Skip to main content

Advertisement

Log in

Methodology of phase II clinical trials in metastatic elderly breast cancer: a literature review

  • Review
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

As the incidence of invasive breast cancer will increase with age, the number of elderly patients with a diagnosis metastatic breast cancer will also rise. But the use of cytotoxic drugs in elderly metastatic breast cancer patients is not systematic and is dreaded by medical oncologists. The need for prospective oncologic data from this population seems increasingly obvious. The main objective of this review is to investigate design and characteristics of phase II trials that assess activity and feasibility of chemotherapies in elderly advanced/metastatic breast cancer patients.

Methods

An electronic search in PUBMED allowed us to retrieve articles published in English language on phase II trials in elderly metastatic breast cancer between January 2002 and May 2016. Sixteen publications were finally included in this review.

Results

The primary endpoint was a simple, a composite, and a co-primary endpoints in 11, three, and two studies, respectively. Efficacy was the primary objective in 15 studies: simple (n = 10), composite (n = 3), co-primary endpoints (n = 2). Composite or co-primary endpoints combined efficacy and toxicity. Thirteen studies used multistage designs.

Conclusions

Only five studies evaluated the feasibility, i.e., to jointly assess efficacy and tolerance to treatment (toxicity, quality of life, etc) as primary endpoint. Development of elderly specific phase III clinical trials might be challenging, it therefore seems essential to conduct phase II clinical trials evaluating jointly efficacy and toxicity in a well-defined geriatric population. Use of multistage designs that take into account heterogeneity would allow to identify a subpopulation at interim analysis and to reduce the number of patients exposed to an inefficient or a toxic treatment regimen. It is crucial to evaluate new therapies (targeted therapies, immunotherapies) using adequate methodologies (Study design, endpoint).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA (2009) Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 27(17):2758–2765

    Article  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  PubMed  Google Scholar 

  3. DeSantis C, Ma J, Bryan L, Jemal A (2014) Breast cancer statistics, 2013. CA Cancer J Clin 64(1):52–62

    Article  PubMed  Google Scholar 

  4. Litvak DA, Arora R (2006) Treatment of elderly breast cancer patients in a community hospital setting. Arch Surg 141(10):985–990

    Article  PubMed  Google Scholar 

  5. Wildiers H et al (2007) Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology. Lancet Oncol 8(12):1101–1115

    Article  PubMed  Google Scholar 

  6. Trimble EL, Cain D, Ungerleider RS, Friedman MA, Carter CL, Freidlin B (1994) Representation of older patients in cancer treatment trials. Cancer 74(S7):2208–2214

    Article  CAS  PubMed  Google Scholar 

  7. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS (1999) Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341(27):2061–2067

    Article  CAS  PubMed  Google Scholar 

  8. de Glas NA et al (2014) Choosing relevant endpoints for older breast cancer patients in clinical trials: an overview of all current clinical trials on breast cancer treatment. Breast Cancer Res Treat 146(3):591–597

    Article  PubMed  Google Scholar 

  9. Wildiers H et al (2013) End points and trial design in geriatric oncology research: a joint European organisation for research and treatment of cancer–Alliance for Clinical Trials in Oncology-International Society Of Geriatric Oncology position article. J Clin Oncol 31(29):3711–3718

    Article  PubMed  Google Scholar 

  10. Mohile SG, Wildiers H (2012) A call for observational cohort studies in geriatric oncology. J Geriatr Oncol 3(3):291–293

    Article  Google Scholar 

  11. ten Tije AJ et al (2004) Weekly paclitaxel as first-line chemotherapy for elderly patients with metastatic breast cancer. A multicentre phase II trial. Eur J Cancer 40(3):352–357

    Article  PubMed  Google Scholar 

  12. Freyer G et al (2004) Unexpected toxicities in elderly patients treated with oral idarubicin in metastatic breast cancer: the GINECO experience. Clin Oncol 16(1):17–23

    Article  Google Scholar 

  13. Del Mastro L et al (2005) Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano di Oncologia Geriatrica (GIOGer). Ann Oncol 16(2):253–258

    Article  PubMed  Google Scholar 

  14. Gupta S et al (2005) A phase II trial of UFT and leucovorin in women 65 years and older with advanced breast cancer. Am J Clin Oncol 28(1):65–69

    Article  CAS  PubMed  Google Scholar 

  15. Bajetta E et al (2005) Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol Off J Am Soc Clin Oncol 23(10):2155–2161

