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Biomedical subjects

E F Smit

Publications and source records attributed to E F Smit.

At least 19 recordsLinked to original sources
PubMed2006

Is a patient's self-reported health-related quality of life a prognostic factor for survival in non-small-cell lung cancer patients? A multivariate analysis of prognostic factors of EORTC study 08975.

BACKGROUND: The aim of this prognostic factor analysis was to investigate if a patient's self-reported health-related quality of life (HRQOL) provided independent prognostic information for survival in non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Pretreatment HRQOL was measured in 391 advanced NSCLC patients using the EORTC QLQ-C30 and the EORTC Lung Cancer module (QLQ-LC13). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap validation technique was used to assess the stability of the outcomes. RESULTS: The final multivariate Cox regression model retained four parameters as independent prognostic factors for survival: male gender with a hazard ratio (HR) = 1.32 (95% CI 1.03-1.69; P = 0.03); performance status (0 to 1 versus 2) with HR = 1.63 (95% CI 1.04-2.54; P = 0.032); patient's self-reported score of pain with HR= 1.11 (95% CI 1.07-1.16; P < 0.001) and dysphagia with HR = 1.12 (95% CI 1.04-1.21; P = 0.003). A 10-point shift worse in the scale measuring pain and dysphagia translated into an 11% and 12% increased in the likelihood of death respectively. A risk group categorization was also developed. CONCLUSION: The results suggest that patients' self-reported HRQOL provide independent prognostic information for survival. This finding supports the collection of such data in routine clinical practice.

Adult↗
PubMed2006

Multicenter phase II trial of accelerated cisplatin and high-dose epirubicin followed by surgery or radiotherapy in patients with stage IIIa non-small-cell lung cancer with mediastinal lymph node involvement (N2-disease).

To assess the therapeutic activity of accelerated cisplatin and high-dose epirubicin with erythropoietin and G-CSF support as induction therapy for patients with stage IIIa-N2 non-small-cell lung cancer (NSCLC). Patients with stage IIIa-N2 NSCLC were enrolled in a phase II trial. They received cisplatin 60 mg m(-2) and epirubicin 135 mg m(-2) every 2 weeks for three courses combined with erythropoietin and G-CSF. Depending on results of clinical response to induction therapy and restaging, patients were treated with surgery or radiotherapy. In total, 61 patients entered from March 2001 to April 2004. During 169 courses of induction chemotherapy, National Cancer Institute of Canada (NCI-C) grade III/IV leucocytopenia was reported in 35 courses (20.7%), NCI-C grade III/IV thrombocytopenia in 26 courses (15.4%) and NCI-C grade III/IV anaemia in six courses (3.6%). Main cause of cisplatin dose reduction was nephrotoxicity (12 courses). Most patients received three courses. There were no chemotherapy-related deaths. Three patients were not evaluable for clinical response. Twenty-eight patients had a partial response (48.3%, 95% CI: 36-61.1%), 24 stable disease and six progressive disease. After induction therapy, 30 patients underwent surgery; complete resection was achieved in 19 procedures (31.1%). Radical radiotherapy was delivered to 25 patients (41%). Six patients were considered unfit for further treatment. Median survival for all patients was 18 months. Response rate of accelerated cisplatin and high-dose epirubicin as induction chemotherapy for stage IIIa-N2 NSCLC patients is not different from more commonly used cisplatin-based regimen.

Adult↗
PubMed2006

Pharmacology of the paclitaxel-cisplatin, gemcitabine-cisplatin, and paclitaxel-gemcitabine combinations in patients with advanced non-small cell lung cancer.

