The analysis of longitudinal quality of life measures with informative drop-out: a pattern mixture approach

The analysis of longitudinal health-related quality of life measures (HRQOL) can be seriously hampered due to informative drop-out. Random effects models assume Missing At Random and do not take into account informative drop-out. We therefore aim to correct the bias due to informative drop-out. Analyses of data from a trial comparing standard-dose and high-dose chemotherapy for patients with breast cancer with respect to long-term impact on HRQOL will serve as illustration. The subscale Physical Function (PF) of the SF36 will be used. A pattern mixture approach is proposed to account for informative drop-out. Patterns are defined based on events related to HRQOL, such as death and relapse. The results of this pattern mixture approach are compared to the results of the commonly used random effects model. The findings of the pattern mixture approach are well interpretable, and different courses over time in different patterns are distinguished. In terms of estimated differences between standard dose and high dose, the results of both approaches are slightly different, but have no consequences for the clinical evaluation of both doses. Under the assumption that drop-out is at random within the patterns, the pattern mixture approach adjusts the estimates to a certain degree. This approach accounts in a relatively simple way for informative drop-out

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 <.0001), the less fatigue was experienced. Joint (P <.0001) and muscle pain (P =.0283) were associated with more fatigue. In conclusion, we found that long-term fatigue occurs in 20 % of the women adjuvantly treated for breast cancer. Fatigue scores did not differ between the two treatment groups or from norm population scores and did not change over time. Anemia plays a small causative role in fatigue, but less than expected. The strongest relationship was found between fatigue and poor mental health. Besides fatigue, patients with a history of breast cancer due to the occurrence menopause or hormonal treatment often report hot flashes. In Chapter 4 an overview is given of the literature with regard the pathophysiologic mechanisms leading to hot flashes, the prevalence and severity of hot flashes in breast cancer patients, their influence on quality of life and the therapeutic options. The underlying pathophysiologic mechanisms of vasomotor symptoms are poorly understood, but estrogen withdrawal is considered to be the instigator for hot flashes. The neurotransmitters serotonin and norepinephrine are both involved in central thermoregulation and seem to play a role in the induction of hot flashes as well. Breast cancer patients experience more frequent and more severe hot flashes than healthy postmenopausal women. This is mainly the result of systemic breast cancer treatment such as chemotherapy and endocrine therapy. Cytotoxic agents induce ovarian damage, which can become clinically manifest by the sudden onset of menopause. The abrupt and premature induction of menopause by chemotherapy may lead to exaggerated menopausal symptoms, including hot flashes. Endocrine agents such as tamoxifen, aromatase inhibitors, and luteinizing hormone releasing hormone (LHRH) analogues are all used in the treatment of early or advanced breast cancer and hot flashes are a frequent side effect. The period over which endocrine therapy is administered has increased to several years and the rising number of treated patients makes the treatment of hot flashes more relevant as they may impair quality of life and may negatively influence adherence to endocrine treatment. Treatment with estrogens is very effective for the reduction of hot flashes, but is contraindicated in breast cancer patients because of the potential risk of tumor recurrence or the development of a new primary breast tumor. Several therapeutic options for hot flashes have been studied but none of them is as effective as estrogen. Clonidine and the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine are two of the most studied and effective non-hormonal drugs. Most studies evaluated non-hormonal drugs for the treatment of hot flashes in breast cancer patients for a maximum period of 4 weeks, this period is too short to evaluate aspects as side effects, quality of life and sexual functioning. It is also not known whether these drugs are effective if administered for a longer time period and what the spectrum of side effects is if used over a longer and more clinical relevant time period. In Chapter 5 we performed a prospective study comparing venlafaxine and clonidine for the treatment of hot flashes in breast cancer patients. The two drugs were compared in a double-blind, cross-over study, with regard to side effects, efficacy, quality of life and sexual functioning. Both drugs were administered for a period of 8 weeks. Sixty breast cancer patients ≤60 years and experiencing 14 or more hot flashes per week were randomized to 8 weeks of venlafaxine 75 mg once daily followed by a 2 weeks wash-out period, and 8 weeks of clonidine 0.05 mg twice daily or vice versa. Hot flash frequency and severity were recorded in a diary. Side effects, health related quality of life and sexuality were assessed using questionnaires. Thirty patients started treatment with venlafaxine and 30 patients started with clonidine. Of the 60 patients, forty patients completed both 8 weeks treatment periods. Premature discontinuation occurred in 15 of the 59 patients during venlafaxine and in 5 out of 53 patients during clonidine (P =.038). Reasons for premature discontinuation were side effects in all but one patient, who initially on venlafaxine stopped study participation early due to cancer progression requiring chemotherapy. During the first 2 weeks of treatment, venlafaxine induced