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PRIORITY PRESS - National Oncology Pharmacy Symposium 2008

Calgary, Alberta / October 17-19, 2008

For the 20% to 25% of women with HER2-positive breast cancer, there is a higher risk of early relapse and a reduced overall survival rate. However, the overexpression of the HER2 protein also represents a therapeutic opportunity. The presence of HER2 in the tumour cells “gives us the ability to produce an antibody against that receptor, which is exactly what was done when trastuzumab was first formulated,” noted medical oncologist Dr. Susan Dent, Ottawa Hospital Cancer Centre, Ontario, in presenting the recommendations of the Canadian Trastuzumab Working Group (CTWG).

The Clinical Evidence

The results from four large randomized controlled trials have led to the adoption of trastuzumab as standard therapy for women with HER2-positive-overexpressing breast cancers, according to Dr. Dent. In the adjuvant setting, these four studies, involving more than 13,000 patients (HERA, BCIRG 006, NCCTG N9831 and NSABP B-31), have provided extensive evidence for the use of the monoclonal antibody (MAb) trastuzumab with taxane and anthracycline chemotherapies. Consistent improvements in disease-free survival, as well as overall reductions of mortality of approximately one-third, have been demonstrated when trastuzumab is added to chemotherapy. As a result of the data from these studies, the 2007 St. Gallen guidelines recommended one year of trastuzumab to be included in all adjuvant therapy for HER2-positive breast cancer. Similarly, the National Comprehensive Cancer Network (NCCN) recommends it for all HER2-positive tumours greater than 1 cm.

Cardiac Toxicity

Both anthracyclines and trastuzumab are known to be potentially toxic to cardiac tissue. However, Dr. Dent explained that there are believed to be two types of toxicity. Type I chemotherapy-related cardiac dysfunction (CRCD) is associated with higher or cumulative doses of anthracyclines, and causes cell death and irreversible myocardial damage. It is believed that the toxicity seen with trastuzumab is type II CRCD. This type of cardiotoxicity results in cellular dysfunction, not cell death, is not related to cumulative dosing and is generally reversible.

Data from the adjuvant studies indicate that the incidence of significant cardiotoxicity experienced by women was quite low. There was some variability seen in these studies which may have been influenced by when women were randomized to receive trastuzumab, stated Dr. Dent. Patients in the sequential HERA study were randomized after completion of chemotherapy treatment, so that patients with cardiotoxicity from anthracylines would have been excluded from the study. Of the patients in HERA who did experience left ventricular ejection fraction (LVEF) reductions (n=118/1678), six of 10 with severe congestive heart failure (CHF) recovered in a median of 124 days, 24 of 36 with symptomatic CHF in 151 days, and 35 of 51 with a significant decrease in LVEF in 191 days, indicating that reversal of trastuzumab myotoxicity does occur, she observed.

Pooled data from the North American studies (NCCTG N9831 and NSABP B-31) show that at three years, the cumulative incidence of severe CHF was 3.8%. No further increase was seen at five years. Furthermore, substantial recovery of LVEF was noted in all three groups of patients in this study over time. In contrast to this figure, the taxane arm in BCIRG 006, in which patients received no anthracyclines, had a severe CHF rate of only 0.4%.

Cardiac Management Recommendations

To address the uncertainty about cardiac management that became evident as trastuzumab usage increased, a number of oncologists and cardiologists from across Canada formed the CTWG. Its purpose was to formulate recommendations for the monitoring and management of cardiac side effects, based on the evidence accumulated during the adjuvant studies.

The guidelines suggest patients with CHF or with a LVEF <50% (or below the institutional norm) should not receive trastuzumab. However, continued Dr. Dent, “What do you do with a patient who has a LVEF of 49% and a very high risk of breast cancer recurrence? For those patients, it is worthwhile consulting with a cardiologist to see if the cardiac risk is manageable,” she told delegates. Risk factors requiring special consideration include ischemic heart disease or significant valvulopathy, baseline LVEF between 50 and 55 %, and a drop in LVEF of more than 15% during therapy, even if the patient remains above the institution’s lower limit of normal (LLN).

