Effects of home-based specialized palliative care and dyadic psychological intervention on caregiver burden: results from a randomized controlled trial.

Background The Domus study, a randomized controlled trial (RCT), evaluated the effect of home-based specialized palliative care (SPC) reinforced with a psychological intervention for the patient-caregiver dyad on increasing advanced cancer patients' time spent at home, as opposed to hospitalized, and the number of home deaths. As palliative care extends to include support for patients' families and may thus assist caregivers and decrease demands on them, in this study we evaluated a secondary outcome, caregiver burden.Material and Methods Patients with incurable cancer and their caregivers were randomized (1:1) to care as usual or home-based SPC. Caregiver burden was assessed using the Zarit Burden Interview (ZBI) at baseline and 2, 4, 8 weeks and 6 months after randomization. Intervention effects were assessed in mixed effects models.Results A total of 258 caregivers were enrolled. Eleven per cent of informal caregivers experienced severe caregiver burden at baseline. Caregiver burden increased significantly over time in both groups (p = 0.0003), but no significant effect of the intervention was seen on overall caregiver burden (p = 0.5046) or burden subscales measuring role and personal strain.Conclusion In line with the majority of previous RCTs, the Domus intervention was not able to significantly reduce caregiver burden. Future interventions should consider targeting only caregivers reporting the greatest caregiver burden.

Cost-effectiveness analysis of systematic fast-track transition from oncological treatment to specialised palliative care at home for patients and their caregivers: the DOMUS trial.

BACKGROUND: While hospitals remain the most common place of death in many western countries, specialised palliative care (SPC) at home is an alternative to improve the quality of life for patients with incurable cancer. We evaluated the cost-effectiveness of a systematic fast-track transition process from oncological treatment to SPC enriched with a psychological intervention at home for patients with incurable cancer and their caregivers. METHODS: A full economic evaluation with a time horizon of six months was performed from a societal perspective within a randomised controlled trial, the DOMUS trial ( Clinicaltrials.gov : NCT01885637). The primary outcome of the health economic analysis was a incremental cost-effectiveness ratio (ICER), which is obtained by comparing costs required per gain in Quality-Adjusted Life Years (QALY). The costs included primary and secondary healthcare costs, cost of intervention and informal care from caregivers. Public transfers were analysed in seperate analysis. QALYs were measured using EORTC QLQ-C30 for patients and SF-36 for caregivers. Bootstrap simulations were performed to obtain the ICER estimate. RESULTS: In total, 321 patients (162 in intervention group, 159 in control group) and 235 caregivers (126 in intervention group, 109 in control group) completed the study. The intervention resulted in significantly higher QALYs for patients when compared to usual care (p-value = 0.026), while being more expensive as well. In the 6 months observation period, the average incremental cost of intervention compared to usual care was €2015 per patient (p value < 0.000). The mean incremental gain was 0.01678 QALY (p-value = 0.026). Thereby, the ICER was €118,292/QALY when adjusting for baseline costs and quality of life. For the caregivers, we found no significant differences in QALYs between the intervention and control group (p-value = 0.630). At a willingness to pay of €80,000 per QALY, the probability that the intervention is cost-effective lies at 15% in the base case scenario. CONCLUSION: This model of fast-track SPC enriched with a psychological intervention yields better QALYs than usual care with a large increase in costs. TRIAL REGISTRATION: The trial was prospectively registered 25.6.2013. Clinicaltrials.gov Identifier: NCT01885637 .

Safety and Activity of Sorafenib in Addition to Vinflunine in Post-Platinum Metastatic Urothelial Carcinoma (Vinsor): Phase I Trial.