    Article  CAS  Google Scholar 

  16. Crivellari D et al (2006) Innovative schedule of oral idarubicin in elderly patients with metastatic breast cancer: comprehensive results of a phase II multi-institutional study with pharmacokinetic drug monitoring. Ann Oncol Off J Eur Soc Med Oncol ESMO 17(5):807–812

    Article  CAS  Google Scholar 

  17. Baweja M et al (2006) Phase II trial of oral vinorelbine for the treatment of metastatic breast cancer in patients > or = 65 years of age: an NCCTG study. Ann Oncol Off J Eur Soc Med Oncol ESMO 17(4):623–629

    Article  CAS  Google Scholar 

  18. Kurtz JE et al (2007) Phase II trial of pegylated liposomal doxorubicin-cyclophosphamide combination as first-line chemotherapy in older metastatic breast cancer patients. Oncology 73(3–4):210–214

    Article  CAS  PubMed  Google Scholar 

  19. Basso U et al (2007) Which benefit from adding gemcitabine to vinorelbine in elderly (> or = 70 years) women with metastatic breast cancer? Early interruption of a phase II study. Ann Oncol Off J Eur Soc Med Oncol ESMO 18(1):58–63

    Article  CAS  Google Scholar 

  20. Hess D et al (2007) Capecitabine and vinorelbine as first-line treatment in elderly patients (> or = 65 years) with metastatic breast cancer. A phase II trial (SAKK 25/99). Oncology 73(3–4):228–237

    Article  CAS  PubMed  Google Scholar 

  21. Addeo R et al (2008) Liposomal pegylated doxorubicin plus vinorelbine combination as first-line chemotherapy for metastatic breast cancer in elderly women > or = 65 years of age. Cancer Chemother Pharmacol 62(2):285–292

    Article  CAS  PubMed  Google Scholar 

  22. Mlineritsch B et al (2009) Multicenter phase II study of pegylated liposomal doxorubicin in combination with vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. Onkologie 32(1–2):18–24

    CAS  PubMed  Google Scholar 

  23. Wang H-Q et al (2010) Capecitabine combined with weekly docetaxel in Chinese patients > 65 years with anthracycline-resistant metastatic breast cancer. Chin Med J (Engl) 123(22):3212–3216

    CAS  Google Scholar 

  24. Addeo R et al (2010) Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. Clin Breast Cancer 10(4):301–306

    Article  CAS  PubMed  Google Scholar 

  25. Dong N, Wang M, Li H, Cui Y, Guo Q (2012) Gemcitabine in combination with vinorelbine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer. Cancer Chemother Pharmacol 69(5):1315–1322

    Article  CAS  PubMed  Google Scholar 

  26. Falandry C et al (2013) Impact of geriatric risk factors on pegylated liposomal doxorubicin tolerance and efficacy in elderly metastatic breast cancer patients: final results of the DOGMES multicentre GINECO trial. Eur J Cancer Oxf Engl 49(13):2806–2814

    Article  CAS  Google Scholar 

  27. Simon R (1999) Bayesian design and analysis of active control clinical trials. Biometrics 55(2):484–487

    Article  CAS  PubMed  Google Scholar 

  28. Katz S (1983) Assessing self-maintenance: activities of daily living, mobility, and instrumental activities of daily living. J Am Geriatr Soc 31(12):721–727

    Article  CAS  PubMed  Google Scholar 

  29. Zanocchi M et al (2004) L’indice medico di non autosufficienza: validazione e comparazione con le scale AFL e IADL. Minerva Med 95(2):143–151

    CAS  PubMed  Google Scholar 

  30. Le Saux O, Falandry C, Gan HK, You B, Freyer G, Péron J (2016) Inclusion of elderly patients in oncology clinical trials. Ann Oncol 27:1799–1804

    Article  PubMed  Google Scholar 

  31. Talarico L, Chen G, Pazdur R (2004) Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol 22(22):4626–4631

    Article  PubMed  Google Scholar 

  32. Balducci L, Extermann M (2000) Management of cancer in the older person: a practical approach. Oncologist 5(3):224–237

    Article  CAS  PubMed  Google Scholar 

  33. Debled M, Bellera C, Donamaria C, Soubeyran P (2011) Chemotherapy treatment for older women with metastatic breast cancer: what is the evidence? Cancer Treat Rev 37(8):590–598

    Article  CAS  PubMed  Google Scholar 

  34. Freyer G et al (2006) Dealing with metastatic breast cancer in elderly women: results from a French study on a large cohort carried out by the ‘Observatory on Elderly Patients’. Ann Oncol 17(2):211–216

