Two-Year Follow-Up of a Multi-centre Randomized Controlled Trial to Study Effectiveness of a Hospital-Based Work Support Intervention for Cancer Patients.

Purpose Purpose is to: (1) study effectiveness of the hospital-based work support intervention for cancer patients at two years of follow-up compared to usual care and (2) identify which early factors predict time to return-to-work (RTW). Methods In this multi-center randomised controlled trial (RCT), 106 (self-)employed cancer patients were randomized to an intervention group or control group and provided 2 years of follow-up data. The intervention group received patient education and work-related support at the hospital. Primary outcome was RTW (rate and time) and quality of life (SF-36), and secondary outcomes were, work ability (WAI), and work functioning (WLQ). Univariate Cox regression analyses were performed to study which early factors predict time to full RTW. Results Participants were diagnosed with breast (61%), gynaecological cancer (35%), or other type of cancer (4%). RTW rates were 84% and 90% for intervention versus control group. They were high compared to national register-based studies. No differences between groups were found on any of the outcomes. Receiving chemotherapy (HR = 2.43, 95% CI 1.59-3.73 p < 0.001), low level of education (HR = 1.65, 95% CI 1.076-2.52 p = 0.02) and low work ability (HR = 1.09 [95% CI 1.04-1.17] p = 0.02) were associated with longer time to full RTW. Conclusions We found high RTW rates compared to national register-based studies and we found no differences between groups. Future studies should therefore focus on reaching the group at risk, which consist of patients who receive chemotherapy, have a low level of education and have a low work ability at diagnosis. TRIAL REGISTRATION: Netherlands Trial Registry (NTR) (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1658): NTR1658.

Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: First results of the randomised MATADOR trial (BOOG 2004-04).

BACKGROUND: Dose-dense administration of chemotherapy and the addition of taxanes to anthracycline-based adjuvant chemotherapy have improved breast cancer survival substantially. However, clinical trials directly comparing the additive value of taxanes with dose-dense anthracycline-based chemotherapy are lacking. PATIENTS AND METHODS: In the multicentre, randomised, biomarker discovery Microarray Analysis in breast cancer to Tailor Adjuvant Drugs Or Regimens (MATADOR) trial, patients with pT1-3, pN0-3 breast cancer were randomised (1:1) between six adjuvant cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks (ddAC) and six cycles of docetaxel 75 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks (TAC). The primary objective was to discover a predictive gene expression profile for ddAC and TAC benefit. Here we report the preplanned secondary end-point recurrence-free survival (RFS) and overall survival (OS). RESULTS: Between 2004 and 2012, 664 patients were randomised. At 5 years, RFS was 87% (95% confidence interval [CI] 83%-91%) in the ddAC-treated patients and 88% (84-92%) in the TAC-treated subgroup (hazard ratio [HR] 0.89, 95% CI 0.62-1.28, P = 0.53). OS at 5 years was 93% (90%-96%) in the ddAC-treated and 94% (91%-97%) in the TAC-treated patients (HR 0.89, 95% CI 0.57-1.39, P = 0.61). Anaemia was more frequent in ddAC-treated patients (62/327 patients [18.9%] versus 15/319 patients [4.7%], P < 0.001) and diarrhoea (21 [6.4%] versus 53 [16.6%], P<0.001) and peripheral neuropathy (15 [4.6%] versus 46 [14.4%], P < 0.001) were observed more often in TAC-treated patients. CONCLUSIONS: With a median follow-up of 7 years, no significant differences in RFS and OS were observed between six adjuvant cycles of ddAC and TAC in high-risk breast cancer patients. TRIAL REGISTRATION NUMBERS: ISRCTN61893718 and BOOG 2004-04.

Paclitaxel and bevacizumab with or without capecitabine as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a multicentre, open-label, randomised phase 2 trial.

