The effectiveness of chlorhexidine-silver sulfadiazine impregnated central venous catheters in patients receiving high-dose chemotherapy followed by peripheral stem cell transplantation.

Immuno-compromised patients are at high risk for all kind of infections. Unfortunately, they need central venous catheters (CVCs), which are associated with infectious complications. In this study we examined the effectiveness of chlorhexidine-silver sulfadiazine impregnated CVCs to prevent catheter-related infections in patients receiving high-dose chemotherapy followed by peripheral stem cell transplantation. This historical cohort study evaluated 139 patients of whom 70 patients were provided with non-impregnated CVCs and 69 patients with impregnated CVCs. Patients were treated for different diagnoses. The median number of days a CVC stayed in situ was 18 in the non-impregnated group and 16 in the impregnated group. The median duration of neutropenia of patients with non-impregnated CVCs was 9 days compared with 7 days of patients with impregnated CVCs. We found less catheter colonization (CC) in patients with chlorhexidine-silver sulfadiazine CVCs (RR 0.63, 95% CI 0.41-0.96; P = 0.03). Catheter-related blood stream infections (CR-BSI) were also diminished, but this result was not statistically significant (RR 0.15, 95% CI 0.02-1.15; P = 0.06). The reduction in CC and CR-BSI did not diminish the incidence of fever. We conclude that the use of chlorhexidine-silver sulfadiazine impregnated CVCs provide an important improvement in the attempt to reduce CC and CR-BSI.

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.

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.

Phase II study of a multi-course high-dose chemotherapy regimen incorporating cyclophosphamide, thiotepa, and carboplatin in stage IV breast cancer.

The purpose of this study was to determine the feasibility and efficacy of multiple courses of high-dose cyclophosphamide, carboplatin and thiotepa with peripheral blood progenitor cell (PBPC) transplantation in women with advanced breast cancer. Forty-one patients with advanced hormone-refractory breast cancer were enrolled in the study. The treatment started with two courses of 5-fluorouracil 500 mg/m(2), epirubicin 120 mg/m(2) and cyclophosphamide 500 mg/m(2) (FE(120)C) followed by PBPC harvesting. The high-dose regimen consisted of three subsequent courses of 'tiny' CTC, cyclophosphamide 4000 mg/m(2), thiotepa 320 mg/m(2) and carboplatin 1060 mg/m(2) (target AUC 13.3 mg/ml/min) (tCTC) divided over 4 consecutive days. The second and third courses were scheduled to begin on day 28 after the previous transplantation. A total of 86 tCTC courses was given to 33 of the 41 enrolled patients. Major toxicities consisted of hemorrhagic cystitis (six patients), prolonged gastro-intestinal toxicity (three patients) and veno-occlusive disease (two patients). There was one therapy-related death (unknown cause). Twenty patients (49%) achieved a complete response, nine (22%) a partial response and three patients stable disease after treatment. The median follow-up of the surviving patients was 43 months (range 25-61). Six patients remain in complete remission beyond 3 years. At 4 years, the progression-free survival (PFS) and overall survival (OS) for the whole patient group were 23 and 30% with a median duration of 12 and 27 months, respectively and for FE(120)C-responsive patients 32 and 36%, respectively with a median duration of 15 and 33 months. In the patient group with a PFS > or = 18 months all patients had limited disease (metastatic disease in only one or two sites) and fewer patients had bone or liver metastases compared to the overall patient group (33% vs 51%). This report shows that three closely spaced courses of tCTC are feasible, with acceptable toxicity. Triple tCTC can achieve complete or partial remission in most patients and long-term PFS in a selected subgroup of patients who have limited metastatic disease and are responsive to conventional-dose chemotherapy.

Adjustment of the interface detector (location 71) to the absolute number of mononuclear cells in the peripheral blood: no improvement of the collection efficiency of the Fenwal CS3000 plus during progenitor cell harvests.

