Psychometric properties of the 45-item supportive care needs survey-partners and caregivers - Dutch (SCNS-P&C45-D) in partners of patients with breast cancer.

OBJECTIVE: To test the psychometric properties of the Dutch 45-item Supportive Care Needs Survey-Partners and Caregivers (SCNS-P&C45-D) among partners of women with breast cancer living in the Netherlands. METHODS: In this cross-sectional validation study, partners of patients with breast cancer were invited to complete a survey on the patient's cancer and the caregiver's level of unmet needs (SCNS-P&C45-D), psychological distress (HADS) and burden (EDIZ). RESULTS: 43% of the invited informal caregivers responded (n = 302). Flooring effects were identified for three items of the SCNS-P&C45-D,which were then deleted from further analysis. The original factor structure and loading pattern of the SCNS-P&C45-D was not replicated. Internal consistency of the SCNS-P&C45-D and all subscales' (emotional and relational needs, health care and illness related needs, practical needs, work and social needs) Cronbach's alpha coefficients exceeded 0.80, the entire measure's Cronbach's alpha is 0.98. Most SCNS-P&C45-D subscales showed moderate correlations with distress and burden from informal care which was in line with expectations based on validity. The domain 'Work and Social needs' showed a high correlation with burden from informal care. Participants reported significantly more or higher unmet needs if they were younger (25.5% vs. 20.3% in older patients, p = 0.004), if diagnosis was less than 1 year ago in one subscale (Health Care and Illness related needs; 19.5% and 18%, p = 0.029, and the total SCNS-P&C45-D; 23.2% vs. 22.4%, p = 0.018). CONCLUSIONS: The SCNS-P&C45-D is able to identify those partners of patients with breast cancer in need and those who are not.

The impact of a false-positive MRI on the choice for mastectomy in BRCA mutation carriers is limited.

PURPOSE: To assess the false-positive rate of breast cancer surveillance by magnetic resonance imaging (MRI) in BRCA mutation carriers and the impact of an abnormal mammography or breast MRI on the patients' decision for prophylactic mastectomy. PATIENTS AND METHODS: A total of 196 BRCA mutation carriers were included with a median follow-up of 2 years (range 1-9) with annual mammography and MRI. Preference for prophylactic mastectomy was registered at first surveillance after the mutation carriership was revealed. RESULTS: In all, 41% (81 of 196) of the women had at least one positive MRI or mammography. Malignancy was detected in 17 women: 11 at surveillance, 4 at an intended prophylactic mastectomy and 2 had an interval cancer. Imaging by mammography and MRI had a sensitivity of 71% and a specificity of 90%. The probability that a positive MRI result is false positive was 83%. In the group with a prior preference for mastectomy with and without a false-positive imaging, prophylactic mastectomy was carried out in 89% and 66%, respectively (P = 0.06), in the group with prior preference for surveillance these percentages were 15% and 11%, respectively (P = 0.47). CONCLUSION: Although the rate of false-positive MRI results is high, the impact on the choice for prophylactic mastectomy is limited and is determined by the woman's preference before the establishment of a BRCA mutation.

Chemotherapy response evaluation with FDG-PET in patients with colorectal cancer.

BACKGROUND: The aim of this prospective study was to evaluate the value of F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) for early assessment of chemotherapy response in patients with advanced colorectal cancer. METHODS: Dynamic FDG-PET was carried out before and at 2 (n = 50) and 6 months (n = 19) after the start of treatment. Quantitative Patlak analysis [metabolic rate of glucose (MRGlu)] and a simplified method to measure glucose metabolism [standardized uptake value (SUV)] were evaluated. The predictive value of changes in glucose metabolism was assessed with Cox proportional regression analysis. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimates. RESULTS: There was an increase in the rates of death (P = 0.049 for DeltaMRGlu PET1-2; P = 0.017 for DeltaSUV PET1-2; P = 0.032 for DeltaMRGlu PET1-3; P = 0.048 for DeltaSUV PET1-3) and progression (P = 0.026 for DeltaMRGlu PET1-2; P = 0.035 for DeltaSUV PET1-2; P = 0.041 for DeltaMRGlu PET1-3; P = 0.081 for DeltaSUV PET1-3) associated with worse response as assessed by PET on Cox proportional regression analysis. The OS and PFS analysis showed a significant predictive value at broad ranges of DeltaMRGlu and DeltaSUV cut-off levels. CONCLUSION: The degree of chemotherapy-induced changes in tumor glucose metabolism is highly predictive for patient outcome. The use of FDG-PET for therapy monitoring seems clinically feasible since simplified methods (SUV) are sufficiently reliable.

Severe fatigue after treatment of ductal carcinoma in situ: A comparison with age-matched breast cancer survivors and healthy controls.