BACKGROUND: The addition of bevacizumab to paclitaxel or capecitabine has demonstrated improved progression-free survival (PFS) and objective response rate (ORR) as compared with chemotherapy alone in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC). We evaluated the efficacy and safety of first-line therapy of paclitaxel and bevacizumab with or without capecitabine in patients with HER2-negative LR/MBC. METHODS: In this multicentre, open-label, randomised phase II trial, women with HER2-negative LR/MBC were randomly assigned in a 1:1 ratio to paclitaxel (90 mg/m2 intravenously [IV] on days 1, 8, and 15) and bevacizumab (10 mg/kg IV on days 1 and 15) every 4 weeks for six cycles, followed by bevacizumab (15 mg/kg IV on day 1) every 3 weeks (AT) or to paclitaxel (90 mg/m2 IV on days 1 and 8), bevacizumab (15 mg/kg IV on day 1) and capecitabine (825 mg/m2 orally twice daily on days 1­14) every 3 weeks for eight cycles, followed by bevacizumab and capecitabine at the same doses every 3 weeks (ATX). The primary end-point was investigator-assessed PFS. Secondary end-points included ORR, duration of response, overall survival (OS) and safety. Exploratory analyses were conducted to evaluate the impact of capecitabine on OS and to validate a novel prognostic model. This trial is registered with EudraCT, number 2006-006058-83. FINDINGS: Median PFS was significantly longer in ATX as compared with AT (11.2 months versus 8.4 months; stratified hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.41­0.67; p < 0.0001). The ORR in ATX patients with measurable disease (n = 268) was higher than that in AT (69% versus 51%; p = 0.01). The median duration of response was 6.8 versus 5.4 months for, respectively, ATX and AT (p < 0.0001). Median OS was 24.2 months for ATX and 23.1 months for AT (p = 0.53). The increased rate of grade 3­4 adverse events related to the addition of capecitabine, being hand-foot syndrome (34% versus 0% for AT) and neutropenia (20% versus 12% for AT), generally did not preclude continuation of treatment. Exploratory analyses indicated that (1) patients receiving capecitabine at some line for treatment have significantly improved OS and (2) a prognostic model can classify patients into three risk groups associated with OS. INTERPRETATION: In patients with HER2-negative LR/MBC, addition of capecitabine to paclitaxel and bevacizumab significantly improved PFS, ORR and response duration. This combination was reasonably well tolerated and may be considered of use as first-line treatment in rapidly progressive disease. FUNDING: F. Hoffmann-La Roche Ltd, the Netherlands.

Red cell distribution width as predictor for mortality in critically ill patients.

BACKGROUND: The objective of this study was to evaluate whether the red cell distribution width (RDW) is a significant risk factor for hospital mortality in critically ill patients and to investigate whether RDW is a parameter indicating inflammation, or a risk factor independent of inflammation. METHODS: We studied all patients admitted to a ten-bed mixed intensive care unit in the Netherlands between May 2005 and December 2011 for whom RDW was available, and who had not received a blood transfusion in the preceding three months. Inflammation was measured by C-reactive protein and leucocyte count. Analyses included correlation, logistic regression analysis, and receiveroperating characteristic (ROC) curves. RESULTS: We included 2915 patients, of whom 387 (13.3%) did not survive to hospital discharge. In univariate analysis higher RDW values were associated with increased hospital mortality. In multivariate analysis RDW remained an independent risk factor for mortality after correction for APACHE II score, age, admission type and mechanical ventilation (odds ratio 1.04, 95% confidence interval 1.02-1.06, for each femtolitre of RDW). Adding RDW to APACHE II, however, increased the area under the ROC curve marginally (from 0.845 to 0.849, p<0.001). RDW was not correlated with C-reactive protein and leucocyte count, refuting the hypothesis that the association between RDW and outcome is mediated through inflammation. CONCLUSION: In critically ill patients, the RDW on ICU admission was an independent predictor of mortality. Since RDW was not correlated with inflammation, the underlying mechanism of this association warrants further investigation.

Bloodstream infections in patients with or without cancer in a large community hospital.