LESSONS LEARNED: First trial to report safety and activity of the microtubule inhibitor vinflunine plus the tyrosine kinase inhibitor sorafenib in post-platinum metastatic urothelial cancer (mUC) patients.A recommended phase II dose was identified for the treatment combination of vinflunine plus sorafenib, with main adverse events including fatigue, febrile neutropenia, neutropenia, hypertension, and hyponatremia.An overall response rate of 41% to second-line vinflunine plus sorafenib treatment in patients with platinum-resistant mUC was confirmed. BACKGROUND: Platinum-progressive metastatic urothelial carcinoma (mUC) is a clinical challenge. The tyrosine kinase inhibitor sorafenib has demonstrated varied activity in mUC. This trial was designed to examine safety and activity of vinflunine plus sorafenib in mUC. METHODS: In addition to standard dose of vinflunine (320 or 280 mg/m2), patients received sorafenib (400, 600, or 800 mg/day), in a 3 + 3 dose-escalation phase I design. RESULTS: Twenty-two patients (median age 62.5 years) were included. Five patients received vinflunine 320 mg/m2 and 17 received 280 mg/m2. The maximum tolerated dose (MTD) of sorafenib with vinflunine 280 mg/m2 was 600 mg, and with vinflunine 320 mg/m2 it was not determined, owing to toxicity. Adverse events (AEs) grades 3 + 4 consisted of neutropenia (6 patients), febrile neutropenia (5), and hyponatremia (5). The overall response rate (ORR) in the efficacy-evaluable patients was 41% (7 of 17), all partial responses evaluated by RECIST version 1.1. Median overall survival (OS) was 7.0 months (1.8-41.7). CONCLUSION: The defined recommended phase II dose (RPTD) was vinflunine 280 mg/m2 plus sorafenib 400 mg. Sorafenib was too toxic in combination with vinflunine 320 mg/m2. The ORR of 41% to this second-line combination treatment of mUC is noteworthy and supports further trials.

Dyadic coping in specialized palliative care intervention for patients with advanced cancer and their caregivers: Effects and mediation in a randomized controlled trial.

OBJECTIVE: Specialized palliative care (SPC) interventions increasingly include patient-caregiver dyads, but their effects on dyadic coping are unknown. We investigated whether an SPC and dyadic psychological intervention increased aspects of dyadic coping in patients with advanced cancer and their caregivers, whether dyad characteristics moderated effects and whether aspects of dyadic coping mediated significant intervention effects on caregivers' anxiety and depression. METHODS: We randomized 258 patients with incurable cancer and their caregivers to care as usual or accelerated transition from oncological treatment to home-based SPC and dyadic psychological support. In secondary outcome analyses, using mixed-effects models, we estimated intervention effects and 95% confidence intervals (CIs) for communication of stress and common coping, and moderation by dyad type and demographics. In path analyses, we investigated whether stress communication and common coping mediated intervention effects on caregivers' symptoms of anxiety and depression. (Clinicaltrials.gov NCT01885637). RESULTS: The intervention significantly increased common coping in patients and caregivers in couples (estimated difference, 0.68; 95% CI, 0.11 to 1.24) and stress communication by partner caregivers (0.97; 0.24 to 1.24). We found some support for different intervention effects for spouses and other dyads, but no evidence of mediation. CONCLUSIONS: Specialized palliative care and dyadic psychological intervention may affect aspects of dyadic coping. Common coping and stress communication did not mediate the previously found significant intervention effects on caregiver anxiety and depression, indicating that other mechanisms may have been central in the intervention.

Effect of home-based specialised palliative care and dyadic psychological intervention on caregiver anxiety and depression: a randomised controlled trial.

BACKGROUND: Specialised palliative care trials often fail to address intervention effects on caregiver anxiety and depression, particularly in bereavement. We evaluate effects of specialised palliative care and dyadic psychological intervention on caregiver anxiety and depression in a randomised controlled trial (RCT). METHODS: Patients with incurable cancer and limited antineoplastic treatment options and their caregivers, recruited from a university hospital oncology department, were randomised (1:1) to care as usual or accelerated transition from oncological treatment to home-based specialised palliative care. We assessed caregivers' symptoms of anxiety and depression with the Symptom Checklist-92 up to six months after randomisation and 19 months into bereavement, and estimated intervention effects in mixed effects models. RESULTS: The 'Domus' trial enrolled 258 caregivers. The intervention significantly attenuated increases in caregivers' symptoms of anxiety overall (estimated difference, -0.12; 95% confidence interval, -0.22 to -0.01, p = 0.0266), and symptoms of depression at eight weeks (-0.17; -0.33 to -0.02; p = 0.0314), six months (-0.27; -0.49 to -0.05; p = 0.0165), and in bereavement at two weeks (-0.28; -0.52 to -0.03; p = 0.0295) and two months (-0.24; -0.48 to -0.01; p = 0.0448). CONCLUSIONS: This first RCT evaluating specialised palliative care with dyadic psychological support significantly attenuated caregiver anxiety and depression before and during bereavement. (Clinicaltrials.gov: NCT01885637).

