Epirubicin and paclitaxel with G-CSF support in first line metastatic breast cancer: a randomized phase II study of dose-dense and dose-escalated chemotherapy.

An increased dose-intensity can be achieved by either higher dose of chemotherapy per cycle (dose-escalation) or by shortening the interval between cycles (dose-dense). This multicenter randomized phase II study assessed the efficacy and safety of two different approaches: epirubicin 110 mg/m(2) combined with paclitaxel 200 mg/m(2) every 21 days and epirubicin 75 mg/m(2) combined with paclitaxel 175 mg/m(2) every 10 days, both supported with G-CSF. Patients with advanced breast cancer and without prior palliative chemotherapy were scheduled for 6 cycles. Evaluable for response were 101 patients and for toxicity 106 patients. Grade ≥ 3 toxicities occurred in 39% of patients in the dose-escalated arm and in 29% of the dose-dense arm, mainly febrile neutropenia, thrombocytopenia, neurotoxicity and (asymptomatic) cardiotoxicity. The median delivered cumulative doses for epirubicin/paclitaxel were 656/1194 and 448/1045 mg/m(2), treatment durations were 126 and 61 days, and delivered dose intensities were 36/67 and 51/120 mg/m(2)/week for the dose-escalated and dose-dense arm, respectively. Response rates were 75 and 70%, the progression-free survival 6 and 7 months, respectively. Dose-dense chemotherapy with a lower cumulative dose, a halved treatment time, but a higher dose-intensity may be as effective and safe as dose-escalated chemotherapy. The value of dose-densification over standard scheduled chemotherapy regimes yet needs to be determined.

A core questionnaire for the assessment of patient satisfaction in academic hospitals in The Netherlands: development and first results in a nationwide study.

BACKGROUND: Patient satisfaction is one of the relevant indicators of quality of care; however, measuring patient satisfaction had been criticised. A major criticism is that many instruments are not reliable and/or valid. The instruments should have enough discriminative power for benchmarking of the results. OBJECTIVE: To develop a "core questionnaire for the assessment of patient satisfaction in academic hospitals" (COPS) that is reliable and appropriate for benchmarking patient satisfaction results. RESEARCH DESIGN: The development of COPS, the testing of its psychometric quality and its use in eight Dutch academic hospitals in three national comparative studies in 2003, 2005 and 2007 are described in this study. Results were reported only if they were significant (p<0.05) and relevant (also Cohen d>0.2). RESULTS: The questionnaire was returned in 2003 by 40,678 patients (77,450 sent, 53%) and by 40,248 patients (75,423 sent, 53%) in 2005. In 2007, the questionnaire was returned by 45,834 patients (87,137, 53%). The six dimensions have good Cronbach α's, varying from 0.79 to 0.88.The results of every item were reported to the individual hospital. A benchmark overview showed the overall comparison of all specialties of the eight hospitals for the clinic and outpatient departments. The 2007 measurement showed relevant differences in satisfaction on two dimensions in the clinical setting. CONCLUSIONS: COPS is shown to be a feasible and reliable instrument to measure the satisfaction of patients in Dutch academic hospitals. It allows comparison of hospitals and gives benchmark information on a hospital as well as data on specialty levels and previous measurements, including best practices.

Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI x anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer.

