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S Rodenhuis

Publications and source records attributed to S Rodenhuis.

At least 19 recordsLinked to original sources
PubMed2006

Molecular subtypes of breast cancer and amplification of topoisomerase II alpha: predictive role in dose intensive adjuvant chemotherapy.

Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour. In a retrospective analysis, we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a randomised study of adjuvant high-dose chemotherapy in breast cancer. In addition, the topoisomerase II alpha (TOP2A) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation. 411 of the 753 tumours (55%) were classified as luminal-like, 137 (18%) as basal-like and 205 (27%) as human epithelial receptor type 2 (HER2) amplified. The basal-like tumours were defined as having no expression of ER and HER2; 98 of them did express epidermal growth factor receptor and/or cytokeratin 5/6. The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups. From the 194 HER2-positive tumours, 47 (24%) were shown to harbour an amplification of TOP2A. Patients with an HER2-amplified tumour randomised to the high-dose therapy arm did worse than those in the conventional treatment arm, possibly caused by the lower cumulative anthracycline dose in the high-dose arm. The tumours with a TOP2A amplification contributed hardly to this difference, suggesting that TOP2A amplification is not the cause of the steep dose-response curve for anthracyclines in breast cancer. Possibly, the difference of the cumulative dose of only 25% between the treatment arms was insufficient to yield a survival difference.

Adult↗
PubMed2006

High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy.

We investigated whether the occurrence of veno-occlusive disease of the liver (VOD) may be associated with individual variations in the pharmacokinetics of high-dose cyclophosphamide. Patients received single or multiple courses of cyclophosphamide (1000 or 1500 mg m-2 day-1), thiotepa (80 or 120 mg m-2 day-1) and carboplatin (265-400 mg m-2 day-1) (CTC) for 4 consecutive days. The area under the plasma concentration-time curves (AUCs) were calculated for cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard based on multiple blood samples. Possible relationships between the AUCs and the occurrence of VOD were studied. A total of 59 patients (115 courses) were included. Four patients experienced VOD after a second CTC course. The first-course AUC of 4-hydroxycyclophosphamide (P=0.003) but not of phosphoramide mustard (P=0.101) appeared to be predictive of the occurrence of VOD after multiple courses. High exposures to bioactivated cyclophosphamide may lead to increased organ toxicity.

Antineoplastic Agents, Alkylating↗
PubMed2006

[Effects and costs of adjuvant chemotherapy for operable lymph node positive breast cancer with HER2/neu overexpression].

Newer forms ofadjuvant chemotherapy can considerably improve the prognosis for breast cancer. The benefits that can be achieved are particularly high for young women (< 50 years) with an unfavourable risk profile (tumour-positive axilliary nodes). The recent application of taxans and trastuzumab has sharply increased the costs of an adjuvant treatment for high-risk mammary breast carcinoma. The cost increase can especially be attributed to trastuzumab. The additional costs of cytostatics (10,079 Euro per life-year gained) appear to be justified if the following is taken into account: women under the age of 50 years still have a life expectancy of approximately 33 years, many have socially relevant positions, and that cure also prevents such things as absence through illness and inability to work as well as expensive palliative care. The pharmaceutical industry spends approximately the same amount on research and innovation as it does on advertising. By reducing marketing costs, there will be more room to lessen the costs of new and socially relevant medications. Ultimately, the pressing question remains on why the Dutch government does not fully compensate hospitals in the Netherlands for the introduction of new, potentially life-saving medications. At present, a substantial percentage of the costs has to be paid by the hospitals themselves out of the regular hospital budget, which is not meant for this. This is happening at the expense of other care to an increasing extent.

Age Factors↗
PubMed2006

Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer.

BACKGROUND: High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many. PATIENTS AND METHODS: 885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil, epirubicin and cyclophosphamide) followed by radiation therapy and tamoxifen, or the same treatment but with high-dose alkylating chemotherapy (cyclophosphamide, thiotepa and carboplatin) replacing the fifth course of FEC. Of these patients, 621 had HER2/neu-negative disease, as determined by immunohistochemistry and chromogenic in situ hybridisation. RESULTS: At a median follow-up of 84 months, a trend for a better relapse-free survival was observed in the high-dose arm: (hazard ratio (HR) 0.84, P = 0.076, two-sided). The 621 patients with HER2/neu-negative disease benefited from high-dose therapy, while patients with HER2/neu-positive disease did not (test for interaction, P = 0.006). There was a marked relapse-free survival benefit for patients with HER2/neu-negative disease (71.5% versus 59.1%, 5 years after randomisation; HR 0.68, P = 0.002) and also a survival benefit (78.2% versus 71.0% at 5 years; HR 0.72, P = 0.02). CONCLUSIONS: The findings from this subgroup analysis provide additional evidence that HER2/neu-positive breast cancer is relatively resistant to alkylating agents. For HER2/neu-negative tumours, however, high-dose chemotherapy should remain the subject of clinical studies.