Dyadic psychological intervention for patients with cancer and caregivers in home-based specialized palliative care: The Domus model.

ABSTRACTObjective:Patients with incurable cancer and their informal caregivers have numerous psychological and psychosocial needs. Many of these patients wish to receive their care and die at home. Few home-based specialized palliative care (SPC) interventions systematically integrate psychological support. We present a psychological intervention for patient-caregiver dyads developed for an ongoing randomized controlled trial (RCT) of home-based SPC, known as Domus, as well as the results of an assessment of its acceptability and feasibility. METHOD: The Domus model of SPC for patients with incurable cancer and their caregivers offered systematic psychological assessment and dyadic intervention as part of interdisciplinary care. Through accelerated transition to SPC, the aim of the model was to enhance patients' chances of receiving care and dying at home. Integration of psychological support sought to facilitate this goal by alleviating distress in patients and caregivers. Psychologists provided needs-based sessions based on existential-phenomenological therapy. Feasibility and acceptability were investigated by examining enrollment, nonparticipation, and completion of psychological sessions. RESULTS: Enrollment in the RCT and uptake of the psychological intervention indicated that it was feasible and acceptable to patients and caregivers. The strengths of the intervention included its focus on dyads, psychological distress, and existential concerns, as well as interdisciplinary collaboration and psychological interventions offered according to need. Its main limitation was a lack of an intervention for other family members. SIGNIFICANCE OF RESULTS: Our results show that psychological intervention can be systematically integrated into SPC and that it appears feasible to provide dyadic needs-based sessions with an existential therapeutic approach. The Domus RCT will provide evidence of the efficacy of a novel model of multidisciplinary SPC.

Surveillance versus adjuvant radiotherapy for patients with high-risk stage I seminoma.

BACKGROUND: The optimal treatment strategy for patients with clinical stage I (CS-1) seminoma is controversial. The objective of the current study was to evaluate the outcomes for patients considered to be at high risk of disease recurrence with a tumor size ≥6 cm. Patients were treated with either adjuvant radiotherapy (RT) or followed with surveillance. METHODS: From the Danish Testicular Cancer database, the authors identified 473 patients with CS-1 seminoma with a tumor size ≥6 cm. Of these, 254 patients underwent adjuvant RT and 219 were followed with surveillance. Cumulative incidence function was applied to estimate the risk of disease recurrence, risk of second malignant neoplasm, and risk of receiving >1 line of treatment. Survival of the 2 groups was compared with the log-rank test and Cox model including age at diagnosis. RESULTS: No significant differences were found with regard to overall survival or risk of a second malignant neoplasm. Patients undergoing adjuvant RT received more treatments per patient than patients followed with surveillance, but there was no significant difference noted with regard to the risk of receiving >1 line of treatment. The 10-year cumulative incidence of disease recurrence was 32% versus 2.8%, respectively, for patients followed with surveillance and adjuvant RT. In patients followed with surveillance who developed disease recurrence, there was a high incidence of second recurrences after RT. CONCLUSIONS: The 10-year overall survival was found to be similar irrespective of primary treatment. Adjuvant RT was found to effectively reduce the rate of disease recurrence but resulted in the overtreatment of approximately two-thirds of the patients. The high incidence of second disease recurrences after RT in the patients followed with surveillance needs be addressed in future studies. Cancer 2017;123:1212-1218. © 2016 American Cancer Society.

Classification of a palliative care population in a comprehensive cancer centre.

