Successful docetaxel rechallenge with cromoglycate after major sensitivity reactions.
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Administration, Oral↗
Biomedical subjects
S Rodenhuis
Publications and source records attributed to S Rodenhuis.
Feasibility of multiple courses of high-dose cyclophosphamide, thiotepa, and carboplatin for breast cancer or germ cell cancer.
PURPOSE: To determine the feasibility and safety of multiple, closely timed courses of high-dose cyclophosphamide, thiotepa, and carboplatin (CTC) with peripheral-blood progenitor-cell transplantation (PBPCT). PATIENTS AND METHODS: Forty-eight patients with advanced cancer were scheduled to undergo either two or three courses of CTC with PBPCT. All PBPCs were harvested before high-dose therapy began. Full-dose CTC courses incorporated cyclophosphamide (6,000 mg/m2), thiotepa (480 mg/m2), and carboplatin (1,600 mg/m2) divided over days -6, -5, -4, and -3. Tiny CTC courses (tCTC) contained 67% of the doses of each of these agents. Second or third courses of CTC or tCTC began on day 28. RESULTS: A sufficient number of PBPC could be harvested from all but two patients. Thirty-five first full-dose courses of CTC were given, 28 second courses, and 10 third courses. Second courses could be given on time and at full dose in 80% of the patients, but there was one toxic death from venoocclusive disease (VOD). Only four of 12 patients scheduled to receive three courses of full-dose CTC could be treated at the time and dose planned. There were three toxic deaths: one of VOD, one of sepsis, and one of hemolytic uremic syndrome (HUS). Eight patients were scheduled to receive three courses of tCTC. Eight first, seven second, and six third courses were given. One of the third courses had to be delayed and one had to be reduced in dose. CONCLUSION: A sufficient number of PBPCs for two or three transplantations can be harvested from most patients without much difficulty before high-dose therapy. Two full-dose CTC courses or three tCTC courses can be given safely and with acceptable toxicity at 5-week intervals. Organ toxicity rather than bone marrow toxicity has become dose-limiting for alkylating agents.
Adult↗
Hemolytic uremic syndrome after high dose chemotherapy with autologous stem cell support.
BACKGROUND: Chemotherapy intensification may lead to new forms of toxicity such as hemolytic uremic syndrome. METHODS: Three patients are described who developed this complication 4 to 6 months after high dose chemotherapy followed by autologous stem cell support. The literature on this subject is reviewed. RESULTS: One patient was conditioned with BEAC (carmustine, etoposide, cytosine arabinoside, and cyclophosphamide) and received autologous bone marrow. The other two underwent triple peripheral stem cell transplantation after conditioning with CTC (carboplatin, cyclophosphamide, and thiotepa). Symptoms were hypertension, microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency. One patient had a retinal vein thrombosis. One patient died of a cardiac arrest shortly after the diagnosis was made. The remaining two achieved a partial remission: one with fresh frozen plasma without plasmapheresis and fresh frozen plasma, but improved on high dose intravenous immunoglobulin and vincristine. CONCLUSIONS: Hemolytic uremic syndrome is a serious complication of the more intensive chemotherapy made possible by stem cell support. Because of the rapidly growing indications for this approach, an increase in this type of vascular complication is expected.
Adult↗
Expression of adhesion molecules on CD34+ cells: CD34+ L-selectin+ cells predict a rapid platelet recovery after peripheral blood stem cell transplantation.
