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Biomedical subjects

H J Keizer

Publications and source records attributed to H J Keizer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group.

PURPOSE: This randomized multicenter study was designed to compare the activity of a high-dose doxorubicin-containing chemotherapy regimen with a conventional standard-dose regimen in adult patients with advanced soft tissue sarcomas (ASTS). PATIENTS AND METHODS: Between 1992 and 1995, 314 patients were randomized to receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m(2) on day 1) and ifosfamide (5 g/m(2) on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m(2) on day 1), the same ifosfamide dose, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; sargramostim, 250 microgram/m(2) on days 3 to 16); all courses were repeated every 3 weeks. RESULTS: The median age of the 294 eligible patients was 50 years. They received a median of five chemotherapy cycles. The median dose and relative doxorubicin dose-intensity achieved were 245 mg and 97% in arm A and 360 mg and 99% in arm B, respectively. Thirty-eight percent and 23% of patients presented with leiomyosarcomas and liver metastases, respectively. Objective responses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P =.65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively. Progression-free survival (PFS) was significantly longer in the intensive arm (P =.03). The median duration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm. There was no difference in overall survival (P =.98) between the two therapeutic arms. Toxicities were manageable in both arms. A grade 3/4 neutropenia and infection occurred in 92% and 4.6% of patients in arm A, respectively, and in 90% and 16.6% in arm B, respectively. Grade 3/4 thrombocytopenia was more frequent in arm B. CONCLUSION: The use of rhGM-CSF allowed safe escalation of chemotherapy doses. Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS. The low complete response rate, the high incidence of leiomyosarcomas, and liver metastases may in part explain these results. However, the lengthening of the PFS in the intensive arm, because of the quality of stable disease and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS.

Adult↗
PubMed1999

Prediction models for the histology of residual masses after chemotherapy for metastatic testicular cancer. ReHiT Study Group.

Patients with metastatic non-seminomatous testicular cancer can be cured by cisplatin-based chemotherapy. After chemotherapy, surgical resection is a generally accepted treatment to remove remnants of the initial metastases since residual tumor may still be present (mature teratoma or viable cancer cells). We review here several policies for the selection of patients for retroperitoneal lymph node dissection. We consider one simple policy as a reference, which bases the selection solely on the diameter of the residual mass (> or = 10 mm). Further, we distinguish 4 rule-based policies, which combine several clinical characteristics (e.g., primary tumor teratoma-positive or insufficient reduction in size), and 2 probability-based policies, where a regression or tree model is used that statistically combines well-known, important clinical predictors for the absence of residual tumor. The policies were evaluated in an international data set containing 716 patients. The reference policy would leave 204 masses < 10 mm unresected, where mature teratoma was present in 50 (25%) and cancer in 11 (5%). Compared with this policy, most of the rule-based policies left fewer patients with residual tumor unresected, at the expense of more resections. The probability-based policies could refine the selection without such an increase in the number of resections. Prediction models for the residual histology therefore merit wider application in clinical practice.

Germinoma↗
PubMed1999

Resection of small, residual retroperitoneal masses after chemotherapy for nonseminomatous testicular cancer: a decision analysis.

BACKGROUND: After chemotherapy for metastatic, nonseminomatous testicular cancer, small, retroperitoneal lymph nodes still harbor mature teratoma or viable cancer cells in less than half of patients with normal tumor markers. Surgical resection is an effective treatment to remove residual masses, but observation may also be considered. METHODS: Using a decision analysis model, the authors estimated the survival achieved with either resection or observation for patients with residual masses measuring 0-20 mm. Prognostic estimates were obtained from an international data set containing 362 patients with masses < or =20 mm and from 10 clinical experts. RESULTS: According to the model, resection prolonged life expectancy by more than 2 years for masses 11-20 mm and by more than 1 year for masses 0-10 mm. The estimated gains in 5-year survival were 4.3% and 2.7%, respectively. In a sensitivity analysis, these results appeared rather robust for changes in the estimates of the experts. The magnitude of the gain in survival, however, depended on the probabilities of the residual histologies, which could be estimated with several well-known predictors, and the assumed benefit of resection for residual mature teratoma or cancer. CONCLUSIONS: Resection may on average be beneficial for patients with small, residual masses. The expected benefit depends on the probability and risks of residual malignancy, regarding which further research is required. For decision-making regarding individual patients, the morbidity and costs of resection and a patient's individual preferences should be considered in addition to any assumed gain in survival.

