Comment www.thelancet.com/oncology Vol 12 March 2011 211 irreversible because of permanent cardiac damage and are associated with poor prognosis. 10 Our analysis has some limitations that should also be taken into consideration. We did not discriminate between asymptomatic cardiac dysfunction, which might not be clinically relevant, and other toxic effects such as significantly reduced left ventricular ejection fraction and congestive heart failure. Finally, one of the studies included was not randomised, 7 which might bias our results. To validate this treatment approach in the clinical setting, a properly powered, randomised phase 3 clinical trial is needed. Such a trial should consider sequential versus concomitant administration of trastuzumab and anthracycline-based chemotherapy. In previous large randomised phase 3 studies, which used the sequential approach in nearly 10 000 patients, a 50% reduction in the risk of relapse at the expense of a risk of congestive heart failure of up to 4% was deemed an acceptable risk–benefit ratio. 3,4 To put this outcome into perspective, a new strategy that entails the combined use of anthracyclines and trastuzumab should achieve a higher risk–benefit ratio (ie, increased benefit without compromising the risk). Until this result is convincingly shown, we strongly discourage the concurrent use of trastuzumab and anthracyclines-based regimens in clinical practice outside of the context of a clinical trial. Ivana Bozovic-Spasojevic, Hatem A Azim Jr, Marianne Paesmans, Thomas Suter, Martine J Piccart, Evandro de Azambuja* Department of Medical Oncology (IB-S, HAA, MJP, EdA), and Data Centre (MP), Institut Jules Bordet, Universite Libre de Bruxelles, 1000 Brussels, Belgium; Swiss Cardiovascular Center, Bern University Hospital, Bern, Switzerland (TS) evandro.azambuja@bordet.be MJP has received payment for honorarium and consultancy work from Roche. EA has received honorarium, and payment for lectures and consultancy work from Roche. TS has received grant and travel support from Roche, and done non-compensated consultancy work for Roche. He has also been paid to give lectures and received travel, meeting expenses from Sanofi-Aventis. HAA has a translational fellowship grant from ESMO. IB-S and MP declare that they have no conflicts of interest. 1 Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008; 100: 14–20. 2 Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–92. 3 Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353: 1659–72. 4 Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673–84. 5 Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005; 23: 3676–85. 6 Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010; 375: 377–84. 7 Untch M, Rezai M, Loibl S, et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 2010; 28: 2024–31. 8 Peto R. Clinical trial methodology. Biomedicine 1978; 28: 24–36. 9 Zuppinger C, Timolati F, Suter TM. Pathophysiology and diagnosis of cancer drug induced cardiomyopathy. Cardiovasc Toxicol 2007; 7: 61–66. 10 Lim CC, Zuppinger C, Guo X, et al. Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 2004; 279: 8290–99. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy Worldwide, more than 386 000 patients are diagnosed with urothelial carcinoma (UC) every year, and more than 150 000 will succumb to the disease. 1 Although from 2003–07, the median age at time of death from UC was 78 years, 2 in the past few decades, the median age for patients enrolled in phase 3 trials that assess cisplatin-based chemotherapy regimens for metastatic UC has been 64 years. 3 This discrepancy, and the associated high rate of renal insufficiency and impaired functional status with advancing age, 4 has resulted in a disconnect between treatment efficacy and treatment effectiveness when applied to the general population of patients with UC. Investigators have long appreciated this disconnect, and have designed trials specifically for patients who are unfit for cisplatin-based chemotherapy; 5 however, variability in the eligibility criteria defining unfit patients has created difficulty in interpretation of the results. A clear and consistent definition is needed of enrolment criteria for future trials of patients with metastatic UC who are unfit for cisplatin-based therapy. In 1997, the European Organisation for Research and Treatment of Cancer (EORTC) did a survey 6 John Bavosi/Science Photo Library