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.

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.

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.

Meta-analysis of predictive factors for non-sentinel lymph node metastases in breast cancer patients with a positive SLN.

AIMS: A meta-analysis was performed to identify the clinicopathological variables most predictive of non-sentinel node (NSN) metastases when the sentinel node is positive. METHODS: A Medline search was conducted that ultimately identified 56 candidate studies. Original data were abstracted from each study and used to calculate odds ratios. The random-effects model was used to combine odds ratios to determine the strength of the associations. FINDINGS: The 8 individual characteristics found to be significantly associated with the highest likelihood (odds ratio >2) of NSN metastases are SLN metastases >2mm in size, extracapsular extension in the SLN, >1 positive SLN, ≤1 negative SLN, tumour size >2cm, ratio of positive sentinel nodes >50% and lymphovascular invasion in the primary tumour. The histological method of detection, which is associated with the size of metastases, had a correspondingly high odds ratio. CONCLUSIONS: We identified 8 factors predictive of NSN metastases that should be recorded and evaluated routinely in SLN databases. These factors should be included in a predictive model that is generally applicable among different populations.

Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11.

CONTEXT: Noonan syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. Short-term effect of GH therapy in NS is beneficial, reports on the effect on adult height are scarce. OBJECTIVE: To determine the effect of long-term GH therapy in children with NS. DESIGN: Twenty-nine children with NS were treated with GH until final height was reached. SETTING: Hospital endocrinology departments. PATIENTS: Children with the clinical diagnosis of NS, with mean age at the start of therapy of 11.0 years, 22 out of 27 tested children had a mutation in the protein tyrosine phosphatase, non-receptor-type 11 gene (PTPN11 gene). Interventions GH was administered subcutaneously at 0.05 mg/kg per day until growth velocity was 1 cm/6 months. MAIN OUTCOME MEASURE: Linear growth (height) was measured at 3-month intervals in the first year and at 6-month intervals thereafter until final height. RESULTS: At the start of treatment, median height SDS (H-SDS) was -2.8 (-4.1 to -1.8) and 0.0 (-1.4 to +1.2), based on national and Noonan standards respectively. GH therapy lasted for 3.0-10.3 years (median, 6.4), producing mean gains in H-SDS of +1.3 (+0.2 to +2.7) and +1.3 (-0.6 to +2.4), based on national and Noonan standards respectively. In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was +1.3, not different from the mean gain in the five children without a mutation in PTPN11+1.3 (P=0.98). CONCLUSION: Long-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.

New reference values for echocardiographic dimensions of healthy Dutch children.

AIM: To renew the echocardiographic reference values of heart dimensions in healthy children. METHODS AND RESULTS: Group 1 consisted of 587 children, of which 361 boys and 226 girls, age from birth to 18 years, body weight over 2500 g, who visited the Pediatric Cardiology outclinic during the period January 2000 till March 2004. All included children were diagnosed as normal, or as having innocent heart murmur. The second group was taken from an earlier study and comprised 160 children (77 boys and 83 girls). The echocardiographic measures were taken from conventional M-mode recording of the left ventricle (LV) parasternal long axis view. End diastolic septal (IVS) and LV posterior wall thickness (LVPW) and end diastolic as well as end systolic LV intracavity dimensions were retrospectively analyzed. The regression lines from all measured sizes are significantly different from those collected in the early eighties. Especially the thickness of the IVS is smaller. The regression lines are independent of gender. CONCLUSIONS: New reference values have been found which should replace the presently used ones. There is no difference between boys and girls. Why the muscular wall thicknesses are thinner than found 20 years ago needs to be further explored.

Homocysteine, glutathione and related thiols affect fertility parameters in the (sub)fertile couple.

BACKGROUND: Thiols are scavengers of reactive oxygen species (ROS). We aim to investigate associations between thiols in various fluids in (sub)fertile couples and fertility outcome parameters. METHODS: In 156 couples undergoing assisted reproduction techniques (ART), we measured the concentrations of glutathione (GSH), cysteine (Cys), homocysteine (Hcy) and cysteinylglycine (CGS) and fertility outcome parameters in the ejaculate, purified spermatozoa and follicular fluid. RESULTS: All thiols were detectable in most ejaculates, spermatozoa and follicular fluids, of which Cys concentrations were highest. Thiol concentrations in the ejaculate were similar in fertile and subfertile men. However, Hcy in follicular fluid was higher in women with endometriosis compared with women in the idiopathic subfertile group (P=0.04). The GSH, Cys, Hcy and CGS concentrations in spermatozoa of subfertile men were significantly higher compared with men in the idiopathic subfertile group and fertile men (P<0.001). Most notably, Hcy concentrations in both the ejaculate and follicular fluid were negatively associated with embryo quality on culture day 3 in the IVF/ICSI procedure. CONCLUSIONS: Spermatozoa of subfertile men contain significantly higher thiol concentrations as compared with those of fertile men. The detrimental effect on embryo quality of a high Hcy concentration in the ejaculate and in follicular fluid is intriguing and may suggest that Hcy is inversely associated with fertility outcome.

Timely withdrawal of G-CSF reduces the occurrence of thrombocytopenia during dose-dense chemotherapy.

BACKGROUND: Post chemotherapy Granulocyte colony stimulating factor (G-CSF) reduces leucopenia, while G-CSF priming shortly before chemotherapy increases myelotoxicity. We performed a trial with a two-schedule crossover design to determine the optimal G-CSF schedule for densified 2-weekly chemotherapy. METHODS: During 2-weekly chemotherapy days 1 and 2, G-CSF was given on days 3-10, with a G-CSF-free interval before the next chemotherapy cycle of 5 days, or on days 3-13, with a G-CSF-free interval of 2 days. In schedule A, cycle II was preceded by a 5 days, cycle III and IV by a 2 days and cycle V by a 5 days G-CSF free interval. In schedule B, this was 2, 5, 5, and 2 days, respectively. RESULTS: Intra-patient comparison for cycles II versus III and cycles IV versus V showed that platelet (PLT) nadir count was significantly lower for cycles preceded by a 2-days compared to a 5-days G-CSF free interval: mean difference 45.7 x 10(9)/l (95% CI 33.2-58.2, p = 0.0001). Neutrophil count did not differ significantly (p = 0.85). CONCLUSION: Timely withdrawal of G-CSF in dose-dense chemotherapy reduces chemotherapy-related thrombocytopenia. Leucopenia was not aggravated, reflecting a protective effect of post-chemotherapy G-CSF.