Adhesion molecules play a role in the migration of hematopoietic progenitor cells and regulation of hematopoiesis. To study whether the mobilization process is associated with changes in expression of adhesion molecules, the expression of CD31, CD44, L-selectin, sialyl Lewisx, beta 1 integrins very late antigen 4 (VLA-4) and VLA-5, and beta 2 integrins lymphocyte function-associated 1 and Mac-1 was measured on either bone marrow (BM) CD34+ cells or on peripheral blood CD34+ cells mobilized with a combination of granulocyte colony-stimulating factor (G-CSF) and chemotherapy. beta 1 integrin VLA-4 was expressed at a significantly lower concentration on peripheral blood progenitor cells than on BM CD34+ cells, procured either during steady-state hematopoiesis or at the time of leukocytapheresis. No differences in the level of expression were found for the other adhesion molecules. To obtain insight in which adhesion molecules may participate in the homing of peripheral blood stem cells (PBSCs), the number of CD34+ cells expressing these adhesion molecules present in leukocytapheresis material was quantified and correlated with hematopoietic recovery after intensive chemotherapy in 27 patients. The number of CD34+ cells in the subset defined by L-selectin expression correlated significantly better with time to platelet recovery after PBSC transplantation (r = -.86) than did the total number of CD34+ cells (r = -.55). Statistical analysis of the relationship between the number of CD34+L-selectin+ cells and platelet recovery resulted in a threshold value for rapid platelet recovery of 2.1 x 10(6) CD34+ L-selectin+ cells/kg. A rapid platelet recovery (< or = 14 days) was observed in 13 of 15 patients who received > or = 2.1 x 10(6) CD34+ L-selectin+ cells/kg (median, 11 days; range, 7 to 16 days), whereas 10 of 12 patients who received less double positive cells had a relative slow platelet recovery (median, 20 days; range, 13 to 37 days). The L-selectin+ subpopulation of CD34+ cells also correlated better with time to neutrophil recovery (r = -.70) than did the total number of reinfused CD34+ cells (r = -.51). However, this latter difference failed to reach statistical significance. This study suggests that L-selectin is involved in the homing of CD34+ cells after PBSC transplantation.
Adult↗
Comparative analysis of p53 gene mutations and protein accumulation in human non-small-cell lung cancer.
A series of 54 resected primary non-small-cell lung carcinomas was analyzed for p53 gene mutations and for p53 protein accumulation and the findings were correlated with clinical parameters. Mutations in exons 5 through 8 of the p53 gene were identified by a denaturing gradient gel electrophoresis (DGGE) assay and cycle sequencing, whereas p53 protein accumulation was detected in paraffin-embedded tissue by immunostaining using 2 different murine monoclonal antibodies (MAbs) (BP53-12 and DO7). A p53 gene mutation and/or p53 protein accumulation was found in 37 of 54 tumors. Mis-sense mutations were closely associated with positive immunostaining, which was intense in 15 out of 17 cases with a mutation. In 10 tumors, obvious p53 accumulation was detected in the absence of mutations in exons 5 through 8. Conversely, only one of 8 p53 non-sense mutations led to detectable p53 accumulation. The most frequent single base changes were G --> T transversions and C --> T transitions. The presence of a p53 alteration was not related to age, tumor size, stage or histology. However, we found a significant inverse correlation between p53 alterations and the presence of a K-ras mutation. This was reflected in the overall postoperative survival data: patients with p53 alterations in their tumors tended to have a better prognosis than those without a p53 alteration; however, this difference was lost when cases with a K-ras mutation were omitted from the analysis.
Adult↗
N- and KRAS mutations in primary testicular germ cell tumors: incidence and possible biological implications.
Recently, conflicting results have been reported on the incidence of RAS mutations in primary testicular germ cell tumors of adults (TGCTs). In four studies a low incidence of mutations (less than 15%) in a variety of TGCTs or derived cell lines was found, whereas in two other studies a high incidence of N- or KRAS mutations (over 40%) was shown. A total of 62 testicular seminomas (SE) and 34 nonseminomatous TGCTs (NS) were studied thus far. The largest series consisted of 42 TGCTs, studied on paraffin embedded tissue. We present the results of analysis for the presence of N- and KRAS mutations, in codons 12, 13, and 61, in snap frozen samples of 100 primary TGCTs, comprising 40 SE and 60 NS. Using the polymerase chain reaction (PCR) and allele specific oligonucleotide hybridization (ASO), mutations were found in five SE (three in NRAS and two in KRAS, all codon 12), and in one NS (KRAS, codon 12). To exclude underestimation of the incidence of RAS mutations in TGCTs due to the presence of an excess of wild type alleles in the analyzed sample, a PCR technique preferentially amplifying KRAS alleles with a mutation in codon 12 was applied to all SE. This approach, allowing a 250 times more sensitive assay, resulted in the detection of only one additional SE with a mutation. Based on a critical analysis of published data and on our results from the largest series of frozen samples investigated thus far, we conclude that N- or KRAS mutations are rare and apparently not essential for initiation or progression of TGCTs.
