Integration Of Systemic Therapy With Radiotherapy In Breast Cancer Patients Receiving Adjuvant Therapy And In Patients With Brain Metastasis Receiving Multidisciplinary Treatment

Part I Interim analysis of prospective, randomized Phase III study to compare the outcome of adjuvant radiotherapy with concomitant or sequential anastrozole in postmenopausal women with receptor positive breast cancerChapter Ⅰ:Analysis of the acute radiation-induced toxicity in relation to the serum TGF-β1 level in postmenopausal women with receptor positive breast cancer receiving adjuvant radiotherapy with concomitant or sequential anastrozolePurpose:To compare acute skin reaction occurrence rate and serum TGF-β1 level in postmenopausal hormone receptor-positive patients with concurrent or sequential anastrozole with radiotherapy. Compare the hematologic toxicity, radiation-induced lung injury and long-term outcome (local recurrence, disease-free survival and overall survival) in these patients.Material and methods:From January 2,2011 to June 20,2012,80 postmenopausal hormone receptor-positive breast cancer patients were enrolled in this prospective study. All patients received adjuvant radiotherapy in the Department of Radiation Oncology, Fudan University Shanghai Cancer Center. All patients were randomly classified as concurrent group (n=40) in which hormonal therapy with anastrozole combined concurrently with radiotherapy, and sequential group (n=40) in which hormonal therapy with anastrozole were followed by radiotherapy. Treatment complications, prognostic outcomes and serum TGF-β1 level were followed up and analyzed.Results:5 patients in the concurrent group and 7 patients in the sequential group had grade 2 or worse skin-related toxicity, the difference between two groups was not statistical significant (P>0.05). The incidence of hematologic adverse reactions of two group patients was no statistically significant difference (P>0.05). There was no radiation pneumonitis in two groups. The overall survival was 100% in both groups, the metastasis-free survival difference between two groups was not statistically significant (P=0.653). Starting from the two weeks before radiotherapy, serum TGF-β1 levels of patients in concurrent group gradually increased to 3 months after radiotherapy and reached a maximum, the difference of serum TGF-β1 level between two weeks before radiotherapy and three months after radiotherapy was statistically significant (P=0.023). In sequential group, the serum levels of TGF-β1 was lowest in four weeks after the start of radiotherapy and highest in three months after radiotherapy, the difference was statistically significant (P=0.011). The serum levels of TGF-β1 in concurrent group were 17.49±5.61ng/ml in patients with grade 2 or worse skin-related toxicity and 17.15±7.20ng/ml in patients with grade 1 skin-related toxicity, the difference was no statistically significant (P=0.963). The serum levels of TGF-β1 in sequential group were 15.58±8.33 ng/ml in patients with grade 2 or worse skin-related toxicity and 15.76±5.57ng/ml in patients with grade 1 skin-related toxicity, the difference was no statistically significant (P=0.963).Conclusion:Adjuvant anastrozole can be safely delivered in concurrent with radiotherapy in postmenopausal women with receptor positive breast cancer with comparable therapeutic outcome. The serum TGF-β1 level in the course of radiotherapy is not sufficient to predict the acute radiation-induced skin toxicity. The peak level of serum TGF-β1 appears in 3 months after the end of radiotherapy and tends to low-down at 6 months.Chapter Ⅱ:Comparison of quality of life in postmenopausal women with receptor positive breast cancer receiving adjuvant radiotherapy with concomitant or sequential anastrozolePurpose:To investigate the quality of life of breast cancer patients who enrolled in this prospective randomized study in chapter one and evaluate whether the sequence of hormone therapy influence the quality of life of these patients.Material and methods:Patients were asked to complete the questionnaires, the Chinese version of EORTC QLQ-C30 and EORTC BR23, before radiotherapy, at the end of radiotherapy, three months after radiotherapy and six months after radiotherapy.Results:The scores of overall quality of life of two groups ranged from 53.74-64.93. Fatigue was the most common symptom for breast cancer patients during treatment. Before radiotherapy, the difference of scores of nausea and vomiting between two groups was not statistically significance, while at the end of radiotherapy and at three and six months after radiotherapy, the scores of nausea and vomiting of concurrent group were higher than those of sequential group, the difference between the two groups was statistically significance (P<0.05). There was not statistically significant difference between the two groups of other scores of quality of life.10 patients (25%) in