A phase I study of the bispecific antibody MDX-H210 in combination with granulocyte colony-stimulating factor (G-CSF) was performed in stage IV breast carcinoma patients, overexpressing HER-2/neu. MDX-H210, constructed by crosslinking antigen binding fragments (F(ab') fragments) of monoclonal antibody (mAb) H22 to Fc gamma receptor I (FcgammaRI), and mAb 520C9 to HER-2/neu, respectively, mediates the lysis of tumour cells in vitro, and in human FcgammaRI transgenic mouse models. The proto-oncogene HER-2/neu is overexpressed in approximately 30% of breast cancer patients, and represents a promising target for antibody-based immunotherapy. Fc gamma receptor I (CD64) is an effective trigger molecule, which is expressed on monocytes/macrophages, immature dendritic cells, and G-CSF-primed polymorphonuclear cells (PMN). Patients received G-CSF (Filgrastim) for 8 consecutive days, and cohorts of three patients were treated on day 4 with escalating, single doses of MDX-H210. A total of 30 patients were included, and treatment was generally well tolerated, without reaching dose-limiting toxicity. Side effects consisted mainly of fever and short periods of chills, which were timely related to elevated plasma levels of interleukin 6 and tumour necrosis factor alpha. In the last two cohorts, MDX-H210 plasma levels exceeded 1 microg ml(-1), and on circulating myeloid cells >50% saturation of FcgammaRI was found until day 4. These effector cells were highly effective in antibody-dependent cell-mediated cytotoxicity. Immunohistochemical analyses of tumour biopsies in individual patients documented infiltration of monocytes and PMN after MDX-H210 infusion. Although the clinical course of the disease was not altered by the single dose of MDX-H210, a favourable toxicity profile--even at high doses--and remarkable biological effects were seen when combined with G-CSF. Therefore, the combination of G-CSF and MDX-H210 should be evaluated in further immunotherapeutical strategies.

High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

[Shortage in admission capacity for acute cases]. / Tekortschietende opnamecapaciteit voor acute patiënten.

According to Poolman et al. (this issue), 6% of patients visiting the casualty department of a large Amsterdam hospital and requiring hospital admission had to be transported elsewhere at the expense of a considerable administrative effort on the part of the emergency-care physicians. Contributing factors are the way the hospital handles capacity problems, discharge procedures and personnel shortages, and, at the level of the city, the system used to allocate budget for acute care according to the relative needs of the hospitals. However, the major factor is the overall capacity problem in Dutch health care resulting from tight budget control. Despite intense discussions, major changes in this system have yet to be implemented. In the near future lack of qualified medical and nursing personnel will be the main factor that will need to be addressed urgently.

Prediction of depression 6 months to 3 years after treatment of head and neck cancer.

BACKGROUND: Head and neck cancer and its treatment can have important psychosocial implications. Many patients become depressed. The aim of this prospective study is to examine whether pretreatment variables can be used to predict depression up to 3 years after treatment. METHODS: Head and neck cancer patients (n = 197) treated with surgery and/or radiotherapy completed both before and after treatment a questionnaire including items on social support, coping, depressive symptoms, physical functioning, and physical symptoms. RESULTS: Eight pretreatment variables (tumor stage, sex, depressive symptoms, openness to discuss cancer in the family, available appraisal support, received emotional support, tumor-related symptoms, and size of the informal social network) were used to calculate a risk score to determine which patients were depressed at 6 months to 3 years after treatment (positive predicted value, 58%; negative predicted value, 83%). CONCLUSIONS: Eight pretreatment variables can be used to predict accurately those head and neck cancer patients who are likely to become depressed up to 3 years after treatment.

Sociodemographic factors and quality of life as prognostic indicators in head and neck cancer.

Pre-treatment quality of life (QOL) has been found to be an independent prognostic factor for survival in cancer patients, in particular in patients with advanced cancer. Sociodemographic factors such as marital and socioeconomic status have also been recognised as prognostic factors. We studied the influence of QOL and mood (measured with the European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) and the Head and Neck Cancer Questionnaire (EORTC QLQ-H&N35), and with the Center for Epidemiologic Studies-Depression Scale (CES-D)) as measured before treatment, the use of cigarettes and alcohol and sociodemographic factors (age, gender, marital status, income and occupation) on recurrence and survival in 208 patients with head and neck cancer prior to treatment with surgery and/or radiotherapy, using Kaplan-Meier and Cox regression analyses. Cognitive functioning and, to a lesser degree, marital status were independent predictors of recurrence and survival, along with medical factors (stage and radicality). Patients with less than optimal cognitive functioning and unmarried patients had a relative risk (RR) of recurrence of 1.72 (95% confidence interval (95% CI) 1.01-2.93) and 1.85 (95% CI 1.06-3.33), respectively, and a RR of dying of 1.90 (95% CI 1.10-3.26) and 1.82 (95% CI 1.03-3.23), respectively. Performance status, physical functioning, mood and global QOL and smoking and drinking did not predict for recurrence and survival. The influence of cognitive functioning might be related to the use of alcohol. Marital status may influence prognosis through mechanisms of health behaviour and/or social support mechanisms.