PURPOSE: Cancer is associated with an increased risk of acquiring bloodstream infection (BSIs). Most knowledge on pathogens and outcome are derived from specialised cancer centres. We here sought to compare causative micro-organisms in BSIs in patients with or without cancer in a 600-bed teaching community hospital. METHODS: We analysed all positive blood cultures from adult patients between January 2005 and January 2011. RESULTS: A total of 4,918 episodes of BSI occurred in 2,891 patients, of whom 13.4% had a diagnosis of cancer (85.5% with a solid tumour). In both patient groups, Gram-positive isolates were more prevalent (58.7 and 61.4% in patients with and without cancer, respectively) than Gram-negative isolates (31.8 and 32.3%, respectively). Amongst Gram-positive organisms, coagulase-negative staphylococci, Staphylococcus aureus and enterococci were the most frequently isolated in both patient groups; in cancer patients, twice as many BSIs were caused by Enterococcus faecalis and E. faecium. Amongst Gram-negative organisms, Escherichia coli was the most common isolate; in cancer patients, twice as many BSIs were caused by Pseudomonas aeruginosa and Enterobacter cloacae. Yeasts were grown from 3.0% of blood cultures from cancer patients compared to 1.5% of cultures from non-cancer patients. Cancer patients had a 90-day mortality of 35.8% following BSI compared to 23.5% in patients without cancer. CONCLUSION: These data demonstrate distinct BSI pathogens and impaired outcomes in patients with cancer in the setting of a large community teaching hospital.

Outcomes of intensive care unit admissions after elective cancer surgery.

BACKGROUND: Postoperative care for major elective cancer surgery is frequently provided on the Intensive Care Unit (ICU). OBJECTIVE: To analyze the characteristics and outcome of patients after ICU admission following elective surgery for different cancer diagnoses. METHODS: We analyzed all ICU admissions following elective cancer surgery in the Netherlands collected in the National Intensive Care Evaluation registry between January 2007 and January 2012. RESULTS: 28,973 patients (9.0% of all ICU admissions; 40% female) were admitted to the ICU after elective cancer surgery. Of these admissions 77% were planned; in 23% of cases the decision for ICU admission was made during or directly after surgery. The most frequent malignancies were colorectal cancer (25.6%), lung cancer (18.5%) and tumors of the central nervous system (14.3%). Mechanical ventilation was necessary in 24.8% of all patients, most frequently after surgery for esophageal (62.5%) and head and neck cancer (50.2%); 20.7% of patients were treated with vasopressors in the acute postoperative phase, in particular after surgery for esophageal cancer (41.8%). The median length of stay on the ICU was 0.9 days (interquartile ranges [IQR] 0.8-1.5); surgery for esophageal cancer was associated with the longest ICU length of stay (median 2.0 days) with the largest variation (IQR 1.0-4.8 days). ICU mortality was 1.4%; surgery for gastrointestinal cancer was associated with the highest ICU mortality (colorectal cancer 2.2%, pancreatico-cholangiocarcinoma 2.0%). CONCLUSION: Elective cancer surgery represents a significant part of all ICU admissions, with a short length of stay and low mortality.

A hospital-based work support intervention to enhance the return to work of cancer patients: a process evaluation.

PURPOSE: To perform a process evaluation of a hospital-based work support intervention for cancer patients aimed at enhancing return to work and quality of life. The intervention involves the delivery of patient education and support at the hospital and involves the improvement of the communication between the treating physician and the occupational physician. In addition, the research team asked patient's occupational physician to organise a meeting with the patient and the supervisor to make a concrete gradual return-to-work plan. METHODS: Eligible were cancer patients treated with curative intent and who have paid work. Data were collected from patients assigned to the intervention group (N = 65) and from nurses who delivered the patient education and support at the hospital (N = 4) by means of questionnaires, nurses' reports, and checklists. Data were quantitatively and qualitatively analysed. RESULTS: A total of 47 % of all eligible patients participated. Nurses delivered the patient education and support in 85 % of the cases according to the protocol. In 100 % of the cases at least one letter was sent to the occupational physician. In 10 % of the cases the meeting with the patient, the occupational physician and the supervisor took place. Patients found the intervention in general very useful and nurses found the intervention feasible to deliver. CONCLUSIONS: We found that a hospital- based work support intervention was easily accepted in usual psycho-oncological care but that it proved difficult to involve the occupational physician. Patients were highly satisfied and nurses found the intervention feasible.

Low complication rates in the use of port-a-caths in oncology patients.