PURPOSE: The purposes of the present study were to classify the palliative care population (PCP) in a comprehensive cancer centre by using information on antineoplastic treatment options and to analyse associations between socio-demographic factors, cancer diagnoses, treatment characteristics and receiving specialist palliative care (SPC). METHODS: This is a cross-sectional screening study of patients with cancer in the Department of Oncology, Rigshospitalet, Copenhagen University Hospital for 6 months. Patients were assessed to be included in the DOMUS study: a randomised controlled trial of accelerated transition to SPC at home (NCT01885637). The PCP was classified as patients with incurable cancer and limited or no antineoplastic treatment options. Patients with performance status 2-4 were further classified as the essential palliative care population (EPCP). RESULTS: During the study period, 3717 patients with cancer were assessed. The PCP comprised 513 patients yielding a prevalence of 14 %. The EPCP comprised 256 patients (7 %). The EPCP was older, more likely inpatients, had a higher comorbidity burden and 38 % received SPC. Women, patients without caregivers and patients with breast cancer were more likely to receive SPC. CONCLUSIONS: By using objective criteria from clinical data and systematic screening, the observed prevalence of the PCP of 14 % may be generalisable to comprehensive cancer centres with similar composition of cancer diagnoses.

The DOMUS study protocol: a randomized clinical trial of accelerated transition from oncological treatment to specialized palliative care at home.

BACKGROUND: The focus of Specialized Palliative Care (SPC) is to improve care for patients with incurable diseases and their families, which includes the opportunity to make their own choice of place of care and ultimately place of death. The Danish Palliative Care Trial (DOMUS) aims to investigate whether an accelerated transition process from oncological treatment to continuing SPC at home for patients with incurable cancer results in more patients reaching their preferred place of care and death. The SPC in this trial is enriched with a manualized psychological intervention. METHODS/DESIGN: DOMUS is a controlled randomized clinical trial with a balanced parallel-group randomization (1:1). The planned sample size is 340 in- and outpatients treated at the Department of Oncology at Copenhagen University Hospital. Patients are randomly assigned either to: a) standard care plus SPC enriched with a standardized psychological intervention for patients and caregivers at home or b) standard care alone. Inclusion criteria are incurable cancer with no or limited antineoplastic treatment options. DISCUSSION: Programs that facilitate transition from hospital treatment to SPC at home for patients with incurable cancer can be a powerful tool to improve patients' quality of life and support family/caregivers during the disease trajectory. The present study offers a model for achieving optimal delivery of palliative care in the patient's preferred place of care and attempt to clarify challenges. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01885637.

Impact of baseline and nadir neutrophil index in non-small cell lung cancer and ovarian cancer patients: Assessment of chemotherapy for resolution of unfavourable neutrophilia.

BACKGROUND: Chronic inflammation has been recognized to foster tumour development. Whether chemotherapy can be used to neutralize chronic inflammation is unclear. METHODS: We evaluated baseline and nadir neutrophils in 111 patients (pts.) with non-small cell lung cancer (NSCLC) and 118 pts. with ovarian cancer (OC) treated with chemotherapy administered with dose-individualization to achieve nadir neutropenia of 1.5. We used predefined baseline neutrophil cut-offs 4.5 × 109/L (NSCLC) and 3.9 × 109/L (OC). RESULTS: Absence of chemotherapy-induced nadir neutropenia (CTCAE grade 0, neutrophils ≥ LLN) was seen in 23% of OC and 25% of NSCLC pts. Absence of nadir neutropenia was associated with decreased overall survival (OS) compared with presence (>grade 0) of neutropenia (9 vs. 14 months, P=0.004 for NSCLC and 23 vs. 56 months; P=0.01 for OC). Obtaining grade 3/4 neutropenia did not improve survival compared with grade 1/2 neutropenia. In multivariate analyses, baseline neutrophils ≥ 4.5 × 109/L (HR: 2.0; 95% CI: 1.11-3.44;P = 0.02) and absence of nadir neutropenia (HR: 1.6; 95% CI: 1.02-2.65;P = 0.04) for NSCLC and absence of nadir neutropenia (HR: 1.7; 95% CI: 1.04;2.93;P = 0.04) for OC were independently associated with short OS. CONCLUSIONS: A neutrophil index comprising elevated baseline neutrophils and absence of neutropenia identified a high risk group of NSCLC and ovarian cancer patients with only modest effect of chemotherapy. New treatment options for this subset of patients are required.