Antineoplastic Agents, Alkylating↗
PubMed2005

Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial.

PURPOSE: This nonrandomized multicenter phase II study was performed to evaluate the activity and safety of Ecteinascidin (ET-743) administered at a dose of 1.5 mg/m(2) as a 24-hour continuous infusion every 3 weeks in patients with pretreated advanced soft tissue sarcoma. PATIENTS AND METHODS: Patients with documented progressive advanced soft tissue sarcoma received ET-743 as second- or third-line chemotherapy. Antitumor activity was evaluated every 6 weeks until progression, excessive toxicity, or patient refusal. RESULTS: One hundred four patients from eight European institutions were included in the study (March 1999 to November 2000). A total of 410 cycles were administered in 99 assessable patients. Toxicity mainly involved reversible grade 3 to 4 asymptomatic elevation of transaminases in 40% of patients, and grade 3 to 4 neutropenia was observed in 52% of patients. There were eight partial responses (PR; objective regression rate, 8%), 45 no change (NC; > 6 months in 26% of patients), and 39 progressive disease. A progression arrest rate (PR + NC) of 56% was observed in leiomyosarcoma and 61% in synovialosarcoma. The median duration of the time to progression was 105 days, and the 6-month progression-free survival was 29%. The median duration of survival was 9.2 months. CONCLUSION: ET-743 seems to be a promising active agent in advanced soft tissue sarcoma, with no cumulative toxicities. The 6-months progression-free survival observed in advanced soft tissue sarcoma compares favorably with those obtained with other active drugs tested in second-line chemotherapy in previous European Organisation for the Research and Treatment of Cancer trials. The median overall survival was unusually long in these heavily pretreated patients mainly due to the high number of patients who benefit from the drug in terms of tumor control.

Adolescent↗
PubMed2005

Early onset of oral aphthous ulcers with weekly docetaxel.

Two patients with metastatic breast cancer developed oral aphthous ulcers after only two administrations of weekly docetaxel without any other toxicity. A treatment delay and dose reduction appears to be an effective management strategy.

Aged↗
PubMed2003

Toxicity of the high-dose chemotherapy CTC regimen (cyclophosphamide, thiotepa, carboplatin): the Netherlands Cancer Institute experience.

High-dose chemotherapy (HD-CT) has a role in the potentially curative treatment of several tumours. The relative efficacies of the different regimens have not been studied in comparative trials, but it is clear that toxicities differ significantly between them. We analysed the immediate and long-term toxicity in the first 100 consecutive patients treated with the CTC regimen (cyclophosphamide 6000 mg m(-2), carboplatin 1600 mg m(-2) (or 20 mg ml(-1) min under the curve (AUC)) both as daily 1 h infusion, thiotepa 480 mg m(-2) as twice daily 30 min infusion, all divided over 4 consecutive days) followed by peripheral blood progenitor cell reinfusion (PBPC-Tx). Most patients had high-risk (n=86) or metastatic (n=4) breast cancer, or a germ cell tumour (n=8). Two patients (with a medulloblastoma and an aesthesioneuroblastoma, respectively) received CTC as off-protocol salvage regimen. The main toxicity was bone marrow suppression. Most patients had PBPC-Tx with granulocyte colony-stimulating factor (G-CSF), and the median time to neutrophil count 500 x 10(6) l(-1) and platelet count >20 x 10(9) l(-1) without transfusion independence was 10 (range 8-25) and 13 (8-60) days, respectively. The toxic death rate was 1%. Other frequent toxicities were neutropenic fever requiring antibiotics (n=65), central catheter-related infection (n=12) or a bleeding episode (n=48), mostly epistaxis (n=26). Reversible cardiac toxicity was seen in six patients and pulmonary events occurred in seven patients (infection (n=6), embolism (n=1)). Grade 3-4 gastrointestinal toxicity was frequent: nausea and vomiting 55%, diarrhoea 28% and mild liver toxicity (transaminase elevations) 9%. One patient pretreated with cisplatin had a kidney transplantation 8 years after HD-CT. Late complications included reversible radiation pneumonitis (n=12) and chronic heart failure (n=2). We found five second solid malignancies and two myelodysplasias. In conclusion, the CTC regimen is associated with a moderate, mainly reversible, toxicity. Future studies need to compare the efficacy and toxicity of the different HD-CT regimens.

