Cancer Res Treat.  2004 Oct;36(5):293-297.

A Phase II Study of Weekly Paclitaxel, Cisplatin and Concurrent Radiation Therapy for Locally-Advanced Unresectable Non-Small Cell Lung Cancer: Early Closure due to Lack of Efficacy

• Park SH
• Kim MK
• Kyung SY
• Lim YH
• An CH
• Park JW
• Jeong SH
• Lee JW
• Lee KC
• Cho EK
• Bang SM
• Shin DB
• Lee JH

Abstract

PURPOSE
In this phase II study, the efficacy and safety of weekly paclitaxel concomitant with cisplatin and thoracic radiotherapy (TRT) was evaluated in patients with locally-advanced unresectable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with stage III NSCLC (without pleural effusion or cervical lymphadenopathy) received TRT (63 Gy in 35 fractions over 7 weeks) with concurrent weekly cisplatin 20 mg/m2 and paclitaxel 40 mg/m2/week infused over 3 hours. In patients without evidence of disease progression, the administration of a further 2 cycles of consolidation chemotherapy, consisting of paclitaxel 175 mg/m2 and cisplatin 75 mg/m2, were planned after completion of the TRT. RESULTS: Between Feb 2000 and Dec 2002, 20 patients were entered into the study; 13 completed all 7 weeks of treatment (median 7.6 weeks; range 3.3 to 9.4). Seven out of 16 (43.8%) objective responses were observed, with 15 (75%) patients experiencing at least one episode of grade 3/4 toxicity. The main toxicities were moderate to severe neutropenia and gastrointestinal toxicity. CONCLUSION: The unsatisfactory response rate and the high incidence of grade 3/4 hematologic and non-hematologic toxicities, including 7 early discontinuations of treatment and exceeding the study stopping rules, prompted the early closure of the study. In view of the activity observed, the protocol was amended to protracted continuous infusion paclitaxel, cisplatin and concurrent TRT.

Keyword

Non-small cell lung carcinoma; Paclitaxel; Cisplatin; Radiotherapy

MeSH Terms

Carcinoma, Non-Small-Cell Lung*
Cisplatin*
Consolidation Chemotherapy
Disease Progression
Humans
Incidence
Neutropenia
Paclitaxel*
Pleural Effusion
Radiotherapy
Cisplatin
Paclitaxel

Figure

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  Fig. 1 Time to progression (dotted line) and overall survival. With a median follow-up duration of 32.4 months, the median time to progression and overall survival were 2.8 and 11.4 months, respectively.

Reference

1. Cox JD, Pajak TF, Herskovic A, Urtasun R, Podolsky WJ, Seydel HG. Five-year survival after hyperfractionated radiation therapy for non-small-cell carcinoma of the lung (NSCCL): results of RTOG protocol 81-08. Am J Clin Oncol. 1991; 14:280–284. PMID: 1650526.

2. Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, Kirkpatrick A, Koolen M, Maat B, Nijs A, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992; 326:524–530. PMID: 1310160.

3. Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, Katagami N, Ariyoshi Y. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 1999; 17:2692–2699. PMID: 10561343.

4. Gandara DR, Edelman M, Lara P, Roberts P, Leigh B. Evolution of combined modality therapy for stage III non-small-cell lung cancer. Oncology Huntingt. 2000; 14(7 Suppl 5):35–41. PMID: 10981289.

5. Greco FA. Paclitaxel-based combination chemotherapy in advanced non-small cell lung cancer. Lung Cancer. 2001; 34(Suppl 4):S53–S56. PMID: 11742703.

6. Hei TK, Piao CQ, Geard CR, Hall EJ. Taxol and ionizing radiation: interaction and mechanisms. Int J Radiat Oncol Biol Phys. 1994; 29:267–271. PMID: 7910816.

7. Milas L, Hunter N, Mason KA, Milross C, Peters LJ. Tumor reoxygenation as a mechanism of taxol-induced enhancement of tumor radioresponse. Acta Oncol. 1995; 34:409–412. PMID: 7779432.