Role functioning before start of adjuvant treatment was an independent prognostic factor for survival and time to failure. A report from the Nordic adjuvant interferon trial for patients with high-risk melanoma.

PURPOSE: To investigate the role of health-related quality of life (HRQoL) at randomization as independent prognostic factors for survival and time to failure, and to explore associations between HRQoL and treatment effects. MATERIAL AND METHODS: In the Nordic adjuvant interferon trial, a randomized trial evaluating if adjuvant therapy with intermediate-dose IFN had the same beneficial effects on overall and disease-free survival in high-risk melanoma as high-dose IFN, 855 patients in Denmark, Finland, Norway, and Sweden were included. The EORTC QLQ-C30 questionnaire was used to assess HRQoL before randomization. RESULTS: A total of 785 (92%) agreed to participate in the HRQoL-study and provided baseline HRQoL data. Prognostic variables included in the multivariate model were age, sex, performance status, tumor thickness, stage, and number of positive lymph nodes. Univariate analyses revealed an association between prolonged survival and age, stage/ number of metastatic lymph nodes and the HRQoL variable role functioning (p ≤ 0.01). After controlling for other prognostic factors, these variables remained independently statistically significant for survival. The univariate analyses of time to failure showed significant associations with the clinical variable stage/nodes and with the HRQoL variables physical functioning and role functioning. Adjusted multivariate analyses including the same clinical conditions as above showed statistically significant relationships between time to failure and global quality of life, physical functioning, role functioning, social functioning and fatigue (p ≤ 0.01). No interactions between HRQoL variables and treatment were found, with the exception for cognitive functioning. CONCLUSION: Role functioning was found to be an independent prognostic factor for time to failure and survival in patients with high-risk melanoma. Thus, also in this early stage of melanoma, HRQoL variables might be useful as important prognostic factors for time to failure and overall survival.

Fear of recurrence and causal attributions in long-term survivors of testicular cancer.

BACKGROUND: The purpose was to examine the prevalence of fear of recurrence (FoR) in long-term testicular cancer survivors (TCSs) and the association between FoR and causal attributions of cancer. METHODS: Testicular cancer survivors were sampled from a clinical register and were sent a questionnaire assessing FoR, depression using Beck Depression Inventory II (BDI-II), physical symptoms (ototoxicity, neuropathy, and Raynaud-like phenomena), and causal attributions of testicular cancer. RESULTS: There were 316 TCSs who completed the questionnaires (response rate, 65%). The mean age was 47.6 years (standard deviation (SD) = 10.9), and the mean time since diagnosis was 12.0 years (SD = 3.0). Among the TCSs, 27.9% reported FoR. Univariate analyses revealed that FoR was associated with a BDI-II sum score of ≥19 (odds ratio (OR) = 7.07, p < 0.001) and attributing the cancer disease to psychological stress (OR = 2.57, p = 0.002). A multivariate analysis revealed associations between FoR and attributing the cancer disease to psychological stress (OR = 2.35, p = 0.010) and a BDI-II sum score ≥19 (OR = 5.82, p = 0.002). CONCLUSIONS: Fear of recurrence is prevalent in long-term TCSs. The observed relationship between FoR and a psychological causal attribution is probably complex and the direction of causality may be twofold: attributing the disease to a factor that is perceived as uncontrollable in nature could induce loss of control, and high levels of FoR may increase the need to gain control over the situation by pointing out factors that could be responsible for the disease such as psychological stress.

Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial.

