- Email: [email protected]
Trastuzumab for early breast cancer
Correspondence
of trastuzumab (Herceptin) in breast cancer. It implies that it is premature to make any decision about its use in the clinic. We feel this is impractical and unhelpful advice. The Editorial offers a counsel of perfection and implies that the drug should be withheld until its clinical benefit has been shown beyond all reasonable doubt. Although this might be a reasonable stance for an anonymous Editorial, it is impractical in the real world where clinicians frequently have to make difficult decisions with inadequate evidence and where the balance of probabilities is a more reasonable test. There is no doubt that the published results are remarkable. They are also quite consistent across two studies involving 8000 women. If correct, they would indeed be expected to lead to a cure for breast cancer, at least for some patients. Your Editorial raises the possibility that the results might be confounded and implies that with further analysis the apparent benefit will prove illusory. The question is not whether this is possible but whether it is likely. To have one aberrant result would be unfortunate, but to have two would be extraordinary. A far more likely hypothesis is that the benefit is genuine but the studies indicate, by chance, the upper limit of this benefit. The question of toxicity is also raised, although without reference to the fact that trastuzumab has been in wide clinical use since 2002 and was in clinical trial use in metastatic breast cancer for years before that. The toxicity profile of trastuzumab is now well known and there have been no suggestions of any delayed or late toxic effects. Yes, regulatory authorities have to make considered decisions on the basis of thorough analysis of mature data. In the meantime, though, clinicians and those purchasing health care must accept that the data available make it very likely that trastuzumab offers a significant improvement in the care of certain patients with breast cancer and the possibility of cure for some who would not otherwise attain it. 108
The challenge now is to decide in which patients the size of the likely benefit outweighs the size of the likely risk. This judgment must involve the patient, those paying for the treatment, and the doctor. As new data emerge, this balance will inevitably be reassessed and clinical judgments revised. A decision simply to ignore the data and to deny all patients treatment until further information is available is a bureaucratic cruelty that is both medically and politically unacceptable. We declare that we have no conflict of interest.
*N S A Stuart, Jill Bishop, Catherine Bale [email protected] University of Bangor, Bangor LL57 2UW, UK (NSAS); North Wales Cancer Centre, Rhyl, UK (JB); and Gwynedd Hospital, Bangor, UK (CB) 1
The Lancet. Herceptin and early breast cancer: a moment for caution. Lancet 2005; 366: 1673.
Your Nov 12 Editorial1 rightly issues a timely warning about the use of trastuzumab (Herceptin) in early breast cancer. However, it is inappropriate to blame the investigators on the trials2,3 for omission of information on cardiotoxicity; these data were published separately.4 Cardiotoxicity is certainly an important concern, since the potential benefit of such treatment could easily be offset by a 4% incidence of cardiotoxicity. Most patients with less than a 20% risk of recurrence after locoregional therapy will gain no net benefit from such an expensive treatment provided they undergo standard systemic therapy. We must also not forget that 18% of patients discontinued trastuzumab owing to a significant fall in their left-ventricular ejection fraction. However, in discussing the potential implications of the results of these trials, many of us have overlooked the ethics of their conduct. We cannot ignore the fact that these three trials, whose designs were not very different, together enrolled 9890 patients. The same difference in disease-free survival could have been detected with adequate power by randomising about 5000 patients in different groups of
one trial. Such a trial could have been designed to answer both questions about trastuzumab use (concomitant or sequential use and duration of therapy), and we would have had these life-saving results (for high-risk patients) 2 years earlier if the next 5000 patients had not been enrolled. We would have had an opportunity to enrol many of these remaining patients in new trials designed to address questions arising out of the first, and all of them could have received the benefit of this new drug. Should investigators indulge in such research just because they can enrol many patients and some company is ready to fund it? Should such research be termed “bad”, as defined by Young and Horton?5 What can we do to prevent such things happening in the future? In my opinion, clinical trial registers should broaden the scope of their activities to collaborate with other registers. Registers, in future, should bring such similar trials under one roof and facilitate negotiations among investigators to prevent harm or undue delay in benefits to our patients. This will also help investigators in not succumbing to industrial pressures. May I appeal to investigators to show the same altruism that our patients show when they enrol themselves in a trial? I declare that I have no conflict of interest.
