Improved survival for sequentially as opposed to concurrently delivered neoadjuvant chemotherapy in non-metastatic breast cancer.

PURPOSE: The INTENS study was designed to determine whether delivering neoadjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. METHODS: Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600-T 100 mg/m2) or six cycles of TAC as triplet chemotherapy (75/50/500 mg/m2) every 3 weeks. The primary outcome was the pathologic complete response (pCR), with disease-free and overall survival as secondary endpoints. RESULTS: In total, 201 patients were included. The pCR rates were 28% for patients treated with AC-T and 19% for patients treated with TAC, with an odds ratio of 1.60 (95% CI 0.90-3.21). With a median follow-up of 6 years (range 0.04-8.41 years), the five-year disease-free survival was 81% for patients treated with sequentially AC-T and 71% for patients treated with concurrent triplet TAC chemotherapy with a stratified hazard ratio (HR) of 0.50 (95% CI 0.29-0.86). Five-year overall survival was 84% versus 76%, respectively, with a stratified HR of 0.55 (95% CI 0.29-1.03). CONCLUSIONS: No differences were observed between the two treatment arms with respect to pCR rate, but the sequentially delivered chemotherapy outperformed the triplet combination chemotherapy in terms of survival, despite a lower cumulative dose per agent. GOV nr NCT00314977.

In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium.

BACKGROUND: The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. PATIENTS AND METHODS: All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. RESULTS: From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. CONCLUSIONS: A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.

Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer?

BACKGROUND: We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients. METHODS: Consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy. RESULTS: Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49-2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy. CONCLUSION: Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.

Characterisation of exposure to total and hexavalent chromium of welders using biological monitoring.

Inhalation exposure to total and hexavalent chromium (TCr and HCr) was assessed by personal air sampling and biological monitoring in 53 welders and 20 references. Median inhalation exposure levels of TCr were 1.3, 6.0, and 5.4 microg/m(3) for welders of mild steel (MS, <5% alloys), high alloy steel (HAS, >5% alloys), and stainless steel (SS, >26% alloys), respectively. The median exposures to HCr compounds were 0.23, 0.20, and 0.08 microg/m(3), respectively. Median concentrations of TCr in urine, blood plasma and erythrocytes were elevated in all welders, compared with the corresponding median concentrations in the reference group (p<0.005). The TCr levels observed in plasma were two-fold higher in welders of SS and HAS than in welders of MS (p<0.01). Exposure to HCr as indicated by median total content of Cr in erythrocytes was 10 microg/L in welders of SS, MS and HAS. Uptake of TCr during the shift was confirmed for welders of SS by a median increase of urinary TCr from pre- to post-shift of 0.30 microg/g creatinine. For welders of MS and HAS as a group TCr was not increased.

Pseudo cluster randomization dealt with selection bias and contamination in clinical trials.

BACKGROUND AND OBJECTIVES: When contamination is present, randomization on a patient level leads to dilution of the treatment effect. The usual solution is to randomize on a cluster level, but at the cost of efficiency and more importantly, this may introduce selection bias. Furthermore, it may slow down recruitment in the clusters that are randomized to the "less interesting" treatment. We discuss an alternative randomization procedure to approach these problems. METHODS: Pseudo cluster randomization is a two-stage randomization procedure that balances between individual randomization and cluster randomization. For common scenarios, the design factors needed to calculate the appropriate sample size are tabulated. RESULTS: A pseudo cluster randomized design can reduce selection bias and contamination, while maintaining good efficiency and possibly improving enrollment. To make a well-informed choice of randomization procedure, we discuss the advantages of each method and provide a decision flow chart. CONCLUSION: When contamination is thought to be substantial in an individually randomized setting and a cluster randomized design would suffer from selection bias and/or slow recruitment, pseudo cluster randomization can be considered.

Age-specific effectiveness of the Nijmegen population-based breast cancer-screening program: assessment of early indicators of screening effectiveness.