Adjuvant chemo-hormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate (MPA) for node-positive cancer patients, update at 12 years follow up.

An update with 10 years of follow up of a study adding adjuvant MPA to CAF chemotherapy is presented. A total of 409 patients were entered, of which 200 were randomized to receive 500 mg of MPA i.m. on days 1-28 and twice per week thereafter for 6 months. There was a significant improvement in metastases-free and overall survival in women >60 years of age receiving MPA (P=0.01 and P=0.02 respectively). A detrimental effect of MPA was seen in women <40 years. Possible reasons for these results are discussed.

Importance of local aromatase activity in hormone-dependent breast cancer: a review.

The cytochrome P-450 enzyme complex aromatase is the rate-limiting step in the production of oestrogens. It catalyses the conversion of androgens to oestrogens. In the treatment of hormone-dependent breast cancer in postmenopausal women, aromatase is the target for treatment with aromatase inhibitors. Recently registered aromatase inhibitors like anastrozole, letrozole and exemestane have proven to be effective therapy for advanced breast cancer in postmenopausal patients failing to respond to treatment with tamoxifen. Intratumoural aromatase activity has predictive value for response to treatment with aromatase inhibitors. Attempts are being made to find an immunohistochemical technique to determine aromatase in tumour tissue, which may serve as a predictive factor. In situ oestrogen synthesis through local aromatase activity in the tumour and adjacent tissue is probably a very important growth-stimulating system in hormone-dependent breast cancer. This synthesis can be blocked with aromatase inhibitors. The regulation of aromatase activity and the cell types that contribute to this process are the subject of extensive research. There seems to be a complex interaction between malignant cells and adjacent cells in which factors such as IL-6 and its soluble receptor, TNF-alpha and prostaglandin E2 play an important role in stimulating aromatase activity.

Aromatase and COX-2 expression in human breast cancers.

We have investigated aromatase and the inducible cyclooxygenase COX-2 expression using immunocytochemistry in tumors of a series of patients with advanced breast cancer treated with aromatase inhibitors. Aromatase was expressed in 58/102 breast cancers. This is similar to the percentage previously reported for aromatase activity. Interestingly, aromatase was expressed in a variety of cell types, including tumor, stromal, adipose, and endothelial cells. Since prostaglandin E2 is known to regulate aromatase gene expression and is the product of COX-2, an enzyme frequently overexpressed in tumors, immunocytochemistry was performed on the tissue sections using a polyclonal antibody to COX-2. Aromatase was strongly correlated (P<0.001) with COX-2 expression. These results suggest that PGE2 produced by COX-2 in the tumor may be important in stimulating estrogen synthesis in the tumor and surrounding tissue. No correlation was observed between aromatase or COX-2 expression and the response of the patients to aromatase inhibitor treatment. However, only 13 patients responded. Nine of these patients were aromatase positive. Although similar to responses in other studies, this low response rate to second line treatment suggests that tumors of most patients were no longer sensitive to the effects of estrogen. Recent clinical studies suggest that greater responses occur when aromatase inhibitors are used as first line treatment. In the intratumoral aromatase mouse model, expression of aromatase in tumors is highly correlated with increased tumor growth. First line treatment with letrozole was effective in all animals treated and was more effective than tamoxifen in suppressing tumor growth. Letrozole was also effective in tumors failing to respond to tamoxifen, consistent with clinical findings. In addition, the duration of response was significantly longer with the aromatase inhibitor than with tamoxifen, suggesting that aromatase inhibitors may offer better control of tumor growth than this antiestrogen.

