Reply to the article “A monoclonal antibody against HER-2 (trastuzumab) for metastatic breast cancer: a model based cost-effectiveness analysis”, by J. Norum et al. (Ann Oncol 2005; 16: 909–914)
Authors: M.E. Bonneterre, J. Bonneterre
Journal: Annals of Oncology (2005)

We were very much interested in Norum's paper [1.Norum J. Risberg T. Olsen J.A. A monoclonal antibody against HER-2 (trastuzumab) for metastatic breast cancer: a model based cost-effectiveness analysis.Ann Oncol. 2005; 16: 909-914Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar] on the cost-effectiveness analysis of trastuzumab for metastatic breast cancer. The conclusion was that trastuzumab was not cost-effective in this setting. Some important points have to be discussed, which could modulate (on both sides) the results of the analysis.The first one is the fact that only two randomized studies have been considered [2.Slamon D.J. Leyland-Jones B. Shak S. et al.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.New Engl J Med. 2001; 344: 783-792Crossref PubMed Scopus (9222) Google Scholar, 3.Extra J.M. Cognetti F. Maraninchi D. et al.Trastuzumab (herceptin) plus taxotere vs taxotere alone as first line treatment of HER2-positive metastatic breast cancer (MBC) results of a randomized multicentre trial.Eur J Cancer. 2004; 2 (Abstr 239): 125Crossref Google Scholar], the two others which are mentioned in Table 1 do not give survival results. Since the first results published by Slamon [2.Slamon D.J. Leyland-Jones B. Shak S. et al.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.New Engl J Med. 2001; 344: 783-792Crossref PubMed Scopus (9222) Google Scholar], it has generally been considered unethical not to give trastuzumab to HER2+++ patients; the number of randomized studies is thus limited. Furthermore, the results obtained in anthracyclin-containing regimens are not relevant, since this chemotherapy regimen cannot be used, due to cardiotoxicity. Conversely, many phase II studies have been carried out; the amount of relevant clinical information is thus limited and a Markov model would be useful to provide more sound information. Similarly the ‘sensitivity analysis’ is a very simple one which is poorly contributive.The second concern relates to the duration of treatment. Based on biological results, it is generally considered that trastuzumab treatment should never be stopped, even in the case of relapse, when the chemotherapy regimen is changed; this has never been confirmed by clinical studies. The assumption that trastuzumab is being given for 40 weeks is not valid, and thus the cost is much higher.A systematic cardiac work-up has to be carried out regularly during trastuzumab treatment; a MUGA scan, or echocardiography, is generally performed every 3 months during treatment, which is an extra cost.Trastuzumab treatment has dramatically changed the history of metastatic breast cancer with patients living longer, but nevertheless relapsing anywhere, even if brain metastases are more frequent in this patient population. Up to now, it has not been considered that prophylactic brain irradiation could be a reasonable approach and, to our knowledge, this has never been studied. In any case, it is difficult to carry out a cost-effectiveness analysis without taking into account the cost of relapses which can occur late during the follow-up. It has been shown repeatedly that the cost of relapses is very high. The decrease in the number of relapses would thus decrease the cost per life year saved.The results of three studies of trastuzumab adjuvant treatment were presented at the last ASCO meeting (abstracts not available); an impressive decrease in the risk of relapse at 2 years was about 50%. It is very likely that, in the near future, trastuzumab will be used routinely as part of the adjuvant treatment in HER2+++ patients.In summary, in this study, the duration of treatment is shorter than usual, which increases the cost, but the treatment of relapses is not considered, which would decrease the cost. We were very much interested in Norum's paper [1.Norum J. Risberg T. Olsen J.A. A monoclonal antibody against HER-2 (trastuzumab) for metastatic breast cancer: a model based cost-effectiveness analysis.Ann Oncol. 2005; 16: 909-914Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar] on the cost-effectiveness analysis of trastuzumab for metastatic breast cancer. The conclusion was that trastuzumab was not cost-effective in this setting. Some important points have to be discussed, which could modulate (on both sides) the results of the analysis. The first one is the fact that only two randomized studies have been considered [2.Slamon D.J. Leyland-Jones B. Shak S. et al.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.New Engl J Med. 2001; 344: 783-792Crossref PubMed Scopus (9222) Google Scholar, 3.Extra J.M. Cognetti F. Maraninchi D. et al.Trastuzumab (herceptin) plus taxotere vs taxotere alone as first line treatment of HER2-positive metastatic breast cancer (MBC) results of a randomized multicentre trial.Eur J Cancer. 2004; 2 (Abstr 239): 125Crossref Google Scholar], the two others which are mentioned in Table 1 do not give survival results. Since the first results published by Slamon [2.Slamon D.J. Leyland-Jones B. Shak S. et al.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.New Engl J Med. 2001; 344: 783-792Crossref PubMed Scopus (9222) Google Scholar], it has generally been considered unethical not to give trastuzumab to HER2+++ patients; the number of randomized studies is thus limited. Furthermore, the results obtained in anthracyclin-containing regimens are not relevant, since this chemotherapy regimen cannot be used, due to cardiotoxicity. Conversely, many phase II studies have been carried out; the amount of relevant clinical information is thus limited and a Markov model would be useful to provide more sound information. Similarly the ‘sensitivity analysis’ is a very simple one which is poorly contributive. The second concern relates to the duration of treatment. Based on biological results, it is generally considered that trastuzumab treatment should never be stopped, even in the case of relapse, when the chemotherapy regimen is changed; this has never been confirmed by clinical studies. The assumption that trastuzumab is being given for 40 weeks is not valid, and thus the cost is much higher. A systematic cardiac work-up has to be carried out regularly during trastuzumab treatment; a MUGA scan, or echocardiography, is generally performed every 3 months during treatment, which is an extra cost. Trastuzumab treatment has dramatically changed the history of metastatic breast cancer with patients living longer, but nevertheless relapsing anywhere, even if brain metastases are more frequent in this patient population. Up to now, it has not been considered that prophylactic brain irradiation could be a reasonable approach and, to our knowledge, this has never been studied. In any case, it is difficult to carry out a cost-effectiveness analysis without taking into account the cost of relapses which can occur late during the follow-up. It has been shown repeatedly that the cost of relapses is very high. The decrease in the number of relapses would thus decrease the cost per life year saved. The results of three studies of trastuzumab adjuvant treatment were presented at the last ASCO meeting (abstracts not available); an impressive decrease in the risk of relapse at 2 years was about 50%. It is very likely that, in the near future, trastuzumab will be used routinely as part of the adjuvant treatment in HER2+++ patients. In summary, in this study, the duration of treatment is shorter than usual, which increases the cost, but the treatment of relapses is not considered, which would decrease the cost.