PURPOSE: Severe fatigue after treatment of ductal carcinoma in situ (DCIS) has not been studied before. The current study examined (i) the prevalence of severe fatigue in DCIS patients versus breast cancer survivors (BCS) and healthy controls (HC), (ii) quality of life and functioning of severely versus non-severely fatigued DCIS patients and BCS, and (iii) the association of fatigue with psychosocial and behavioral factors in DCIS patients. METHODS: 89 patients treated for DCIS were matched on age and gender to 67 BCS and 178 HC (ratio 1:1:2). Fatigue was measured with the Fatigue Severity subscale of the Checklist Individual Strength. RESULTS: 23% of DCIS patients, 25% of BCS, and 6% of HC were severely fatigued (DCIS versus HC: p < 0.001). Severely fatigued DCIS patients had a lower quality of life and were more impaired in all domains of functioning than non-severely fatigued DCIS patients. Sleep problems, dysfunctional cognitions regarding fatigue, avoidance of activities, all-or-nothing behavior, perceived lack of social support, DCIS-related coping problems, and fear of future cancer occurrence were related to fatigue. CONCLUSIONS: The prevalence of severe fatigue in DCIS patients was similar to BCS, but higher than in HC. Severely fatigued DCIS patients had a lower quality of life and more functional impairments. The psychosocial and behavioral fatigue-related factors in DCIS patients are known to perpetuate fatigue in BCS. These factors can be targeted in interventions for cancer-related fatigue. Our findings suggest that the same treatment elements might be applicable to severely fatigued DCIS patients.

Effect of carbogen breathing on the pharmacodynamics of 5-fluorouracil in a murine colon carcinoma.

To determine whether carbogen breathing has an effect on 5-fluorouracil (5-FU) uptake, retention and metabolism in C38 murine colon tumours grown in C57Bl/6 mice, we used in vivo 19F nuclear magnetic resonance (NMR) spectroscopy. Eleven tumour-bearing mice were treated with 150 mg/kg of 5-FU given intraperitoneally (i.p.). Five mice received carbogen gas (95% O(2) and 5% CO(2)) for 9.5 min, starting 1 min before 5-FU administration. We found increased levels of 5-FU and its anabolites and catabolites by sequential ¿19F NMR spectroscopy in the group treated with 5-FU in combination with carbogen compared with the group treated with 5-FU alone. The maximum of normalised values of 5-FU and its metabolites, reached after carbogen breathing, was almost 2-fold higher than after treatment with 5-FU alone. Despite these increased concentrations no significant effect of carbogen on growth inhibition of the tumour by 5-FU was observed, which may be related to the size as well as the well vascularised and perfused conditions of the tumours studied.

Recombinant human erythropoietin attenuates weight loss in a murine cancer cachexia model.

BACKGROUND: Within hypoxic tumor regions anaerobic dissimilation of glucose is the sole source of energy generation. It yields only 5% of the ATP that is normally gained by means of oxidative glucose catabolism. The increased need for glucose may aggravate cancer cachexia. We investigated the impact of recombinant human erythropoietin (RhEPO) and increased inspiratory oxygen concentrations on weight loss in tumor-bearing mice. METHODS: Fragments of the murine C26-B adenocarcinoma were implanted in 60 BALB/c-mice. The mice were divided into four groups and assigned to: (A) no treatment; (B) RhEPO- administration (25 IU daily from day 1-11, three times per week from day 12); (C) RhEPO and 25% oxygen; and (D) RhEPO and 35% oxygen. Three control groups of four healthy mice each received the same treatment as groups A, B, and D, respectively. Hematocrit and hemoglobin levels, tumor volume, and body weight were monitored. At day 17 the experiment was terminated and the serum lactate concentration was measured. The tumors were excised and weighed and, for each mouse, the percentage weight loss was calculated. The impact of tumor weight and the treatments on lactate concentration and weight loss was evaluated. RESULTS: Significant positive correlations were found between tumor weight and lactate concentration and between tumor weight and percentage weight loss. In the mice with the largest tumors, RhEPO displayed a significant weight loss-reducing effect, and a significant negative correlation was found between hemoglobin concentration and weight loss. An oxygen-rich environment did not appear to influence weight loss. CONCLUSION: Anaerobic glycolysis in a growing C26-B tumor is related to weight loss. RhEPO administration results in a reduction of the percentage weight loss; this effect is probably mediated by an increased hemoglobin concentration.

Double alternate modulation of high-dose 5-Fluorouracil by interferon-alpha-2b and phosphonacetyl-L-aspartic Acid in patients with advanced colorectal-cancer.