Adult↗
PubMed2003

Marker genes for circulating tumour cells predict survival in metastasized breast cancer patients.

We investigated the prognostic significance of circulating breast cancer cells in peripheral blood detected by quantitative RT-PCR of marker genes in patients with advanced breast cancer. Blood samples from 94 breast cancer patients with metastatic disease (M1) were examined for circulating tumour cells by studying the mRNA expression of CK19, p1B, PS2 and EGP2 by real-time PCR. Using a score function, developed for predicting circulating tumour cells by quadratic discriminant analysis (QDA), the four expression levels were combined into a single discriminant value. Tumour cells were present in 24 out of 94 (31%) of the patients. In 77% (72 out of 94) of the patients distant metastatic disease was localised in the bone. In 36% (26 out of 72) of the patients with bone metastases at the time of blood sampling, a positive QDA for the four genes was found, in contrast to only 14% (three out of 22) without bone involvement. Overall survival rates by Kaplan-Meier revealed no prognostic effect for the presence of bone metastases (P=0.93). However, patients with a positive QDA value did have a progression-free survival at 1 year of 3% and overall survival at 2 years of 17%, against 22 and 36% for patients with a negative QDA value (P=0.015 and 0.0053, respectively). Breast cancer patients with metastatic disease have a significantly worse progression-free and overall survival when circulating tumour cells can be detected in their peripheral blood.

Antigens, Neoplasm↗
PubMed2003

Breast cancer response to neoadjuvant chemotherapy: predictive markers and relation with outcome.

The aim of this study was to provide a better insight into breast cancer response to chemotherapy. Chemotherapy improves outcome in breast cancer patients. The effect of cytotoxic treatment cannot be predicted for individual patients. Therefore, the identification of tumour characteristics associated with tumour response and outcome is of great clinical interest. We studied 97 patients, who received anthracycline-based neoadjuvant chemotherapy. Tumour samples were taken prior to and after chemotherapy. We quantified the response to chemotherapy clinically and pathologically and determined histological and molecular tumour characteristics. We assessed changes in the expression of Bcl-2, ER, P53 HER2 and Ki-67. Association with response and outcome was tested for all parameters. The experimental results showed 15 clinical (17%) and three (3%) pathological complete remissions. There were 18 (20%) clinical vs 29 (33%) pathological nonresponders. The expression of most markers was similar before and after chemotherapy. Only Ki-67 was significantly decreased after chemotherapy. Factors correlated with response were: large tumour size, ER negativity, high Ki-67 count and positive P53 status. Tumour response and marker expression did not predict disease-free or overall survival. In conclusion, clinical and pathological response assessments are poorly associated. Proliferation decreases significantly after chemotherapy. ER negativity and a high proliferation index are associated with better response. HER2 status does not predict response, and outcome is not related to tumour response.

Adult↗
PubMed2003

Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study.

The aim of this study was to assess the antitumour response and time to progression (TTP) of patients treated with imatinib mesylate (Glivec, Gleevec, formerly STI-571) who had advanced and/or metastatic gastrointestinal stroma tumours (GIST) or other soft tissue sarcomas (STS). Patients with measurable lesions and adequate organ function were entered. They were treated with imatinib mesylate at the dose of 400 mg twice daily (bid). All tumours were subject to a stringent pathological review by an expert panel. Immunohistochemical expression of KIT expression was evaluated. A total of 51 patients (27 GIST, 24 other STS), median age 53 years, median World Health Organization (WHO) performance score 1, were entered. 71% of the patients had received prior chemotherapy. The most frequent side-effects were anaemia (92%), periorbital oedema (84%), skin rash (69%), fatigue (76%), nausea (57%), granulocytopenia (47%) and diarrhoea (47%). Most of these side-effects were mild to moderate and no patient was taken off study due to side-effects. Skin rash and periorbital oedema frequently seem to be self limiting, despite continued treatment. In GIST patients, the current response rates (RRs) are 4% complete remission (CR), 67% partial remission (PR), 18% stable disease (SD) and 11% progression (PD). 73% of GIST patients are free from progression at 1 year. In the other STS group, there were no objective responses. The median time to progression in this subgroup was only 58 days. Imatinib mesylate is well tolerated at a dose of 400 mg bid. This dose is active in patients with KIT-positive GIST, but patients with other STS subtypes unselected for a molecular target are unlikely to benefit.

