DR LOVE: Sandy, how would you treat this woman?
DR SWAIN: This patientís age puts her at a higher risk of experiencing cardiotoxicity with an anthracycline followed by trastuzumab, so Iím a proponent of TCH. I administer it routinely in practice and I believe the BCIRG 006 trial supports its use.
This patient is also a candidate for the BETH trial, which is evaluating chemotherapy with trastuzumab with or without bevacizumab (1.5). For NSABP and CIRG group members, the chemotherapy regimen used is TCH. She could also be considered for the ALTTO trial, evaluating adjuvant lapatinib versus trastuzumab versus the combination or sequence of both agents.
DR LOVE: Cliff, how would you treat this patient on and off study?
DR HUDIS: In my mind, clinical trials always take precedence. I support the BETH trial, and I would also consider the ALTTO study. Off study, if she has a normal ejection fraction, the risk of cardiac problems is less than one percent, so I would use dose-dense AC followed by paclitaxel/trastuzumab.
DR LOVE: How was the patient treated?
DR TETREAULT: She was enrolled on the BETH trial and assigned to the bevacizumab arm. This trial is easy to present to patients. First you discuss with them the TCH data and then you present the trial. Being a nurse, this patient loved the idea of participating in this study.
DR LOVE: Sandy, can you discuss the rationale for the BETH trial?
DR SWAIN: Dennis Slamon and Mark Pegram examined the synergy between various chemotherapy drugs and devised the TCH regimen. People were up in arms when BCIRG 006 was opened and included a nonanthracycline-containing regimen, but the results showed that TCH was highly effective and significantly better than the nontrastuzumab-containing regimen (Slamon 2005).
Examination of approximately 600 tumors showed that patients whose tumors had high VEGF levels and HER2 amplification had the worst prognosis (Konecny 2004). Some laboratory data demonstrated that the combination of bevacizumab and trastuzumab was beneficial, so Pegram conducted Phase I and II studies evaluating the combination. He reported a high response rate simply with these two monoclonal antibodies and no chemotherapy as first-line treatment for HER2-amplified breast cancer (Pegram 2006).
DR LOVE: Can you discuss the cardiac data from the trial combining bevacizumab and trastuzumab that Denise Yardley presented at the San Antonio meeting?
DR SWAIN: Dr Yardley presented preliminary safety data on patients who received TCH with bevacizumab in a Phase II randomized trial of adjuvant bevacizumab with three different docetaxel-containing regimens (1.6). They reported one Grade III/IV cardiac event among the patients who received bevacizumab/trastuzumab but no anthracycline and three events in the anthracycline-containing arms.
The risk of cardiotoxicity is probably not zero when youíre dealing with a drug like bevacizumab that causes hypertension, increased afterload and the like, so our recommendation is to critically assess blood pressure and treat elevations aggressively.
DR LOVE: How aggressive are you, Cliff, with regard to blood pressure and bevacizumab?
DR HUDIS: In general, weíre treating patients with metastatic disease, in which the long-term consequences are probably far less. That said, we have strict institutional guidelines for monitoring blood pressure and the administration of bevacizumab. For example, we canít administer bevacizumab on any day that the patientís blood pressure is above a set threshold, which I believe is 140/90.
DR LOVE: Do we know to what extent anthracyclines affect a womanís risk of cardiotoxicity?
DR SWAIN: We all know that using anthracyclines, even using one dose, will cause some myocardial necrosis. The Pinder trial examined the Medicare database and showed that among women aged 66 to 70, the incidence of heart failure diagnosis was approximately nine percent higher for those who had received an anthracycline as adjuvant therapy compared to those who received a nonanthracycline-based regimen or no adjuvant chemotherapy (Pinder 2007).
Those are retrospective data using diagnoses in the Medicare database, and they could be biased because physicians knew who received anthracyclines and therefore may have been more likely to make that diagnosis. However, the patients did at least present with symptoms that could be heart failure.
We are all considering the risk of cardiotoxicity more in the adjuvant setting because these patients may be cured and we need to consider how it will affect them in 10 to 20 years.
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