We conducted a multicenter phase II trial in patients with advanced colorectal cancer to investigate the antitumor efficacy of double alternate modulation of high-dose infusional 5-fluorouracil (5FU) (60 mg/kg/48 h = 2400 mg/m(2)/48 h) by interferon alpha-2b (IFN alpha) (10 MU/dose s.c. prior to and halfway 5FU, uneven cycles) and phosphonacetyl-L-aspartic acid (PALA) (250 mg/m(2) i.v. 24 h before 5FU, even cycles). Cycles were given weekly for 4 weeks and once every 2 weeks thereafter. Twenty one patients with progressive or symptomatic disease were treated ambulatory. Two patients (10%, 95% confidence interval 1-30%) achieved a partial response. Therefore, this schedule of double alternate modulation of 5FU is unlikely to be superior to single modulation of 5FU in patients with advanced colorectal cancer. Since no grade III/IV toxicity (WHO) occurred during 251 cycles, which is in contrast to our previous studies using the same 5FU schedule, it might be possible that alternate modulation allows more intense 5FU schedules compared to single or double modulation schedules.

Provocation tests in extrinsic allergic alveolitis in mushroom workers.

The clinical diagnosis of extrinsic allergic alveolitis can be supported by a positive provocation test. Twenty-eight common mushroom (Agaricus bisporus) workers, 4 oyster mushroom (Pleurotus ostreatus) workers and 6 Shii Take mushroom (Lentinus edodes) workers, whose medical history indicated a possible extrinsic allergic alveolitis, were examined. The provocation test consisted of a control day, an exposure day, and half a day of follow-up observation. On the control and exposure days, the body temperature, leucocyte count and lung function were measured every 2 h. The chest X-ray and arterial blood gas sample were taken once. The exposure consisted of a 1-h presence on the common mushroom farm in spawning conditions or inhaling a suspension of spores of Pleurotus or Shii-Take in the laboratory. Eighteen of the 28 people employed on the common mushroom farm, all 4 Pleurotus workers and 4 of the 6 Shii-Take workers were diagnosed as having extrinsic allergic alveolitis, according to the following criteria: a positive history and 2 or more of the following findings: increase in leucocyte count, rise in temperature and decrease in inspiratory vital capacity (IVC) and total lung capacity (TLC).

Prediction of chemotherapeutic response of colorectal liver metastases with dynamic gadolinium-DTPA-enhanced MRI and localized 19F MRS pharmacokinetic studies of 5-fluorouracil.

Systemic chemotherapy is effective in only a subset of patients with metastasized colorectal cancer. Therefore, early selection of patients who are most likely to benefit from chemotherapy is desirable. Response to treatment may be determined by the delivery of the drug to the tumor, retention of the drug in the tumor and by the amount of intracellular uptake, metabolic activation and catabolism, as well as other factors. The first aim of this study was to investigate the predictive value of DCE-MRI with the contrast agent Gd-DTPA for tumor response to first-line chemotherapy in patients with liver metastases of colorectal cancer. The second aim was to investigate the predictive value of 5-fluorouracil (FU) uptake, retention and catabolism as measured by localized (19)F MRS for tumor response to FU therapy. Since FU uptake, retention and metabolism may depend on tumor vascularization, the relationship between (19)F MRS and the DCE-MRI parameters k(ep), K(trans) and v(e) was also examined (1). In this study, 37 patients were included. The kinetic parameters of DCE-MRI, k(ep), K(trans) and v(e), before start of treatment did not predict tumor response after 2 months, suggesting that the delivery of chemotherapy by tumor vasculature is not a major factor determining response in first-line treatment. No evident correlations between (19)F MRS parameters and tumor response were found. This suggests that in liver metastases that are not selected on the basis of their tumor diameter, FU uptake and catabolism are not limiting factors for response. The transfer constant K(trans), as measured by DCE-MRI before start of treatment, was negatively correlated with FU half-life in the liver metastases, which suggests that, in metastases with a larger tumor blood flow or permeability surface area product, FU is rapidly washed out from the tumor.

Weekly chronomodulated 48 h infusion of high-dose 5-fluorouracil modulated by methotrexate and (6S)-leucovorin in advanced colorectal cancer: a phase IB study.

In this phase IB study, 24 patients with advanced colorectal cancer were treated with escalating doses of weekly chronomodulated 48 h infusions of 5-fluorouracil (5-FU) biochemically modulated by methotrexate 40 mg/m2 and (6S)-leucovorin 8 x 45 mg orally. Two daily peak delivery periods (PDP), during which 65% of the daily dose was administered, were investigated: from 18.00 to 0.30 h and from 0.00 to 06.30 h. The maximal tolerated dose of 5-FU was 2800 mg/m2/48 h, with a PDP from 18.00 to 0.30 h.

5-Fluorouracil in colorectal cancer: rationale and clinical results of frequently used schedules.