Prediction of depressive symptomatology after treatment of head and neck cancer: the influence of pre-treatment physical and depressive symptoms, coping, and social support.

BACKGROUND: Head and neck cancer and its treatment can have important psychosocial implications, and many patients become depressed. The aim of this prospective study is to examine whether pretreatment variables can be used to predict depression 6 and 12 months later. METHODS: Head and neck cancer patients (155) treated with surgery and/or radiotherapy completed a questionnaire including items on social support, coping, depressive symptoms, physical functioning, and physical symptoms before and after treatment. RESULTS: By using 5 variables (physical symptoms, depressive symptoms, emotional support, extent of the social network, and avoidance coping), it was possible to predict those patients who would have symptoms at 6 (81%) and 12 months (67%) after treatment. Inclusion of actual physical symptoms reported at follow-up increased these percentages to 89% and 82%. CONCLUSIONS: It is concluded that screening for psychosocial variables and physical symptoms before treatment can be used to determine which patients are at risk of developing depressive symptoms after treatment.

Pretreatment factors predicting quality of life after treatment for head and neck cancer.

BACKGROUND: Quality of life (QOL) has become an important issue in head and neck cancer. Explanation of factors predicting QOL after treatment has important implications for patient management. METHODS: In this prospective study we analyzed which pretreatment factors predicted QOL after surgery and/or radiotherapy with curative intent in a cohort of 153 patients with cancer of the oral cavity, oropharynx, hypopharynx, or larynx. The patients completed the EORTC Core Questionnaire, the EORTC Head and Neck Cancer module, and the Center for Epidemiologic Studies Depression scale before treatment and 6 and 12 months later. The influence of gender, age, performance status, and depressive symptoms at baseline, site, stage, and treatment on QOL (and its dimensions) and depressive symptoms after 6 and 12 months was studied, using linear regression analysis. RESULTS: A high level of depressive symptoms and a low performance status at baseline and combination treatment were significant predictors of increased severity of symptoms and poor functioning after treatment. Treatment was a predictor of head and neck symptoms, whereas performance status and depressive symptoms were predictors of general symptoms and functioning. Gender and age had little predictive value. CONCLUSIONS: Patients with depressive symptoms or a low performance status who receive combination treatment for cancer of the head and neck are at risk for physical and psychologic morbidity after treatment. Special attention should be given to these patients in rehabilitation programs.

Dose-dense epirubicin and paclitaxel with G-CSF: a study of decreasing intervals in metastatic breast cancer.

Anthracyclines and taxanes are very effective drugs in the treatment of advanced breast cancer. With G-CSF support, the dose-intensity of this combination can be increased by reducing the interval between chemotherapy cycles, the so-called 'shortening of cycle time'. We treated 36 patients with advanced breast cancer in a multicentre phase I/II study. The treatment regimen consisted of epirubicin 75 mg m(-2) followed by paclitaxel 135 mg m(-2) (3 h) in combination with G-CSF. At least six patients were treated in each cohort and were evaluated over the first three cycles. Starting at an interval of 14 days, in subsequent cohorts of patients the interval could be shortened to 10 days. An 8-day interval was not feasible due mainly to incomplete neutrophil recovery at the day of the next scheduled cycle. In the 10-day interval cohort it was feasible to increase the paclitaxel dose to 175 mg m(-2). The haematological and non-haematological toxicity was relatively mild. No cumulative myelosuppression was observed over at least three consecutive cycles. In combination with G-CSF, epirubicin 75 mg m(-2) and paclitaxel 175 mg m(-2) could be safely administered every 10 days over at least three cycles, enabling a dose intensity of 52 and 122 mg m(-2) per week, respectively.

