Radiotherapy & Adjuvant Trastuzumab in Operable BC: Tolerability & Adverse Event Data

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From the NCCTG Phase III Trial N9831
J Clin Oncol. 2009 Apr 6;[Epub ahead of print], MY Halyard, TM Pisansky, AC Dueck, V Suman, L Pierce, L Solin, L Marks, N Davidson, S Martino, P Kaufman, L Kutteh, SR Dakhil, EA Perez


Combined analyses of data from the North Central Cancer Treatment Group (NCCTG) N9831 trial and the National Surgical Adjuvant Breast and Bowel Project B-31 trial demonstrated significant survival benefits when trastuzumab was added to systemic therapy. Patients treated with doxorubicin and cyclophosphamide followed by paclitaxel plus trastuzumab survived significantly longer than patients treated with doxorubicin and cyclophosphamide followed by paclitaxel alone. However, in the N9831 trial, a potential safety signal for cardiac toxicity was detected among trastuzumab-treated patients. Because trastuzumab is typically given concurrently with radiation therapy (RT), the concern exists that radiosensitization toxicity. This concern is especially relevant to use of anthracyclines, which are already associated with an increased cardiotoxicity risk.

Hayland et al conducted further analysis of NCCT N9831 data to determine the effect of trastuzumab on the incidence of RT-related adverse events (AEs) and cardiac toxicity. Results showed no association between trastuzumab and increased incidence of acute AEs.

The NCCT N9831 study involved 2148 women with HER2-positive breast adenocarcinoma. Node-positive disease was required during the initial enrollment. However, after May 2003, eligibility permitted enrollment of women with node-negative tumors if the tumor was >2 cm in diameter (for women with either positive or negative hormone receptor status) or >1 cm in diameter (for women with receptor-negative disease). The current analysis involved 1503 of the enrolled patients (70%), who received adjuvant RT after lumpectomy (n = 703) or mastectomy (n = 800). The treatment groups were as follows: doxorubicin (A), cyclophosphamide (C), and paclitaxel (T) (AC-T group; n = 521), AC-T plus trastuzumab fro 40 weeks (AC-T-H group; n = 543), and AC-T-H plus Hfor 52 weeks (AC-TH-H group; n = 439).

The median dose of whole-breast radiation was 50 Gy (range, 22.5 to 60.4 Gy). A boost dose was administered to 1084 patients. Overall, 1126 patients received supraclavicular radiation and 499 patients received axillary nodal irradiation. Internal mammary node (IMN) RT was not permitted but was received by 44 patients.

During the acute period (RT initiation to 90 days after completion of RT), no significant differences in grade 1 RT-related AEs were reported among the 3 treatment groups, except for leukopenia, which was more prevalent in the AC-T-H patients than in the AC-T group (odds ratio, 1.89; 95% CI, 1.25 - 2.88). Overall, grade 3 AEs were uncommon. RT interruption was reported in 24.2%, 24.6%, and 26.3% of patients in the AC-T, AC-T-H, and AC-TH-H groups, respectively. Early discontinuation of RT was more common in the AC-T group (2.8%) than in the AC-T-H group (0.6%) or the AC-TH-H group (1.4%). Cardiac toxicity was assessed in 1418 patients who received RT. No increase in cardiac events was associated with concurrent RT and H use, regardless of age, hormone receptor status, or antihypertensive use. Results for cardiac events were similar in the 44 patients who underwent IMN RT.

The results showed that, except for leukopenia, concurrent treatment with RT and adjuvant trastuzumab following chemotherapy with doxorubicin and cyclophosphamide does not increase RT-related or cardiac events in women with early HER2-positive breast cancer. Trastuzumab with concurrent IMN RT using cardiac-sparing techniques also appeared to be safe. Analysis of late RT-associated AEs is warranted. Results from the ongoing phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial are expected to provide useful data regarding concomitant use of adjuvant trastuzumab and RT.

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