BACKGROUND: The benefits of mammographic screening for breast cancer are not clear for women less than 50 years old. PURPOSE: Our aim was to evaluate the effectiveness of breast cancer screening in different age groups. METHODS: A mammographic breast cancer-screening program with a 2-year screening interval has been under way in Nijmegen, The Netherlands, since 1975. After eight rounds, more than 40,000 women have been invited to participate. All breast cancer cases diagnosed in the invited population, whether detected by screening or clinically, have been considered in this study. The age groups are younger than 50 years, 50-69 years, and 70 years or older at last invitation before diagnosis. Our assessment of the effectiveness of screening is based on the proportion of screen-detected cancers among all cancers and on the disease stage at diagnosis. RESULTS: For women younger than 50, compliance was 75%, and 37% (85/230) of the cancers were detected by screening. The age group 50-69 years had a compliance of 65% with 48% (288/595) of cancers detected by screening, and the group 70 years or older had a 25% compliance with 35% (108/305) of cancers detected by screening. The sizes of the cancers detected by screening were smaller than those detected clinically for all age groups. The age group under 50 showed no substantial difference in the proportion of positive axillary lymph node status between screening-detected and clinically diagnosed cancers, while among older women, the proportion of lymph node involvement was substantially higher for clinically detected cases. A significantly lower frequency of advanced stages was observed in screen-detected compared with clinically diagnosed cancers for women 50 years of age or older (P < .001) but not in women under 50 (P = .35). CONCLUSIONS: No positive effect of the biennial screening program is apparent for women under age 50. For women aged 50 and above, the screen-detected cancers have a more favorable stage distribution than clinically diagnosed cancers, a prerequisite for a reduction in breast cancer mortality.

Twenty-five minutes between blood pressure readings: the influence on prevalence rates of isolated systolic hypertension.

The aim of the present study was to investigate the influence of a 25-min time interval between the first and the last reading of a series of six, on systolic (SBP) and Phase V diastolic (DBP) blood pressure and its implications for prevalence rates of hypertension. Readings were taken from 5999 persons (2889 men and 3110 women) by two observers using a Hawksley random-zero sphygmomanometer. The first reading was taken 5 min after entering the examining room. The study showed a considerable fall in mean SBP (men, 10.3 mmHg; women, 10.4 mmHg) and hardly a difference in mean DBP (men, 0.8 mmHg; women, 0.1 mmHg) between the first and sixth reading. The fall in SBP was independent of observer and sex and hardly correlated with age or Quetelet's index. The study also showed the implications for the classification of hypertension. Prevalence rates of isolated systolic hypertension dropped remarkably (men, 4.0 to 0.5%; women, 0.9 to 0.1%) between both readings while prevalence rates of severe, moderate and mild diastolic hypertension were nearly similar for the first and sixth reading.

The effectiveness of cervical screening: a population-based case-control study.

The cervical smear histories of 36 women with invasive cervical cancer were compared to those of 120 age-matched controls, drawn from local registrar's offices. Of the cases 47% were screened at least once, while for the controls this figure was 68%. The relative risk of getting invasive cervical cancer for women screened at least once compared to women who were never screened was 0.32. The most important confounding factor was age at first intercourse. Contrary to other studies however, it was found that women who were younger when having first intercourse were screened more often. After correcting the relative risk of screened vs unscreened for age at first intercourse, the relative risk became 0.22. When the length of the interval since the last smear was considered, the relative risk was 0.18 when the smear was made between 2 and 5 years earlier and 0.30 when this smear was made more than 5 years earlier. These results support the assumption that screening is effective in the prevention of invasive cancer of the uterine cervix. Even a screening interval of more than 5 years provides considerable protection.

A study on effectiveness of screening mammograms.

BACKGROUND: So far, no randomized controlled trials with a mean mammographic screening interval of > or = 2 years has demonstrated statistically significant mortality reduction for women younger than age 50. The issue of screening frequency is vital in detection of primary breast cancer. METHODS: The study group consisted of cancers diagnosed in women who participated in a serial screening programme with a mean screening interval of 2 years. To study the effectiveness of the screening, a comparison is made between the distribution of age at which the tumour could be detected when biennial mammographic screening is the only detection method, and the distribution of age at which the tumour would be detected by either biennial mammographic screening or the development of symptoms. Some recently developed statistic methods, such as bootstrap, the maximum likelihood distribution estimator for doubly censored data and the EM algorithm, are used in estimation of these distributions. RESULTS: The hypothesis tests and confidence intervals show that the difference between the two distributions was statistically significant for women younger than 50 and 50-70 years old, but not for women over 70 years. CONCLUSIONS: The statistical analysis indicates that for women younger than 50, and 50-70 years of age, a screening mammogram every other year is not frequent enough to detect primary breast cancer, but for women over 70 years, it might be sufficient.