PURPOSE: To compare the pharmacology of the paclitaxel-cisplatin, gemcitabine-cisplatin and paclitaxel-gemcitabine combinations in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-four chemo-naive patients with advanced NSCLC were randomized to receive one of the three regimens. Plasma pharmacokinetics and pharmacologic parameters in mononuclear cells were compared and related to toxicity and efficacy. RESULTS: Pharmacological parameters of gemcitabine and cisplatin were not influenced by the combination with one of the other agents, while the paclitaxel clearance was significantly lower for the combination with cisplatin as compared to gemcitabine (P=0.024). The percentage decrease in platelets was significantly higher for the gemcitabine combinations (P=0.004) and related to the dFdCTP-Cmax (P=0.030). Pharmacologic parameters were not related to response or survival. CONCLUSIONS: Gemcitabine and cisplatin pharmacology were not influenced by the combination with one of the other agents, while paclitaxel has a lower clearance in combination with cisplatin as compared to gemcitabine.

Adult↗
PubMed2005

A randomised phase II trial of docetaxel vs docetaxel and irinotecan in patients with stage IIIb-IV non-small-cell lung cancer who failed first-line treatment.

Response rate and toxicity of second-line therapy with docetaxel (75 mg m(-2)) or docetaxel, irinotecan, and lenogastrim (60 mg m(-2), 200 mg m(-2), and 150 microg m(-2) day(-1), respectively) were compared in 108 patients with stage IIIb-IV non-small-cell lung cancer. Addition of irinotecan to docetaxel does not improve response rate, and increases gastrointestinal toxicity.

Adolescent↗
PubMed2005

Expression of the p16(INK4a) gene product, methylation of the p16(INK4a) promoter region and expression of the polycomb-group gene BMI-1 in squamous cell lung carcinoma and premalignant endobronchial lesions.

It is generally assumed that squamous cell carcinoma develops in a stepwise manner from normal bronchial epithelium towards cancer by the accumulation of (epi)genetic alterations. Several mechanisms including mutations and homozygous deletions or hypermethylation of the p16(INK4a) promoter region can cause loss of p16 expression. Recent studies suggest overexpression of the polycomb-group gene BMI-1 might also down-regulate p16 expression. In this study, we analyzed the p16 expression in relation to the methylation status of the p16 promoter region of the p16(INK4a) gene and the expression of BMI-1 in bronchial squamous cell carcinomas (SCC) and its premalignant lesions. Nine (69%) SCC showed loss of p16 expression and 10 (77%) showed expression of BMI-1. Of four p16 positive samples two (50%) were BMI-1 positive, whereas among nine p16 negative samples, eight (89%) revealed BMI-1 staining. Four (44%) p16 negative samples were hypermethylated at the p16(INK4a) promoter region; the other p16 negative tumors that showed no hypermethylation revealed BMI-1 staining. Only two premalignant lesions showed absence of p16 expression, of which one (carcinoma in situ) was hypermethylated at the p16(INK4a) promoter region and the other (severe dysplasia) showed BMI-1 expression. In total, 11 precursor lesions (48%) revealed BMI-1 expression. In conclusion, the results of this study suggest that loss of p16 expression by promoter hypermethylation is inconsistently and occurs late in the carcinogenic process at the level of severe dysplasia. To what extent overexpression of the polycomb-group protein BMI-1 attributes to down regulating of p16 expression remains unclear.

Aged↗
PubMed2004

[Chemotherapy for metastased non-small cell lung cancer].

Only a select group of patients with metastased non-small cell lung cancer are eligible for treatment with chemotherapy. The standard treatment for patients with a good performance score, and possibly also for those with physical limitations as a consequence of the disease, is chemotherapy consisting of cisplatin or carboplatin in combination with a third-generation cytotoxic agent together with maximum supportive care. The optimal duration of this chemotherapy treatment is at least 3 to 4 cures, less in the case of disease progression. For older patients (> 70 years) with a good performance score, chemotherapy with maximum supportive care is the standard treatment. However, which form of chemotherapy should be given is not yet clear. Symptomatic improvement is important for improving the quality of life. For patients with tumour relapse or disease progression after first-line chemotherapy who still have a good performance score, the standard treatment is once again chemotherapy with maximum supportive care, as this improves the chance of survival and quality of life, and is possibly cost effective.