Adult↗
PubMed1999

[Results of 15 years of treatment of nonseminoma testicular cancer: 84% 5-year survival rate].

OBJECTIVE: To review the results 5 years after treatment of patients with testicular non-seminoma. DESIGN: Retrospective, descriptive. METHOD: The records were studied of the 146 patients treated in Leiden University Hospital, the Netherlands, in 1979-1993 for non-seminoma of the testicle. The median age was 27 years (range: 16-76). The median follow-up duration was 65 months (range: 4-172). The Kaplan-Meier method was used to calculate the recurrence and survival rates. RESULTS: In all, 21 of the 146 patients died (5-year survival rate: 84%). Five patients died as a result of treatment. A relapse occurred in 14 of the 49 stage I patients after frequent controls according to the European Organization for Research and Treatment of Cancer (EORTC) standards. One of these patients died after he refused further treatment for his relapse (5-year survival rate: 96%), 92 patients, including 13 from the stage I group, were treated according to protocol with chemotherapy because of metastatic disease, of whom 51 underwent surgery following primary treatment. The histology of the resected material showed vital tumour tissue in 14 of the 51 patients (27%). Seven patients never reached complete remission after chemotherapy and died. In 12 of the 92 patients a relapse occurred after chemotherapy; seven of these died despite further treatment. The 5-year survival rate of the 92 patients with metastatic disease was 82%. None of the surviving patients developed a second primary or major pulmonary, renal or auditory problem. CONCLUSION: The chance of cure and survival in patients suffering from testicular non-seminoma with the help of chemotherapy and surgery is over 80%. In stage I patients intensive surveillance, and chemotherapy in case of a relapse, is effective. Even patients with metastatic disease have a high probability of being cured with few long-term side effects.

Adolescent↗
PubMed1999

Chemotherapy for operable gastric cancer: results of the Dutch randomised FAMTX trial. The Dutch Gastric Cancer Group (DGCG).

The aim of this trial was to investigate whether pre-operative chemotherapy leads to a 15% higher curative resectability rate in patients with operable gastric cancer. In this randomised trial, patients were allocated to receive either four courses of chemotherapy using 5-fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery only. Patients younger than 75 years of age with a good physical and mental condition and a histologically proven adenocarcinoma of the stomach without clinical or radiographic (computed tomography scan) evidence of distant metastases were eligible for this trial. Early gastric cancer or cardia carcinoma were excluded. The response to chemotherapy was evaluated after two and four courses. In case of progressive disease (PD) after two courses, patients were operated upon as soon as possible. Otherwise complete response (CR) partial response (PR) or stable disease (SD), two more courses were scheduled. The standard surgical procedure was a limited lymphadenectomy (D1) with staging biopsy of the para-aortic lymph nodes. Between September 1993 and February 1996, 56 eligible and evaluable patients were entered: 27 were randomised to receive FAMTX before surgery and 29 to undergo surgery only. In the FAMTX + surgery treatment group, 15/27 (56%) had curative resections versus 18/29 (62%) in the surgery only arm. There was no difference in the frequency of TNM stages I + II in both treatment arms: 15/27 versus 15/29. Due to PD and/or toxicity, 12 patients (44%) could not complete the planned four courses of FAMTX. Response evaluation after chemotherapy was possible in 25 patients: 2 CR, 6 PR, 8 SD and 9 PD. The difference in curative resectability rate was 6.5% (95% confidence interval -32 to +19%) in favour of surgery only. Downstaging for stages I + II did not occur. PD was more often the reason for not completing the planned four courses than toxicity. More active regimens than FAMTX are required for future randomised trials.

Adenocarcinoma↗
PubMed1999

A multi-center prospective phase II study of high-dose chemotherapy in germ-cell cancer patients relapsing from complete remission.

