Non–Platinum-Based Paclitaxel Combinations in Advanced Non–Small-Cell Lung Cancer

ABSTRACT: Patients with advanced non–small-cell lung cancer benefit mainly from chemotherapy using cisplatin (Platinol)-based combinations. Platinum compounds, however, due to their toxicity profile, have limited use in combination with many cytoxic drugs. Paclitaxel (Taxol) is one of the most active cytoxic drugs available for chemonaive patients with advanced non–small-cell lung cancer, yielding response rates of about 20% to 25%. Paclitaxel has been combined with other agents active in this disease with the aim of producing synergistic, or additional, antitumor activity with better tolerance. Several of these combinations are described in this article. The most promising of these appears to be paclitaxel and etoposide.[ONCOLOGY 13(Suppl 4):48-50, 1999]

Introduction

With an overall response rate of about 20% to 25%, paclitaxel (Taxol) is one of the most active cytoxic drugs currently available for chemonaive patients with advanced non–small-cell lung cancer. Cisplatin (Platinol) is a major agent in the treatment of this disease and is most frequently used in combination with other drugs. The benefit of chemotherapy in patients with advanced non–small-cell lung cancer has been reported mainly with cisplatin-based combinations.[1] Nevertheless, the toxicity profile of platinum compounds limits their use in combination with several cytoxic drugs. Paclitaxel has been combined with various other agents considered active in non–small-cell lung cancer with the hope of obtaining synergistic or additional antitumor activity with better tolerance.

Paclitaxel and Etoposide

The combination of paclitaxel and etoposide has been tested in more than 100 patients (Table 1).[2-4] It appears to be schedule-dependent in the study reported by Rosell et al,[3] where 175 mg/m² of paclitaxel was given on day 4, after 100 mg/m² of etoposide on days 1, 2, and 3; a 41% response rate in 21 patients was achieved, compared to no response in 18 patients in whom paclitaxel was given on day 1 followed by etoposide at a same dose.

The addition of a platinum compound to this combination has offered a promising response rate in the study reported by Dow et al.[5] Paclitaxel was given at a dose of 35 to 50 mg/m² per day for 5 consecutive days; cisplatin at a dose of 15 mg/m² per day for 5 consecutive days; and etoposide at a dose of 35 to 50 mg/m² per day for 5 consecutive days. An objective response rate of 76% was observed in 37 patients. In a second study by Neill et al[6] paclitaxel was administered at 200 mg/m², carboplatin at an area under the concentration-time curve of 6 (AUC in mg/mL · min), and etoposide at 80 to 100 mg/m² for 3 days plus granulocyte colony-stimulating factor (G-CSF) (filgrastim [Neupogen]). No response was observed among four patients with advanced non–small-cell lung cancer.

Paclitaxel and Gemcitabine

Gemcitabine (Gemzar), with an overall response rate of 22% in 535 chemonaive patients with advanced non–small-cell lung cancer, is also active in this disease setting. The combination of paclitaxel at doses ranging from 90 to 240 mg/m² on day 1 and gemcitabine at a dose of 900 to 1,000 mg/m² on days 1 and 8 of each 3-week cycle has given overall response rates ranging from 29% to 42% in 100 patients.[7-9] The impact of this combination on survival is still to be determined, however (Table 2).

Paclitaxel and Ifosfamide

Ifosfamide has been reported to be one of the most active single drugs in patients with advanced non–small-cell lung cancer, with a response rate of 27% in 130 untreated patients. The combination of paclitaxel and ifosfamide at a dose of 3 to 5 g/m² (plus mesna) has been evaluated in a total of 141 patients.[10-13] The response rate ranges from 21% to 34%, and median survival, when available, does not reach 40 weeks (Table 3). No synergistic effect of these two drugs has been observed. The addition of vinorelbine (Navelbine) to paclitaxel and ifosfamide (plus G-CSF) has been evaluated in 55 patients, and only a 17% objective response rate was observed.[14]

The triplet paclitaxel/ifosfamide/carboplatin (AUC of 5) has been reported in 26 patients with a promising 64% response rate,[15] but the addition of etoposide to this triplet offered only a 27% response rate in 34 patients.[16]

Paclitaxel and Doxorubicin

Doxorubicin (Adriamycin) is not recognized as a major drug in the treatment of advanced non–small-cell lung cancer. Nevertheless its combination with paclitaxel has shown a high level of activity in advanced breast cancer, so it was logical to evaluate this doublet in non–small-cell lung cancer.