BACKGROUND: Port-a-caths (PACs) represent an important component of the care of cancer patients, in particular for administration of chemotherapy. We sought to analyse the longevity and complications of PACs in cancer patients in a large community hospital. METHODS: We retrospectively analysed the indications, duration of use, complications and reasons for removal of PACs in cancer patients treated in our centre from January 2005 to December 2010, and compared these with findings in patients who received a PAC in the same period for reasons not related to cancer. RESULTS: During the study period 152 cancer patients received a total of 170 PACs; in the same period, 21 patients received a total of 35 PACs for reasons unrelated to cancer. The total analysis comprised 70,919 days of PAC use. Most cancer patients had a solid tumour (97%). PACs were removed because of a complication in 25 cases in cancer patients (14.7%) vs 15 cases in non-cancer patients (42.9%, p.

Splenectomy-induced long-term remission in a patient with multicentric Castleman's disease.

Castleman's disease (CD) is a rare lymphoproliferative disorder with a poorly understood pathogenesis. Multicentric CD can progress in different patterns, none of which can be cured with the current treatment options. We present a patient with multicentric CD in complete remission, eight years after a splenectomy without any other systemic treatment. We discuss the possible mechanism causing this long episode of complete remission in this patient.

Validation of 70-gene prognosis signature in node-negative breast cancer.

PURPOSE: The 70-gene prognosis signature (van't Veer et al., Nature 415(6871):530-536, 2002) may improve the selection of lymph node-negative breast cancer patients for adjuvant systemic therapy. Optimal validation of prognostic classifiers is of great importance and we therefore wished to evaluate the prognostic value of the 70-gene prognosis signature in a series of relatively recently diagnosed lymph node negative breast cancer patients. METHODS: We evaluated the 70-gene prognosis signature in an independent representative series of patients with invasive breast cancer (N = 123; <55 years; pT1-2N0; diagnosed between 1996 and 1999; median follow-up 5.8 years) by classifying these patients as having a good or poor prognosis signature. In addition, we updated the follow-up of the node-negative patients of the previously published validation-series (Van de Vijver et al., N Engl J Med 347(25):1999-2009, 2002; N = 151; median follow-up 10.2 years). The prognostic value of the 70-gene prognosis signature was compared with that of four commonly used clinicopathological risk indexes. The endpoints were distant metastasis (as first event) free percentage (DMFP) and overall survival (OS). RESULTS: The 5-year OS was 82 +/- 5% in poor (48%) and 97 +/- 2% in good prognosis signature (52%) patients (HR 3.4; 95% CI 1.2-9.6; P = 0.021). The 5-years DMFP was 78 +/- 6% in poor and 98 +/- 2% in good prognosis signature patients (HR 5.7; 95% CI 1.6-20; P = 0.007). In the updated series (N = 151; 60% poor vs. 40% good), the 10-year OS was 51 +/- 5% and 94 +/- 3% (HR 10.7; 95% CI 3.9-30; P < 0.01), respectively. The DMFP was 50 +/- 6% in poor and 86 +/- 5% in good prognosis signature patients (HR 5.5; 95% CI 2.5-12; P < 0.01). In multivariate analysis, the prognosis signature was a strong independent prognostic factor in both series, outperforming the clinicopathological risk indexes. CONCLUSION: The 70-gene prognosis signature is also an independent prognostic factor in node-negative breast cancer patients for women diagnosed in recent years.

Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation.

Chemotherapy plus bevacizumab is currently considered as the standard 1st line treatment of advanced colorectal cancer (ACC). Whereas GI perforation is a known side effect of bevacizumab, the development of GI ulcers has not been reported. We identified 18 patients with ACC who participated in a phase III multicentre trial which included chemotherapy and bevacizumab, who developed a GI ulcer (n = 6), perforation (n = 8) or both (n = 4). The risk of developing a symptomatic GI ulcer or perforation was 1.3% and 1.6%, respectively. Central review of the histology specimens showed ulceration and/or granulation tissue with neovascularisation. The majority (89%) of events developed early during treatment. Given these observations, as well as the relationship between VEGF and mucosal injury healing, we suggest that GI ulcers may occur as a side effect of treatment with bevacizumab and may herald perforation.