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Tamoxifen and radiotherapy both are known to cause pulmonary fibrosis mediated by TGF-β. This phase 3  randomized trial was done to compare lung toxicity and oncological outcomes of concurrent vs sequential Tamoxifen with radiotherapy in adjuvant treatment of breast cancer (NCT00896155).

Women with large operable breast cancer (pT/cT >5cm) and estrogen receptor and/or progesterone receptor positive status who were planned for hormonal therapy with tamoxifen were randomly assigned after breast conservative surgery (BCS) or modified radical mastectomy (MRM) to receive either concurrent or sequential Tamoxifen with radiotherapy. Stratification was done on the basis of BCS versus MRM and Central Lung Distance (CLD) > 2 cm. Radiation was given to chest wall / whole breast and supraclavicular region with 6MV X rays or telecobalt to a dose of 50Gy/25#/5weeks along with a boost of 15Gy/6#/1week to the tumor bed in BCS. Tamoxifen was administered once daily to a dose of 20 mg for 5 years. The primary end point of the study was development of  lung fibrosis evaluated using high resolution computed tomography (HRCT) scan, symptoms and clinical findings. HRCT was done pre-radiation therapy and at 24 months. Fibrosis was graded according to the EORTC/RTOG scale. The secondary end points were loco regional and distant failure.

Between December 2008 to February 2017, 259 women were randomized to receive either concurrent (N=129) or sequential (N=130) tamoxifen. The patient, tumour and treatment characteristics were well balanced between the 2 arms. Forty two patients were excluded from the final analysis- 15 lost to follow up at 24 month time point, 14 developed metastasis, 7  missed the HRCT scan and 4 scans were not retrievable due to technical error. Of the 217 patients, 103 were in the concurrent arm while 114 were in the sequential arm. All the patients scored Grade 0 at baseline HRCT scan before RT. Of 217 patients, 77 (35.48%) had evidence of pulmonary changes between the baseline scans and 24 months after RT. RTOG ≥ Grade II toxicity was observed in 13 (12.6%) patients in the concurrent arm while it was 9 (7.9%) patients in sequential arm (p=0.249). Twenty two percent of patients with CLD >2 cm developed ≥ Grade II fibrosis vs. only 5.7% in patients with CLD <2 cm (p=0.0001). There was no difference in the lung toxicity amongst BCT and MRM patients.

The median follow up of the entire cohort was 74 months (inter quartile range 37-110 months). The 5 year locoregional control was 90.4% in the concurrent arm while it was 88% in the sequential arm (p=0.72). The 5 year distant failure free survival was 68% in the concurrent arm while it was 66% in the sequential arm (p=0.55).

Concurrent administration of tamoxifen does not lead to increase in the pulmonary fibrosis in hormone positive women receiving postoperative adjuvant radiotherapy for breast cancer. Hence, Tamoxifen can be safely administrated concurrently with postoperative radiation therapy