BACKGROUND: Adjuvant high-dose interferon alfa-2b improves relapse-free survival (RFS) in patients with high-risk melanoma, although benefits in overall survival are uncertain. Because of the toxic effects of high-dose regimens, intermediate doses are being explored. We investigated whether adjuvant therapy with intermediate-dose interferon alfa-2b for 1 or 2 years would improve outcomes in patients with stage IIB-IIC or III resected cutaneous melanoma. METHODS: This randomised, open-label, phase 3, parallel-group trial was undertaken between 1996 and 2004. 855 patients were randomly assigned at 35 centres in the Nordic countries by block randomisation to three groups: observation only (group A); 4 weeks of induction (interferon alfa-2b 10 million units flat dose subcutaneously 5 days per week) followed by 12 months of maintenance therapy (interferon alfa-2b 10 million units flat dose subcutaneously 3 days per week; group B); or 1 month of induction and 24 months of maintenance (group C). Neither investigators nor patients were masked to treatment assignment. Patients were stratified for country and tumour stage; patients with stage III disease were further stratified for presence of metastatic lymph nodes at primary diagnosis versus at relapse, palpable versus non-palpable lymph-node metastases, and number of metastatic lymph nodes. The primary endpoint was overall survival in the two interferon alfa-2b groups combined. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01259934. FINDINGS: 284 patients were assigned to group A, 285 to group B, and 286 to group C; all patients were analysed. The median follow-up time was 72·4 months (IQR 46·9-98·0). We recorded no significant improvement in overall survival in patients given interferon alfa-2b compared with observation: median overall survival was 56·1 months (IQR 22·3 to >120·0) in group A, 72·1 months (25·8 to >120) in group B, and 64·3 months (24·7 to >120) in group C (p=0·600). Hazard ratios (HR) for overall survival were 0·91 (95% CI 0·74-1·10; p=0·642) for groups B and C combined versus observation; 0·91 (0·72-1·14; p=0·652) for group B versus observation; and 0·91 (0·72-1·15; p=0·858) for group C versus observation. Median RFS was 23·2 months (IQR 5·6 to <120) in group A, 37·8 months (10·8 to >120) in group B, and 28·6 months (8·6 to >120) in group C (p=0·034). HRs for RFS were 0·80 (0·67-0·96; p=0·030) for groups B and C combined versus observation, 0·77 (0·63-0·96; p=0·034) for group B versus observation, and 0·83 (0·68-1·03; p=0·178) for group C versus observation. The most common grade 3 and 4 adverse events were fatigue (five in group A [1·8%], 28 in group B [9·8%], and 32 in group C [11·2%]), myalgia (three [1·1%], 15 [5·3%], 14 [4·9%], respectively), and thrombocytopenia (15 [5·3%], 23 [8·1%], eight [2·8%], respectively). INTERPRETATION: Adjuvant therapy with intermediate-dose interferon alfa-2b did not significantly improve overall survival. Interferon alfa-2b with 1-year maintenance therapy significantly improved RFS, but we recorded no significant effect for 2-year maintenance therapy. Further research is in progress to define the subgroup of patients who benefit from adjuvant interferon alfa-2b. FUNDING: Schering-Plough (now Merck); the Radiumhemmet Research Funds, Stockholm; the Stockholm County Council; and the Swedish Cancer Society.

Value of post-operative reassessment of estrogen receptor α expression following neoadjuvant chemotherapy with or without gefitinib for estrogen receptor negative breast cancer.

The NICE trial was designed to evaluate the possible benefits of adding epidermal growth factor receptor targeted therapy to neoadjuvant chemotherapy in patients with estrogen receptor α (ER) negative and operable breast cancer. Preclinical data have suggested that signalling through the ErbB receptors or downstream effectors may repress ER expression. Here the authors investigated whether gefitinib, given neoadjuvant in combination with epirubicin and cyclophosphamide (EC), could restore ER expression. Eligible patients in the NICE trial were women with unilateral, primary operable, ER negative invasive breast cancer ≥ 2 cm. Material from patients randomized and completing treatment (four cycles of neoadjuvant EC plus 12 weeks of either gefitinib or placebo) in the NICE trial having available ER status both at baseline and after neoadjuvant treatment were eligible for this study. Tumors with indication of changed ER phenotype (based on collected pathology reports) were immunohistochemically reassessed centrally. 115 patients were eligible for this study; 59 patients in the gefitinib group and 56 patients in the placebo group. Five (4.3%) of 115 tumors changed ER phenotype from negative to positive. A change was seen in three patients in the gefitinib (5.1%) and in two patients in the placebo (3.6%) group with a difference of 1.51% (95% CI, -6.1-9.1). Results of the NICE trial have been reported previously. Post-operative reassessment of ER expression changed the assessment of ER status in a small but significant fraction of patients and should, whenever possible, be performed following neoadjuvant chemotherapy for ER negative breast cancer. Gefitinib did not affect the reversion rate of ER negative tumors.