Adult↗
PubMed2002

Reinfusion of autologous lymphocytes with granulocyte-macrophage colony-stimulating factor induces rapid recovery of CD4+ and CD8+ T cells after high-dose chemotherapy for metastatic breast cancer.

PURPOSE: Repeated high-dose chemotherapy (HDCT) followed by peripheral-blood progenitor cell (PBPC) transplantation can induce a complete remission in patients with metastatic breast cancer sensitive to standard chemotherapy (CT), but the majority of patients relapse within 1 to 2 years. The immune system is seriously compromised after HDCT, which precludes the development of effective immunotherapy. We investigated whether autologous lymphocytes, reinfused after HDCT, could induce a rapid recovery of T cells. PATIENTS AND METHODS: Three patients were monitored for immune recovery without reinfusion of lymphocytes. In the next 11 patients, stem cells were harvested after CT + granulocyte colony-stimulating factor (G-CSF) and lymphocytes were harvested after CT + granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2. These patients received stem cells and G-CSF after the first HDCT; stem cells, G-CSF, and lymphocytes after the second; and stem cells, GM-CSF, and lymphocytes after the third HDCT. RESULTS: Patients not receiving lymphocyte reinfusion had a very slow recovery of lymphocytes. In particular, CD4 counts remained low (< 200/microL for 9 months). Lymphocyte reinfusion had a significant effect on the recovery of lymphocytes, T cells, and CD8+ T cells (normalized on day 25). Recovery of CD4+ T cells was significantly accelerated by lymphocyte reinfusion and GM-CSF, leading to counts of 500/microL at 25 days. CONCLUSION: Lymphocyte reinfusion with G-CSF had a significant effect on the recovery of CD8+ T cells, whereas rapid recovery of CD4+ T cells required lymphocyte reinfusion and GM-CSF, which possibly acts as a survival factor through activation of antigen presenting cells. Whether the rapid recovery of CD4+ and CD8+ T cells prevents or delays relapse of the disease should be further investigated.

Adult↗
PubMed2002

Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy.

Reversible alopecia is a commonly observed, important and distressing complication of chemotherapy. Permanent alopecia, however, is rare after standard-dose therapy, but has occasionally been observed after high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC). We evaluated the relationships between total exposure to these three compounds and their different metabolites in the high-dose CTC regimen, and the subsequent development of irreversible alopecia. Twenty-four patients received two or three courses of high-dose CTC, each followed by peripheral blood progenitor cell transplantation. Plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its active metabolite tepa, and carboplatin were determined, and the area-under-the-plasma concentration-versus-time curves (AUC) of the compounds were calculated. Eight of the 24 patients included in the study developed permanent alopecia, while seven had normal hair regrowth and nine patients developed incomplete and/or thin hair regrowth. The carboplatin AUC and the summed AUC of thiotepa and tepa were both significantly associated with increasing irreversibility of hair loss. These results suggest that high exposure to carboplatin and the sum of the thiotepa and tepa exposure may lead to the development of permanent alopecia. This knowledge could guide therapeutic drug monitoring in order to prevent the occurrence of permanent alopecia and thereby improve the patients' quality of life.

Adolescent↗
PubMed2002

Relationship between exposure and toxicity in high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin.