Two studies[17,18] have included 29 and 15 patients, respectively. In the first study, paclitaxel was given at a dose of 150 mg/m², administered over 3 hours with 40 mg/m² of doxorubicin; an objective response rate of 30% in the whole population was achieved, including an objective response of 53% in chemonaive patients. In the second study, paclitaxel was delivered at a dose of 135 mg/m² over 24 hours and doxorubicin at a dose of 50 mg/m². The response rate was 33%. This range of activity merits further studies with the combination of paclitaxel and anthracyclines in advanced non–small-cell lung cancer.

Paclitaxel and Vinorelbine

Vinorelbine has been shown to be active in the treatment of non–small-cell lung cancer with an objective response rate of 32% in 165 chemonaive patients. Two studies have evaluated the combination of paclitaxel andvinorelbine.[19,20] In the first, paclitaxel was given at a dose of 100

to 135 mg/m² over 1 hour on day 1 and vinorelbine at a dose of 20 to 25 mg/m² on days 1 and 8 of each 3-week cycle. The objective response rate was 24% in 18 patients. In the second study, paclitaxel was given at 175 mg/m² and vinorelbine at 25 mg/m² (plus G-CSF) with the same schedule; the response rate was 18% in 20 patients with a median survival of 22 weeks. The response rate for the combination does not appear higher than the one observed for each of the drugs used alone.

Paclitaxel and Topotecan

Wiesenfeld et al[21] reported a combination of paclitaxel given at the dose of 190 mg/m² and topotecan (Hycamtin) 1 mg/m² on days 1 through 5 (plus G-CSF). The objective response rate was 24% in 61 patients with a median survival of 26 weeks. These results do not appear superior to paclitaxel alone.

Paclitaxel and Hydroxyurea

Finally, Stewart et al[22] have evaluated the activity of the combination of paclitaxel at a dose of 135 to 200 mg given over 1 hour and hydroxyurea (Hydrea) at a dose of 500 mg orally 3 days a week in patients with previously treated non–small-cell lung cancer. Results were negative with an objective response rate of 3% in 30 patients and a median survival of 20 weeks.

Conclusion

In conclusion, at this stage of development of paclitaxel combinations, it appears that the most promising association of paclitaxel with a non-platinum compound is the combination of paclitaxel and etoposide. The addition of cisplatin or carboplatin (Paraplatin) to this doublet offers a higher response rate and an apparent impact on survival, both of which warrant confirmatory studies.

References:

1. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small-cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 311:899-909, 1995.

2. Boyer MJ, Zalcberg J, Olver IN, et al: Phase I study of paclitaxel and oral etoposide in previously untreated non-small-cell and extensive small-cell lung cancer. Ann Oncol 8:485-489, 1997.

3. Rosell R, Felip E, Massuti B, et al: A sequence-dependent paclitaxel/etoposide phase II trial in patients with non-small-cell lung cancer. Semin Oncol 24:S12/56-S12/60, 1997.

4. Ukena D, Berg M, et al: A phase I study of paclitaxel in combination with etoposide in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). Lung Cancer 19:31-36, 1998.

5. Dow E, Anderson N, Coco F, et al: Paclitaxel, platinol and etoposide combination chemotherapy: A multifractionated dose schedule for non-small-cell lung cancer (abstract 1677). Proc Am Soc Clin Oncol 16:467a, 1997.

6. Neill HB, Miller AA, Clamon GH, et al: A phase II study evaluating the efficacy of carboplatin, etoposide, and paclitaxel with granulocyte colony-stimulating factor in patients with stage IIIB and IV non-small-cell lung cancer and extensive small cell lung cancer. Semin Oncol 24:S12/130-S12/134, 1997.

