Adjuvant radiotherapy (RT) and trastuzumab in stage I-IIA breast cancer: Toxicity data from North Central Cancer Treatment Group Phase III trial N9831

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: June 5, 2006

Presenter: M.Y. Halyard
Presenter's Affiliation: Mayo Clinic, Rochester, MN
Type of Session: Scientific

Background

Breast cancer affects more than 200,000 American women every year and is responsible for 40,000 deaths.
Some of the effective therapies for breast cancer can potentially cause heart failure including anthracyclines, trastuzumab, and radiation therapy.
Trastuzumab is a monoclonal antibody that targets the extracellular portion of the HER-2 receptor
Approximately 25-30% of breast cancers overexpress HER–2, and tend to grow faster and be more aggressive than breast tumors that do not overproduce HER–2.
Many women receive radiation therapy (RT) to the breast/chest wall +/- regional lymph nodes after breast surgery and an increasing number of patients whose tumors overexpress HER-2 are also prescribed trastuzumab.
Preclinical data suggest that trastuzumab may exert a radiosensitizing effect of on breast cancer cells.
There is uncertainty regarding whether normal tissues can be radiosensitized by trastuzumab.

Materials and Methods

NCCTG N9831 is a 3-arm randomized Phase III trial comparing the safety and efficacy of doxorubicin/cyclophosphamide (AC) followed by weekly paclitaxel vs the same chemotherapy with 1 yr of trastuzumab given either concurrently with paclitaxel or after paclitaxel.
Eligible women had either pT1-3N1-2M0, pT2-3N0M0, or pT1cN0M0 (ER/PR-) disease that overexpressed HER-2.
Radiation therapy was performed within 5 weeks of completing the paclitaxel.
Post lumpectomy breast +/- nodal radiation was recommended, as was post-mastectomy chest wall + nodal radiation (for > 3 positive nodes).
Internal mammary radiation was prohibited; however, 41 patients (3%) did receive internal mammary radiation but were judged to have cardiac sparing dosimetrically.
Women with normal left ventricular ejection fraction (LVEF) assessed by MUGA or echocardiogram were eligible.
LVEF evaluation was repeated post-AC, 6, 9 and 18 months after entry.
Interim analyses were planned after 100, 300, and 500 evaluable patients per arm began post-AC therapy and were followed for additional 6 months.
The primary endpoint was proportion of cardiovascular events in each arm (congestive heart failure (CHF) and definite or probable cardiac deaths).
1499 patients who received radiation were available for analysis of radiation associated adverse events.
1286 patients who received trastuzumab (908 with radiation, 378 without radiation) were available for analysis of cardiac events.
Median follow-up is 1.5 years.

Results

Amongst the radiation receiving patients, the only grade > 1 adverse event that was significantly different in the three treatment arms was leucopenia (7.3% without trastuzumab, 12.8% in the sequential trastuzumab arm, and 10.1% in the concurrent trastuzumab arm, p=0.01).
The rates of grade > 3 adverse events were very low and not different in the three arms.
Radiation did not increase the frequency of cardiac events.
The number of cardiac events was low in all three arms (0.7% without trastuzumab, 5.2% in the sequential trastuzumab arm, and 7.5% in the concurrent trastuzumab arm).
There was no difference seen in the number of cardiac events between left and right sided radiation fields in either trastuzumab arm.
Radiation did not increase the number of cardiac events in the arms containing trastuzumab (2.5% with RT vs 2.7% without RT in the sequential arm, 1.7% with RT vs 5.8% without RT in the concurrent arm).
For the 41 patients who received internal mammary nodal irradiation in all three arms, an increased risk of cardiac events was not seen compared to patients who did not receive radiation.

Author's Conclusions

Concurrent radiation therapy with adjuvant trastuzumab does not appear to increase cardiac events or radiation associated adverse events (except leucopenia).
The practice of concurrent radiation with trastuzumab may be continued.
Internal mammary nodal radiation therapy appears feasible when cardiac dose is limited.
Longer follow-up is required to determine whether longterm cardiac toxicity emerges.

Clinical/Scientific Implications

The authors presented an early analysis of a large phase III randomized trial comparing the safety and efficacy of doxorubicin/cyclophosphamide (AC) followed by weekly paclitaxel (T) vs the same chemotherapy with 1 yr of trastuzumab given either concurrently with paclitaxel or after paclitaxel. Patients received radiation therapy concurrently with trastuzumab. The main point of this abstract is that radiation therapy given concurrently with trastuzumab appears safe from a cardiac standpoint. This conclusion is limited by the fact that there is a relatively short amount of patient follow-up in this study (median follow-up 1.5 years). Radiation therapy is known to cause late appearing toxicities, and cardiac damage from radiation could manifest as far out as 10-15 years following treatment. Thus it seems somewhat premature to conclude that trastuzumab given concurrently with radiation is completely safe. When this data has matured, we will have a better idea as to the benefits and risks of these combination regimens.