more toxicity, namely nausea, constipation, taste alteration and appetite loss than clonidine. At the end of the 8-week treatment periods less toxicity was reported, indicating that most side effects resolved with time although women reported more appetite loss (24% vs 4%; P =.03), but less sleep disturbance (55% vs 75%; P = .03) on venlafaxine compared to clonidine. The median reduction in hot flash score was 49% for venlafaxine and 55% for clonidine (ns). The patients that experienced a ≥50% reduction in hot flash score after 8 weeks of venlafaxine reported an improvement in several aspects of health related quality of life. The mean scores of the subscales mental health, physical functioning, social functioning, and role-physical showed a clinically meaningful improvement. Patients with a ≥50% reduction on clonidine demonstrated only an improved vitality score. Only half of the patients was sexually active and no effects of venlafaxine or clonidine on sexual functioning in this group could be found. At study completion 33% of the patients chose to continue clonidine, 29% venlafaxine (ns), whereas 38% declined further treatment. Summarized we found that side effects are the main reason for drug discontinuation, during the first weeks of treatment and occurred more often with venlafaxine. After 8 weeks however, both drugs are well tolerated. Venlafaxine and clonidine are equally, but moderately effective in hot flash reduction in breast cancer patients. Endocrine treatment is based on the presence or absence of estrogen receptor and/or progesterone receptor status of the breast cancer cells. Drugs used for endocrine tumor treatment are targeted either directly at the estrogen receptor (tamoxifen) or at eliminating the estrogen production. The latter is achieved by inhibiting the conversion of androgens into estrogens (aromatase inhibitors) or by acting on the hypothalamic-pituitary axis (LHRH analogues). Another way of acting on the hypothalamic-pituitary axis is surgical ablation (surgical removal of the ovaries). Endocrine treatment plays an important role in the adjuvant and palliative treatment of breast cancer patients. The long-term impact of endocrine therapies is increasingly relevant, as patients are treated for years, the number of breast cancer survivors is increasing and more young women are treated with this modality. Chapter 6 provides a literature-based overview of side effects of hormonal treatment in pre- and postmenopausal breast cancer patients both in the adjuvant and palliative setting and the influence on the HRQoL and sexuality. There are several types of endocrine treatments available such as selective estrogen receptor modulators (SERMs), non-steroidal and steroidal aromatase inhibitors, pure ER-antagonists, progestins and luteinising hormone-releasing hormone (LHRH) agonists, which play an important role in breast cancer treatment. The long-term impact of endocrine therapies is increasingly relevant, as patients are treated for years, the number of breast cancer survivors is increasing and more young women are treated with this modality. HRQoL data can assist in recommendations for future treatment. In the review relevant clinical studies were identified by using the Medline database, limited to literature in English from between 1977-2006. Side effect profiles of tamoxifen and aromatase inhibitors vary but no significant difference in overall HRQoL was observed. Looking at the balance between efficacy and side effects, the aromatase inhibitors seem to outperform tamoxifen. Tamoxifen increases the incidence of endometrial cancer. Fewer thromboembolic events occur during aromatase inhibitors than with tamoxifen. The incidence of muscle pain and stiffness, joint disorders, and bone fractures was highest during aromatase inhibitors. Although patients may experience a wide range of symptoms, there are only minor differences in HRQoL ratings and they are generally rated as “good”. Further research should allow healthcare professionals to tailor their care even more specifically to patients’ individual circumstances, providing better disease control while maintaining HRQoL. The oldest endocrine drug for the treatment of breast cancer is tamoxifen, a non-steroidal anti-estrogen. As a consequence of its agonistics effects on the endometrium versus an antagonistic effect on the breast tumor an increased incidence of endometrial hyperplasia, polyps and 2-3 fold increased risk of endometrial adenocarcinoma and endometrial sarcoma have been described in tamoxifen using breast cancer patients. In Chapter 7.1 a case report of a postmenopausal breast cancer using tamoxifen is described which illustrates that tamoxifen can induce gynaecological changes that raise diagnostic problems. After 2 years of tamoxifen use this patient was referred with vaginal blood loss and a large pelvic mass. Transvaginal ultrasound (TVU) revealed an enlarged uterus with markedly increased endometrial thickness of 7-8 cm with a multicystic aspect. Because of persistent bleeding a total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Histology showed a large, benign endometrial polyp. A multicystic endometrium or benign polyps, such as found in our patient, are typical for chronic tamoxifen users, and may wrongly raise the impression of a malignancy. In Chapter 7.2 we investigated the influence of tamoxifen on the endometrium and the menstrual cycle in premenopausal breast cancer patients. Breast cancer patients using tamoxifen and 55 years of age or younger were investigated. The patients last menstrual period registered and the endometrial response measured by TVU every 6 months. Premenopausal status was defined as serum levels of estradiol (E2) ≥0.10 nmol/L and follicle stimulating hormone (FSH) ≤30 IU/L. Patients with an endometrial response of >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 endometrial

The influence of endocrine treatments for breast cancer on health-related quality of life

Many hormonal modalities are available for breast cancer treatment, such as selective oestrogen receptor modulators (SERMs), aromatase inhibitors, progestins and luteinising hormone-releasing hormone (LHRH) agonists. The Long-term impact of these endocrine manipulations is an issue, because the duration of adjuvant treatment is still increasing, as is the number of breast cancer survivors. Premature menopause is induced at a young age, and may often be permanent after chemotherapy. The purpose of this review is to provide a literature-based overview of the side effects of endocrine treatment in pre- and postmenopausal breast cancer patients and the influence on HRQoL, especially on sexual functioning. The collection of health-related quality of life (HRQoL) data can result in better treatment recommendations during endocrine therapy. Methods: This review was Limited to prospective randomised studies in English Literature from between 1977 and 2007 and provides an overview of the effects on HRQoL and sexuality of various hormonal treatment in pre- and postmenopausal breast cancer patients, both in the adjuvant and palliative setting. Relevant clinical studies were identified by using the Medline database. Results: HRQoL mostly is severely influenced by chemotherapy and part of these symptoms may be tasting, especially when associated with the induction of premature menopause. Similar symptoms may be encountered during ovarian suppression therapy by LHRH analogs, but they will. usually prove to be reversible. The varying side effect profiles of tamoxifen and aromatase inhibitors did not lead to significant difference in overall HRQoL. HRQoL during progestins and the SERM fulvestrant has been compared to this during aromatase inhibitors, and a large number of studies on HRQoL during endocrine therapy wilt be discussed. (C) 2008 Elsevier Ltd. All rights reserved

Blood pressure after PREeclampsia/HELLP by SELF monitoring (BP-PRESELF): rationale and design of a multicenter randomized controlled trial

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Effect of tamoxifen on the endometrium and the menstrual cycle of premenopausal breast cancer patients

OBJECTIVE: Tamoxifen, a nonsteroidal antiestrogen, is the agent of choice in the treatment of premenopausal receptor-positive breast cancer. This study aimed to investigate the influence of tamoxifen on the menstrual cycle and serum hormone levels and the subsequent endometrial response in premenopausal breast cancer patients. METHODS: In tamoxifen-using breast cancer patients aged 55 years or younger, the last menstrual period was registered, serum hormone levels measured, and the endometrial response visualized by transvaginal ultrasonography every 6 months. Premenopausal status was defined as serum levels of estradiol (E2) 0.10 nmol/L or more and follicle-stimulating hormone 30 IU/L or less. Premenopausal patients with an endometrial response of greater than 12 mm were offered a hysteroscopy and curettage. RESULTS: In 121 patients, a total of 241 measurements were performed. Amenorrhea predicted menopausal status incorrectly in 85 (35%) of the 241 measurements in 47 patients. In 8 of 47 endocrinologic premenopausal patients, transvaginal ultrasonography showed an endometrial response of greater than 12 mm (range,15-29 mm). Histopathology in women with an endometrial thickness of greater than 12 mm showed no malignancy. No relation between E2 levels and endometrial thickness was found. CONCLUSIONS: Tamoxifen leads to a disconnection between clinical and endocrinologic menopause in breast cancer patients aged 55 years or less. In premenopausal patients, tamoxifen has a predominantly antiestrogenic effect on the endometrium without a correlation between E2 levels and endometrial response

Venlafaxine versus clonidine for the treatment of hot flashes in breast cancer patients:a double-blind, randomized cross-over study

Purpose Breast cancer patients with treatment-induced menopause experience frequent and severe hot flashes (HF). We compared venlafaxine and clonidine for the treatment of HF with regard to side effects, efficacy, quality of life and sexual functioning. Methods In a double-blind, cross-over study, 60 breast cancer patients experiencing HF were randomized to 8 weeks venlafaxine followed by 2 weeks wash-out, and 8 weeks clonidine or vice versa. HF frequency and severity, side effects, quality of life and sexuality were assessed. Results Thirty patients started with venlafaxine and 30 with clonidine. Premature discontinuation for toxicity occurred in 14/59 during venlafaxine and 5/53 during clonidine (P = .038). Venlafaxine induced more side effects. Median reduction in HF score was 49% for venlafaxine and 55% for clonidine (ns). Conclusion Venlafaxine and clonidine are equally, but moderately effective in HF reduction. Side effects are the main reason for drug discontinuation, occurring more often with venlafaxine

Prospective study of long-term impact of adjuvant high-dose and conventional-dose chemotherapy on health-related quality of life

PURPOSE: To evaluate and compare health-related quality of life (HRQOL) after conventional- and high-dose adjuvant chemotherapy in patients with high-risk breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to either a conventional or high-dose chemotherapy regimen; both regimens were followed by radiotherapy and tamoxifen. HRQOL was evaluated until disease progression using the Short Form-36 (SF-36), Visual Analog Scale, and Rotterdam Symptom Checklist and assessed every 6 months for 5 years after random assignment. For the SF-36, data from healthy Dutch women with the same age distribution served as reference values. RESULTS: Eight hundred four patients (conventional-dose chemotherapy, n = 405; high-dose chemotherapy, n = 399) were included. Median follow-up time was 57 months. Directly after high-dose chemotherapy, HRQOL decreased more compared with 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 role-physical and role-emotional subscales, but 1 year after treatment, these differences were minor and not clinically relevant. During follow-up, patients with a lower educational level and many complaints before chemotherapy experienced a worse HRQOL. CONCLUSION: Shortly after high-dose chemotherapy, HRQOL was more affected than after conventional-dose chemotherapy. One year after random assignment, differences were negligible. Identifying patients who have a higher chance of persistent impaired quality of life after treatment (which, in the present study, included patients with a lower educational level and many complaints before chemotherapy) is important and may open the way for better patient-tailored prevention strategie