and one complete remission). An additional patient with melanoma had a complete response, and one patient with gastric cancer had a partial response. All responders with small-cell lung cancer had been previously treated, and all had been off treatment for more than 3 months before relapse. The maximum tolerated dose, without cytokine support, is paclitaxel at 135 mg/m², carboplatin at an AUC of 5.0, and topotecan at 0.75 mg/m²/day on days 1, 2, and 3 (Table 2). This regimen does produce thrombocytopenia; however, grade 3/4 thrombocytopenia was seen in only about 12% of all courses. This is an active regimen, particularly in small-cell lung cancer and further study is warranted. Phase II trials can be considered for several tumor types, including non–small-cell lung cancer, small-cell lung cancer, ovarian cancer, gastric cancer, and melanoma. Discussion These triplet combinations represent attempts to improve the efficacy of the paclitaxel and carboplatin combination regimen. Any improvement is likely to translate to an even more important effect in patients with earlier stage disease, particularly those with resectable stages IB, II, and IIIA disease. Whether these three-drug combinations are superior to the two-drug combination of paclitaxel and carboplatin remains to be determined by results of prospective comparisons. Efforts now are exploring non-platinum two-drug combinations, and comparing these with our two triplet combinations. A four-arm, phase II, randomized prospective trial has been initiated in patients with stage IIIB and IV non–small-cell lung cancer comparing paclitaxel, carboplatin, and gemcitabine vs paclitaxel, carboplatin, and vinorelbine vs paclitaxel and gemcitabine vs gemcitabine and vinorelbine. Toxicity and response rates will be compared and the study will be enlarged to a phase III design if any of these combinations look particularly interesting. Neoadjuvant and Adjuvant Approaches There is now sound logic for neoadjuvant or adjuvant therapy for patients with stages IB, II, and IIIA non–small-cell lung cancer. In all of these stages, the cure rate is below 50% with surgery alone for patients with resectable tumors. Survival rates for patients with IB disease are around 35%, whereas those with stage II and IIIA disease are considerably lower. The current logic for neoadjuvant and adjuvant treatment is outlined in Table 3. The newer combinations, particularly the combination of paclitaxel and carboplatin, are well tolerated and produce response rates in cooperative group trials of 28% to 48%. Furthermore, the 1-year survival rate in patients with stage IV disease is about 40%, and the 2-year survival rate is approximately 20%. The clinical biology of non–small-cell lung cancer has been known for many years. Most patients, even with resectable tumors, harbor micrometastasis and will die of progressive cancer when no other effective therapy is administered. Although there are no reports yet of randomized comparisons to definitively prove that neoadjuvant or adjuvant therapy with the newer drug combinations is superior to no therapy at all, there is now a logical basis for treatment. The historical experience with breast cancer can serve as an analogy. The first major successful adjuvant chemotherapy program included cyclophosphamide (Cytoxan), methotrexate (Folex), and 5-FU (CMF), which improved survival in a randomized study vs no other therapy after surgery. At that time, the CMF regimen produced a 30% to 40% response rate in patients with advanced metastatic breast cancer. The 1-year survival was very similar to what we now see in patients with stage IV non–small-cell lung cancer (approximately 40%), as was the 2-year survival rate (approximately 20%). CMF was subsequently accepted as capable of improving survival in at least certain subsets of patients in the adjuvant setting. In non–small-cell lung cancer, several pilot studies are currently evaluating adjuvant and neoadjuvant therapy (Table 4 and Table 5). Some of these include older cisplatin-based chemotherapy with none of the newer drugs. Several randomized comparisons are either beginning or will begin soon. Phase II Studies There are two pilot studies that have accumulated some information. The first pilot or feasibility phase II study is being conducted by the Minnie Pearl Research Network and includes patients with stages IB to IIIB disease in the neoadjuvant and adjuvant settings.[5] Paclitaxel (200 mg/m²) and carboplatin (AUC of 6) are given every 3 weeks for three courses (40 patients neoadjuvant, 21 patients adjuvant). Patients with unresectable tumors or those resected with stages II to IIIB also receive radiotherapy (45 to 60 Gy) concurrently with weekly paclitaxel (50 mg/m²) and carboplatin (AUC of 2) for 6 weeks. Of the 40 neoadjuvant patients, 16 have been resected and 10 unresected. The unresected patients received radiotherapy and the weekly chemotherapy. The 38 evaluable neoadjuvant patients received three courses of paclitaxel and carboplatin. Of these patients, 19 (50%) had objective responses and 14 (38%) were stable. Of the 16 patients who underwent surgery, three (16%) had a complete pathologic response, six (32%) a partial response (one microscopic residual), and seven (43%) were considered stable. Radiotherapy and weekly chemotherapy was completed by 16 patients (10 unresectable, 6 resectable). Of the 21 adjuvant patients, 18 completed three courses of chemotherapy, and 12 patients (stages II to IIIB) completed radiotherapy and weekly chemotherapy. Follow-up is brief, but the toxicity is acceptable with no treatment-related deaths. This neoadjuvant or adjuvant approach is feasible, has the potential to improve survival, and certainly warrants further study in a randomized setting. The second pilot phase II neoadjuvant study is being conducted by several university centers in the UnitedStates (Bi-Modality Lung Oncology Team [BLOT]).[6] Patients with stage IB and II, all with negative mediastinoscopy received paclitaxel (225 mg/m² and carboplatin (AUC = 6) for two courses every 3 weeks preoperatively, and three courses postoperatively. A total of 31 patients have been treated; 27 of these have completed preoperative chemotherapy. Major responses were seen in 19 of 27 patients (70%); 25 patients were eligible for surgery; and 23 were completely resected. One pathologic response was observed and no unexpected toxicity was seen. This approach is feasible, does not compromise surgery, and should be tested in a randomized prospective trial. These two studies illustrate an exciting area of clinical research, which hopefully will improve the survival of patients with early stage non–small-cell lung cancer. References: 1. Greco FA, Hainsworth JD: Multidisciplinary approach to potentially curable non–small-cell carcinoma of the lung. Oncology 1:27-36, 1997. 2. Bunn PA, Kelly K: New chemotherapeutic agents prolong survival and improve quality of life in non–small-cell lung cancer: A review of the literature and future directions. Clin Cancer Res 5:1087-1100, 1998. 3. Hainsworth JD, Raefsky EL, Greco FA: Paclitaxel administered by a one-hour infusion: A phase I/II trial comparing two schedules. Cancer J Sci Am 1:281-287, 1995. 4. Greco FA, Hainsworth JD: One-hour paclitaxel plus carboplatin for advanced non–small-cell lung cancer. Oncology 12(1 suppl 2):71-73, 1998. 5. Greco FA, Burris HA, Calvert S, et al: Paclitaxel and carboplatin, surgery and radiotherapy for stages IB to IIIB non–small-cell lung cancer: A pilot study of the Minnie Pearl Research Network. (abstract) Proc Am Soc Clin Oncol 17:486A, 1998. 6. Pisters KMW, Ginsberg RJ: Phase II trial of induction paclitaxel and carboplatin in early stage (T2N0, T1-2N, and selected T3N0-1) non–small-cell lung cancer. Proc Am Soc Clin Oncol 17:451A, 1998.