Circulating Forms of Urokinase-Type Plasminogen Activator Receptor in Plasma Can Predict Recurrence and Survival in Patients with Urothelial Carcinoma of the Bladder.

Urothelial carcinoma of the bladder is a highly aggressive disease characterised by a very heterogeneous clinical outcome. Despite cystectomy, patients still have a high recurrence risk and shortened survival. Urokinase-type plasminogen activator receptor (uPAR) is present in tumour tissue specimens from patients with urothelial carcinoma. The different uPAR forms in blood are strong prognostic markers in other cancer types. We investigate the presence of different uPAR forms in tumour tissue and test the hypothesis that preoperative plasma levels of the uPAR forms predict recurrence free survival, cancer specific survival, and overall survival in patients treated with cystectomy for urothelial carcinoma. Using Western blotting we analyse neoplasia and adjacent benign-appearing urothelium from randomly selected patients for the presence of intact and cleaved uPAR forms. Prospectively collected preoperative plasma samples from 107 patients who underwent radical cystectomy for urothelial carcinoma are analysed. The different uPAR forms are measured by time-resolved fluorescence immunoassays. uPAR in tumour tissue from patients with urothelial carcinoma is demonstrated in both an intact and cleaved form. The different uPAR forms in plasma are all significantly associated with both recurrence free survival, cancer specific survival, and overall survival, high concentrations predicting short survival. uPAR (I) has the strongest association with a HR of 2.56 for overall survival. In the multivariable survival analysis uPAR (I) is significantly associated with cancer specific survival and overall survival.

Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma.

PURPOSE: The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory immune cells, thus potentially compromising this treatment option for patients with metastatic renal cell carcinoma. The impact of IL-2-based therapy on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal cell carcinoma is unknown. EXPERIMENTAL DESIGN: Baseline (n = 58) and on-treatment (n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before and during IL-2-based immunotherapy. Immunohistochemical expression of FOXP3 was estimated by stereological counting technique and correlated with other immune cell subsets and overall survival. RESULTS: A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing baseline (median 23 cells/mm2; range, 0-183) and on-treatment biopsies (median, 89 cells/mm2; range, 11-388; P < 0.001). The relative increase in individual patients was median 4.7-fold, range 0.3 to 230. FOXP3-positive cells were positively correlated with CD3-positive, CD4-positive, and CD8-positive tumor-infiltrating immune cells at baseline and during treatment (P < 0.05 in all comparisons). All patients achieving high numbers (>180 cells/mm2) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months (n = 11), whereas patients with low numbers (<180 cells/mm2) of on-treatment FOXP3-positive cells (n = 31) had a 5-year survival rate of 19% (hazard ratio, 2.2; confidence interval, 1.03-4.5; P = 0.043). All long-term survivors were characterized by low-baseline FOXP3-positive cells and a modest absolute rise in FOXP3-positive cells. CONCLUSION: Intratumoral FOXP3-positive regulatory immune cells significantly increased during IL-2-based immunotherapy, and high numbers of on-treatment FOXP3-positive cells were correlated with poor prognosis in patients with metastatic renal cell carcinoma.

Oncology to specialised palliative home care systematic transition: the Domus randomised trial.