[Adjuvant systemic therapy for patients with resectable breast cancer: guideline from the Dutch National Breast Cancer Platform and the Dutch Society for Medical Oncology]. / Adjuvante systemische therapie voor patiënten met resectabel mammacarcinoom; richtlijn van het Nationaal Borstkanker Overleg Nederland en de Nederlandse Vereniging voor Medische Oncologie.

There is an abundance of evidence that adjuvant systemic therapy with chemotherapy or endocrine therapy results in better survival for all patients with resectable breast cancer. The absolute 10-year survival advantage however varies for the different patient groups. Therefore, for each individual patient the choice of adjuvant therapy must take into account the potential benefits and the possible side effects. A group of medical oncologists from the Dutch National Breast Cancer Platform (NABON) and the Dutch Society for Medical Oncology (NVMO) prepared a guideline for the treatment of patients with early resectable breast cancer. The criterium for choosing adjuvant systemic therapy for the individual patient is an expected increase in 10-year survival of 5% or more. In the guideline a difference is made between patients with and without axillary lymph node metastasis. In patients with axillary lymph node metastasis the choice for adjuvant systemic therapy depends on the following prognostic factors: menopausal status, age, and the presence of estrogen and progesterone receptors in the tumour. In patients without axillary lymph node metastasis the choice depends also on the following prognostic factors: the size of the tumour, the mitotic activity index, or the histopathologic grade of differentiation.

Anti-apoptotic phenotype is associated with decreased locoregional recurrence rate in breast cancer.

PURPOSE: Tumor stage and nodal status are the most important factors predicting locoregional recurrence in breast cancer. We wanted to investigate the prognostic value of some newer molecular genetic markers for the occurrence of a locoregional recurrence, in order to improve the selection of patients for locoregional adjuvant therapy. METHODS: Bcl-2, p53, MIB-1, pS2 and CD44v6 were determined immunohistochemically on formalin-fixed and paraffin embedded tumour tissues of 163 patients treated by modified radical mastectomy between 1982 and 1987. Postoperative irradiation was given to 35 patients to the intermammary chain only and to only 13 (8%) patients to the chest wall with or without the regional lymph nodes. Node-positive patients were treated with CAF adjuvant chemotherapy and were randomized for whether or no additional Medroxyprogesteroneacetate (MPA). A multivariate analysis was performed on a number of potential prognostic factors. The risk for locoregional recurrence was estimated using the competing risk approach. RESULTS: After a median period of 7.5 years 28 patients developed a locoregional recurrence. The cumulative incidence of loco-regional recurrence at 10 years was 17%. Bcl-2 and p53 were found to be independent factors predicting locoregional recurrence, whereas a trend was found for MIB-1. Increased Bcl-2 as well as p53 expression were associated with a decreased risk, whereas the increased presence of MIB-1 was associated with an increased risk. CONCLUSION: Results indicate that molecular markers of apoptosis as well as proliferation provide additional information for the risk of locoregional recurrence after modified radical mastectomy. If confirmed, these markers may play a role in the selection of appropriate locoregional adjuvant treatment after primary surgery.

Distress in MEN 2 family members and partners prior to DNA test disclosure. Multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant early-onset cancer disorder. In the Netherlands presymptomatic genetic testing for MEN 2 is offered to testees from the age of five years. We report on adults requesting testing for themselves (n=90) and on parents who want an at-risk child to be tested (n=26). Sociodemographic, personality, and attitude characteristics, and levels of psychological distress, were determined for applicants and their partners in the predisclosure phase of testing. These participants showed only mildly increased levels of psychological distress, defined as heightened scores on measures of general and test-related anxiety, and of psychological complaints. Compared with a normal population, high levels of anxiety and health complaints were found in applicants who were younger than 25 years and single, and in persons who generally tended to react to distressful situations with anxiety or depression. These characteristics were particularly evident in young applicants (<25 years). Our study shows that people who feel ambivalent towards DNA testing and who are more vulnerable to psychological distress are more likely to agree to participate in the test as part of a collective application by members of a hereditary cancer family.

