Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 5, pp 1103–1110 | Cite as

A multicenter phase II study of docetaxel, oxaliplatin, and bevacizumab in first-line therapy for unresectable locally advanced or metastatic non-squamous cell histology non-small-cell lung cancer (NSCLC)

  • Luis E. RaezEmail author
  • Edgardo S. Santos
  • R. Timothy Webb
  • James Wade
  • Roger A. Brito
  • Melissa Karr
  • Andra Kennah
  • Barrett H. Childs
Original Article



Platinum-based doublets are standard of care for advanced non-small-cell lung cancer (NSCLC). The combination of docetaxel and oxaliplatin has shown acceptable toxicity and encouraging activity. This phase II study aimed to determine the safety and efficacy of this doublet with bevacizumab as first-line treatment for stage IIIB/IV NSCLC.


Newly diagnosed patients ≥18 years with histologically proven non-squamous NSCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 received six 21-day cycles of docetaxel, oxaliplatin, and bevacizumab followed by single-agent bevacizumab for a total of 1 year. Primary efficacy end point was radiographically documented progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), time to treatment failure, and safety.


Fifty-three patients were enrolled. Median age was 62.0 years, 71.7 % male, 79.2 % Caucasian. A total of 88.7 % had stage IV or recurrent disease; 94.3 % adenocarcinoma; and 94.3 % ECOG PS 0 or 1. Efficacy results are as follows: median PFS 5.6 months, ORR 30.2 % (complete response 1.9 %, partial response 28.3 %); 37.7 % stable disease; and OS 14.0 months. At least one adverse event (AE) was reported in all patients (n = 52); 98.1 % of AEs were treatment related. The most common treatment-emergent grade ≥3 AEs were neutropenia (15.4 %), diarrhea (13.5 %), and fatigue (11.5 %). A serious AE was present in 32.7 %; the most common were pneumonia (7.7 %) and abdominal pain (5.8 %). Dehydration, diarrhea, febrile neutropenia, sepsis, and supraventricular tachycardia each occurred in 3.8 %.


The addition of bevacizumab to docetaxel/oxaliplatin is effective with an acceptable safety profile in patients with chemotherapy-naïve advanced NSCLC.


Oxaliplatin Docetaxel Bevacizumab Non-small-cell lung cancer Metastatic disease 



Dr. Luis E. Raez was a member of the Speakers’ Bureau of Genentech, sanofi-aventis, and Eli Lilly US Oncology. Dr. Raez receives research support from Genentech and Eli Lilly Oncology. Dr. Edgardo S. Santos is a member of the Speakers’ Bureau of Genentech, sanofi-aventis, and Eli Lilly US Oncology. This study was sponsored by Sanofi US. All summaries and statistical analyses were performed by United BioSource Corporation.