OBJECTIVES: To assess the effect of a systematic, fast-track transition from oncological treatment to specialised palliative care at home on symptom burden, to explore intervention mechanisms through patient and intervention provider characteristics and to assess long-term survival and place of death. MEASURES: The effect of a systematic, fast-track transition from oncological treatment to specialised palliative care at home on patient symptom burden was studied in the Domus randomised clinical trial. Participants had incurable cancer and limited treatment options. The intervention was provided by specialised palliative home teams (SPT) based in hospice or hospital and was enriched with a psychological intervention for patient and caregiver dyad. Symptom burden was measured with Edmonton Symptom Assessment System (ESAS-r) at baseline, 8 weeks and 6 months follow-up and analysed with mixed models. Survival and place of death was analysed with Kaplan-Meier and Fisher's exact tests. RESULTS: The study included 322 patients. Tiredness was significantly improved for the Domus intervention group at 6 months while the other nine symptom outcomes were not significantly different from the control group. Exploring the efficacy of intervention provider demonstrated significant differences in favour of the hospice SPT on four symptoms and total symptom score. Patients with children responded more favourably to the intervention. The long-term follow-up demonstrated no differences between the intervention and the control groups regarding survival or home deaths. CONCLUSIONS: The Domus intervention may reduce tiredness. Moreover, the intervention provider and having children might play a role concerning intervention efficacy. The intervention did not affect survival or home deaths. TRIAL REGISTRATION NUMBER: NCT01885637.

Prevalence and risk of depressive symptoms 3-4 months post-surgery in a nationwide cohort study of Danish women treated for early stage breast-cancer.

BACKGROUND: Elevated levels of depressive symptoms are generally found among cancer patients, but results from existing studies vary considerably with respect to prevalence and proposed risk factors. PURPOSE: To study the prevalence of depressive symptoms and major depression 3-4 months following surgery for breast cancer, and to identify clinical risk factors while adjusting for pre-cancer sociodemographic factors, comorbidity, and psychiatric history. PATIENTS AND METHODS: The study cohort consists of 4917 Danish women, aged 18-70 years, receiving standardized treatment for early stage invasive breast cancer during the 2 1/2 year study period. Of these, 3343 women (68%) participated in a questionnaire study 12-16 weeks following surgery. Depressive symptoms (Beck's Depression Inventory II) and health-related behaviors were assessed by questionnaire. The Danish Breast Cancer Cooperative Group (DBCG) and the surgical departments provided disease-, treatment-, and comorbidity data for the study cohort. Information concerning sociodemographics and psychiatric history were obtained from national longitudinal registries. RESULTS: The results indicated an increased prevalence of depressive symptoms and major depression (13.7%) compared to population-based samples. The pre-cancer variables: Social status, net-wealth, ethnicity, comorbidity, psychiatric history, and age were all independent risk factors for depressive symptoms. Of the clinical variables, only nodal status carried additional prognostic information. Physical functioning, smoking, alcohol use, and BMI were also independently associated with depressive symptoms. CONCLUSION: Risk factors for depressive symptoms were primarily restricted to pre-cancer conditions rather than disease-specific conditions. Special attention should be given to socio-economically deprived women with a history of somatic- and psychiatric disease and poor health behaviors.

Long-term cognitive function following chemotherapy in patients with testicular cancer.

Cancer patients frequently report cognitive complaints following chemotherapy, but the results from the available studies, mainly of women with breast cancer, are inconsistent. Our aim was to compare cognitive function of men with testicular cancer (TC) who had orchiectomy and chemotherapy (bleomycin, etoposide, cisplatin) with men who had orchiectomy only or orchiectomy and radiotherapy. Thirty-six chemotherapy patients and 36 nonchemotherapy patients were tested 2-7 years after treatment for TC with standardized neuropsychological tests. Chemotherapy and nonchemotherapy patients displayed similar performances on cognitive tests (p values adjusted for multiple comparisons: .63-1.00). Moreover, there was no difference in the proportion of cognitively impaired patients in the chemotherapy group (5.6%) compared to the nonchemotherapy group (8.3%) (chi2 = 0.22, p = .64). Our results are discordant with previous findings indicating cognitive impairment following chemotherapy and suggest that TC patients do not need to fear long-term cognitive consequences following chemotherapy.