PURPOSE: To prospectively determine the efficacy of repeated high-dose alkylating chemotherapy to salvage patients with germ-cell tumors who relapsed after adequate first-line chemotherapy. PATIENTS AND METHODS: Patients with germ-cell cancers relapsing from a first, second or third complete remission induced by chemotherapy were offered to participate in a Dutch national prospective trial with broad entry criteria. The salvage treatment began with a conventional dose of ifosfamide (4 g/m2 on day 1) and etoposide (100 mg/m2 on days 1, 2 and 3) followed by daily s.c. administration of G-CSF (10 micrograms/kg) until peripheral blood progenitor cells had been harvested. Immediately after bone marrow recovery, an intermediate dose chemotherapy course of carboplatin (target AUC: 10 mg.ml-1 min on day 1) and etoposide (500 mg/m2 on days 1, 3 and 5) was given with G-CSF daily s.c. After bone marrow recovery, two subsequent courses of high-dose 'CTC' chemotherapy were given, each containing cyclophosphamide (6 g/m2), thiotepa (480 mg/m2) and carboplatin (target AUC: 20 mg.ml-1 min). The high-dose chemotherapy was administered as 30-60-minute infusions, divided over 4 days and the stem-cell transplants were given 48-72 hours after the last chemotherapy infusion. Whenever possible, residual masses were resected at the end of treatment. RESULTS: Thirty-five patients were treated between January 1994 and October 1997. The toxicity of the treatment was manageable. Second CTC courses were administered in 25 patients and were associated with hemorrhagic cystitis and veno-occlusive disease in 3 and 4 patients, respectively. One patient who had recently undergone a partial hepatectomy, died of veno-occlusive disease. At the time of analysis, the median follow-up of the surviving patients was 37 months (range 12-56 months). The median progression-free survival for all patients was 44 months, and the median overall survival has not been reached. According to the internationally accepted criteria for predicting the outcome of salvage chemotherapy in germ-cell cancer (Beyer et al. J Clin Oncol 1996; 14: 2638-45), 30 patients had 'good risk' criteria. Of these, 29 received high-dose chemotherapy. Of this group, the salvage rate at two years was 65% (95% confidence interval: 49.5%-85.1%). CONCLUSIONS: Over half of the germ-cell cancer patients relapsing from a chemotherapy-induced complete remission can be salvaged by a treatment strategy that incorporates high-dose chemotherapy, even when treatment is given in a multi-center setting. These data confirm the international prognostic model proposed by Beyer et al. in a prospectively studied, independent patient group and provide further evidence that high-dose therapy has a role in the salvage setting of patients with germ-cell cancer.

Adult↗
PubMed1999

Treatment of mesenteric desmoid tumours with the anti-oestrogenic agent toremifene: case histories and an overview of the literature.

Desmoid tumours are histologically benign but due to their infiltration and compression of surrounding structures potentially life-threatening fibromatous lesions of unknown aetiology. The annual incidence rate is 2-4 per million people. The mesenteric variant constitutes about 10% of all desmoid tumours, although in familial adenomatous polyposis (FAP) patients this may be up to 70%. Due to the small number of patients with mesenteric desmoids the therapy is mainly empirical. This report describes the rationale as well as the value of the short- and long-term treatment (up to 6 years) with the anti-oestrogenic agent toremifene in combination with sulindac in two patients suffering from such a mesenteric desmoid tumour. These patients did not respond to sulindac alone and previous treatment with tamoxifen together with this non-steroidal anti-inflammatory drug had also failed. An overview of the literature on the management of these dismal tumours is presented.

Adult↗
PubMed1998

High-performance liquid chromatographic determination of stabilized 4-hydroxyifosfamide in human plasma and erythrocytes.