  1. 1.
    Fossella F, Pereira JR, von Pawel J et al (2003) Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 21:3016–3024PubMedCrossRefGoogle Scholar
  2. 2.
    Georgoulias V, Ardavanis A, Agelidou A et al (2004) Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol 22:2602–2609PubMedCrossRefGoogle Scholar
  3. 3.
    Shepherd FA, Dancey J, Ramlau R et al (2000) Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095–2103PubMedGoogle Scholar
  4. 4.
    Dancey J, Shepherd FA, Gralla RJ et al (2004) Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: results of a prospective, randomized phase III trial. Lung Cancer 43:183–194PubMedCrossRefGoogle Scholar
  5. 5.
    Kouroussis C, Agelaki S, Mavroudis D et al (2003) A dose escalation study of docetaxel and oxaliplatin combination in patients with metastatic breast and non-small cell lung cancer. Anticancer Res 23:785–791PubMedGoogle Scholar
  6. 6.
    Raez LE, Santos ES, Lopes G et al (2006) Efficacy and safety of oxaliplatin and docetaxel in patients with locally advanced and metastatic non-small-cell lung cancer (NSCLC). Lung Cancer 53:347–353PubMedCrossRefGoogle Scholar
  7. 7.
    Sandler A, Gray R, Perry MC et al (2006) Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550PubMedCrossRefGoogle Scholar
  8. 8.
    Manegold C, von Pawel J, Zatloukal P (2007) Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704. J Clin Oncol 25((18 suppl)):LBA7514Google Scholar
  9. 9.
    Patel JD, Hensing TA, Rademaker A et al (2009) Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol 27:3284–3289PubMedCrossRefGoogle Scholar
  10. 10.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  11. 11.
    Schiller JH, Harrington D, Belani CP et al (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98PubMedCrossRefGoogle Scholar
  12. 12.
    Chow SC, Shao J, Wang H (eds) (2003) Sample size calculations in clinical research. CRC Press, New York, NYGoogle Scholar
  13. 13.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  14. 14.
    Brookmeyer R, Crowley J (1982) A confidence interval for the median survival time. Biometrics 38:29–41CrossRefGoogle Scholar
  15. 15.
    Kalbfleisch JD, Prentice RL (2002) The statistical analysis of failure time data, 2nd edn. John Wiley & Sons, Inc., New York, NYCrossRefGoogle Scholar
  16. 16.
    William WN Jr, Kies MS, Fossella FV et al (2010) Phase 2 study of carboplatin, docetaxel, and bevacizumab as frontline treatment for advanced nonsmall-cell lung cancer. Cancer 116:2401–2408PubMedGoogle Scholar
  17. 17.
    Reck M, von Pawel J, Zatloukal P et al (2010) for the BO17704 Study Group. Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomized phase III trial (AVAiL). Ann Oncol 21:1804–1809PubMedCrossRefGoogle Scholar
  18. 18.
    Kubota K, Kawahara M, Ogawara M et al (2008) for the Japan Multi-National Trial Organisation. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study. Lancet Oncol 9:1135–1142PubMedCrossRefGoogle Scholar
  19. 19.
    Dols MC, Chamorro EV, Díaz IA (2006) Gemcitabine and vinorelbine followed by weekly docetaxel in patients with advanced non-small-cell lung cancer: a phase II trial of sequential chemotherapy. Clin Transl Oncol 8:742–749CrossRefGoogle Scholar
  20. 20.
    Laack E, Dickgreber N, Müller T et al (2004) Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group. J Clin Oncol 22:2348–2356PubMedCrossRefGoogle Scholar
  21. 21.
    Rixe O, Ortuzar W, Alvarez A et al (1996) Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s Anticancer Drug Screen panel. Biochem Pharmacol 52:1855–1865PubMedCrossRefGoogle Scholar
  22. 22.
    Schmidt W, Chaney SG (1993) Role of carrier ligand in platinum resistance of human carcinoma cell lines. Cancer Res 53:799–805PubMedGoogle Scholar
  23. 23.
    Rietbroek RC, van de Vaart PJM, Haveman J et al (1997) Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells. J Cancer Res Clin Oncol 123:6–12PubMedCrossRefGoogle Scholar
  24. 24.
    Mamenta EL, Poma EE, Kaufmann WK et al (1994) Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines. Cancer Res 54:3500–3505PubMedGoogle Scholar
  25. 25.
    Chang MH, Kim KH, Jun HJ et al (2009) Irinotecan and oxaliplatin combination as the first-line treatment for patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol 64:917–924PubMedCrossRefGoogle Scholar
  26. 26.
    Radhakrishnann A, Bitran JD, Milton DT et al (2009) Docetaxel and oxaliplatin as first-line therapy for advanced non-small cell lung cancer: a phase II trial. J Chemother 21:439–444Google Scholar
  27. 27.
    Trédaniel J, Becht C, Bekradda M et al (2009) An open phase II trial of gemcitabine, oxaliplatin, and vinorelbine combination as first-line therapy in advanced non-small cell lung cancer patients. Lung Cancer 63:259–263PubMedCrossRefGoogle Scholar
  28. 28.
    Heist RS, Fidias P, Huberman M et al (2008) A phase II study of oxaliplatin, pemetrexed, and bevacizumab in previously treated advanced non-small cell lung cancer. J Thorac Oncol 3:1153–1158PubMedCrossRefGoogle Scholar
  29. 29.
    Lilenbaum R, Raez L, Tseng J et al (2008) Efficacy and safety of oxaliplatin and gemcitabine with bevacizumab in advanced non-small cell lung cancer. J Thorac Oncol 3:511–515PubMedCrossRefGoogle Scholar
  30. 30.
    Kakolyris S, Ziras N, Vamvakas L et al (2006) Gemcitabine plus oxaliplatin combination (GEMOX regimen) in pretreated patients with advanced non-small-cell lung cancer (NSCLC): a multicenter phase II study. Lung Cancer 54:347–352PubMedCrossRefGoogle Scholar
  31. 31.
    Cappuzzo F, Novello S, De Marinis F et al (2005) Phase II study of gemcitabine plus oxaliplatin as first-line chemotherapy for advanced non-small-cell lung cancer. Br J Cancer 93:29–34PubMedCrossRefGoogle Scholar
  32. 32.
    Winegarden JD, Mauer AM, Otterson GA et al (2004) A phase II study of oxaliplatin and paclitaxel in patients with advanced non-small-cell lung cancer. Ann Oncol 15:915–920PubMedCrossRefGoogle Scholar
  33. 33.
    Monnet I, de Cremoux H, Soulié P et al (2002) Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study. Ann Oncol 13:103–107PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Luis E. Raez
    • 1
    Email author
  • Edgardo S. Santos
    • 2
  • R. Timothy Webb
    • 3
  • James Wade
    • 4
  • Roger A. Brito
    • 5
  • Melissa Karr
    • 6
  • Andra Kennah
    • 7
  • Barrett H. Childs
    • 7
  1. 1.Thoracic Oncology ProgramMemorial Cancer Institute, Memorial Health Care SystemPembroke PinesUSA
  2. 2.Thoracic and Head and Neck Cancer Programs, Lynn Cancer InstituteBoca Raton Regional HospitalBoca RatonUSA
  3. 3.Genesis Cancer CenterHot SpringsUSA
  4. 4.Decatur Memorial HospitalDecaturUSA
  5. 5.Hematology and Medical OncologyBoynton BeachUSA
  6. 6.Sylvester Comprehensive Cancer CenterMiamiUSA
  7. 7.SanofiBridgewaterUSA

Personalised recommendations