Age Factors↗
PubMed2004

Glufosfamide administered by 1-hour infusion as a second-line treatment for advanced non-small cell lung cancer; a phase II trial of the EORTC-New Drug Development Group.

The activity of glufosfamide (beta-D-glucosylisophosphoramide mustard) was tested in a multicentre phase II clinical trial in patients with advanced non-small cell lung cancer (NSCLC) who had received one prior line of platinum-based chemotherapy. Patients were treated with 5000 mg/m(2) glufosfamide by a 1-h intravenous (i.v.) infusion every 3 weeks following registration at the European Organisation for Research and Treatment of Cancer (EORTC) Data Center. Patients were randomised between hydration and no hydration to evaluate the nephroprotective effects of forced diuresis. Patients experiencing >/= 35 micromol/l increase of serum creatinine compared with baseline values were taken off the treatment. The Response evaluation criteria in solid tumours (RECIST) criteria were applied for the response assessment. Blood sampling was performed for a pharmacokinetic analysis. 39 patients from seven institutions were registered and a median of three cycles was given (range 0-6) cycles; 20 patients were randomised to the hydration arm. Haematological toxicity was mild, but treatment-related metabolic and electrolytic abnormalities and increases of serum creatinine occurred in several patients. Hydration did not have any significant influence on the plasma pharmacokinetics of glufosfamide and did not show any nephroprotective effect. Only one confirmed partial remission was observed (response rate 3%; 95% (Confidence Interval (CI) 0-14) and 18 cases with stable disease (49%) were recorded as assessed by an independent panel. Median survival of all patients treated was 5.8 months (95% CI 4.2-7.9). In conclusion, glufosfamide administered by a 1-h infusion every 3 weeks has modest activity in advanced NSCLC patients after one prior platinum-based chemotherapy.

Adolescent↗
PubMed2004

Towards a minimally invasive staging strategy in NSCLC: analysis of PET positive mediastinal lesions by EUS-FNA.

STUDY OBJECTIVE: To asses the value of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) in the nodal staging of patients with (suspected) non-small cell lung cancer (NSCLC) and a (18)FDG positron emission tomography (PET) scan suspect for N2/N3 mediastinal lymph node (MLN) metastases. BACKGROUND: Due to the imperfect specificity of positron emission tomography, PET positive MLN should be biopsied in order to confirm or rule out metastasis. Currently, invasive surgical diagnostic techniques such as mediastinoscopy/-tomy are standard procedures to obtain MLN tissue. The minimally invasive technique of EUS-FNA has a high diagnostic accuracy (90-94%) for the analysis of MLN in patients with enlarged MLN on computed tomography of the chest (CT). DESIGN AND PATIENTS: Thirty-six patients with proven n=26 or suspected n=10 non-small cell lung cancer and a PET scan suspect for N2/N3 lymph node metastases underwent EUS-FNA. When EUS-FNA did not confirm metastasis and the PET lesion was within reach of mediastinoscopy, a mediastinoscopy was performed. EUS-FNA negative patients with PET lesions beyond the reach of mediastinoscopy or those with a negative mediastinoscopy were referred for surgical resection of the tumour and MLN sampling or dissection. RESULTS: EUS-FNA confirmed N2/N3 disease in 25 of the 36 patients (69%) and was highly suspicious in one. In the remaining 10 patients, one PET positive and one PET negative N2 metastasis was detected at thoracotomy. The PPV, NPV, sensitivity, specificity and accuracy of EUS-FNA in analysing PET positive MLN were 100%, 80%, 93%, 100% and 94%, respectively. No complications of EUS-FNA were recorded. CONCLUSIONS AND SIGNIFICANCE: EUS-FNA yields minimally invasive confirmation of MLN metastases in 69% of the patients with potential mediastinal involvement at FDG PET. The combination of PET and EUS-FNA might qualify as a minimally invasive staging strategy for NSCLC.

