Breast cancer patients who underwent surgery at the University Hospital of Brussels from June 2007 to July 2011 were screened according to the eligibility criteria in the protocol of the TomoBreast study (ClinicalTrials.gov registration NCT00459628):
1. Women aged 18 years or older.
2. Histologically proven invasive unilateral breast carcinoma, stage I or II (T1-3N0 or T1-2N1 M0, American Joint Committee on Cancer (AJCC)/TNM 6th edition).
3. BCS or MA with clear margins and pathological nodal status assessed by axillary lymph node dissection or sentinel node biopsy.
4. At least one pre-operative medical imaging scan available (computed tomography, magnetic resonance imaging, or positron emission tomography).
5. Informed consent obtained.
Patients who did not meet the inclusion criteria, or with the following criteria, were excluded:
1. Prior breast or thoracic radiotherapy.
2. Pregnancy or lactation.
3. Fertile without effective contraception.
4. Psychiatric or addictive disorder.
A total of 123 eligible patients gave written informed consent and were included in the study. These patients were randomized to the CR (control) or TT (experimental) arms using Efron's biased coin design
]. Patients were stratified by nodal status (N0 vs. N1), type of surgery (MA vs. BCS), and chemotherapy sequence (none vs. sequential vs. concomitant chemotherapy). Two patients who were randomized to the control arm were later excluded from the study. One of these patients had bilateral breast cancer, which was not in accordance with the eligibility criteria, and the other patient could not participate because she was enrolled in a different study. The participant flow chart is presented in Figure
. In November 2011, the 121 eligible patients had all been followed up for at least 3 months after the completion of radiotherapy.
CR patients received a dose of 50 Gy delivered in 25 fractions over 5 weeks to the chest wall using tangential photon fields, and in patients with pN1 status, to the supraclavicular, infraclavicular, and axillary nodes using an anterior field matched to the tangential fields. BCS patients received a sequential boost of 16 Gy delivered in 8 fractions over 2 weeks to the initial tumor bed using a direct electron field (cumulative dose 66 Gy over 6.5 or 7 weeks depending on maintenance procedures). TT patients received a dose of 42 Gy delivered in 15 fractions over 3 weeks to the chest wall of MA patients or to the whole breast of BCS patients, and to the supraclavicular, infraclavicular, and axillary nodes in patients with pN1 status, using the image-guided Tomotherapy® system. BCS patients received a simultaneous integrated boost of 9 Gy delivered in 15 fractions over the 3 weeks (cumulative dose 51 Gy over 3 weeks).
Concurrent or sequential adjuvant systemic treatments were allowed. According to the protocol, radiotherapy should start within 6 weeks after breast surgery, or in cases of sequential chemotherapy, within 6 weeks after the completion of chemotherapy (Table
). In reality, CR started an average of 39 days after surgery and TT started an average of 50 days after surgery in patients who did not receive chemotherapy. CR started an average of 43 days after surgery and TT started an average of 49 days after surgery in patients with concurrent chemotherapy. One patient who received neo-adjuvant chemotherapy received radiotherapy 36 days after surgery. Patients with sequential chemotherapy started CR an average of 23 days, or TT an average of 25 days, after the completion of chemotherapy.
Mean nr of days to start RT after last breast surgery or last chemotherapy
The European Organisation for Research and Treatment of Cancer (EORTC) general cancer quality of life score (QLQ-C30) questionnaire and its breast cancer module (QLQ-BR23) were used to measure HRQOL in this study. These questionnaires were specifically designed for cancer patients, have undergone extensive testing, and have been confirmed as reliable and valid when measuring QOL outcomes
]. The EORTC QLQ-C30 questionnaire consists of 30 questions which assess functioning (physical, role, cognitive, emotional, social) and symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulty), and a global health status score that assesses overall QOL. The EORTC QLQ-BR23 questionnaire consists of 23 questions assessing functioning (body image, sexual functioning, sexual enjoyment, future perspective) and symptoms (systemic side effects, upset by hair loss, breast symptoms, arm symptoms). Both questionnaires use a four-point response scale (not at all, a little, quite a bit, and very much) to assess each functional or symptom item, and a seven-point response scale is used to assess global health status (from very poor to excellent). Raw scores were linearly transformed into a score of 0–100 for processing according to the EORTC manual
]. Higher scores in the functioning and global health status scales represented better functioning and QOL, whereas higher scores in the symptom scales indicated greater problems.
