SHORT TERM ANTHRACYCLINE CARDIOTOXICITY IS LOW

November 16, 2009 — Anthracyclines are a common component of adjuvant breast cancer treatment regimens, but the long-term use of these agents has been associated with the development of cardiomyopathy and congestive heart failure.

However, in a new study that addresses the short-term cardiac safety of dose-dense doxorubicin and cyclophosphamide (ddAC) with or without concurrent bevacizumab (Avastin), researchers report that the regimen is not associated with frequent acute or short-term declines in left ventricular ejection fraction (LVEF).

In the study, published online November 9 in the Journal of Clinical Oncology, the authors report that post-ddAC LVEF at 2 months was normal in all of the patients except 1. Median baseline LVEF was 68% (range, 52% to 82%), and was the same 2 months after therapy whether they received bevacizumab (median, 68%; range, 53% to 80%) or not (median, 68%; range, 47% to 81%).

"Although there was no direct comparison with standard regimens, we now have the additional information that early cardiotoxicity with dose-dense regimens is not prohibitive," write Michael S. Ewer, MD, JD, from the University of Texas M.D. Anderson Cancer Center in Houston, and Steven M. Ewer, MD, from the University of Wisconsin School of Medicine and Public Health in Madison, in an accompanying editorial.

These early data are also important for patients who hope to benefit from subsequent trastuzumab, they note, because it doesn't appear that dose-dense regimens will significantly interfere with candidacy for further adjuvant treatment.

"However, any assumption that these regimens will not cause future problems is perhaps premature," they write.

Cardiologists and oncologists should continue to work together to find ways of identifying patients most at risk and those with impaired cardiac reserves, the editorialists note. "Despite the fact that we continually learn more about the cardiotoxicity of anthracyclines, the problem is not likely to go away any time soon," they say.

How to Interpret the Data

Lead study author Patrick G. Morris, MD, from Memorial Sloan Kettering Cancer Center in New York City, pointed out that, as discussed in the editorial, asymptomatic short-term declines in ejection fraction measured by multiple gated acquisition scan and/or echocardiogram do not reliably predict long-term risk for congestive heart failure.

There is also a need for biomarkers for cardiac injury, which his team is currently working on, he said.

"The cardiac safety of adjuvant trastuzumab beyond 5 years is unknown since there are no data from the adjuvant trastuzumab studies," Dr. Morris told Medscape Oncology. "But it is already known from AC followed by paclitaxel CALGB 9741 that dose-dense chemotherapy is associated with one half the rate of grade 3 to 4 cardiac events, compared with conventionally scheduled AC."

Based on their results, Dr. Morris concluded that "we did not identify a significant incidence of short-term cardiac toxicity and we believe that, for appropriately selected patients, trastuzumab can safely be incorporated into dose-dense anthracycline-based regimens."

"What is critical is that we did not identify an increase in the expected rate of cardiac safety events for doxorubicin when the biologics were added," he said.

Study Details: 3 Cohorts

In this study, a multicenter team prospectively evaluated the short-term cardiac safety of ddAC, with or without bevacizumab, in women with breast cancer who were eligible for adjuvant/neoadjuvant therapy.

From January 2005 to May 2008, 245 patients were enrolled in 1 of 3 sequential clinical trials. Patients with human epidermal growth-factor receptor 2 (HER2)-positive breast cancer were treated in trials 1 and 2, and patients with HER2-normal breast cancer (node positive or high-risk node negative) were treated in trial 3.

Women in all 3 trials received intravenous (IV) AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m²) once every 14 days, supported by pegfilgrastim. The protocols were as follows:

• In trial 1, AC therapy was followed by IV paclitaxel (175 mg/m²) every 2 weeks for 4 cycles, and pegfilgrastim 6 mg subcutaneously (SQ) on day 2. IV trastuzumab (Herceptin) was given weekly (4 mg/kg loading dose followed by 2 mg/kg), starting with paclitaxel, and was continued every 3 weeks (6 mg/kg) after the completion of chemotherapy for 1 year.
• In trial 2, AC was followed by weekly paclitaxel (80 mg/m²) for 12 doses. Trastuzumab therapy was the same as in trial 1, but oral lapatinib (Tykerb) 1000 mg daily was added concurrently with paclitaxel/trastuzumab for 1 year.
• In trial 3, AC was given concurrently with bevacizumab (10 mg/kg) once every 2 weeks. This was followed by IV nab-paclitaxel (Abraxane) 260 mg/m² every 2 weeks for 4 cycles, with pegfilgrastim (6 mg SQ) on day 2. After chemotherapy was completed, bevacizumab was changed to 15 mg/kg once every third week for 12 cycles to complete the year of treatment.

Patients also received tamoxifen or aromatase inhibitors as appropriate, and radiation therapy was recommended, as per institutional guidelines.

Data on LVEFs were available for 241 patients in the cohort at 2 months, and post-ddAC LVEF was normal in 240 of 241 women (99%). Overall, 96 patients (40%) had LVEF declines of less than 10%, and the majority had stable or improved LVEFs, compared with their baseline values.

Change in LVEF After Dose-Dense AC With or Without Bevacizumab at 2 Months

Change in LVEF	Number of Patients (n = 241)	Percent
≥16%	2	0.8
10%–15%	7	3.0
<10%	96	40.0
<5%–10%	35	15.0
<5%	61	25.0
Stable or improved	136	56.0

At 6 months, LVEF was normal in 217 of the 222 patients who were available for follow-up (98%). Median LVEF was 65% (range, 24% to 80%), and there was little difference between patients who received bevacizumab (median, 64%; range, 51% to 77%) and those who did not (median, 65%; range, 24% to 80%). An asymptomatic decline in LVEF to below the normal limit was observed in 3 patients, and an asymptomatic decline of more than 15% was observed in 6 patients (3%). In the latter group, all 6 patients experienced subsequent improvement in LVEF.

Change in LVEF After Dose-Dense AC With or Without Bevacizumab at 6 Months

Change in LVEF	Number of Patients (n = 222)	Percent
≥16%	7	3
10%–15%	24	11
<10%	102	46
<5%–10%	46	21
<5%	56	25
Stable or improved	89	40

The authors note that LVEF declines of less than 10% were common and occurred in 102 of 222 patients (46%), and the LVEF was stable or improved in 89 patients (40%).

Congestive Heart Failure Uncommon

Congestive heart failure developed in 3 of 245 patients (1.2%) within 6 months of initiating chemotherapy, all of whom had received anti-HER2 therapy (1 patient in trial 1 and 2 patients in trial 2). At month 12, an additional patient treated in trial 2 developed congestive heart failure, and 1 patient in trial 3 developed congestive heart failure at month 15 (3 months after completing therapy).

The authors point out that longer-term follow-up of cardiac toxicity of ddAC, with and without bevacizumab, and lapatinib is ongoing. "Assessment of biomarkers for cardiac injury in ongoing and future trials may allow us to see if there is any correlation with asymptomatic declines in LVEF," they note.

Several of the study authors report serving as a consultant or in an advisory role, or receiving honoraria or research funding from 1 or more pharmaceutical companies; see paper for details. Dr. Michael S. Ewer reports serving as a consultant/advisor for Hoffman La Roche, Genentech, GlaxoSmithKline, and Methylgene; and receiving honoraria from Roche Canada and Sanofi-Aventis. Dr. Steven M. Ewer reports receiving honoraria from Sanofi-Aventis.

J Clin Oncol. Published online November 9, 2009. Abstract, Abstract