Concurrent versus sequential radiotherapy and tamoxifen in breast cancer – The CONSET trial is launched

To the Editor,

Carcinoma breast is the leading cause of cancer in the female population of the world. The management of carcinoma breast involves a multimodality approach of surgery, radiotherapy, chemotherapy and hormonal therapy. Sequencing of treatment in breast cancer has been a cardinal riddle for oncologists dealing with breast cancer. The findings of an Intergroup trial presented at ASCO in 2002 lead the world community to avoid using concurrent chemotherapy and hormonal therapy [1]. The question of sequencing of radiotherapy and hormonal therapy has however not been completely answered so far. Critical issues in this context are local control, disease free survival, overall survival, cosmetic outcome, lung toxicity and quality of life. Addressing the first three issues, a set of three retrospective studies revealed no difference in concurrent versus sequential radiotherapy and hormonal therapy. In the study by Harris et al., with a median follow-up of ten years, the local recurrence rates, disease free survival and overall survival were 3% vs. 7%, 85% vs. 76% and 81% and 86% respectively (p-value insignificant) [2]. The findings were similar in two other studies [3,4].

Radiotherapy to the breast or the chest wall usually irradiates a portion of the lung. A possible consequence of this is pulmonary fibrosis (PF) [5]. Post radiotherapy, the severity of PF is related to the volume of the lung irradiated and the dose and fractionation schedule. Further, tamoxifen and radiotherapy are both known to induce lung fibrosis mediated by TGF b [6,7]. In an exciting animal study, 21 female Wistar albino rats were randomized into three groups, irradiated, given tamoxifen and sacrificed 16 weeks after the start of irradiation for assessing pulmonary fibrosis [8]. The incidence of pulmonary fibrosis was 3%, 10% and 36% in the arms of RT only, sequential treatment and concurrent arms respectively (p<0.005). In a prospective non-randomized clinical study, pulmonary fibrosis developed in 26 of 74 patients (35%) who were treated with radiotherapy and tamoxifen combination as compared to only five of 37 women (13%) treated with radiotherapy alone (p=0.01) [9].

With improving overall survival (OS) rates in breast cancer, there is emerging focus on the quality of life (QOL) after adjuvant treatment. These issues have never been previously discussed in the context of hormonal therapy and radiation sequencing [10]. Finally, in patients with breast conservation, cosmesis is the end result of a range of factors which fall under the broad head of surgery, radiotherapy, chemotherapy and hormonal treatment. All of these modalities (including their sequencing) can play a role in compromising cosmetic outcome [11].

At the Tata Memorial Hospital in Mumbai we are conducting an investigator initiated, IRB approved, Indian Council of Medical Research (ICMR) sponsored Phase III randomized study to answer the question of CONcurrent versus SEquential Tamoxifen and radiotherapy (CONSET). (NCT00896155) Inclusion criteria are patients with large operable lesions (pT/cT > 5 cm) or locally advanced breast cancers undergoing (MRM) modified radical mastectomy or breast conservative surgery (BCS) who need adjuvant postoperative radiotherapy. After inclusion in the study, all the patients are being randomized into two arms. The patients will be stratified for the following factors a) BCS versus MRM (modified radical mastectomy), b) Central lung distance (CLD) > 2 cm. Arm 1 receives tamoxifen given concurrently with radiotherapy while arm 2 receives sequential radiotherapy followed by tamoxifen. Both the arms receive tamoxifen for a period of five years. The primary end point of the study is lung fibrosis and the secondary end points are loco regional and distant failure. Also, late breast sequelae and fibrosis in patients with breast conservation are being assessed. Patients are being assessed by serial high resolution CT (HRCT) and DTPA aerosol assessments for assessment of lung morphology and function. Further quality of life assessment is being done at regular intervals by EORTC questionnaires (QLQ 30 and BR 23 and lung questionnaires). This trial which opened in December 2008 is being funded by Indian Council of Medical Research (ICMR) and aims to accrue 260 patients over three years. Two hundred and sixty patients will be accrued into the study. The number is designed taking in consideration the incidence of overall rate of pulmonary fibrosis from previous studies [8,9]. These studies have shown an incidence of 35% in the concurrent radiotherapy and tamoxifen schedule and 13% in the sequential radiotherapy and tamoxifen schedule, the difference being 35%–13% = 22%. We have assumed that the concurrent tamoxifen arm will have a pulmonary fibrosis rate of 30% and the sequential tamoxifen arm will have a pulmonary fibrosis rate of 15% and are therefore testing for smaller difference compared to retrospective studies. After inclusion in the study, all the patients will be randomized into two arms. Since this trial started accrual in December 2008, 95 patients have been accrued into the trial so far.

This phase III randomized controlled trial shall provide the final answer to question of appropriate sequencing of tamoxifen and radiotherapy in breast cancer.

Acknowledgements

The CONSET trial is funded by the Indian Council of Medical Reseach (ICMR). We are also thankful to the EORTC and the Breast Cancer Working Group at Tata Memorial Hospital.