Negative and positive influences of social support on depression in patients with head and neck cancer: a prospective study.

Patients with head and neck cancer have to cope not only with a life threatening diagnosis, but also with an altered facial appearance and the loss or impairment of important functions as a result of treatment. As a consequence they are prone to psychosocial problems. Social support might influence their ability to adapt to the illness and its treatment. The aim of this prospective study is to examine the influence of different aspects of social support on the depressive symptomatology in head and neck cancer patients treated with surgery and/or radiotherapy. Patients completed a questionnaire relating to available and received support, the extent of the social network, depressive symptoms, and general health complaints before and 6 months after treatment. Received support was found to be associated with more depressive symptomatology at baseline and available support led to less depressive symptomatology. The relationship between social support and depressive symptoms was especially apparent in patients with few general health complaints. Whereas the availability of support seemed to be beneficial regardless of the situation, the effect of received support was equivocal. The provision of support should be tailored to the needs of the individual patient.

Radioimmunodiagnosis and therapy.

Although promising results with radioimmunotherapy and radioimmunodiagnosis in haematological diseases, have been reported, they are less encouraging results in solid tumours. Experimental mathematical models suggest that optimization of antibody-based therapy and diagnosis is possible and that further research towards improvement is warranted. In this review, the major problems of radioimmunotherapy and diagnosis are discussed. Particular items adressed include tumour uptake of antibodies and antibody-fragments, the target/non-target ratio, immunogenicity and the selection of radionuclides.

Long-term quality of life of patients with head and neck cancer.

OBJECTIVES: To describe prospectively the long-term changes of quality of life and mood in patients with squamous cell carcinoma of the head and neck treated with surgery and/or radiotherapy. PATIENTS AND METHODS: One hundred seven patients completed the European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire, the EORTC Head and Neck Cancer Module, and the Center for Epidemiological Studies Depression Scale before treatment, and 6, 12, 24, and 36 months later. RESULTS: There was limited deterioration of physical and role functioning and of many head and neck symptoms at 6 months, with improvement thereafter. After 36 months only physical functioning, taste/ smell, dry mouth, and sticky saliva were significantly worse, compared with baseline. Female sex, higher cancer stage, and combination treatment were associated with more symptoms and worse functioning. Despite physical deterioration, there was a gradual improvement of depressive symptomatology and global quality of life. CONCLUSION: Treatment for head and neck cancer results in short-term morbidity, most of which resolves within 1 year. Despite an initially high level of depressive symptomatology, there is gradual improvement of psychological functioning and global quality of life over the course of 3 years. In this prospective study, the impact of the disease and its treatment in long-term survivors seems to be less severe than it is often assumed to be.

Interferon-alpha induced changes in CEA expression in patients with CEA-producing tumours.

Enhancement of antigen expression could result in improved tumour targeting using antibodies directed to the antigen. In this study we performed radioimmunoscintigraphy using 99mTc-CEA-Scan to analyse the effect of interferon-alpha (IFN-alpha) in enhancing the expression of carcinoembryonic antigen (CEA) in ten patients with CEA-producing tumours. Furthermore, we investigated the feasibility of a future therapeutic study with this antibody fragment labelled with rhenium-186. Although IFN-alpha gave rise to a significant increase in antibody uptake by the tumour, the absolute antibody uptake in the tumour appeared to be poor, with a mean of 0.475% of injected dose (ID) in the tumour before IFN-alpha, rising to 0.562% ID in the tumour after IFN-alpha. Pharmacokinetic analysis demonstrated no significant alterations after IFN-alpha. In conclusion, the administration of IFN-alpha is an attractive way to achieve enhanced tumour targeting, although the increase was of little clinical significance in this patient population and using this antibody fragment.