Colorectal cancer is one of the most frequent cancers in the western world. Approximately half of the patients will die of their disease because of metastases. The most active cytotoxic agent used to date is 5-fluorouracil (5-FU). However, clinical responses are achieved only in a minority of patients. Based on the current knowledge of the mechanism of action of 5-FU, many attempts have been made to improve the clinical results. These include the use of biochemical modulators and different methods of administration, and these are the subject of this review. Specifically, of five different modulators, i.e. leucovorin, methotrexate, interferon-alpha, N-(phosphonacetyl)-L-aspartate and trimetrexate glucuronate, the biochemical background and the clinical results obtained with these modulators are discussed. In order to get more insight, an overview of the 5-FU metabolism has been given. In addition, the different methods of systemic administration of 5-FU as well as possible mechanisms underlying 5-FU resistance are described.

5-Fluorouracil metabolite patterns in viable and necrotic tumor areas of murine colon carcinoma determined by 19F NMR spectroscopy.

High-resolution 19F NMR spectroscopy at 9.4 T was used to study the difference in the metabolite pattern of 5-fluorouracil (5-FU) between viable and necrotic tissues of C38 murine colon tumors grown in C57BI/6 mice. Studies were performed on perchloric acid extracts of these tumor fractions after 5-FU treatment. The 19F nuclear magnetic resonance spectra exhibited resonances representing 5-FU, the catabolites alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine, as well as several fluoronucleotide anabolites. The absolute concentrations of anabolites and catabolites and the anabolite-to-catabolite ratio were significantly lower in the necrotic fraction than in the viable tumor fraction 50 min after administration of 5-FU, whereas the absolute concentration of 5-FU was the same. Therefore, in 5-FU metabolism studies with NMR spectroscopy, it is important to consider the necrotic contribution to the tumor volume.

Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma.

Following an i.p. dose of 150 mg x kg(-1) 5-fluorouracil (5-FU), drug uptake and metabolism over a 2-h period were studied by in vivo (19)F magnetic resonance spectroscopy (MRS) for the murine colon carcinoma lines C26-B (5-FU-insensitive; n=11) and C26-10 (5-FU-sensitive; n=15) implanted s.c. in Balb/C mice. Time courses for tumour growth, intracellular levels of FdUMP, thymidylate synthase (TS) activity, and 5-FU in RNA were also determined, and the effects of a 9.5-min period of carbogen breathing, starting 1 min before drug administration, on MRS-detected 5-FU metabolism and tumour growth curves were examined. Both tumour variants generated MRS-detectable 5-FU nucleotides and showed similar initial growth inhibition after treatment. However, the growth rate of C26-B tumours returned to normal, while the sensitive C26-10 tumours, which produced larger fluoronucleotide pools, still showed moderate growth inhibition. Carbogen breathing did not significantly influence 5-FU uptake or fluoronucleotide production but did significantly enhance growth inhibition in C26-10 tumours. While both tumour variants exhibited incorporation of 5-FU into RNA and inhibition of TS via FdUMP, clearance of 5-FU from RNA and recovery of TS activity were greater for the insensitive C26-B line, indicating that these processes, in addition to 5-FU uptake and metabolism, may be important determinants of drug sensitivity and treatment response.

Continuous infusion of high-dose 5-fluorouracil in combination with leucovorin and recombinant interferon-alpha-2b in patients with advanced colorectal cancer. A Multicenter Phase II study.

BACKGROUND: 5-Fluorouracil (5-FU), when combined with leucovorin (LV) or interferon-alpha (IFN-alpha), may result in improved response rates compared with 5-FU alone in patients with advanced colorectal cancer. The authors investigated the clinical efficacy of combining these three agents for patients in this group. METHODS: Forty-five patients were administered outpatient high-dose 5-FU, 60 mg/kg/48 hours (2400 mg/m2/48 hours) continuous intravenous infusion on days 1 and 2; LV, 90 mg orally every 6 hour, 8 times during 5FU infusion; and recombinant IFN-alpha-2b, 10 x 10(6) IU/dose subcutaneously on days 1, 3, and 5. Cycles were repeated weekly for 4 weeks and every 2 weeks thereafter. RESULTS: Forty-four patients were evaluable for response, and 11 patients (25%; 95% confidence interval, 12-38%) achieved a partial response with a median duration of 11 months. Median survival time for all patients was 11 months. Grade 3 and Grade 4 toxicities occurred in 21 patients (47%), which necessitated discontinuation of treatment in 2 patients (4%); permanent dose reductions were necessary in 11 patients (24%). The addition of IFN-alpha produced more 5-FU-related toxicity compared with a previous study in which the same dosage and schedule of 5-FU plus LV was used. CONCLUSIONS: The efficacy of 5-FU continuous infusion combined with LV and IFN-alpha does not appear to differ significantly from earlier reports on treatment using 5-FU plus LV or 5-FU plus IFN-alpha for patients with colorectal cancer. However, this schedule of 5-FU combined with LV and IFN-alpha produces less toxicity compared with previous trials using bolus 5-FU plus IFN-alpha.