Alleles↗
The use of the Calvert formula to determine the optimal carboplatin dosage.
Carboplatin is a chemotherapeutic agent frequently used in the treatment of various malignancies. The myelotoxicity and clinical efficacy of carboplatin correlate with the clearance of the drug, which is correlated to the glomerular filtration rate (GFR). Dosing of this agent based solely upon the patients body surface area is therefore not accurate enough; the GFR, and thus the clearance of carboplatin differ in each patient irrespective of the body area. Consequently, some patients undergo a higher systemic exposure, expressed as the area under the plasma concentration/time curve (AUC), than others when dosages of carboplatin are given on the basis of the body surface area. A high AUC correlates with increased toxicity, thus increasing the risks of the treatment, but in the case of a low AUC the therapeutical efficacy decreases. This indicates that an individual dosing strategy is warranted to obtain the optimal AUC. In this article, the development and application of a simple equation, known as the Calvert formula, are discussed. This formula can be used to calculate the carboplatin dose accurately in order to obtain a target AUC by using only the GFR. The formula is: dose (mg) = AUC (mg ml-1 min) x [GFR (ml/min) + 25 (ml/min)]. This formula has proven to be, in both retrospective and prospective studies, a reliable tool to calculate the optimal dose of carboplatin Future studies should determine the value of the creatinine clearance as a measure for the GFR.
Carboplatin↗
Prognostic factors in NSCLC. Recent experiences.
In recent years, a group of new prognostic factors have been added to the list of well-known clinical prognostic factors of non-small cell lung cancer. Among these are mutations in the K-ras oncogene, abnormalities in p53, the presence of N-CAM expression as measured by Mab immunostaining and elevated serum levels of NSE. These factors have provided important clinical insights into the biology of lung cancer and prospective studies using these biomarkers are now warranted to provide further important clues about their potential significance in treatment selection of patients.
Biomarkers, Tumor↗
High-dose chemotherapy regimens for solid tumors.
High-dose chemotherapy with blood progenitor cell transplantation is increasingly recognized as a potentially valuable treatment for breast cancer, germ cell cancer, ovarian cancer and other solid tumors. A variety of cytotoxic drugs, particularly alkylating agents, have been investigated either alone or in combinations. Current, predominantly small, phase I and phase II clinical trials to not adequately compare the efficacy of these regiments and patterns of dose-limiting extramedullary toxicity are emerging. Busulfan, carmustine (BCNU) and mitomycin C cause veno-occlusive disease (VOD) of the liver in some patients and the latter two agents also cause interstitial pneumonitis. Cisplatin and ifosfamide only allow minor dose escalation before renal failure becomes prohibitive. Cyclophosphamide, thiotepa, melphalan and etoposide allow substantial dose escalation above standard and are mainly associated with mucositis. Moderate dose escalations of mitoxantrone and carboplatin are possible, limited by cardiotoxicity and neurotoxicity, respectively. Advances in supportive care have abolished bone marrow suppression as the dose-limiting toxicity in chemotherapy. Severe and potentially fatal extramedullary toxicity following high-dose chemotherapy can only be avoided by administering agents with predictable toxicity patterns and by carefully considering their clinical pharmacology.
Antineoplastic Agents↗
High-dose carboplatin, thiotepa and cyclophosphamide (CTC) with peripheral blood stem cell support in the adjuvant therapy of high-risk breast cancer: a practical approach.