Long term breast cancer screening in Nijmegen, The Netherlands: the nine rounds from 1975-92.

STUDY OBJECTIVE: To assess the performance of breast cancer screening in different age categories over two decades. DESIGN: Important determinants of reduced breast cancer mortality such as attendance, mammography performance, cancer detection, and disease stage were recorded. SETTING: Nijmegen, The Netherlands, 1975-92. SUBJECTS: Since 1975 more than 40,000 women aged 35 years and older have been invited biennially for breast screening in a population based project in Nijmegen. MAIN RESULTS: Rates of attendance, referral, detection, and disease stage were calculated, as well as the specificity of screening mammography and the predictive value of referral and biopsy. From round 3 onwards, the attendance rate of women younger than 50 years stabilised at 70%, in women of 50-69 years it was 62%, and in women aged 70 and over it was 22%. In these three age categories, the referral rates of a positive screening mammography per 1000 screened women were 4.9, 6.2, and 11.8, respectively. Specificity rates were between 99% and 100%. Current predictive values of referral were high: in the specific age categories 39%, 59%, and 68% of the referred women had cancer. Detection rates remained fairly stable over the rounds 4-9, at 1.9, 3.6, and 8.0 cancers per 1000 screened women. In the two year period between screening the numbers of interval cancers per 1000 screened women were 2.2, 2.2, and 2.9, for the three age categories respectively. With regard to invasive cancers detected during screening, the percentage of small tumours (< or = 20 mm on the mammogram) was 84% in each age category. For women younger than 50 years, the proportion of intraductal carcinoma in all the cancers detected at screening was 40%, while it was 15% in the other age categories. CONCLUSION: Throughout the nine rounds, the screening outcomes were found to be adequate, particularly considering the high specificity rate and the predictive value of referral without the interference of a low detection rate. Although the occurrence of interval cancers seemed high, it was similar to other screening programmes. Despite a relatively low referral rate, the ratios of screen detected versus interval cancer cases were favourable. Well organised screening programmes can achieve good mammography results without too many false positives. It is important that women continue to participate in a screening programme because cancer can still be detected even after several successive negative screening examinations.

Sample size determination for a trial of breast cancer screening under age 50: population versus case mortality approach.

OBJECTIVE: To determine the efficacy of screening for breast cancer in women aged 40 to 49. METHODS: A large number of women will have to be enrolled to ensure adequate statistical power. Attention will be restricted to the deaths from breast cancer that occur among comparable groups of patients with breast cancer rather than to an analysis in which all women entering into the trial are considered at risk of dying from breast cancer (population mortality analysis). As the new trial is likely to be conducted in regions where screening has been established for all women from age 50 onward, comparability may be reached by including the breast cancers detected at the routine screening examination at age 50. CONCLUSIONS: When comparability of cases can be reached, such a case mortality analysis requires 15-30% fewer women to be enrolled than a population approach.

Repeated mammographic screening reduces breast cancer mortality along the continuum of age.

OBJECTIVE: The optimal age boundaries for breast cancer screening are still under debate. A case-referent design was used to describe the effect of mammographic screening on breast cancer mortality along the continuum of age, based on a 20 year follow up period. SETTING: The population based breast cancer screening programme in Nijmegen, The Netherlands, which has biennially invited women over 35 years since 1975. METHODS: Cases, defined as women who died from primary breast cancer between 1987 and 1997, were selected from the group of women who received at least one invitation to the screening programme. For 157 cases, 785 women from the same group were selected as referents. Information on the index screening (the screening examination preceding diagnosis of the case) was collected for both cases and referents. The risk of dying from breast cancer was calculated per 10 year moving age group for women who had attended the index screening versus those who had not. RESULTS: The youngest 10 year age group showing an effect in our study were women aged 45-54 at their index screening. Breast cancer mortality for women in this group who attended the index screening was 32% lower, although not significant, than for women who did not (odds ratio (OR) 0.68, 95% confidence interval (95% CI) 0.33 to 1.41). This reduction in risk was not explained solely by an effect in women over 50 because the OR in women aged 45-49 was 0.56 (95% CI 0.20 to 1.61). Reductions in mortality became smaller with increasing age. Nevertheless, for women over 60 at index screening, participation in screening over a maximum 4 year period before diagnosis of the case yielded protective effects at least up to an age around 80. CONCLUSIONS: Although our results are based on a relatively small number of cases, they suggest that even in a programme with a 2 year screening interval there may be a benefit of starting screening around age 45. Also older women who participate at least once every 4 years still have much to gain from screening.

