Can trastuzumab emtansine (ado-trastuzumab emtansine) be administered with radiation therapy to the breast in adjuvant settings?

Concurrent T-DM1 and Radiation Therapy in the Adjuvant Setting

Trastuzumab emtansine (T-DM1) can be safely administered concurrently with radiation therapy to the breast in the adjuvant setting for patients with HER2-positive breast cancer who have residual disease after neoadjuvant therapy. 1, 2

Evidence Supporting Concurrent Administration

The standard approach is to begin radiation therapy after 12 weeks of T-DM1 therapy and continue T-DM1 concurrently with radiation. 3 This timing was established in the ATEMPT trial, which demonstrated that concurrent T-DM1 and radiation therapy is well-tolerated with acceptable toxicity profiles. 3

• The KATHERINE trial, which established T-DM1 as standard of care for residual disease after neoadjuvant therapy, showed a favorable safety profile when radiation was administered concurrently. 4
• T-DM1 should be administered for exactly 14 cycles in the adjuvant setting, with radiation integrated during this treatment course. 1, 2

Acute Toxicity Profile

Skin toxicity is the most common acute side effect, with grade 2 or higher dermatitis occurring in approximately 34% of patients receiving concurrent T-DM1 and radiation. 3

• Grade 3 skin toxicity is uncommon but can occur, reported in approximately 3 patients out of 35 in one institutional series. 4
• Hypofractionated radiation (≥2.5 Gy/fraction) results in significantly lower grade ≥2 acute skin toxicity (17.9%) compared to conventional fractionation (44.7%), even with concurrent anti-HER2 therapy. 3
• Pneumonitis is rare, occurring in approximately 1% of patients receiving concurrent T-DM1 and radiation. 3

Cardiac Monitoring Requirements

Regular cardiac monitoring with left ventricular ejection fraction (LVEF) assessment is mandatory before starting, during treatment, and following HER2-targeted therapy. 1, 2

• Reversible grade 2 LVEF decreases can occur in a small subset of patients (approximately 14% in one series). 5
• LVEF should be assessed at baseline, before radiation therapy, and after radiation therapy completion. 5

Other Toxicities to Monitor

Hepatotoxicity requires monitoring, as alanine aminotransferase (ALT) elevations can occur after cycle 4 of T-DM1, particularly when given with radiation. 5

• Grade 1-3 ALT increases have been reported in approximately 21% of patients receiving concurrent therapy. 5
• The most common adverse events with T-DM1 include thrombocytopenia, elevated liver enzymes, fatigue, nausea, and headache, with grade 3 or higher events occurring in 26.1% of patients. 1

Critical Contraindication

T-DM1 should never be given concomitantly with anthracyclines due to unacceptable cardiotoxicity risk. 1 This is distinct from the concurrent radiation scenario, which is safe and recommended.

Efficacy with Concurrent Radiation

Local recurrences are uncommon when T-DM1 is combined with radiation therapy, attesting to the efficacy of this combined approach. 3

• Three-year invasive disease-free survival was 97.8% in patients receiving T-DM1 with radiation. 3
• Among patients receiving breast-conserving surgery, isolated locoregional recurrences occurred in only 2 patients in the T-DM1 arm. 3

Practical Implementation

For patients requiring both T-DM1 and radiation therapy, initiate T-DM1 first, begin radiation after 12 weeks of T-DM1, and continue both treatments concurrently. 3

• Whole breast radiation is required after breast-conserving surgery. 3
• Consider hypofractionated radiation regimens to minimize acute skin toxicity. 3
• Post-mastectomy radiation is permitted and can be safely delivered concurrently with T-DM1. 3

Important Caveat About Trastuzumab

While there is limited historical concern about potential radiosensitization with trastuzumab (the parent antibody component of T-DM1), with one case report of radiation-induced myelitis at lower-than-expected doses 6, the extensive clinical trial experience with T-DM1 and concurrent radiation has demonstrated an acceptable safety profile. 4, 5, 3 The benefits of concurrent administration outweigh theoretical radiosensitization concerns when appropriate monitoring is performed.