Improvement of the collection efficiency (CE) of the Fenwal CS3000 plus in collecting circulating progenitor cells (CPC) might diminish the number of leukapheresis procedures (LP) required to obtain the CPC required to assure engraftment. We analyzed whether adjustment of the optical setting (location 71,L71) to the number of MNC present in the peripheral blood could enhance the CE of the MNC. Thirty-five patients underwent 121 LP with an adjusted L71. We compared the results retrospectively with 26 LP performed with a fixed L71 (1:100) in 12 patients. The CPC were mobilized with chemotherapy followed by subcutaneous administration of granulocyte colony-stimulating factor (G-CSF) in both groups. Adjustment of the L71 did neither improve the CE of the MNC, the estimated CE of CD34+ cells nor diminished granulocyte contamination. For the total 121 LP with an adjusted L71 and for the total 26 LP with a fixed L71 the mean CE of MNC were, respectively, 44.6 +/- 18.3% and 46.4 +/- 14%. The mean granulocyte contamination, determined by manual white blood cell differentiation, was 1.7 +/- 2.3% for the adjusted L71 group and 2.3 +/- 3 for the fixed L71 group. There was no difference in the median number of LP required to obtain 3 x 10(6) CD34+ cells/kg between both groups. We found a weak significant correlation between WBC and pre-LP MNC count and the CE of MNC (r = 0.36, P = 0.012, resp.r = 0.33, P = 0.023), but no correlation between the CE of MNC and the estimated CE of CD34+ cells (r = 0.24, P = 0.113). In conclusion, adjustment of the L71 to the MNC did not improve the CE of MNC of the Fenwal CS3000. The lack of correlation between the CE and MNC and the estimated CE of CD34+ cells should be further explored.

Mobilisation of blood progenitor cells with ifosfamide and etoposide (VP-16) in combination with recombinant human G-CSF (Filgrastim) in patients with malignant lymphomas or solid tumours.

The mobilisation characteristics of ifosfamide and etoposide followed by Granulocyte Colony-Stimulating Factor fGCSF, filgrastim) were analysed in 17 patients with malignant lymphoma and 24 patients with solid tumours, with respect to the optimum time to harvest progenitor cells and to the yields of progenitor cells that could be achieved. In addition, we analysed patient characteristics which could influence the size of the progenitor cell harvest. Clinical parameters which were co-related with the size of the circulating progenitor cells (CPC) harvests were: the dose of G-CSF, dose of if osfamide, sex, age, diagnosis and extent of pretreatment. CPC were mobilised with 3 g/m2 (n = 11) or 4 g/m2 (n = 30) ifosfamide on day 1 and etoposide 100 mg/m2/day, on days 1-3 i.v., followed by daily s.c. injections with filgrastim 5 micrograms/kg (n = 26) or 10 micrograms/kg (n = 15) from day 4. The maximal progenitor cell harvest was achieved on either day 12 or day 13 after the start of the ifosfamide/etoposide course. The median number of leukaphereses necessary to harvest the target quantity of 3 x 10(6) CD34+ cells/kg body weight was 1 (range 1-9). Thirteen/41 (32%) of the patients did not achieve the target yield of 3 x 10(6) CD34+ cells/kg. By multivariate analysis, the dose of GCSF and prior irradiation were associated with the number of progenitor cells harvested, while all other parameters, induding the dose of if osfamide and number of previous chemotherapy courses, were not. Sixteen patients received two or more mobilisation courses. Despite the fact that the same mobilisation schedule was used, the progenitor cell yields after the first mobilisation course did not predict the results after the subsequent mobilisation courses, indicating that unknown transient factors may significantly influence the CPC yield.

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.

Efficacy of up-front 5-fluorouracil-epidoxorubicin-cyclophosphamide (FEC) chemotherapy with an increased dose of epidoxorubicin in high-risk breast cancer patients.