Assessment of myocardial velocities in healthy children using tissue Doppler imaging.

The objective was to determine the normal range of tissue velocities in paediatric hearts as measured by tissue Doppler imaging. A prospective study was carried out involving 160 healthy children (mean age 10.8 y, range 4.0-17.9 y). Using tissue Doppler imaging (TDI) from parasternal long axis and apical views, peak velocities and peak myocardial velocity differences across the right ventricular anterior wall, interventricular septum and left ventricular posterior wall were assessed during systole, early and late diastole. The existence of transmyocardial velocity differences between the left and right side of the interventricular septum, as well as between the endocardium and epicardium of the left ventricular posterior wall was observed throughout the heart cycle. With range-gated TDI from apical four-chamber view, peak velocities were measured within the basal, mid and apical parts of the interventricular septum, and the left and right free ventricular walls. The highest peak systolic, early and late diastolic velocities were measured within the basal parts of all myocardial walls. The ranges of the calculated velocity ratios (early-to-late diastolic velocity and early diastolic-to-systolic velocity) for the various wall parts appeared to be overlapping. The correlations of peak myocardial tissue velocities and their ratios with age and weight were weak and practically irrelevant. These normal values of peak myocardial velocities, transmyocardial velocity differences and the ratios of peak wall velocities can be used as reference values in future investigations of ventricular dysfunction in this age group.

A review on family history of breast cancer: screening and counseling proposals for women with familial (non-hereditary) breast cancer.

With the aim to specify screening recommendations for women with familial (non-hereditary) breast cancer (FBC) we analysed 59 studies using quantitative methods of pooling. The pooled relative risk (RR) and cumulative probability were used to estimate breast cancer risk. The RRs for women with a family history of breast cancer in a first-degree relative was 2.03 (95% CI 1.09-2.22). The highest RR is observed for women with a family history and atypical hyperplasia in their breast biopsy specimen (RR = 10.87, 95% CI 6.05-19.69). A high cumulative probability before the age of 50 was only found for women with a combination of two risk factors: a family history and atypical hyperplasia, namely 19% (95% CI 11-33%). The cumulative probabilities of women aged 50 to 70 years who have a family history were between 11% (95% CI 9-13%, a family history in combination with age at first birth before 22 years) and 53% (95% CI 35-75%, a family history in combination with atypical hyperplasia). These high risks suggest that women over 50 years of age who have a family history of FBC have to be actively encouraged to participate in a screening program consisting of a biannual palpation by a specialist, an annual mammogram and a monthly self-control. Yearly screening is recommended for women under 50 years of age who have a family history and atypical hyperplasia. These recommendations remain valid until the effectiveness of such screening programs is assessed.

Intra- or extrauterine transport? Comparison of neonatal outcomes using a logistic model.

In a retrospective study a comparative analysis of mortality by way of transport (maternal, neonatal, or not referred) was performed on 163 liveborn newborns with a gestational age of less than 32 wk or a birth weight of less than 1500 g. The occurrence of potential mortality risk factors in the subgroups was taken into account. Of these, caesarean section, sex, Apgar score, intubation after delivery, birth weight and gestational age showed a relationship with mortality. Logistic regression analysis regarding the relationship between mortality and way of transport revealed that mortality in the neonatal transport group was significantly higher than in the maternal transport group, taking into account the confounding risk factors sex, caesarean section, fetal growth retardation, birth weight and gestational age.

[Noninvasive blood pressure determination in newborn infants]. / Non-invasieve bloeddrukmeting bij de pasgeborene.