In 29 chemotherapy-naive patients with stage II-III breast cancer, peripheral blood stem cells (PBSCs) were mobilised following fluorouracil 500 mg m-2, epirubicin 90-120 mg m-2 and cyclophosphamide 500 mg m-2 (FEC) and granulocyte colony-stimulating factor (G-CSF; Filgrastim) 300 microgram s.c. daily. In all but one patient, mobilisation was successful, requiring three or fewer leucocytopheresis sessions in 26 patients; 28 patients subsequently underwent high-dose chemotherapy consisting of carboplatin 1600 mg m-2, thiotepa 480 mg m-2 and cyclophosphamide 6 g m-2 (CTC) followed by PBSC transplantation. Haemopoietic engraftment was rapid with a median time to neutrophils of 500 x 10(6) l(-1) of 9 days (range 8-10) in patients who received G-CSF after PBSC-transplantation; platelet transfusion independence was reached within a median of 10 days (range 7-16). Neutropenic fever occurred in 96% of patients. Gastrointestinal toxicity was substantial but reversible. Renal, neural or ototoxicity was not observed. Complications related to the central venous catheter were encountered in 64% of patients, with major vein thrombosis occurring in 18%. High-dose CTC-chemotherapy with PBSC-transplantation, harvested after mobilisation with FEC and G-CSF, is reasonably well tolerated without life-threatening toxicity and is a suitable high-dose strategy for the adjuvant treatment of breast cancer.
Adenocarcinoma↗
Monitoring carboplatin concentrations in saliva: a replacement for plasma ultrafiltrate measurements?
There is an increasing interest in using saliva as a biological matrix for drug monitoring, because it can be obtained by a noninvasive and patient-friendly means. In this article we describe our experience with respect to the practical use of saliva for pharmacokinetic monitoring of the anticancer agent carboplatin. Plasma ultrafiltrate (pUF), unstimulated, and citric acid-stimulated saliva samples were obtained from 17 patients receiving 175-350 mg/m2 carboplatin in different combination regimens. Platinum concentrations of carboplatin were determined by using a validated Zeeman atomic absorption spectrometric method. Carboplatin was detectable both in saliva and in pUF for at least 24 h after intravenous administration. Maximum concentrations in saliva ranged between 0.13 and 1.15 mg/L and were reached approximately 1.3 h (range 0-3.8 h) after the end of the infusion. The ratios of carboplatin levels in pUF and saliva were time dependent and patient dependent. The ratios of the clinically relevant carboplatin area under the concentration-time curve (AUC) in pUF and saliva varied between 11 and 150 (mean 45). Based on this large variation, we conclude that in this setup, saliva drug concentrations are not a reliable replacement for carboplatin analysis in pUF.
Adolescent↗
Absence of ras gene mutations in early gastric carcinomas.
The aims of this study were to assess the prevalence and type of activating point mutations at codons 12, 13, and 61 of the Ki-, Ha-, and N-ras genes in a series of early gastric carcinomas in white patients and to correlate these ras gene mutations, if any, with the histological type (Lauren classification), the type of growth pattern, and with the Helicobacter pylori status. Haematoxylin and eosin and Giemsa stained sections from 45 formalin fixed, paraffin wax embedded early gastric carcinomas were used to assess the Lauren type, the type of growth pattern, and the antral H pylori status. DNA was extracted according to standard procedures. Mutations at codon 12 of the Ki-ras gene were examined with a polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) method and dot blot hybridisation with allele-specific 32P-labelled oligodeoxynucleotide (ASO) probes. All other ras genes were analysed with specific PCR amplification and dot blot hybridisation with ASO probes. Mutations were detected by overnight autoradiography at -70 degrees C. Some 20 intestinal-type and 25 diffuse-type early gastric carcinomas were seen. According to growth pattern, there were 24 small mucosal type early gastric carcinomas, five superficial spreading type early gastric carcinomas, and 16 penetrating type early gastric carcinomas (four penetrating A type, 12 penetrating B type). H pylori was found in the antral mucosa of 28 early gastric carcinomas (62%). Activating ras gene mutations were not found. It was discovered that activating point mutations at codons 12, 13, and 61 of the Ki-, Ha-, and N-ras genes do not play a part in the development of early gastric carcinomas in white subjects, irrespective of Lauren type. Moreover, differences in biological behaviour between early carcinomas with different types of growth pattern are not related to these ras gene mutations. Finally, H pylori positive and H pylori negative gastric carcinomas cannot be discriminated on the basis of ras gene mutational analysis.