Mangesh Thorat [email protected] Department of Surgical Oncology, Tata Memorial Hospital, Dr E Borges Marg, Parel, Mumbai 400012, Maharashtra, India 1 2
3
4
5
The Lancet. Herceptin and early breast cancer: a moment for caution. Lancet 2005; 366: 1673. 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. 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. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2–overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005; 23: 7811–19. Young C, Horton R. Putting clinical trials into context. Lancet 2005; 366: 107–08.
www.thelancet.com Vol 367 January 14, 2006
of trastuzumab (Herceptin) in breast cancer. It implies that it is premature to make any decision about its use in the clinic. We feel this is impractical and unhelpful advice. The Editorial offers a counsel of perfection and implies that the drug should be withheld until its clinical benefit has been shown beyond all reasonable doubt. Although this might be a reasonable stance for an anonymous Editorial, it is impractical in the real world where clinicians frequently have to make difficult decisions with inadequate evidence and where the balance of probabilities is a more reasonable test. There is no doubt that the published results are remarkable. They are also quite consistent across two studies involving 8000 women. If correct, they would indeed be expected to lead to a cure for breast cancer, at least for some patients. Your Editorial raises the possibility that the results might be confounded and implies that with further analysis the apparent benefit will prove illusory. The question is not whether this is possible but whether it is likely. To have one aberrant result would be unfortunate, but to have two would be extraordinary. A far more likely hypothesis is that the benefit is genuine but the studies indicate, by chance, the upper limit of this benefit. The question of toxicity is also raised, although without reference to the fact that trastuzumab has been in wide clinical use since 2002 and was in clinical trial use in metastatic breast cancer for years before that. The toxicity profile of trastuzumab is now well known and there have been no suggestions of any delayed or late toxic effects. Yes, regulatory authorities have to make considered decisions on the basis of thorough analysis of mature data. In the meantime, though, clinicians and those purchasing health care must accept that the data available make it very likely that trastuzumab offers a significant improvement in the care of certain patients with breast cancer and the possibility of cure for some who would not otherwise attain it. 108
The challenge now is to decide in which patients the size of the likely benefit outweighs the size of the likely risk. This judgment must involve the patient, those paying for the treatment, and the doctor. As new data emerge, this balance will inevitably be reassessed and clinical judgments revised. A decision simply to ignore the data and to deny all patients treatment until further information is available is a bureaucratic cruelty that is both medically and politically unacceptable. We declare that we have no conflict of interest.
*N S A Stuart, Jill Bishop, Catherine Bale [email protected] University of Bangor, Bangor LL57 2UW, UK (NSAS); North Wales Cancer Centre, Rhyl, UK (JB); and Gwynedd Hospital, Bangor, UK (CB) 1
The Lancet. Herceptin and early breast cancer: a moment for caution. Lancet 2005; 366: 1673.
Your Nov 12 Editorial1 rightly issues a timely warning about the use of trastuzumab (Herceptin) in early breast cancer. However, it is inappropriate to blame the investigators on the trials2,3 for omission of information on cardiotoxicity; these data were published separately.4 Cardiotoxicity is certainly an important concern, since the potential benefit of such treatment could easily be offset by a 4% incidence of cardiotoxicity. Most patients with less than a 20% risk of recurrence after locoregional therapy will gain no net benefit from such an expensive treatment provided they undergo standard systemic therapy. We must also not forget that 18% of patients discontinued trastuzumab owing to a significant fall in their left-ventricular ejection fraction. However, in discussing the potential implications of the results of these trials, many of us have overlooked the ethics of their conduct. We cannot ignore the fact that these three trials, whose designs were not very different, together enrolled 9890 patients. The same difference in disease-free survival could have been detected with adequate power by randomising about 5000 patients in different groups of
one trial. Such a trial could have been designed to answer both questions about trastuzumab use (concomitant or sequential use and duration of therapy), and we would have had these life-saving results (for high-risk patients) 2 years earlier if the next 5000 patients had not been enrolled. We would have had an opportunity to enrol many of these remaining patients in new trials designed to address questions arising out of the first, and all of them could have received the benefit of this new drug. Should investigators indulge in such research just because they can enrol many patients and some company is ready to fund it? Should such research be termed “bad”, as defined by Young and Horton?5 What can we do to prevent such things happening in the future? In my opinion, clinical trial registers should broaden the scope of their activities to collaborate with other registers. Registers, in future, should bring such similar trials under one roof and facilitate negotiations among investigators to prevent harm or undue delay in benefits to our patients. This will also help investigators in not succumbing to industrial pressures. May I appeal to investigators to show the same altruism that our patients show when they enrol themselves in a trial? I declare that I have no conflict of interest.
Mangesh Thorat [email protected] Department of Surgical Oncology, Tata Memorial Hospital, Dr E Borges Marg, Parel, Mumbai 400012, Maharashtra, India 1 2
3
4
5
The Lancet. Herceptin and early breast cancer: a moment for caution. Lancet 2005; 366: 1673. 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. 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. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2–overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005; 23: 7811–19. Young C, Horton R. Putting clinical trials into context. Lancet 2005; 366: 107–08.
www.thelancet.com Vol 367 January 14, 2006