Adult↗
PubMed2004

Combination therapy with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, gemcitabine and cisplatin in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to investigate the tolerability, pharmacokinetic interaction and antitumor activity of gefitinib ("Iressa", ZD1839), an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, combined with gemcitabine and cisplatin in chemotherapy-naïve patients with advanced solid tumors. PATIENTS AND METHODS: This was an open-label feasibility trial evaluating two doses of gefitinib (250 and 500 mg/day) in combination with gemcitabine and cisplatin. Gefitinib was administered daily from day 2 onwards. Gemcitabine 1250 mg/m(2) was given on days 1 and 8 and cisplatin 80 mg/m(2) on day 1 for up to six 3-week cycles. Patients could then continue to receive gefitinib monotherapy. RESULTS: Eighteen patients were entered, nine at each gefitinib dose level. Two patients developed dose-limiting toxicity: one grade 3 convulsion (250 mg/day dose group) and one grade 3 rash (500 mg/day dose group). The most frequently occurring adverse events in the combination phase were vomiting (17 patients), asthenia (16), nausea (14), diarrhea (14) and skin rash (13). The most common grade 3/4 adverse events were vomiting (seven patients), asthenia (six), thrombocytopenia (six), diarrhea (five) and anorexia (five). Pharmacokinetic analyses showed no apparent pharmacokinetic interaction between gefitinib and cisplatin or gemcitabine, with the exception of a possible small increase in the geometric mean exposure to gemcitabine seen on day 8 of therapy when given alone with the higher dose of gefitinib. Of 17 evaluable patients, nine had confirmed partial responses, seven had stable disease and one had progressive disease. CONCLUSIONS: Combination therapy of gefitinib with cisplatin and gemcitabine had a manageable and predictable safety profile, no major effect on exposure to any of the three drugs and antitumor activity.

Adult↗
PubMed2003

The value of [18F]fluoro-2-deoxy-D-glucose positron emission tomography in the selection of patients with stage IIIA-N2 non-small cell lung cancer for combined modality treatment.

Combined modality treatment (CMT) for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is at present studied extensively. To select patients with truly stage IIIA-N2 disease, however, proves to be difficult with current diagnostic tests. Distant metastases may become clinically overt during induction chemotherapy (IC) or shortly after, revealing the inaccuracies of current staging algorithms. A prospective study with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in IIIA-N2 NSCLC patients was performed to assess its value in the selection of this patient group. Fifty-seven patients received a whole body FDG PET scan as part of an ongoing response monitoring trial. Results were compared with conventional staging. In 32/57 (56%) PET suggested upstaging, which was confirmed in 17/57 (30%) with a median follow-up of 16 (range 2-49) months. These results show that using the conventional staging algorithm a substantial group of patients was understaged. FDG PET improves the selection of patients suitable for CMT.

Adenocarcinoma↗
PubMed2003

Critical factors for patient management.

The main critical factors for lung cancer patient management, apart from TNM staging, include expertise required to offer optimal management and conditions related to the patient, including performance status and weight loss and the presence of lung, cardiac or other comorbidities. Performance status and weight loss must be assessed for all patients. The minimal pulmonary functional evaluation should include spirometry. The minimal cardiac evaluation should consist of a clinical history and evaluation for cardiac risk factors and disease and at least preoperatively, and ECG. Age per se is not a contraindication for curative treatment.

Age Factors↗
PubMed2003

Temozolomide in patients with advanced non-small cell lung cancer with and without brain metastases. a phase II study of the EORTC Lung Cancer Group (08965).