Base Sequence↗
Phase I clinical and pharmacokinetic study of topotecan administered by a 24-hour continuous infusion.
PURPOSE: To determine the maximum-tolerable dose (MTD) and to investigate the pharmacokinetics and pharmacodynamics of topotecan in a phase I study. Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. Broad preclinical activity rationalized further clinical evaluation. PATIENTS AND METHODS: In this phase I trial, topotecan was administered by 24-hour continuous infusion every 21 days to patients with solid malignant tumors. RESULTS: A total of 25 eligible patients, of whom 22 were pretreated, entered the study. They received the following dosages of topotecan: 2.5, 3.75, 5.60, 8.4, and 10.5 mg/m2 by 24-hour infusion. Reversible leukopenia and thrombocytopenia were dose-limiting, with mild anemia occurring regularly. Other toxicities, such as alopecia, mucositis, nausea, and vomiting were sporadic and mild. Responses were not observed. However, eight patients had stable disease. The plasma concentration-time curves were not compatible with standard linear pharmacokinetic models, and indications were found for the occurrence of nonlinear (saturation) kinetics at the dosages studied. CONCLUSION: The recommended dose for phase II studies is 8.4 mg/m2 when administered as a 24-hour infusion, which is well tolerated. Further studies will be necessary to account for the putative nonlinear behavior of the drug.
Adult↗
Subsets of CD34+ cells and rapid hematopoietic recovery after peripheral-blood stem-cell transplantation.
PURPOSE: To study whether there is a relationship between transplanted cell dose and rate of hematopoietic recovery after peripheral-blood stem-cell (PBSC) transplantation, and to obtain an indication whether specific subsets of CD34+ cell populations contribute to rapid recovery of neutrophils or platelets. PATIENTS AND METHODS: Based on data from 59 patients, we calculated for each day after PBSC transplantation the dose of CD34+ cells that resulted in rapid recovery of either neutrophils or platelets in the majority (> 70%) of patients. Using dual-color flow cytometry, subsets of peripheral-blood CD34+ cells were quantified and the numbers of CD34+ cells belonging to each of the reinfused subsets correlated with hematopoietic recovery following high-dose chemotherapy. RESULTS: The calculated threshold values with a high probability of engraftment showed a steep dose-effect relationship between CD34+ cell dose and time to recovery of both neutrophils or platelets. Predominantly CD34+ cells with the phenotype of myeloid precursors were mobilized. A minority of CD34+ cells expressed the erythroid and megakaryocytic lineage-associated antigens and a low but distinct population of CD34+ cells expressed antigens associated with multipotent stem cells. Analysis showed that the number of CD34+CD33- cells (r = -.74, P < .05), as well as the number of CD34+CD41+ cells (r = -.81, P < .005), correlated significantly better with time to neutrophil and platelet recovery, respectively, than with the total number of CD34+ cells (r = -.55 and r = -.56, respectively). CONCLUSION: The numbers of CD34+CD33- cells and CD34+CD41+ cells may help to predict short-term repopulation capacity of PBSCs, especially when relatively low numbers of CD34+ cells per kilogram are reinfused.
Adolescent↗
Pilot study of a high-dose carboplatin-based salvage strategy for relapsing or refractory germ cell cancer.
Eleven patients with germ cell cancer relapsing from a complete remission and 7 patients with refractory germ cell cancer and/or an unresectable partial remission received salvage chemotherapy with one to two courses of carboplatin (800 mg/m2) and etoposide (500 mg/m2 on days 1, 3, and 5), followed by either one or two courses of carboplatin (1600 mg/m2), cyclophosphamide (6 g/m2), and thiotepa (480 mg/m2) divided over 4 days with autologous bone marrow transplantation and/or peripheral stem cell support. Eight of 11 relapsing patients (73%) were salvaged (with a follow-up of 21+ to 56+ months), but only 1 of the 7 refractory patients survived (34+ months). The high-dose carboplatin-based salvage regimen is feasible and deserves further evaluation in patients relapsing from a complete remission. Even more intensive treatment strategies may be required to salvage patients who are refractory to standard doses of platinating agents.
