Tumor Biology

, Volume 35, Issue 10, pp 10409–10418

Risk/benefit profile of panitumumab-based therapy in patients with metastatic colorectal cancer: evidence from five randomized controlled trials

  • Na-Ping Tang
  • Hua Li
  • Yun-Liang Qiu
  • Guo-Min Zhou
  • Yan Wang
  • Jing Ma
  • Yan Chang
  • Qi-Bing Mei
Research Article

Abstract

This study aims to evaluate the risk and benefit profiles of panitumumab-based therapy (PBT) in patients with metastatic colorectal cancer (mCRC). Relevant randomized controlled trials were identified by searching PubMed, Medline, EMBASE and Cochrane Library. Data on progression-free survival (PFS), overall survival (OS), all grade and severe (grade ≥3) adverse events were extracted and pooled to calculate hazard ratios (HRs) and risk ratios (RRs) with 95 % confidence intervals (CIs). Number needed to treat (NNT) for PFS and number needed to harm (NNH) for significantly changed toxicities were calculated. A total of 4,155 patients were included in the analysis. PBT significantly improved PFS (HRrandom = 0.66, 95 % CI = 0.45–0.95) but not OS (HRfixed = 0.93, 95 % CI = 0.83–1.04) when used in the subsequent-line setting. The effect on PFS was more evident in patients with wild-type KRAS (HRrandom = 0.64, 95 % CI = 0.47–0.87) and the NNT for PFS is 11 to 23at 1 year. PBT did not benefit patients when used in the first-line setting. In addition, PBT significantly increased the risk of skin toxicity, infections, diarrhea, dehydration, mucositis, hypokalemia, fatigue, hypomagnesemia, pulmonary embolism and paronychia. The NNHs for skin toxicity, diarrhea, infection, hypokalemia and mucositis are less than 23. In conclusion, when used in the subsequent-line setting, PBT can improve the disease progression, especially in mCRC patients with wild-type KRAS. Regarding the adverse events associated with the PBT, close monitoring and necessary preparations are recommended during the therapy.