This study was performed to evaluate the activity of single-agent temozolomide in two groups of chemotherapy-naïve non-small cell lung cancer (NSCLC) patients, with (12 patients) and without (13 patients) brain metastases (BM). Patients in both groups were treated with temozolomide 200 mg/m(2)/day, administered orally for 5 consecutive days of a 28-day cycle. Treatment was continued for up to six cycles, disease progression or unacceptable toxicity. The median number of received cycles was only one in the group with and two in the group without BM, and early disease progression was the main reason for treatment discontinuation. Toxicity was moderate-in the group of patients with BM, the most frequently observed grade 3 or 4 side-effects included thrombocytopenia (17%), granulocytopenia (17%), lethargy (17%); other neurological (17%) and other genitourinary toxicity (17%). Patients without BM experienced anaemia (15%), thrombocytopenia (23%), nausea (15%) and lethargy (15%). This trial was designed according to Simon one-sample two-stage testing procedure and both groups of patients were assessed separately. No objective response was observed in either group and the study was closed after the first step of accrual with the conclusion of a lack of therapeutic activity of single-agent temozolomide in patients with stage IV NSCLC.

Adult↗
PubMed2003

Carboplatin and paclitaxol (Taxol) as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer. an EORTC phase II study (EORTC 08958).

The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-naïve patients with NSCLC, median age of 60 years, stage IIIA N2 disease and the ability to tolerate a pneumonectomy received paclitaxel 200 mg/m2 as a 3-h infusion followed by carboplatin at an area under the concentration curve (AUC) of 6 every 3 weeks for three courses. Most patients received three courses. No grade 3/4 anaemia or thrombocytopenia was documented. Over all of the cycles, 6% (3 patients) experienced grade 3 leucopenia while 63% (32/51 patients) experienced grade 3-4 neutropenia. There was 1 patient (2%) with febrile neutropenia, no early or toxic deaths and no hypersensitivity reactions. Severe non-haematological toxicity was uncommon, with the exception of grade 3 alopecia in 39%, lethargy in 8% and myalgia in 6%. Of the eligible patients (n=52), there was one complete response (CR) and 32 partial responses (PR), resulting in a response rate of 64% (95% Confidence Interval (CI) 49%-76%). Of the 15 eligible patients randomised to surgery after induction chemotherapy, 3 patients did not receive surgery and 2 patients (n=12) had no tumour in the mediastinal nodes (17%). Resections were considered complete in 2 of the 12. Median survival for all eligible patients (n=52) was 20.5 months (95% CI 16.1-31.2), with an estimated 1-year survival rate of 68.5% (95% CI 55.2-81.7). In patients with N2 stage IIIA NSCLC, paclitaxel/carboplatin is an active and very well-tolerated induction regimen.

Adult↗
PubMed2003

ALIMTA (pemetrexed disodium) as second-line treatment of non-small-cell lung cancer: a phase II study.

BACKGROUND: The purpose of this study was to evaluate ALIMTA (pemetrexed disodium, LY231514), a multi-targeted antifolate with first-line activity against non-small-cell lung cancer (NSCLC), in a second-line setting. PATIENTS AND METHODS: Patients with NSCLC were eligible for this phase II study if they had progressive disease within 3 months after first-line chemotherapy or progression while being treated with first-line chemotherapy. In 81 patients studied, two cohorts of patients were assigned based on whether the first-line therapy had included a platinum regimen. ALIMTA was administered at 500 mg/m2 by 10-min intravenous infusion once every 21 days. RESULTS: The response rate in the 79 evaluable patients with poor prognostic features was 8.9% [95% confidence interval (CI) 2.6% to 15.1%]. The response rate in the platinum-pretreated group was 4.5% and 14.1% in the non-platinum-pretreated group. The median duration of response was 6.8 months (95% CI 3.4-7.8 months, 0% censoring). The median survival time was 5.7 months (95% CI 4.0-8.3 months, 7.6% censoring). The probability of survival for at least 6 months was estimated to be 48%. The median time to disease progression was 2 months (95% CI 1.4-2.8 months, 0% censoring). The principal toxicity was myelosuppression, which was reversible. CONCLUSIONS: ALIMTA is active in a second-line setting in non-platinum-pretreated NSCLC patients progressing within 3 months of first-line chemotherapy. This study demonstrates that it is possible to evaluate new drugs against NSCLC in a second-line setting.

Adult↗
PubMed2003

Prospective use of serial questionnaires to evaluate the therapeutic efficacy of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in suspected lung cancer.