A method using reversed-phase high-performance liquid chromatography (RP-HPLC) is described for the measurement of the stabilized activated metabolite of ifosfamide, 4-hydroxyifosfamide (4-OHIF), in human plasma and erythrocytes. Immediately after sample collection and plasma-erythrocyte separation at 4 degrees C, 4-OHIF was stabilized by derivatization with semicarbazide (SCZ). The sample pretreatment involved liquid-liquid extraction with ethyl acetate. RP-HPLC was executed with a C8 column and acetonitrile-0.025 M potassium dihydrogenphosphate buffer (pH 7.40)-triethylamine (13.5:86:0.5, v/v) as mobile phase. The analyte was determined with UV detection at 230 nm. Complete validation, optimisation and stability studies were performed and the method proved to be specific, sensitive and with a stable analyte in the range of clinically relevant concentrations (0.1-10 microg/ml) after conventional dosing. The lower limit of quantitation was 100 ng/ml using 1.00 ml of sample. Accuracy was between 94.1 and 107.0%. Within-day and between-day precisions were less than 6.2% and 7.2%, respectively. 4-OHIF-SCZ was found to be stable in the biological matrix at -20 degrees C for at least 1 month. A pharmacokinetic study conducted in a patient receiving 9 g/m2 over 3 days by means of a continuous infusion, demonstrated the applicability of this method.

Acetonitriles↗
PubMed1998

Cisplatin-DNA adducts and protein-bound platinum in blood of testicular cancer patients.

DNA adducts formed by cisplatin [cis-diamminedichloroplatinum(II)] were measured in blood samples from 48 testicular cancer patients treated in four centers in Europe during four to six cycles with cisplatin infusions on five successive days (total samples, 112). Total protein-bound platinum (Pt) in blood was also measured (total samples, 84). The mean on the main DNA adduct, cis-Pt(NH3)2d(pGpG) (Pt-GG), was 0.75 fmol/microg DNA [standard deviation (SD) = 0.66] on the first day of the first cycle, increased after the infusion at day 5 of the cycle (mean 1.74 fmol/microg DNA, SD = 0.90) and decreased on the following day (mean 1.09 fmol/microg DNA, SD = 0.62). In subsequent cycles, there was a tendency to an increase in the mean Pt-GG levels. The values of protein-bound Pt in blood showed little reduction between day 5 and 6 of each cycle, and a stable increase during the course of the therapy. Strong correlations were seen between day 1, 5 and 6 of the first cycle for both Pt-GG and protein-bound Pt in blood. A strong correlation (r = 0.62, p < 0.001, 69 pairs) was found between the levels of Pt-GG and protein-bound Pt. Only two patients relapsed during the follow-up; therefore, the analysis of the association between Pt-GG levels and response to therapy was not informative. The results of this study suggest that DNA adducts formed by cisplatin at the beginning of chemotherapy are predictive of values found during later days and cycles, and that the value of protein-bound Pt in blood is predictive of the value of DNA adducts.

Adult↗
PubMed1998

Use of granisetron in patients refractory to previous treatment with antiemetics.

A multicenter, open-label, compassionate-use trial studied the antiemetic efficacy and tolerability of granisetron in patients who had failed other antiemetic therapies in previous cycles of cytostatic chemotherapy. The antiemetics that had been used previously included metoclopramide, dexamethasone and ondansetron. A total of 517 patients, 456 of whom had failed other antiemetics, were treated in up to 15 successive cycles of chemotherapy. The numbers of patients treated in the first six of these cycles were large enough to allow the drawing of meaningful conclusions from the results. During that period, a complete response was achieved in 53-60% of patients. In addition, antiemetic efficacy was sustained throughout these six repeated treatment cycles. Granisetron was less effective against high-dose cisplatin chemotherapy than against other cytostatic regimens. The treatment was well tolerated--the main adverse events reported were headache and constipation; no serious adverse events were considered to be attributable to the drug. It is concluded that granisetron treatment was effective and well tolerated in patients who had previously failed other antiemetic therapies, including treatment with 5-hydroxytryptamine3 antagonists.

Adolescent↗
PubMed1998

Validity of predictions of residual retroperitoneal mass histology in nonseminomatous testicular cancer.