Effects of Specific Regimens

There was insufficient evidence for the CTWG to make recommendations on sequential vs. concurrent administration of trastuzumab with the taxane phase of chemotherapy in terms of cardiac risk. However, in the NCCTG N9831 trial, the incidence of grade 3/4 CHF was 3.3% with concurrent treatment and 2.8% with sequential therapy. In Canada, clinics frequently take a middle course between European and US approaches, giving one cycle of taxane alone following anthracycline, before introducing trastuzumab, Dr. Dent observed. However, with high-risk disease, “start trastuzumab with your first cycle of taxane if you can,” she proposed.

A comparison of regimens with and without an anthracycline component in the BCIRG 006 trial indicated a fivefold decrease in severe cardiotoxicity in anthracycline-free therapy (0.4% vs. 1.9% for the docetaxel/carboplatin/trastuzumab arm compared to the doxorubicin/cyclophosphamide/docetaxel/trastuzumab arm, respectively). CTWG members favoured the former regimen in the presence of pre-existing cardiac risk factors.

For patients with node-positive or node-negative disease and tumour size of more than 1 cm, trastuzumab is the standard of care. Studies are underway to determine its effectiveness with shorter duration therapy, but until new data are available, the CTWG recommend one year of treatment, said Dr. Dent. This is consistent with the duration used in the adjuvant trials.

Monitoring

Baseline LVEF must be established for all patients, emphasized Dr. Dent. The baseline should be established before initiation of trastuzumab (after chemotherapy in a sequential regimen). Monitoring should be repeated every three months. Echocardiogram (the Simpson method is preferred) or multigated acquisition scan (MUGA) can be used, but the same test should be used consistently. Patients with risk factors or cardiotoxicity may require more stringent monitoring. Management of Cardiotoxicity

Toxicity management consists of two components, withdrawing trastuzumab for a period of time, and treating cardiac dysfunction, explained Dr. Dent. The recommended protocol for holding/withdrawing trastuzumab is a modified version of the protocol used in study NSABP B-31.

Where LVEF reductions are not excessive, continued monitoring or temporary withholding of trastuzumab may suffice. However, patients with <u>></u>15% decrease in LVEF and/or a reduction of <u>></u>6% from LLN may also need an ACE inhibitor and other therapies, stated Dr. Dent. She emphasised the importance of early consultation with a cardiologist when cardiotoxicity becomes evident. Where trastuzumab is discontinued according to the recommendations, therapy can be resumed according to the original protocol if the LVEF increases to within normal values once more.

The CTWG suggested a number of cardiac drug therapies for LVEF dysfunction, as recommended by the Canadian Cardiovascular Society. However, the group stressed titration of these medications should be accelerated to one- or two-weekly dose increases in order to obtain optimal therapeutic effects as quickly as possible. Duration of treatment should be individualized according to patient response. Here again, the expertise of a cardiologist should be sought. “I do not, as a medical oncologist, feel comfortable titrating cardiac medications or trying to wean women off these drugs,” remarked Dr. Dent.

There is some question surrounding the total duration of trastuzumab therapy if there has been discontinuation during treatment. In Ontario, for instance, trastuzumab may not be given for longer than 14 months, so interruptions may mean that not all cycles of treatment can be completed.

Dr. Dent emphasized that trastuzumab is not a cytotoxic drug, therefore there is no need to discontinue it for other reasons, (e.g. elective surgery), as it will not affect blood counts or wound healing. Similarly, there is no evidence to support suspending trastuzumab therapy during adjuvant radiation as no safety issues emerged, according to data from more than 13,000 patients continuing trastuzumab during radiation therapy.

Summary

For the treatment of HER2-positive early breast cancer, trastuzumab has proven to be a highly valuable addition by almost halving the three-year recurrence risk and reducing mortality by a third. In following CTWG recommendations, the clinician can ensure that patients obtain maximum benefit from this agent with minimal risk.