BACKGROUND: A study was undertaken to study the effect of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the diagnosis and management of clinically problematic patients with suspected non-small cell lung cancer (NSCLC). METHODS: A prospective before-after study was performed in a cohort of all 164 patients (university/community settings) referred for PET between August 1997 and July 1999. PET was restricted to cases where non-invasive tests had failed to solve clinical problems. The impact on diagnostic understanding and management was assessed using questionnaires (intended treatment without PET, actual treatment choice after PET, post hoc clinical assessment). RESULTS: Diagnostic problems especially pertained to unclear radiological findings (n=112; 63%), mediastinal staging (n=36; 20%), and distant staging issues (n=16; 9%). PET findings were validated by reviewing medical records. PET had a positive influence on diagnostic understanding in 84%. Improved diagnostic understanding solely based on PET was reported in 26%. According to referring physicians, PET resulted in beneficial change of treatment in 50%. Cancelled surgery was the most frequent change in treatment after PET (35%). CONCLUSION: FDG PET applied as "add on" technology in patients with these clinical problems appears to be a clinically useful tool, directly improving treatment choice in 25% of patients. The value of increased confidence induced by PET scanning requires further evaluation.

Carcinoma, Non-Small-Cell Lung↗
PubMed2002

[Positron emission tomography in the Netherlands: need to expand the capacity].

Positron emission tomography with 18fluor-2-deoxy-D-glucose (FDG-PET) is increasingly used in clinical practice, especially in oncology. However, in the Netherlands, guidelines for its routine use are lacking, probably due to the limited availability and costs of PET technology. The increasing demand for evidence of a positive effect on patient management (and outcome) following the introduction of new diagnostic tests, also plays an important role. For non-small cell lung cancer (NSCLC) such evidence is now available. In a prospective randomised multicentre study performed in the Comprehensive Cancer Centre in Amsterdam, FDG-PET reduced the number of futile thoracotomies in patients with suspected NSCLC by 50%. This and other studies resulted in a regional guideline (formulated by pulmonologists, surgeons, radiotherapists, radiologists and nuclear medicine physicians) for the use of FDG-PET in patients with (suspected) NSCLC. Several, predominantly multicentre, studies to evaluate the effectiveness of FDG-PET in subgroups of patients with colorectal cancer, breast cancer, oesophageal cancer, ENT tumours, non-Hodgkin's lymphoma and NSCLC (early in the diagnostic workup), are currently being undertaken in the Netherlands. The results of these might facilitate a cost-effective positioning of PET technology for routine patient care in the Netherlands. A recent report from the Comprehensive Cancer Centre in the south of the Netherlands, based on scenarios in Belgium and the United States, indicates that the availability of PET facilities should increase substantially over the next decade, so as to ensure access to all patients who may benefit from this technology.

Cost-Benefit Analysis↗
PubMed2002

A phase II EORTC study of temozolomide in patients with malignant pleural mesothelioma.

The aim of this study was to investigate the anti-tumour activity of temozolomide in patients with malignant pleural mesothelioma. 27 chemotherapy-naïve patients with histologically-proven malignant mesothelioma were treated with temozolomide 200 mg/m2/day, given orally on days 1-5 of each 28-day cycle. Therapy continued up to 10 cycles unless disease progression or excessive toxicity mandated discontinuation. Toxicity, symptom improvement and pain intensity were regularly assessed. With a median relative dose intensity of 97%, toxicity was moderate with grade 3 or more nausea, vomiting, thrombocytopenia, leucocytopenia, neutropenia, febrile leucocytopenia, arthralgia, infection and fever with infection occurring in 13, 13, 10, 3, 7 and 3% of patients for the remaining events, respectively. Overall, 1 objective response was observed (response rate 4%, 95% Confidence Interval (CI): 0.1-19). Median survival was 8.2 months. Symptom assessment showed no improvement and an increase of pain was observed during the study. Thus, oral temozolomide is an inactive agent in malignant mesothelioma.

Adult↗