PURPOSE: To validate predictions of the histology (necrosis, mature teratoma, or cancer) of residual retroperitoneal masses in patients treated with chemotherapy for metastatic nonseminomatous testicular germ cell tumor. PATIENTS AND METHODS: We studied 172 testicular cancer patients who underwent resection while tumor markers were normal. Predictive characteristics for the residual histology were registered, including the presence of teratoma elements in the primary tumor, the prechemotherapy level of tumor markers (alpha-fetaprotein [AFP], human chorionic gonadotropin [HCG], lactate dehydrogenase [LDH]), the size of the residual mass, and the percentage of shrinkage in mass diameter. We calculated the predicted probability of necrosis and the ratio of cancer and mature teratoma with previously published logistic regression formulas. RESULTS: The distribution of the residual histology was necrosis in 77 (45%), mature teratoma in 72 (42%), and cancer in 23 (13%). Necrosis could be well distinguished from other tissue, with an area under the receiver operating characteristic (ROC) curve of 82%. No tumor was found in 15 patients with a predicted probability of necrosis over 90%. The predicted probabilities corresponded reliably with the observed probabilities (goodness-of-fit tests, P > .20), although a somewhat higher probability of necrosis was observed in patients treated with chemotherapy containing etoposide. Conversely, cancer could not reliably be predicted or adequately discriminated from mature teratoma. CONCLUSION: The predicted probabilities of necrosis have adequate reliability and discriminative power. These predictions may validly support the decision-making process regarding the need and extent of retroperitoneal lymph node dissection.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Chromatographic analysis of the enantiomers of ifosfamide and some of its metabolites in plasma and urine.

The enantiomers of the cytostatic drug ifosfamide and the two metabolites 2- and 3-dechloroethylifosfamide were isolated from plasma and urine by liquid-liquid extraction with ethyl acetate, resolved on a Chirasil-L-val gas chromatographic column and detected by a nitrogen-phosphorus-selective flame ionisation detector. Resolution of the racemic compounds for identification purposes was also accomplished with high-performance liquid chromatography on a chiral column. The validated gas chromatographic method was suitable to determine the total concentrations and the enantiomeric composition of ifosfamide and its dechloroethylated metabolites in plasma and urine samples from treated patients. Some metabolic preferences in the metabolism of ifosfamide were found.

Adult↗
PubMed1997

Residual pulmonary masses after chemotherapy for metastatic nonseminomatous germ cell tumor. Prediction of histology. ReHiT Study Group.

BACKGROUND: After chemotherapy for a metastatic nonseminomatous germ cell tumor, pulmonary masses may be seen on a computed tomography scan. These residual masses may contain one of three histologic elements: necrosis, mature teratoma, or cancer. Because surgical resection of masses containing only necrosis is unnecessary, the authors aimed to predict the histology of these residual masses. METHODS: Six study groups contributed patient data on a total of 215 patients undergoing thoracotomy after cisplatin-based induction chemotherapy for metastatic testicular nonseminomatous germ cell tumors. Logistic regression analysis was used to estimate the probability of necrosis, mature teratoma, and cancer in relation to predictors known before thoracotomy. RESULTS: The pulmonary mass histology was necrosis in 116 patients (54%), mature teratoma in 70 (33%), and cancer in 29 (13%). Necrosis was found at thoracotomy in 89% of those patients with necrosis at retroperitoneal lymph node dissection (RPLND). Other predictors included the primary tumor histology, prechemotherapy tumor marker levels, change in mass size during chemotherapy, and the presence of a single, unilateral mass. Multivariate combination of predictors yielded reliable models (goodness-of-fit tests, P > 0.20), which discriminated necrosis well from other histologies, especially if RPLND histology was available (area under the receiver operating characteristic curve, 0.86). CONCLUSIONS: This analysis indicated subgroups of patients with a high probability of necrosis and a low risk of cancer for whom close follow-up of the residual pulmonary mass might be considered. In most patients, a RPLND should be performed before a thoracotomy is considered, because the probability of necrosis is generally higher at thoracotomy than at RPLND and the histology at RPLND is a strong predictor of the histology at thoracotomy.

