Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Improving the evaluation of new cancer treatments: challenges and opportunities

Nature Reviews Cancer volume 3, pages 303–309 (2003)Cite this article

Abstract

There are, at present, ten times more anticancer drugs being tested in clinical trials than there were 15 years ago. Many of the new classes of agents, however, are predicted to work in only small subpopulations of patients, target unconventional aspects of tumour development and interact with other agents in an unpredictable manner. How can clinical trials be re-designed to accommodate the new features of targeted anticancer drugs?

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Number of new drugs approved for oncological indications by the US Food and Drug Administration (FDA).
Figure 2: Number of claims approved for oncological indications by the US Food and Drug Administration (FDA).

Similar content being viewed by others

References

  1. Pharmaceutical Research and Manufacturers Association. Pharmaceutical Industry Primer 2001: A Century of Progress [online], (cited 7 Mar 2003), <http://www.phrma.org/publications/publications//2001-07-09.508.pdf> (1991).

  2. Burris, H. A. et al. Improvements in survival and clinical benefit with gemcitabine as front-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997).

    Article  CAS  Google Scholar 

  3. Rothenberg, M. L. et al. A multicenter phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal cancer. Cancer 85, 786–795 (1999).

    Article  CAS  Google Scholar 

  4. Pitot, H. C. et al. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J. Clin. Oncol. 15, 2910–2919 (1997).

    Article  CAS  Google Scholar 

  5. Rougier, P. et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluororuracil failure in patients with metastatic colorectal cancer. Lancet 352, 1407–1412 (1998).

    Article  CAS  Google Scholar 

  6. Shepherd, F. A. et al. 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, 2095–2103 (2000).

    Article  CAS  Google Scholar 

  7. Nabholtz, J. M. et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J. Clin. Oncol. 18, 3758–3767 (2000).

    Article  CAS  Google Scholar 

  8. Osborne, C. K. et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J. Clin. Oncol. 20, 3386–3395 (2002).

    Article  CAS  Google Scholar 

  9. Buzdar, A. et al. Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J. Clin. Oncol. 19, 3357–3366 (2001).

    Article  CAS  Google Scholar 

  10. Saltz, L. et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer that expresses epidermal growth factor receptor. Proc. Am. Soc. Clin. Oncol. 20, 3a (2001).

    Google Scholar 

  11. Herbst, R. S. et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a Phase I trial. J. Clin. Oncol. 20, 3815–3825 (2002).

    Article  CAS  Google Scholar 

  12. Nelson, A. R., Fingleton, B., Rothenberg, M. L. & Matrisian, L. M. The matrix metalloproteinases: biologic activity and clinical implications. J. Clin. Oncol. 18, 1135–1149 (2000).

    Article  CAS  Google Scholar 

  13. Kerbel, R. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nature Rev. Cancer 2, 727–739 (2002).

    Article  CAS  Google Scholar 

  14. Sirotnak, F. M., Zakowski, M. F., Miller, V. A., Scher, H. I. & Kris, M. G. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin. Cancer Res. 6, 4885–4892 (2000).

    CAS  PubMed  Google Scholar 

  15. Wakeling, A. E. et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 62, 5749–5754 (2002).

    CAS  PubMed  Google Scholar 

  16. Schuetz, J. D. et al. Potent BCRP inhibition by the ErbB1 inhibitor ZD1839 (Iressa) dramatically enhances oral bioavailability of topotecan and irinotecan in mice. Proc. Am. Assoc. Cancer Res. 43, 272 (2002).

    Google Scholar 

  17. Bramhall, S. R. et al. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomized trial. Br. J. Cancer 86, 1864–1870 (2002).

    Article  CAS  Google Scholar 

  18. Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nature Genet. 33, 1–6 (2003).

    Article  Google Scholar 

  19. Johnston, P. G. et al. Thymidylate synthase gene and protein expression are associated and correlate with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 55, 1407–1412 (1995).

    CAS  PubMed  Google Scholar 

  20. Betensky, R. A., Louis, D. N. & Cairncross, J. G. Influence of unrecognized molecular heterogeneity on randomized clinical trials. J. Clin. Oncol. 20, 2495–2499 (2002).

    Article  Google Scholar 

  21. Buchdunger, E. et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors. J. Pharmacol. Exp. Ther. 295, 139–145 (2000).

    CAS  Google Scholar 

  22. Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

    Article  CAS  Google Scholar 

  23. Salonga, D. et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin. Cancer Res. 6, 1322–1327 (2000).

    CAS  PubMed  Google Scholar 

  24. Relling, M. V. et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J. Natl Cancer Inst. 91, 2001–2008 (1999).

    Article  CAS  Google Scholar 

  25. Ino, Y. et al. Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis. Clin. Cancer Res. 7, 839–845 (2001).

    CAS  PubMed  Google Scholar 

  26. Bramhall, S. R., Rosemurgy, A., Brown, P. D., Bowry, C. & Buckels, J. A. C. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J. Clin. Oncol. 19, 3447–3455 (2001).