Patients completed the HRQOL questionnaires (EORTC QLQ-C30 and BR-23) during hospital visits at baseline (prior to radiotherapy), on the last day of radiotherapy, at 1–3 months after the completion of radiotherapy, and then yearly for 3 years. Clinical evaluations were performed at the same time points, and any recurrence of cancer was documented. The Radiation Therapy Oncology Group (RTOG)/EORTC morbidity scoring schema
] was used to assess acute morbidity, and the RTOG/EORTC and the Subjective Objective Management Analytic/Late Effects on Normal Tissues (SOMA/LENT) toxicity scales
] were used to assess late morbidity.
Patients usually completed the HRQOL questionnaires during their hospitals visits, but if they did not have time, they were asked to return them by mail. This achieved a 100% return rate at all time points except on the last day of radiotherapy (96% compliance), when five patients (two CR patients and three TT patients) declined to complete the questionnaires for various reasons (inconvenient, too busy, too tired, etc.). Six patients (two CR patients and four TT patients) withdrew from the study for various reasons (the patient did not want to undergo all the tests, the hospital was too far from the home, the family was not available to accompany the patient for hospital visits). These patients therefore did not complete the HRQOL questionnaires after their withdrawal from the study: one TT patient withdrew at the end of radiotherapy, one CR patient withdrew at 3 months after radiotherapy, one CT patient withdrew at 1 year, two TT patients withdrew at 2 years, and one TT patient withdrew at 3 years.
The mean (± standard error) of each score was calculated at each time point: baseline, last day of radiotherapy, 3 months, and 1, 2, and 3 years after the completion of radiotherapy. Consistent with previous studies, only differences of greater than ten points on the transformed questionnaire scale were considered clinically meaningful
Data were analyzed by the intention-to-treat (ITT) principle. For each patient, the baseline HRQOL score was subtracted from the score at each subsequent time point. The average change at each time point was compared between treatment arms using the two-sample t
-test (Additional file
: adjusted QLQ mean scores.xls). A positive change indicated improvement of functioning or worsening of symptoms, and a negative change indicated worsening of functioning or improvement of symptoms. Proportions were compared using Fisher's exact test and mean scores were compared using the t-test (two-sided), with the level of significance set at p < 0.05. Mean scores were also compared using the Bonferroni correction and repeated measures ANOVA. Statistical analyses were conducted using JMP version 8.0.1 (SAS Institute Inc., Cary, NC, USA).
Efron's biased coin design was used to randomize patients to treatment arms
]. Patients in each treatment arm (CR and TT) were stratified by nodal status, type of surgery, and chemotherapy sequence. The baseline patient and tumor characteristics, adjuvant radio-chemotherapy schedules, and hormonal treatments are presented in Table
Baseline quality of life scores
The mean baseline scores of the EORTC QLQ-C30 and BR-23 questionnaires in each treatment arm are shown in Table
. There were no significant differences in any of the scores between treatment arms at baseline. Only eight CR patients and 13 TT patients had hair loss at baseline. Of these, two CR patients and five TT patients who had received adjuvant chemotherapy before the start of radiotherapy described the hair loss as "very much" at baseline, and the other patients with hair loss due to other reasons described it as "quite a bit" at baseline. Some patients did not answer the questions about sexual functioning and enjoyment for personal reasons (such as religion or being widowed).
Baseline mean scores (SD) by treatment arm