Analysis of Variance↗
PubMed1997

Residual masses after chemotherapy for metastatic testicular cancer: the clinical implications of the association between retroperitoneal and pulmonary histology. Re-analysis of Histology in Testicular Cancer (ReHiT) Study Group.

PURPOSE: We determined the need and sequence of retroperitoneal lymph node dissection and thoracotomy in patients with nonseminomatous testicular cancer, and with residual retroperitoneal and pulmonary masses after chemotherapy. MATERIALS AND METHODS: We studied 159 patients undergoing retroperitoneal lymph node dissection and a thoracotomy following cisplatin based induction chemotherapy for metastatic testicular nonseminomatous germ cell tumor. Several well-known predictors for residual histology (necrosis, mature teratoma and cancer) were evaluated. RESULTS: As expected, necrosis was found more often at retroperitoneal lymph node dissection if the primary tumor was negative for teratoma, the residual mass was small or the decrease in size was great. Contrary, neither residual mass size nor the decrease in size was predictive of the histological status of the residual lung lesion. Histological findings in the retroperitoneum and lung were strongly correlated, such that necrosis at retroperitoneal lymph node dissection was associated with an 89% probability of necrosis in the lung. CONCLUSIONS: Retroperitoneal lymph node dissection should be performed before thoracotomy is considered, since the histological status at dissection is a strong predictor of that at thoracotomy.

Germinoma↗
PubMed1996

Lack of glutathione conjugation of melphalan in the isolated in situ liver perfusion in humans.

Tumor cell resistance against melphalan (LPAM) has been associated with increased cellular reduced glutathione (GSH) levels and glutathione S-transferase activity. Therefore, GSH conjugation of LPAM has been hypothesized to be a key factor in tumor cell resistance. In the present study, we evaluated GSH conjugation of LPAM by the perfused liver in patients with colorectal cancer metastases undergoing a Phase II study of isolated liver perfusion as well as in the rat. To evaluate whether LPAM-GSH conjugates were synthesized in the rat in vivo, LPAM was infused i.v. at a rate of 2.0 micromol/kg/min. In bile samples obtained during the infusion, two major GSH conjugates were identified by mass spectrometry: mono-hydroxy-mono-GSH-LPAM and di-GSH-LPAM. The maximum biliary excretion rate of these two conjugates accounted for only 1.3% of the LPAM infusion rate. In bile or perfusate samples from patients treated for 60 min initially with 0.3 mM LPAM in the perfusion medium via isolated liver perfusion (200 mg LPAM in approximately 2 liters perfusion medium), none of the above-mentioned conjugates were detected. When comparable rat liver perfusions were performed initially with 66 microM or 0.66 mM LPAM in the perfusion medium, bile samples did contain GSH-LPAM conjugates; the cumulative biliary excretion of the two conjugates amounted to 0.4 and 0.2% of the LPAM dose, respectively. These data suggest that both in rats and humans, hepatic GSH conjugation plays a very minor (if any) role in the elimination of LPAM and, therefore, that modulation of GSH levels is unlikely to affect the rate of elimination of this drug.

Animals↗
PubMed1996

Surveillance versus adjuvant chemotherapy in stage I non-seminomatous testicular cancer: a decision analysis.

In stage I non-seminomatous testicular cancer, the decision between surveillance and adjuvant chemotherapy rests heavily upon the valuation of quality of life. Decision analysis was used to assess at what relapse rate adjuvant chemotherapy is preferred when patients' and clinicians' evaluations are considered. Probabilities were obtained from the literature and from experts. Evaluations of the disease states were obtained from patients (n = 68) and clinicians (n = 50). Results from the model were compared with a treatment preference question, asking for the relapse rate directly. Adjuvant chemotherapy was preferred at relapse rates above 50% when patient evaluations were used. The evaluations of the disease states had a strong impact on the decision. Using clinician evaluations, adjuvant chemotherapy was preferred at relapse rates above 73%. The relapse rates from the treatment preference question were lower: 46% for patients and 35% for clinicians. The results indicate that when patient preferences are accounted for, adjuvant chemotherapy should be considered more often.

Attitude of Health Personnel↗