Changes in Left Ventricular Function after Radiation Therapy and Trastuzumab: Analysis of North Central Cancer Treatment Group Phase III Trial N9831

Reviewer: Christine Hill-Kayser, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 9, 2009

Presenter: M. Halyard
Presenter's Affiliation: Mayo Clinic, Scottsdale, AZ
Type of Session: Scientific

Background

Radiotherapy for breast cancer has recently been associated with increased risk of coronary artery disease in patients receiving radiotherapy to the left breast or chest wall (Harris EE, JCO, 2006). Since this time, much attention has been turned to methods through which scattered dose to the heart may be reduced during radiation.
Many breast cancer patients require multimodality treatment, which may also contribute to cardiac risk. Adriamycin is well recognized to cause long-term cardiac toxicity, although dose relationships are not well-understood.
As breast cancer treatments have evolved, the small molecule tyrosine kinase inhibitor trastuzumab has been demonstrated to be efficacious in 25% of breast cancers, and is used widely in patients with Her2 overexpressing tumors.
Recent data has demonstrated that trastuzumab may be associated with cardiotoxicity, ranging from asymptomatic left ventricular dysfunction to congestive heart failure.
Incidence of this toxicity has not been well-understood, as it has not been studied systematically.
In addition, cardiac risk from multidisciplinary treatment, including trastuzumab, Adriamycin, and radiotherapy, while widely discussed, has not been formally investigated.
The study described here was undertaken to assess changes in left ventricular function in patients treated with adjuvant trastuzumab and radiation therapy.

Materials and Methods

The North Central Cancer Treatment Group (NCCTG) trial N9831 was a randomized phase III trial designed to assess efficacy of addition of trastuzumab to breast cancer treatment regimens.
Patient were randomized to one of the following arms:
- Adriamycin and cyclophosphamide (AC), followed by weekly paclitaxel (T) (Arm A).
- AC followed by T, followed by trastuzumab (H) (Arm B).
- AC followed by TH, followed by H (Arm C).
Eligible patients included those with Her2 positive pT1-3, N1-2, M0, pT2-3,N0,M0, or pT1cN0M0 (Estrogen receptor and progesterone receptor negative) breast cancers.
Post-lumpectomy radiation was recommended, as was radiation to the chest wall and nodal regions for mastectomy patients with greater than thee positive lymph nodes.
Radiotherapy was initiated within 5 weeks of completion of paclitaxel therapy, and was allowed to overlap with trastuzumab therapy.
A total of 2148 patients were enrolled on NCCTG N9831 prior to April, 2004.
Of these, 576 patients who received radiotherapy were available for left ventricular ejection fraction (LVEF) measurement within 4 weeks of beginning radiotherapy, and within 2-4 months after radiotherapy.
- 311 had right-sided tumors, and 265 had left-sided.
- 479 remained available for LVEF measurement 10-14 months post-radiotherapy.
The degree of change in LVEF compared to pre-radiotherapy values in left versus right sided patients was compared via chi-squared test within each treatment arm.

Results

At 2-4 months post-radiotherapy, the percentage of patients with greater than 5% decline from pre-radiation LVEF did not differ for patient treated with left versus right-sided tumors in any arm of the study:
- In arm A (no trastuzumab), 23% of left-sided patients had > 5% decline versus 25% of right-sided patients (p = 0.76).
- In arm B (trastuzumab given after paclitaxel), 27% of left-sided patients had > 5% decline vs. 36% of right-sided patients (p = 0.17).
- In arm C (trastuzumab given with and after paclitaxel), 22% of left-sided patients had > 5% decline vs. 25% of right-sided patients (p = 0.62).
- Of all patients, 2% (11 of 576) had greater than 15% decline.
  - 2 from arm A had left-sided tumors
  - 5 from arm B had left-sided tumors
  - 4 from arm B had right-sided tumors
At 10-14 months after radiation, the percentage of patients with greater than 5% decline from pre-radiation LVEF also did not differ for patients treated with left versus right-sided treatment in any study arm:
- In arm A (no trastuzumab), 20% of left-sided patients had > 5% decline versus 21% of right-sided patients (p = 0.93).
- In arm B (trastuzumab given after paclitaxel), 39% of left-sided patients had > 5% decline vs. 33% of right-sided patients (p = 0.5).
- In arm C (trastuzumab given with and after paclitaxel), 28% of left-sided patients had > 5% decline vs. 23% of right-sided patients (p = 0.51).
- Of all patients, 3% (12 of 479) had greater than 15% decline.
  - 2 from arm A had left-sided tumors
  - 3 from arm A had right-sided tumors
  - 1 from arm B had a left-sided tumor
  - 1 from arm B had a right-sided tumor
  - 3 from arm C had left-sided tumors
  - 2 from arm C had right-sided tumors.

Author's Conclusions

The authors conclude that administration of adjuvant radiotherapy in combination with trastuzumab in early-stage breast cancer patients is not associated with significant difference in LVEF change between patients receiving right and left-sided radiation.
They note that further follow-up to fully assess long-term effects of use of these modalities in combination is warranted.

Clinical/Scientific Implications

This is an important study that will no doubt alleviate practitioner concern regarding delivery of left-sided breast and chest wall irradiation to patients receiving trastuzumab.
Although both radiotherapy and trastuzumab have been demonstrated to portend risk of cardiac toxicity, mechanisms appear to be very different. While left-sided chest radiation has been demonstrated to increase risk of coronary artery disease (Harris, 2006), mechanism of trastuzumab-induced cardiac disease is likely specific to the myocardium. While these differences may prevent additive effect of toxicity between the two modalities, certainly risk of multiple insults to the heart must be kept in mind.
In addition, all patients in this study received Adriamycin chemotherapy, well documented to cause risk of left ventricular dysfunction. Additive effects of these therapies were not studied in this analysis but would be of interest in the future.
As the authors point out, longer-follow-up is also need for full understanding of the impact of these multiple risks. Late cardiac morbidity following left sided radiation has been demonstrated to occur over 20 years after completion of radiation (Harris, 2006). Further analysis of the patients presented here with longer follow-up would certainly be of interest.
Having said this, the authors present an interesting preliminary analysis demonstrating no adverse effects from use of concurrent trastuzumab and left-sided radiotherapy. Their findings will certainly factor into clinical decision making as more mature data are awaited.