In 69 newborns (birth weight 900-3820 grams; gestational age 27-41 weeks) the Dinamap device was used to establish normative values for systolic and diastolic blood pressure, mean arterial pressure and pulse pressure for this indirect, non-invasive blood pressure monitoring system. Reference values for the first day after delivery in different birth weight groups are given and the changes during the first three days of life are shown. Blood pressure variability as a possible additional parameter in neonatal monitoring was found to be independent of birth weight and gestational age.

Incidence of and risk factors for persistent gram-positive bacteraemia and catheter-related thrombosis in haematopoietic stem cell transplantation.

A cohort of 439 haematopoietic SCT recipients was analysed to determine the incidence of Gram-positive coccal bacteraemia and thromboembolic events associated with the use of central venous catheters (CVCs) and to determine risk factors for these complications. The incidences of persistent coagulase-negative staphylococcal (CoNS) bacteraemia, symptomatic thrombosis and thrombophlebitis were 25%, 9.6% and 6.6%, respectively. Duration of neutropenia (in days, odds ratio (OR) 1.02; P=0.04) and left-sided placement of the CVCs (OR 1.73; P=0.03) were independent risk factors for the occurrence of persistent CoNS bacteraemia, whereas the use of less mucotoxic conditioning regimens was associated with a lower risk (high-dose melphalan (HDM)/BEAM vs other regimens, OR 0.24; P<0.001). Use of TBI, persistent CoNS bacteraemia and tip colonisation were all significantly associated with an increased risk of symptomatic thrombosis (OR 6.03, 3.36 and 2.80, respectively; P0.02). The risk factors found in this cohort of SCT recipients differed from those found in the general cancer population, showing an important role for persisting bacteraemia in the pathogenesis of CVC-associated thrombosis. Therefore, we constructed a new algorithm in order to improve catheter management and prevent these CVC-related complications.

Assessment of the Memorial Sloan-Kettering Cancer Center nomogram to predict sentinel lymph node metastases in a Dutch breast cancer population.

AIM: Sentinel lymph node (SLN) biopsy is an accepted alternative to axillary lymph node dissection to assess the axillary tumour status in breast cancer patients. Memorial Sloan-Kettering Cancer Center (MSKCC) developed a nomogram to predict the likelihood of SLN metastases in breast cancer patients. Nomogram performance was tested on a Dutch population. METHODS: Data of 770 breast cancer patients who underwent successful SLN biopsy were collected. SLN metastases were present in 222 patients. A receiver operating characteristic (ROC) curve was drawn and the area under the curve was calculated to assess the discriminative ability of the MSKCC nomogram. A calibration plot was drawn to compare actual versus nomogram-predicted probabilities. RESULTS: The area under the ROC curve for the predictive nomogram was 0.67 (95% confidence interval 0.63-0.72) as compared to 0.75 in the original population. The nomogram was well-calibrated in the Dutch population. CONCLUSIONS: In a Dutch population, the MSKCC nomogram estimated risk of sentinel node metastases in breast cancer patients well (i.e. calibration) with reasonable discrimination (area under ROC curve). Nomogram performance on core needle biopsy data has to be evaluated prospectively.

Reduction in screening for retinopathy of prematurity through risk factor adjusted inclusion criteria.

AIMS: To develop a new national screening guideline for retinopathy of prematurity (ROP). METHODS: Included were infants of the 2009 prospective ROP inventory in The Netherlands with gestational age (GA) <32 weeks and/or birth weight (BW) <1500 g. Five models were studied, based on GA and BW in combination with no, one or a set of five risk factors for ROP. Risk factors were determined by logistic regression. In MEDLINE and EMBASE, additional risk factors were searched. A precondition was that no infants with severe ROP would be missed. Receiver operating characteristic curves or classical measures were used to determine diagnostic accuracy. RESULTS: The model including all infants with severe ROP comprised screening of infants with GA <30 weeks and/or BW <1250 g and a selection of infants with GA 30-32 weeks and/or BW 1250-1500 g, with at least one of the following risk factors: artificial ventilation (AV), sepsis, necrotising enterocolitis (NEC), postnatal glucocorticoids or cardiotonica. This model would not detect 4.8% (95% CI 2.5% to 8.0%) of infants with mild ROP and would reduce infants eligible for screening by 29%. CONCLUSIONS: In The Netherlands, screening may be safely reduced using a new guideline based on GA, BW, AV, sepsis, NEC, postnatal glucocorticoids and cardiotonica.