    Article  CAS  PubMed  Google Scholar 

  35. D’hondt R et al (2004) Safety and efficacy of weekly docetaxel in frail and/or elderly patients with metastatic breast cancer: a phase II study. Anticancer Drugs 15(4):341–346

    Article  PubMed  Google Scholar 

  36. Beuselinck B, Wildiers H, Wynendaele W, Dirix L, Kains J-P, Paridaens R (2010) Weekly paclitaxel versus weekly docetaxel in elderly or frail patients with metastatic breast carcinoma: a randomized phase-II study of the Belgian Society of Medical Oncology. Crit Rev Oncol Hematol 75(1):70–77

    Article  PubMed  Google Scholar 

  37. Biganzoli L et al (2012) Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol 13(4):e148–e160

    Article  PubMed  Google Scholar 

  38. Rousseau F et al (2010) Impact of an all-oral capecitabine and vinorelbine combination regimen on functional status of elderly patients with advanced solid tumours: a multicentre pilot study of the French geriatric oncology group (GERICO). Crit Rev Oncol Hematol 76(1):71–78

    Article  CAS  PubMed  Google Scholar 

  39. Fleming TR (1982) One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143–151

    Article  CAS  PubMed  Google Scholar 

  40. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10

    Article  CAS  PubMed  Google Scholar 

  41. Bryant J, Day R (1995) Incorporating toxicity considerations into the design of two-stage phase II clinical trials. Biometrics 51:1372–1383

    Article  CAS  PubMed  Google Scholar 

  42. Zee B, Melnychuk D, Dancey J, Eisenhauer E (1999) Multinomial phase II cancer trials incorporating response and early progression. J Biopharm Stat 9(2):351–363

    Article  CAS  PubMed  Google Scholar 

  43. Chang MN, Devidas M, Anderson J (2007) One-and two-stage designs for phase II window studies. Stat Med 26(13):2604–2614

    Article  PubMed  Google Scholar 

  44. Pusztai L, Anderson K, Hess KR (2007) Pharmacogenomic predictor discovery in phase II clinical trials for breast cancer. Clin Cancer Res 13(20):6080–6086

    Article  CAS  PubMed  Google Scholar 

  45. Jones CL, Holmgren E (2007) An adaptive Simon two-stage design for phase 2 studies of targeted therapies. Contemp Clin Trials 28(5):654–661

    Article  PubMed  Google Scholar 

  46. Tournoux-Facon C, De Rycke Y, Tubert-Bitter P (2011) How a new stratified adaptive phase II design could improve targeting population. Stat Med 30(13):1555–1562

    Article  PubMed  Google Scholar 

  47. Parashar D, Bowden J, Starr C, Wernisch L, Mander A (2016) An optimal stratified Simon two-stage design. Pharm Stat 15(4):333–340

    Article  PubMed  PubMed Central  Google Scholar 

  48. Repetto L et al (2002) Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol 20(2):494–502

    Article  PubMed  Google Scholar 

  49. Easterbrook PJ, Gopalan R, Berlin JA, Matthews DR (1991) Publication bias in clinical research. Lancet 337(8746):867–872

    Article  CAS  PubMed  Google Scholar 

  50. van Lent M, Overbeke J, Out HJ (2014) Role of editorial and peer review processes in publication bias: analysis of drug trials submitted to eight medical journals. PLoS ONE 9(8):e104846

    Article  PubMed  PubMed Central  Google Scholar 

  51. Christman K, Muss HB, Case LD, Stanley V (1992) Chemotherapy of metastatic breast cancer in the elderly: the Piedmont Oncology Association experience. JAMA 268(1):57–62

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank “La Ligue Nationale Contre le Cancer, France” (Comité des Pyrénées-Orientales, Comité de la Meuse, Comité du Maine-et-Loire) for their financial support.

Funding

This study was funded by “La Ligue Nationale Contre le Cancer, France” (PI: Thomas Filleron).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thomas Filleron.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

M. E. Rougé-Bugat and Thomas Filleron have been contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 22 kb)

Supplementary material 2 (DOC 109 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cabarrou, B., Mourey, L., Dalenc, F. et al. Methodology of phase II clinical trials in metastatic elderly breast cancer: a literature review. Breast Cancer Res Treat 164, 505–513 (2017). https://doi.org/10.1007/s10549-017-4278-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-017-4278-5

Keywords

Navigation