    Article  CAS  Google Scholar 

  27. Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).

    Article  CAS  Google Scholar 

  28. Shepherd, F. A. et al. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J. Clin. Oncol. 20, 4434–4439 (2002).

    Article  CAS  Google Scholar 

  29. Bramhall, S. R. et al. A double-blind placebo-controlled, randomized study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br. J. Cancer 87, 161–167 (2002).

    Article  CAS  Google Scholar 

  30. Sparano, J. A. et al. Randomized Phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: an Eastern Cooperative Oncology Group trial (E2196). Proc. Am. Soc. Clin. Oncol. 21, 44a (abst 173) (2002).

    Google Scholar 

  31. King, J., Clingan, P. & Morris, D. L. Placebo control double-blind randomised clinical trial of the matrix metalloproteinase inhibitor marimastat in patients with inoperable colorectal cancer liver metastases: significant survival advantage in patients with musculoskeletal symptoms. Proc. Am. Soc. Clin. Oncol. 21: 135a (abst 537) (2002).

    Google Scholar 

  32. British Biotech PLC. Results of Marimastat Study 131 in Patients with Glioblastoma [online], (cited 7 Mar 2003), <www.britbio.com/news/131.pdf> (2000).

  33. Bissett, D. et al. Phase III study of the matrix metalloprotease inhibitor prinomastat in combination with gemcitabine and cisplatin in non-small cell lung cancer. Proc. Am. Soc. Clin. Oncol. 21, 296a (abst 1183) (2002).

    Google Scholar 

  34. Smylie, M. et al. Phase III study of the matrix metalloprotease inhibitor prinomastat in patients having advanced non-small cell lung cancer. Proc. Am. Soc. Clin. Oncol. 20, 307a (abst 1226) (2001).

    Google Scholar 

  35. Ahmann, F. R. et al. Interim results of a Phase III study of the matrix metalloprotease inhibitor prinomastat in patients having metastatic, hormone-refractory prostate cancer. Proc. Am. Soc. Clin. Oncol. 20L, 174a (abst 692) (2001).

    Google Scholar 

  36. Moore, M. J. et al. A comparison between gemcitabine and the matrix metalloproteinase inhibitor BAY 12–9566 in patients with advanced pancreatic cancer. Proc. Am. Soc. Clin. Oncol. 19, 240a (abst 930) (2000).

    Google Scholar 

  37. Bayer Pharmaceutical Division. Bayer Halts Clinical Trials Evaluating MMPI [online], (cited 7 Mar 2003), <www.bayerusa.com/news/co0221.asp> (1999).

  38. Johnson, D. H. et al. ZD1839 (Iressa) in combination with paclitaxel and carboplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer: results from a Phase III clinical trial (INTACT 2). Ann. Oncol. 13 (Suppl. 5), 127 (abst 4680) (2002).

    Google Scholar 

  39. Giaccone, G. et al. A Phase III trial of ZD 1839 (Iressa) in combination with gemcitabine and cisplatin in chemotherapy-naïve patients with non-small-cell lung cancer (INTACT1). Ann. Oncol. 13 (Suppl. 5), 2 (abst 40) (2002).

    Google Scholar 

  40. van Cutsem, E. et al. Phase III trial comparing gemcitabine + R115777 (Zarnestra) versus gemcitabine + placebo in advanced pancreatic cancer. Proc. Am. Soc. Clin. Oncol. 21, 130a (abst 517) (2002).

    Google Scholar 

  41. Genentech. Phase III Trial with Avastin in Relapsed Breast Cancer Does Not Meet Primary Endpoint [online], (cited 7 Mar 2003), <www.genentech.com/gene/news/press-releases/detail.jsp?detail=5427> (2002).

  42. SUGEN. Letter to SU5416 Investigators, February, 2002.

Download references

Acknowledgements

Supported, in part, by National Institutes of Health grants and the Ingram Charitable Trust.

Author information

Authors and Affiliations

  1. the Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, 37232-6307, Tennessee, USA

    Mace L. Rothenberg, David P. Carbone & David H. Johnson

Authors
  1. Mace L. Rothenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David P. Carbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David H. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mace L. Rothenberg.

Related links

Related links

DATABASES

Cancer.gov

breast cancer

colorectal cancer

non-small-cell lung cancer

pancreatic cancer

LocusLink

ABL

EGFR

ERBB2

KIT

platelet-derived growth factor

FURTHER INFORMATION

FDA approval statistics

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rothenberg, M., Carbone, D. & Johnson, D. Improving the evaluation of new cancer treatments: challenges and opportunities. Nat Rev Cancer 3, 303–309 (2003). https://doi.org/10.1038/nrc1047

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1047

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing