Relationship between specific adverse events and efficacy of exemestane therapy in early postmenopausal breast cancer patients.

BACKGROUND: Many adverse events (AEs) associated with aromatase inhibitors (AIs) involve symptoms related to the depletion of circulating estrogens, and may be related to efficacy. We assessed the relationship between specific AEs [hot flashes (HF) and musculoskeletal AEs (MSAE)] and survival outcomes in Dutch and Belgian patients treated with exemestane (EXE) in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Additionally, the relationship between hormone receptor expression and AEs was assessed. METHODS: Efficacy end points were relapse-free survival (RFS), overall survival (OS) and breast cancer-specific mortality (BCSM), starting at 6 months after starting EXE treatment. AEs reported in the first 6 months of treatment were included. Specific AEs comprised HF and/or MSAE. Landmark analyses and Cox proportional hazards models assessed survival differences up to 5 years. RESULTS: A total of 1485 EXE patients were included. Patients with HF had a better RFS than patients without HF [multivariate hazard ratio (HR) 0.393, 95% confidence interval (CI) 0.19-0.813; P = 0.012]. The occurrence of MSAE versus no MSAE did not relate to better RFS (multivariate HR 0.677, 95% CI 0.392-1.169; P = 0.162). Trends were maintained for OS and BCSM. Quantitative hormone receptor expression was not associated with specific AEs. CONCLUSIONS: Some AEs associated with estrogen depletion are related to better outcomes and may be valuable biomarkers in AI treatment.

Quality of life in relation to tamoxifen or exemestane treatment in postmenopausal breast cancer patients: a Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial side study.

Tamoxifen and aromatase inhibitors are associated with side effects which can significantly impact quality of life (QoL). We assessed QoL in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial and compared these data with reported adverse events in the main database. 2,754 Dutch postmenopausal early breast cancer patients were randomized between 5 years of exemestane, or tamoxifen (2.5-3 years) followed by exemestane (2.5-2 years). 742 patients were invited to participate in the QoL side study and complete questionnaires at 1 (T1) and 2 (T2) years after start of endocrine treatment. Questionnaires comprised the EORTC QLQ-C30 and BR23 questionnaires, supplemented with FACT-ES questions. 543 patients completed questionnaires at T1 and 454 patients (84%) at T2. Overall QoL and most functioning scales improved over time. The only clinically relevant and statistically significant difference between treatment types concerned insomnia; exemestane-treated patients reported more insomnia than tamoxifen-treated patients. Discrepancy was observed between QoL issue scores reported by the patients and adverse events reported by physicians. Certain QoL issues are treatment- and/or time-specific and deserve attention by health care providers. There is a need for careful inquiry into QoL issues by those prescribing endocrine treatment to optimize QoL and treatment adherence.

Professionals' opinion on follow-up in breast cancer patients; perceived purpose and influence of patients' risk factors.

AIM: To provide insight into professionals' opinions on breast cancer follow-up to facilitate implementation of new follow-up strategies. The study focuses on current practice, purpose and perceived effects, and preferred frequency and duration of follow-up. DESIGN: A 29-item questionnaire on professionals' demographics, current practice, opinion on the current guideline, preferences in frequency and duration of tailored follow-up, and the purpose and perceived effects of follow-up was sent to 633 Dutch professionals. RESULTS: The current national guideline is followed by 81% of respondents. All different specialists are involved in follow-up. Sixty-nine percent of respondents' report nurse practitioners to be involved in follow-up. When asked for tailored follow-up, professionals indicate more factors for increased follow-up (age<40 years, pT3-4 tumour, pN2-3, treatment related morbidity, and psychosocial support), than for reduced schedules (age >70 years and DCIS histology). Alternative forms of follow-up are not endorsed by >90% of respondents. Detection of a new primary tumour of the breast is considered the most important purpose of follow-up (98%), 57% still indicates detecting metastases as a goal. CONCLUSIONS: Professionals tend towards longer and more intensive follow-up than the current guideline for a large group of patients. Limitations and developments in follow-up need to be considered to facilitate alternative follow-up strategies.

Tailored follow-up for early breast cancer patients: a prognostic index that predicts locoregional recurrence.

AIMS: After treatment, early breast cancer patients undergo follow-up according to standard regimens. After the first year, the main goal is particularly to detect locoregional recurrences (LRR). Our aim was to develop a simple prognostic index to predict LRR to tailor the follow-up programme. METHODS: We used data from four large international clinical randomised trials and constructed the prognostic index using Cox proportional hazards regression. The bootstrap (a resampling method) was used for internal validation. RESULTS: A total of 6516 patients treated according to current guidelines with complete covariable information were used for analysis. Covariables important for LRR in patients treated with breast conserving therapy were age, pathological tumour status, boost and surgical margins. The same variables were important for patients treated with a mastectomy, however, instead of the boost, the pathological nodal status was important. The index is composed to consist of three groups based on LRR risk after 10-years. CONCLUSIONS: We constructed a simple prognostic index that can be used to estimate risks of LRR in patients with early breast cancer. The prognostic index enables patients to be stratified into three subgroups with different outcomes with regard to LRR.

Variations in locoregional therapy in postmenopausal patients with early breast cancer treated in different countries.

BACKGROUND: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial is an international randomized trial evaluating the efficacy and safety of exemestane, alone or following tamoxifen. The large number of patients already recruited offered the opportunity to explore locoregional treatment practices between countries. METHODS: Patients were enrolled in Belgium, France, Germany, Greece, Ireland, Japan, the Netherlands, the UK and the USA. The core protocol had minor differences in eligibility criteria between countries, reflecting variations in national guidelines and practice regarding adjuvant endocrine therapy. RESULTS: Between 2001 and 2006, 9779 patients of mean(s.d.) age 64(9) years were randomized. Some 58.4 per cent had T1 tumours (range between countries 36.8-75.9 per cent; P < 0.001) and 47.3 per cent were axillary node positive (range 25.9-84.6 per cent; P < 0.001). Independent factors for type of breast surgery were country, age, tumour status and calendar year of surgery. After breast-conserving surgery, radiotherapy was given to 93.2 per cent of patients, 86.0 per cent in the USA and 100 per cent in France. Axillary lymph node dissection was performed in 82.0 (range 74.6-99.1) per cent. CONCLUSION: Despite international consensus guidelines, wide global variations were observed in treatment practices of early breast cancer. There should be further efforts to optimize locoregional treatment for breast cancer worldwide.

Intelligence of very preterm or very low birthweight infants in young adulthood.

OBJECTIVE: To examine the effect of intrauterine and neonatal growth, prematurity and personal and environmental risk factors on intelligence in adulthood in survivors of the early neonatal intensive care era. METHODS: A large geographically based cohort comprised 94% of all babies born alive in the Netherlands in 1983 with a gestational age below 32 weeks and/or a birth weight >1500 g (POPS study). Intelligence was assessed in 596 participants at 19 years of age. Intrauterine and neonatal growth were assessed at birth and 3 months of corrected age. Environmental and personal risk factors were maternal age, education of the parent, sex and origin. RESULTS: The mean (SD) IQ of the cohort was 97.8 (15.6). In multiple regression analysis, participants with highly educated parents had a 14.2-point higher IQ than those with less well-educated parents. A 1 SD increase in birth weight was associated with a 2.6-point higher IQ, and a 1-week increase in gestational age was associated with a 1.3-point higher IQ. Participants born to young mothers (<25 years) had a 2.7-point lower IQ, and men had a 2.1-point higher IQ than women. The effect on intelligence after early (symmetric) intrauterine growth retardation was more pronounced than after later (asymmetric) intrauterine or neonatal growth retardation. These differences in mean IQ remained when participants with overt handicaps were excluded. CONCLUSIONS: Prematurity as well as the timing of growth retardation are important for later intelligence. Parental education, however, best predicted later intelligence in very preterm or very low birthweight infants.

Preterm birth and later insulin resistance: effects of birth weight and postnatal growth in a population based longitudinal study from birth into adult life.

AIMS/HYPOTHESIS: An increased risk of type 2 diabetes mellitus is associated with low birthweight after full-term gestation, including amplification of this risk by weight gain during infancy and adult body composition. Premature birth is also associated with insulin resistance, but studies conducted so far have not provided follow-up into adulthood. We studied the effects of (1) lower birthweight (as standard deviation score [SDS]) and infancy weight gain on insulin resistance in 19-year-olds born before 32 weeks of gestation, and (2) the interaction between lower birthweight SDS and infancy weight gain, as well as between lower birthweight and adult body composition, on insulin resistance. METHODS: This was a prospective follow-up study in 346 subjects from the Project on Preterm and Small-for-gestational-age infants cohort, in whom fasting glucose, insulin and C-peptide levels were measured at 19 years. Insulin resistance was calculated with homeostatic modelling (homeostatic model assessment for insulin resistance index [HOMA-IR]). RESULTS: Birthweight SDS was unrelated to the outcomes. Rapid infancy weight gain until 3 months post-term was weakly associated with higher insulin level (p=0.05). Adult fatness was positively associated with insulin and C-peptide levels and HOMA-IR (all p<0.001). On these parameters, there was a statistical interaction between birthweight SDS and adult fat mass (p=0.002 to 0.03). CONCLUSIONS/INTERPRETATION: In subjects born very preterm, rapid infancy weight gain until 3 months predicted higher insulin levels at 19 years, but the association was weak. Adult obesity strongly predicted higher insulin and C-peptide levels as well as HOMA-IR. The effect of adult fat mass on these parameters was dependent on its interaction with birthweight SDS.

Nonresponse bias in a follow-up study of 19-year-old adolescents born as preterm infants.

OBJECTIVE: To assess the effect of demographic and neonatal risk factors and outcome at the last available assessment on the probability of full responders, postal responders (those who only responded to the mailed questionnaire), or nonresponders in a follow-up study of 19-year-old adolescents who were born as preterm infants. DESIGN: The 19-year follow-up program was part of a large ongoing collaborative study in The Netherlands on the long-term effect of prematurity and dysmaturity on various medical, psychological, and social parameters. In the original cohort, 1338 infants (94%) with a gestational age of < 32 weeks and/or a birth weight of < 1500 g were enrolled. Neonatal mortality was 23% (n = 312), and another 67 children had died between the ages of 28 days and 19 years, leaving 959 survivors (72% of the original cohort) for follow-up at the present assessment. To study the effect of nonresponse, we divided the 959 survivors into 3 groups: full responders (596 [62.1%]), postal responders (109 [11.4%]), and nonresponders (254 [26.5%]). In the 3 groups we compared demographic and neonatal data, as well as outcome at the last available assessment. RESULTS: The odds ratios (ORs) for male versus female for the probabilities of nonresponse and postal response were statistically significant: 2.7 (95% CI: 1.9-3.9) and 1.6 (95% CI: 1.0-2.5), respectively. The same holds for the ORs for non-Dutch versus Dutch and low versus high maternal education for nonresponse: 2.0 (95% CI: 1.3-3.2) and 3.7 (95% CI: 2.0-6.7), respectively. Special education and severe handicap showed a statistically significant influence on nonresponse (OR: 1.6; 95% CI: 1.1-2.4 and OR: 2.6; 95% CI: 1.3-5.2) and postal response (OR: 2.0; 95% CI: 1.2-3.3 and OR: 4.4; 95% CI: 2.0-9.9), respectively. At the age of 19 years, primary school and special education were found significantly more frequent in the postal responders than in the full-response group (20% and 21% vs 6% and 12%). The full responders, on the other hand, were higher educated than were the postal responders. CONCLUSIONS: In this follow-up study at the age of 19 years, boys, non-Dutch adolescents, and low maternal education were overrepresented in the nonresponse and postal-response groups. Nonresponse decreased the proportion of infants with adverse outcome in assessed children. To be able to present reliable results for the total group of survivors in long-term follow-up studies, the nonresponse bias needs to be quantified. Therefore, it is evident that more research using statistical methods such as imputation of missing data is needed.

Is attrition bias a problem in neonatal follow-up?

AIM: To assess whether attrition rate influences outcome in the follow-up of very preterm infants. STUDY DESIGN: In a national follow-up study of infants born alive in 1983 in the Netherlands with a gestational age less than 32 weeks and/or a birth weight less than 1500 g, outcome was assessed separately for adolescents who responded early or late to a follow-up invitation at age 14 years. Neonatal data and outcome results of earlier assessments from early and late responders were compared to those of non-responders by univariate and nominal (polytomous logistic) regression analysis. SUBJECTS: There were 723 (76%) early responders, 130 (14%) late responders and 109 (11%) non-responders. RESULTS: We found significantly more non-Dutch origin and more disabilities and school problems at age 10 years in late- and especially in non-responders. At age 14 years, the health utility index was significantly lower in late responders compared to early responders. School outcome did not show difference in relation to the response groups. CONCLUSION: The results suggest that the incidence of adverse outcome in very preterm infants is underestimated when follow-up is incomplete and hence response rate is not a negligible problem in the assessment of late outcome. Therefore, follow-up studies should include a drop-out analysis to enable comparison to other studies.

Preeclampsia and its interaction with common variants in thrombophilia genes.

Recently, it has been proposed that abnormalities in coagulation and fibrinolysis contribute to the development of preeclampsia by increasing the thrombotic tendency. This hypothesis was tested in women who have had preeclampsia (cases) compared with matched controls. Polymorphisms in the thrombophilia genes [plasminogen activator inhibitor type 1 [PAI-1 -675(4G/5G)], thrombin activatable fibrinolysis inhibitor (TAFI -438G/A and 1040C/T), methylenetetrahydrofolate reductase (MTHFR 677C/T), factor V (FV Leiden R/Q506), prothrombin (FII 20210G/A) and factor XIIIA (FXIIIA V/L34)] were determined in 157 women with preeclampsia and 157 women with uncomplicated pregnancy. The associated risk of preeclampsia was analyzed using logistic regression methods. The frequency distributions of the genotypes of these six polymorphisms in thrombophilia genes were similar in the case and control groups. We found no differences in the prevalence of genetic risk factors of thrombosis in women with preeclampsia compared with controls, which makes it unlikely that these polymorphisms are risk factors for preeclampsia.

Implementation of a nation-wide automated auditory brainstem response hearing screening programme in neonatal intensive care units.

AIM: As part of a future national neonatal hearing screening programme in The Netherlands, automated auditory brainstem response (AABR) hearing screening was implemented in seven neonatal intensive care units (NICUs). The objective was to evaluate key outcomes of this programme: participation rate, first stage success rate, pass/referral rates, rescreening compliance, diagnostic referral rates, age of first diagnostic evaluation and prevalence of congenital hearing loss (CHL). METHODS: This prospective cohort study collected data on 2513 survivors. NICU graduates with one or more risk factors according to the Joint Committee on Infant Hearing were included in a two-stage AABR hearing screening programme. Conventional ABR was used to establish a diagnosis of CHL. RESULTS: A total of 2513 newborns enrolled in the programme with a median gestational age of 31.6 (range 24-43) wk and a median birthweight of 1450 (range 510-4820) g. In 25 (1%) cases parents refused screening. Four out of 2513 newborns were initially lost; 2484 newborns have been tested initially. A final 98% participation rate (2465/2513) was obtained for the whole programme. After a median postmenstrual age at the first test of 33.7 (range 27-54) wk, a pass rate of 2284/2484 (92%) resulted at the first stage. The rescreening compliance after the first test was 92% (184/200). A referral rate for diagnostic ABR of 3.1% (77/2484) resulted. Of the 77 referrals 14 (18.2%) had normal screening thresholds, 15 (19.5%) had unilateral CHL and 48 (62.3%) had bilateral CHL. The prevalence of unilateral CHL was 0.6% (15/2484) and of bilateral CHL 1.9% (48/2484). CONCLUSION: A financially supported two-stage AABR hearing screening programme can be successfully incorporated in NICU centres and detects a high prevalence of CHL in NICU graduates. Neonatal hearing screening should be part of standard clinical practice in all NICU infants.