Adult↗
Association of H-ras mutations with adenocarcinomas of the parotid gland.
We have examined 17 adenocarcinomas and 2 mixed tumors of the salivary glands for mutational activation of the oncogenes H-ras, K-ras and N-ras. The presence of mutations was determined by in vitro amplification of gene fragments spanning codons 12, 13 and 61 and the use of mutation-specific oligonucleotide hybridization. ras mutations were present in 3 of 13 adenocarcinomas (23%) of the parotid gland. The mutations were confirmed and characterized by means of cycle sequencing of polymerase chain reaction (PCR) fragments. In all 3 cases, the mutation was an A:T to G:C transition at the second position of codon 61 of the H-ras gene. This rather unusual ras mutation could provide a clue to identify one or more carcinogens involved in the pathogenesis of parotid cancer.
Adenocarcinoma↗
The pharmacokinetics of reduced folates after intraperitoneal and intravenous administration of racemic [6S,R]-folinic acid.
We investigated the pharmacokinetics of tetrahydrofolates following the administration of [6S,R]-folinic acid and 5-flurouracil delivered i.v., i.p., and by a combination of both routes in patients with colon cancer. The concentrations of the biologically active tetrahydrofolates ([6S]-folinic acid and 5-methyltetrahydrofolate) and the relatively inert diastereomer [6R]-folinic acid were monitored using a selective on-line coupled achiral-chiral high-performance liquid chromatographic method. In plasma, a target concentration of 5 microM active tetrahydrofolates, which is considered necessary for an optimal synergistic effect, could be achieved after i.v. or combined i.v. and i.p. administration but was not reached in a patient receiving i.p. [6S,R]-folinic acid alone. In three patients receiving i.p. [6S,R]-folinic acid a high level of [6S]-folinic acid was observed in ascites, suggesting that the peritoneal cavity may act as a storage site for tetrahydrofolates after i.p. administration. In these patients, only a trace level of the active metabolite 5-methyltetrahydrofolate was detected in ascites, which may indicate that tetrahydrofolate derivatives penetrate only minimally, if at all, into the peritoneal cavity from the central compartment. These data would indicate that a combination of i.p. and i.v. administration may, from the pharmacological point of view, indeed contribute to an improved treatment of minimal residual disease persisting in the peritoneal cavity.
Ascites↗
Validation of a limited sampling model for carboplatin in a high-dose chemotherapy combination.
A limited sampling model for the estimation of the carboplatin area under the concentration versus time curve (AUC), as developed by Sørensen et al., was validated prospectively for the use in a high-dose combination chemotherapy schedule. The model allows an estimation of the AUC on the basis of only one timed plasma drug concentration, sampled at exactly 2.75 h after a 1-h carboplatin infusion. Pharmacokinetic curves were obtained from nine patients receiving carboplatin (400 mg/m2 per day) combined with cyclophosphamide (1500 mg/m2 per day), thiotepa (120 mg/m2 per day), and mesna (3 g/day) for 4 consecutive days. Peripheral blood stem-cell transplantation (PBSCT) was performed 3 days later to restore hematopoiesis. Using this combination of high doses, the model proved to be unbiased (MPE -3.40%; SE, 1.22%) and highly precise [root mean squared prediction error (RMSE), 5.15%; SE, 0.17%] for estimation of the AUC during 4 consecutive days. The validated limited sampling model provides a starting point for future pharmacokinetic studies in a larger population of patients, which might lead to more insight into the relationships with the pharmacodynamic outcome of carboplatin and may help in achieving more rational dosing of patients on the basis of an AUC determination.
Antineoplastic Combined Chemotherapy Protocols↗