concurrent group and 15 patients (37.5%) in sequential group presented with hot flashes.23 patients (57.5%) in concurrent group and 25 patients (62.5%) in sequential group presented with bone and joint discomfort. The difference between the two groups was not statistically significance (P>0.05).Conclusion:The quality of life of postmenopausal hormone receptor-positive breast cancer patients was in the middle level. Taking anastrozole in concurrent with radiotherapy may increase the incidence of nausea and vomiting.Chapter III:Cosmetic outcome in postmenopausal women with receptor positive breast cancer receiving adjuvant radiotherapy after breast conserving surgery with concomitant or sequential anastrozolePurpose:To investigate the cosmetic outcome of breast cancer patients who receiving breast conserving surgery and enrolled in this prospective randomized study in chapter one and evaluate whether the sequence of hormone therapy influence the cosmetic outcome of these patients.Material and methods:From January 2,2011 to June 20,2012,20 postmenopausal hormone receptor-positive breast cancer patients were enrolled. All patients received whole breast radiotherapy and tumor bed boost after breast conserving surgery. All patients were randomly classified as concurrent group (n=7) and sequential group (n=13). Subjective cosmetic outcome was evaluated by the radiation oncologist and patients using the JCRT criteria. The pBRA (percentage of breast retraction assessment) was measured by radiation oncologist at one year after radiotherapy or last follow-up. The difference between the two groups was analysed.Results:Reported by patients, all 7 patients in concurrent group rated as excellent or good,12 of 13 patients in sequential group rated as excellent or good, there was no statistically significant difference between the two groups (P=0.452). Reported by radiation oncologist,6 of 7 patients in concurrent group rated as excellent or good,12 of 13 patients in sequential group rated as excellent or good, there was no statistically significant difference between the two groups (P=0.639). The pBRA of concurrent group patients was 8.74±1.99 and that of sequential group patients was 8.85±4.92, there was no statistically significant difference between the two groups (P=0.957).Conclusions:Although the sample size is limited in the current analysis, taking anastrozole concurrent with radiotherapy or followed by radiotherapy was not found to affect the cosmetic outcome of breast cancer patients who receiving breast conserving surgery.Part II Prognostic Analysis of patients with brain metastases from breast cancer receiving whole-brain radiotherapy(WBRT) and the role of systemic treatment after WBRT.Purpose:The purpose of this study was to examine the efficacy of systemic treatments following whole brain radiotherapy (WBRT) in breast cancer patients with brain metastasis (BM) who had different clinical characteristics based on the classification of the Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) and the breast cancer-specific Graded Prognostic Assessment (Breast-GPA).Material and methods:101 breast cancer patients with BM treated at the Fudan University Shanghai Cancer Center between 2006 and 2010 were analyzed. These patients were divided into four biological subgroups based on the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Prognostic analysis was performed based on clinico-pathologic characteristics, systemic treatment following WBRT and RPA classes.Results:The median interval between breast cancer diagnosis and identification of BM in the triple-negative patients was shorter than in the luminal A subtype (26 vs.36 months, respectively; p=0.021). The univariate analysis showed that age at BM diagnosis, Karnofsky performance status/recursive partitioning analysis (KPS/RPA) classes, number of BM, primary tumor control, extracranial metastases and systemic treatment following WBRT were significant prognostic factors for OS (p<0.05). The multivariate analysis revealed that KPS/RPA classes and systemic treatments following WBRT remained the significant prognostic factors for OS. In the entire group, the median survival in RPA Classes Ⅰ, Ⅱ and Ⅲ was 24,18 and 3 months, respectively (p<0.001). The median OS of patients with the Breast-GPA scores of 0.0 to 1.0,1.5 to 2.0,2.5 to 3.0, and 3.5 to 4.0 were 2,8,17, and 34 months, respectively (p<0.001). For RPA Class Ⅰ, the median survival with and without systemic treatments following WBRT was 25 and 22 months, respectively (p=0.819), while for RPA Class Ⅱ/Ⅲ systemic treatments significantly improved survival from 7 and 2 months to 11 and 5 months, respectively (p<0.05).Conclusions:Our results suggested that triple-negative patients had a shorter interval between initial diagnosis and the development of BM than luminal A patients. Systemic treatments following WBRT improved survival for RPA Class II/III patients.