7. Georgoulias V, Kourousis C, Kakolyris S, et al: Second-line treatment of advanced non-small-cell lung cancer with paclitaxel and gemcitabine: A preliminary report on an active regimen. Semin Oncol 24:S12/61-S12/66, 1997.

8. Giaccone G, Postmus PE, Splinter TAW, et al: Paclitaxel and gemcitabine in advanced non-small-cell lung cancer. Preliminary analysis of a phase I-II study. Proc ECCO 9:10-11, 1997.

9. Tortoriello A, Facchini G, Caponigro F, et al: Gemcitabine + paclitaxel in NSCLC. Preliminary data of a phase I/II study (abstract p434). Proceedings of the 7th International Congress of Anti-Cancer Treatment, Paris, 1997.

10. Shepard F, Eisenhauer E, Latreille J, et al: Phase I trial of paclitaxel plus ifosfamide in previously untreated patients with non-small cell lung cancer (NSCLC) (abstract 0908). Proceedings of the European Society for Medical Oncology, Lisbon, 1994.

11. Hoffman PC, Masters GA, Drinkard LC: Ifosfamide plus paclitaxel in advanced non-small-cell lung cancer: A phase I study. Ann Oncol 7:314-316, 1996.

12. Perry MC, Ihde DC, Herndon J, et al: Paclitaxel/ifosfamide chemotherapy for advanced non-small-cell lung cancer: CALGB 9532 (abstract 1721). Proc Am Soc Clin Oncol 16:478a, 1997.

13. Thongprasert S: A phase II study of paclitaxel (Taxol) and ifosfamide (Holoxan) in advanced non-small-cell lung cancer (abstract 78). Lung Cancer 18(suppl 1), 1997.

14. Masters G, Hoffman P, Samuels B, et al: A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with G-CSF support in advanced non-small-cell lung cancer (abstract 1705). Proc Am Soc Clin Oncol 16: 474a, 1997.

15. Zaniboni A, Merriggi F, Rizzi A, et al: Paclitaxel, ifosfamide, and carboplatin for the treatment of stages IIIB and IV non-small-cell lung cancer: Preliminary results. Semin Oncol 24:S12/70-S12/72, 1997.

16. Strauss GM, Lynch TJ, Elias AD, et al: Ifosfamide, carboplatin, etoposide, paclitaxel in advanced lung cancer: Update and preliminary survival analysis. Semin Oncol 24:S12/73-S12/80, 1997.

17. Chen MC, Chiang AA, Wang CC, et al: Paclitaxel and doxorubicin in treating advanced non-small-cell lung cancer (NSCLC): Taiwan experience (abstract 1249). Proc Am Soc Clin Oncol 15:408, 1996.

18. Greenberg R, Friedland D, Holroyde C, et al: Phase II trial of Taxol and Adriamycin in stage IV non-small-cell lung carcinoma (abstract 1157). Proc Am Soc Clin Oncol 14:374, 1995.

19. Breton JL, Jacoulet P, Pellae-Cosset B, et al: Phase I study of paclitaxel (P) over one hour infusion in combination with vinorelbine (V) in advanced non-small-cell lung cancer (NSCLC) (abstract 202). Lung Cancer 18(suppl 1), 1997.

20. Chang AY, DeVore R, Johnson D: Pilot study of vinorelbine (Navelbine) and paclitaxel in patients with refractory non-small cell lung cancer. Semin Oncol 23:19-23, 1996.

21. Wiesenfeld M, Marks R, Grill J, et al: A randomized phase II study of topotecan and cisplatin with filgrastim (G-CSF) versus topotecan and paclitaxel (Taxol) with filgrastim in patients with advanced non-small-cell lung cancer (abstract 1755). Proc Am Soc Clin Oncol 16:488a, 1997.

22. Stewart DJ, Tomiak EM, Goss G, et al: Paclitaxel plus hydroxyurea as second line therapy for non-small-cell lung cancer. Lung Cancer 15:115-123, 1996.