Keywords

Panitumumab Colorectal cancer Metastatic Efficacy Adverse events 

References

  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Center MM, Jemal A, Ward E. International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev. 2009;18:1688–94.CrossRefPubMedGoogle Scholar
  3. 3.
    Center MM, Jemal A, Smith RA, Ward E. Worldwide variations in colorectal cancer. CA Cancer J Clin. 2009;59:366–78.CrossRefPubMedGoogle Scholar
  4. 4.
    Jemal A, Simard EP, Dorell C, etal. Annual report to the nation on the status of cancer, 1975–2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst. 2013;105:175–201.Google Scholar
  5. 5.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.CrossRefPubMedGoogle Scholar
  6. 6.
    Addeo R, Caraglia M, Cerbone D, etal. Panitumumab: a new frontier of target therapy for the treatment of metastatic colorectal cancer. Expert Rev Anticancer Ther. 2010;10:499–505.Google Scholar
  7. 7.
    Mitry E, Bouvier AM, Esteve J, Faivre J. Benefit of operative mortality reduction on colorectal cancer survival. Br J Surg. 2002;89:1557–62.CrossRefPubMedGoogle Scholar
  8. 8.
    Engebraaten O, Bjerkvig R, Pedersen PH, Laerum OD. Effects of EGF, bFGF, NGF and PDGF(bb) on cell proliferative, migratory and invasive capacities of human brain-tumour biopsies invitro. Int J Cancer. 1993;53:209–14.CrossRefPubMedGoogle Scholar
  9. 9.
    Vecchione L, Jacobs B, Normanno N, Ciardiello F, Tejpar S. EGFR-targeted therapy. Exp Cell Res. 2011;317:2765–71.CrossRefPubMedGoogle Scholar
  10. 10.
    van Cutsem E, Peeters M, Siena S, etal. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658–64.Google Scholar
  11. 11.
    Amado RG, Wolf M, Peeters M, etal. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.Google Scholar
  12. 12.
    Hecht JR, Mitchell E, Chidiac T, etal. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27:672–80.Google Scholar
  13. 13.
    Douillard JY, Siena S, Cassidy J, etal. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28:4697–705.Google Scholar
  14. 14.
    Peeters M, Price TJ, Cervantes A, etal. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706–13.Google Scholar
  15. 15.
    Seymour MT, Brown SR, Middleton G, etal. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013;14:749–59.Google Scholar
  16. 16.
    Moher D, Pham B, Jones A, etal. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352:609–13.Google Scholar
  17. 17.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.CrossRefPubMedGoogle Scholar
  18. 18.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Foxtrot Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol. 2012;13:1152–60.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Middleton G, Brown S, Lowe C, etal. A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in Colorectal cancer therapy trial (PICCOLO). Eur J Cancer. 2013;49:3507–16.Google Scholar
  21. 21.
    Bennett L, Zhao Z, Barber B, etal. Health-related quality of life in patients with metastatic colorectal cancer treated with panitumumab in first- or second-line treatment. Br J Cancer. 2011;105:1495–502.Google Scholar
  22. 22.
    Odom D, Barber B, Bennett L, etal. Health-related quality of life and colorectal cancer-specific symptoms in patients with chemotherapy-refractory metastatic disease treated with panitumumab. Int J Colorectal Dis. 2011;26:173–81.Google Scholar
  23. 23.
    Peeters M, Siena S, Van Cutsem E, etal. Association of progression-free survival, overall survival, and patient-reported outcomes by skin toxicity and KRAS status in patients receiving panitumumab monotherapy. Cancer. 2009;115:1544–54.Google Scholar
  24. 24.
    Sartore-Bianchi A, Moroni M, Veronese S, etal. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol. 2007;25:3238–45.Google Scholar
  25. 25.
    Douillard JY, Oliner KS, Siena S, etal. Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.Google Scholar
  26. 26.
    Poulin-Costello M, Azoulay L, Van Cutsem E, etal. An analysis of the treatment effect of panitumumab on overall survival from a phase 3, randomized, controlled, multicenter trial (20020408) in patients with chemotherapy refractory metastatic colorectal cancer. Target Oncol. 2013;8:127–36.Google Scholar
  27. 27.
    Peeters M, Oliner KS, Parker A, etal. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res. 2013;19:1902–12.Google Scholar
  28. 28.
    Helbling D, Bodoky G, Gautschi O, etal. Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07. Ann Oncol. 2013;24:718–25.Google Scholar
  29. 29.
    Ibrahim EM, Abouelkhair KM. Clinical outcome of panitumumab for metastatic colorectal cancer with wild-type KRAS status: a meta-analysis of randomized clinical trials. Med Oncol. 2011;28:S310–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Schwartzberg LS, Rivera F, Karthaus M, etal (2014) PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol [Epub ahead of print]Google Scholar
  31. 31.
    Laux I, Jain A, Singh S, Agus DB. Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies. Br J Cancer. 2006;94:85–92.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55:657–70.CrossRefPubMedGoogle Scholar
  33. 33.
    Ouwerkerk J, Boers-Doets C. Best practices in the management of toxicities related to anti-EGFR agents for metastatic colorectal cancer. Eur J Oncol Nurs. 2010;14:337–49.CrossRefPubMedGoogle Scholar
  34. 34.
    Vincenzi B, Santini D, Tonini G. Biological interaction between anti-epidermal growth factor receptor agent cetuximab and magnesium. Expert Opin Pharmacother. 2008;9:1267–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Costa A, Tejpar S, Prenen H, Van Cutsem E. Hypomagnesaemia and targeted anti-epidermal growth factor receptor (EGFR) agents. Target Oncol. 2011;6:227–33.CrossRefPubMedGoogle Scholar
  36. 36.
    Groenestege WM, Thebault S, van der Wijst J, etal. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest. 2007;117:2260–7.Google Scholar
  37. 37.
    Tejpar S, Piessevaux H, Claes K, etal. Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol. 2007;8:387–94.Google Scholar
  38. 38.
    Petrelli F, Cabiddu M, Borgonovo K, Barni S. Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials. Ann Oncol. 2012;23:1672–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Kang SP, Saif MW. Infusion-related and hypersensitivity reactions of monoclonal antibodies used to treat colorectal cancer—identification, prevention, and management. J Support Oncol. 2007;5:451–7.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Na-Ping Tang
    • 1
    • 2
  • Hua Li
    • 2
  • Yun-Liang Qiu
    • 2
  • Guo-Min Zhou
    • 2
  • Yan Wang
    • 2
  • Jing Ma
    • 2
  • Yan Chang
    • 2
  • Qi-Bing Mei
    • 1
    • 3
  1. 1.Department of Pharmacology, School of Life SciencesNorthwestern Polytechnical UniversityXi’anChina
  2. 2.National Shanghai Center for New Drug Safety Evaluation and ResearchShanghaiChina
  3. 3.Department of Pharmacology, School of Pharmacythe Fourth Military Medical UniversityXi’anChina

Personalised recommendations