Long-term side effects of adjuvant breast cancer treatment

Breast cancer is the most common malignancy in women. Breast cancer accounts for one-third of all cancers in females and 24% of the patients are younger than 55 years of age. More than 10% all Dutch women will develop breast cancer and 70-80% of all breast cancer patients will survive over 5 years. In the absence of distant metastases, patients receive loco-regional therapy with or without adjuvant systemic therapy. Loco-regional therapy consists of either a modified radical mastectomy, in some cases followed by local radiotherapy or breast-conserving surgery with removal of the primary tumor and axillary lymphadenectomy followed by irradiation. Adjuvant therapy consisting of chemotherapy, hormonal treatment and the antibody trastuzumab against the epidermal growth factor HER2, or a combination have successfully resulted in a lowering of the risk of recurrence and death of this disease. The side effects of adjuvant treatments however can cause physical and psychological problems and the number of patients receiving adjuvant systemic therapy is rising. The higher change to survive in combination with the rising number of treated patients makes the long-term side effects of breast cancer treatment of utmost value. Health Related Quality of Life (HRQoL) is a broad concept, which takes many factors into account, including physical, emotional, sexual, social, and cognitive functions, as well as symptoms of disease and treatment. All these various functions and symptoms are assessed by and from the perspective of the patient. Better knowledge about the impact of adjuvant therapy on HRQoL is important for the evaluation of treatment, for adequate information to patients about future health effects, for treatment decision by physicians and patients and for interventions that reduce the negative effects of the treatment. This thesis focuses on a number of potential long-term side effects of adjuvant breast cancer treatment. Because of the dismal prognosis of patients with extensive axillary nodal involvement, over the last 10 years a variety of new treatment regimens has been tested. These include adjuvant dose-dense, as well as high-dose chemotherapy with hematopoietic stem-cell reinfusion. In a large multicenter prospective Dutch study, patients were randomized between a conventional and high-dose chemotherapy regimen, both followed by radiotherapy and tamoxifen. In this study HRQoL was included as a secondary endpoint. In Chapter 2 we evaluated and compared HRQoL after conventional- and high-dose adjuvant chemotherapy in patients with high-risk breast cancer. Patients were randomized between these regimens and both were followed by radiotherapy and tamoxifen. HRQoL was evaluated until disease progression, using the Short-Form (SF-36), Visual Analogue Scale (VAS) and Rotterdam Symptom Checklist (RSCL) and assessed every 6 months for 5 years following randomization. For the SF-36 data from healthy Dutch women with the same age distribution served as reference value. A total of 804 patients (405 conventional-dose, 399 high-dose chemotherapy) were included. Median follow-up was 57 months. Directly after high-dose chemotherapy HRQoL decreased more compared to conventional chemotherapy for all SF-36 subscales. After 1 year the reference value of healthy women was reached in both groups. Small differences were observed between the two groups in the subscale role-physical and role-emotional, but 1-year after treatment these differences were minor and not clinically relevant. The most prevalent symptoms of the RSCL were tiredness, decreased sexual interest, painful muscles and sweating. During follow-up, 10% of all patients experienced 3 or 4 of these symptoms for at least 50% of the time. Only a lower educational level could distinguish these patients. Shortly after high-dose chemotherapy, HRQoL was more affected than after conventional-dose chemotherapy. One year after randomization differences were negligible and only 10% of the patients experienced symptoms regularly. Patients with many symptoms after 5 years scored significantly lower on all SF-36 subscales at randomization and at the 11 measurement points thereafter compared with other patients. Eighty percent of patients with few symptoms at randomization reported few complaints after 5 years and half of all patients scoring many symptoms at randomization again reported many symptoms after 5 yeas. This indicates that having complaints before chemotherapy predicts a worse HRQoL outcome. A frequently mentioned symptom by many patients in above study was fatigue. Other studies also found that many cancer survivors report fatigue after the completion of cancer treatment. Fatigue can be highly distressing to patients and is limiting the quality of life. A better understanding of long-term fatigue in cancer survivors is, therefore fundamental to the development of appropriate intervention strategies. In Chapter 3 fatigue was studied in a prospective longitudinal way. In breast cancer patients it was evaluated whether conventional or high-dose chemotherapy affected changes in fatigue, hemoglobin, mental health, muscle and joint pain, and menopausal status. We also evaluated whether fatigue was associated with these factors. Eight hundred four breast cancer patients were randomly assigned between high-dose and conventional-dose chemotherapy both followed by radiotherapy and tamoxifen. Fatigue was assessed using vitality scale (score ≤ 46 defined as fatigue) and poor mental health using mental health scale (score ≤ 56 defined as poor mental health) both of SF-36. Muscle and joint pain were assessed with the Rotterdam Symptom Checklist. The SF-36, the RSCL and hemoglobin levels were assessed before and 1, 2 and 3 years after chemotherapy. Fatigue was reported in 20% of 430 evaluable disease free patients (202 conventional-dose, 228 high-dose) with at least a 3-year follow-up. Mean hemoglobin levels were lower following high-dose chemotherapy. Only 5% of patients experienced fatigue and anemia. In the 3 years after treatment, no significant differences in fatigue were found between conventional and high-dose chemotherapy and the norm population. Fatigue did not change over time. Sixteen percent of the patients in the present study experienced poor mental health at 3 years after therapy. Joint pain was observed in 20 % and muscle pain in 27 % of the patients at 3 years. Mental health score was the strongest fatigue predictor at all assessment moments. Menopausal status had no effect on fatigue. Linear mixed effect models showed that the higher the hemoglobin level (P =.0006) and mental health score (P 12 mm were offered an hysteroscopy and curettage. A total of 241 TVU measurements were performed in 121 patients. Amenorrhea predicted menopausal status incorrectly in 85 of the 241 (35%) measurements in 47 patients. In 8 of the 47 premenopausal patients TVU showed an endometrial response of 12 of more mm (range15-29 mm). Histopathology revealed no malignancy in 6 of the 8 women with an increased endometrial thickness. No relation between estradiol levels and endometrial response was found. In conclusion, tamoxifen leads to a disconnection between clinical and endocrinological menopause in breast cancer patients 55 years of age or younger. In premenopausal patients tamoxifen has a predominantly anti-estrogenic effect on the endometrium without a correlation between estradiol levels and endometria