BACKGROUND: High-dose chemotherapy in combination with peripheral blood progenitor cell transplantation is widely used in the treatment of several malignancies. The use of high-dose chemotherapy can be complicated by the occurrence of severe and sometimes life threatening toxicity. A wide interpatient variability in toxicity is encountered, which may be caused by variability in the pharmacokinetics of the agents. The aim of this study was to establish the pharmacokinetics of cyclophosphamide, thiotepa, carboplatin and all relevant metabolites in a widely used high-dose combination and to study possible relationships between the pharmacokinetics and toxicity. PATIENTS AND METHODS: Blood samples were collected from patients treated with modifications of the CTCb regimen consisting of cyclophosphamide (1000-1500 mg/m2/day), carboplatin (265-400 mg/m2/day) and thiotepa (80-120 mg/m2/day) as short infusions for four consecutive days. Thiotepa and its main metabolite tepa, ultrafilterable carboplatin, cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard were determined. Pharmacokinetics were assessed with the use of population pharmacokinetic analyses. Relationship between the area under the concentration-time curves (AUCs) of these compounds and toxicity were tested. RESULTS: A total of 46 patients (83 courses of chemotherapy) was included. Relationships were identified between elevation of transaminases and the thiotepa and tepa AUC, mucositis and the tepa AUC and ototoxicity and the carboplatin AUC. A strong trend between the 4-hydroxycyclophosphamide AUC and veno-occlusive disease was found. CONCLUSIONS: The complex pharmacokinetics of the different agents and their metabolites have been established and several relationships between the pharmacokinetics and toxicity were identified. These findings may form the basis for further treatment optimisation and dose-individualisation in this high-dose chemotherapy combination.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: final analysis with 7 years of follow-up.

BACKGROUND: The aim of this study was to present an update of overall (OS) and disease-free survival (DFS) and to evaluate the correlation between outcome and pathological findings at surgery in a randomized trial of high-dose chemotherapy following neoadjuvant chemotherapy and surgery in high-risk breast cancer patients. PATIENTS AND METHODS: Ninety-seven women <60 years of age with breast cancer and extensive axillary lymph node involvement received three courses of FE120C (5-fluorouracil 500 mg/m2, epirubicin 120 mg/m2, cyclophosphamide 500 mg/m2) followed by surgery. Eighty-one patients were randomized to receive either a fourth FE120C course alone or a fourth FE120C course followed by high-dose chemotherapy (cyclophosphamide 6 g/m2, thiotepa 480 mg/m2, carboplatin 1600 mg/m2). We performed a univariate analysis on possible prognostic factors and analyzed the sites of relapse. RESULTS: After a median follow-up of 6.9 years, 47 (48%) patients were alive, of whom 36 (38%) were without disease. Sixty patients relapsed after treatment. One patient died of myelodysplastic syndrome, without a relapse. In intention-to-treat analysis, the 5-year DFS rates were 47.5% in the conventional treatment arm and 49% in the high-dose arm, and the 5-year OS rates were 62.5% and 61%, respectively. In the univariate analysis, the clinical T-stage before chemotherapy and the number of tumor-positive axillary lymph nodes after induction chemotherapy (P = 0.027) were significant prognostic factors for OS. The same factors (both P = 0.06) plus the estrogen receptor (P = 0.08) were borderline significant factors for DFS. CONCLUSIONS: After a median follow-up of 6.9 years there was no difference in OS or DFS rates between the two treatment groups. The number of tumor-positive axillary lymph nodes after induction chemotherapy and the clinical T-stage before chemotherapy were significant factors for OS.

Adult↗
PubMed2002

Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients.

BACKGROUND: Neuropsychological examinations have shown an elevated risk for cognitive impairment 2 years after therapy in breast cancer patients randomized to receive adjuvant high-dose cyclophosphamide, thiotepa, carboplatin (CTC) chemotherapy compared with a non-treated control group of stage I breast cancer patients. Patients randomized to receive standard-dose fluorouracil, epirubicin, cyclophosphamide (FEC) chemotherapy showed no elevated risk compared with controls. However, breast cancer patients treated with conventional cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy showed a higher risk of cognitive impairment. The present study was designed to obtain a greater insight into these long-term neuropsychological sequelae following chemotherapy and their course in time. PATIENTS AND METHODS: At 4 years post-therapy, 22 of the original 34 CTC patients, 23 of 36 FEC patients, 31 of 39 CMF patients and 27 of 34 control patients were re-examined with neuropsychological tests. RESULTS: Improvement in performance was observed in all chemotherapy groups, whereas in the control group there was a slight deterioration in test results. A differential attrition was observed among the groups, with a relatively high percentage of initially cognitively impaired patients from the CTC group dropping out due to factors related to disease progression. CONCLUSIONS: The results suggest that cognitive dysfunction following adjuvant chemotherapy in breast cancer patients may be transient. Additional studies are needed to investigate the differential attrition of patients with cognitive impairment.

Adult↗