8. Jekunen AP, Christen RD, Shalinsky DR, Howell SB. Synergistic interaction between cisplatin and taxol in human ovarian carcinoma cells in vitro. Br J Cancer. 1994; 69:299–306. PMID: 7905279.

9. Zanelli GD, Quaia M, Robieux I, Bujor L, Santarosa M, Favaro D, Spada A, Caffau C, Gobitti C, Trovo MG. Paclitaxel as a radiosensitiser: a proposed schedule of administration based on in vitro data and pharmacokinetic calculations. Eur J Cancer. 1997; 33:486–492. PMID: 9155536.

10. Frasci G, Comella P, Scoppa G, Guida C, Gravina A, Fiore F, Casaretti R, Daponte A, Parziale A, Comella G. Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study. J Clin Oncol. 1997; 15:1409–1417. PMID: 9193333.

11. Bryant J, Day R. Incorporating toxicity considerations into the design of two-stage phase II clinical trials. Biometrics. 1995; 51:1372–1383. PMID: 8589229.

12. Pearson FG, DeLarue NC, Ilves R, Todd TR, Cooper JD. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg. 1982; 83:1–11. PMID: 7054602.

13. Scott C, Sause WT, Byhardt R, Marcial V, Pajak TF, Herskovic A, Cox JD. Recursive partitioning analysis of 1592 patients on four Radiation Therapy Oncology Group studies in inoperable non-small cell lung cancer. Lung Cancer. 1997; 17(Suppl 1):S59–S74. PMID: 9213303.

14. Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996; 88(17):1210–1215. PMID: 8780630.

15. Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995; 87:198–205. PMID: 7707407.

16. Roth JA, Atkinson EN, Fossella F, Komaki R, Bernadette Ryan M, Putnam JB Jr, Lee JS, Dhingra H, De Caro L, Chasen M, Hong WK. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer. 1998; 21:1–6. PMID: 9792048.

17. Rosell R, Gomez-Codina J, Camps C, Javier Sanchez J, Maestre J, Padilla J, Canto A, Abad A, Roig J. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer. 1999; 26:7–14. PMID: 10574676.

18. 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. BMJ. 1995; 311:899–909. PMID: 7580546.

19. Isokangas OP, Joensuu H, Halme M, Jekunen A, Mattson K. Paclitaxel (Taxol) and carboplatin followed by concomitant paclitaxel, cisplatin and radiotherapy for inoperable stage III NSCLC. Lung Cancer. 1998; 20:127–133. PMID: 9711531.

20. Adelstein DJ, Rice TW, Rybicki LA, Greskovich JF Jr, Ciezki JP, Carroll MA, DeCamp MM. Accelerated hyperfractionated radiation, concurrent paclitaxel/cisplatin chemotherapy and surgery for stage III non-small cell lung cancer. Lung Cancer. 2002; 36:167–174. PMID: 11955651.

21. Lee SW, Choi EK, Oh SJ, Suh C, Kim SW, Lee JS, Kim DS, Kim WD, Kim WS, Lee SD, Kim JH, Ahn SD, Kim KJ, Noh YJ. Preliminary results of paclitaxel, cisplatin and concurrent high-dose radiation therapy for locally advanced non-small cell lung cancer. Cancer Res Treat. 2002; 34:345–351.

22. Robert F, Spencer SA, Childs HA 3rd, Zhang R, Meredith RF, Wheeler RH, Hawkins MH, Carey D. Concurrent chemoradiation therapy with cisplatin and paclitaxel for locally advanced non-small cell lung cancer: long-term follow-up of a phase I trial. Lung Cancer. 2002; 37:189–199. PMID: 12140142.

23. Dowell JE, Sinard R, Yardley DA, Aviles V, Machtay M, Weber RS, Weinstein GS, Chalian AA, Carbone DP, Rosenthal DI. Seven-week continuous-infusion paclitaxel concurrent with radiation therapy for locally advanced non-small cell lung and head and neck cancers. Semin Radiat Oncol. 1999; 9(2 Suppl 1):97–101. PMID: 10210547.