The prognosis of patients with stage IIIB breast carcinoma with tumour spread to the apical axillary lymph nodes has hardly improved despite adequate locoregional control and the introduction of systemic adjuvant therapy. A combined modality regimen that includes anthracyclin-based chemotherapy, high-dose chemotherapy with peripheral stem cell support and radiation and hormonal therapy is currently under investigation in this subset of patients. The present study aims to document the efficacy and feasibility of dose-intensive epidoxorubicin in combination with a standard dose of 5-fluorouracil and cyclophosphamide as up-front chemotherapy in this setting. A preoperative chemotherapy regimen consisting of three courses of 5-fluorouracil 500 mg m-2, epidoxorubicin 120 mg m-2 and cyclophosphamide 500 mg m-2 (FE120C) was administered at 21 day intervals without haematopoietic growth factors to 70 patients with apex node-positive disease. All patients were below 60 years of age and had not had prior chemotherapy or radiotherapy. Sixty-six patients were evaluable for clinical response and histopathological examination could be performed in 62 of these. Thirteen patients achieved a clinical complete response (20%). Of these patients, microscopic examination of the mastectomy specimen revealed absence of malignant cells in two and exclusively ductal carcinoma in situ (DCIS) in another two patients. In addition, of the 46 patients (70%) with a clinical partial response, at pathological examination one patient had sclerosis only and four had DCIS. This results in a pathological complete response in three (5%) of all patients and absence of invasive carcinoma in 10%. None of the patients progressed during chemotherapy. The major toxicity was moderate bone marrow suppression with a median white blood count (WBC) nadir of 1800 microliters-1 (range 500-4900). Other toxicities were mild. The full planned dose could be given without delays in 66 of 70 patients FE120C is well tolerated and is highly effective as up-front chemotherapy in relatively young patients with high-risk breast cancer, with a 90% (CI 74-98%) clinical objective response rate.

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.

Bone marrow reconstitution after high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation: effect of graft size.

BACKGROUND: Peripheral blood progenitor cell transplantation is rapidly replacing autologous bone marrow transplantation as hematological support after high-dose chemotherapy for lymphoma or solid tumors. Controversy exists concerning the number of progenitor cells required for rapid and sustained bone marrow recovery, and as to which of the widely available methods for estimating this number should be employed. METHODS: Forty consecutive patients with solid tumors or lymphomas received high-dose chemotherapy followed by autologous peripheral stem cell reinfusion. All stem cell harvests had been performed after mobilization with standard-dose chemotherapy followed by 300 micrograms G-CSF daily. Hematopoietic reconstitution was studied in relation to pertinent patient characteristics, to the size of the graft (in terms of the total number of mononuclear cells (MNC), the number of granulocyte/macrophage colony-forming units (CFU-GM) and the number of CD34+ cells, and to the use of G-CSF after stem cell reinfusion. RESULTS: Both the numbers of CFU-GM and CD34+ cells reinfused, but not those of the MNC, correlated with granulocyte and platelet recovery. Patients who received at least 5 x 10(6) CD34+ cells/kg body weight achieved platelet transfusion independence on day 12 after reinfusion (range: day 7-37), significantly earlier than patients who had received less (p = 0.001). Thirty patients who received G-CSF (300 micrograms s.c. daily) after reinfusion achieved granulocyte recovery (> or = 500 x 10(6)/l) on day 9 (range: day 8-12), while this took a median of 15 days (range: day 10-28) in 10 consecutive patients not receiving G-CSF (p = 0.0003). In one patient who had received 1.4 x 10(6) CD34+ cells/kg, secondary bone marrow failure developed 3 months after transplantation. Reinfusion of cryopreserved autologous bone marrow was followed by prompt recovery. CONCLUSION: Peripheral stem cells, mobilized by moderate-dose chemotherapy and G-CSF, lead to rapid and durable engraftment after high-dose chemotherapy when at least 3-5 x 10(6) CD34+ cells/kg are reinfused. Lower numbers may also be satisfactory, but are associated with slower granulocyte and platelet recoveries. A moderate dose of G-CSF after reinfusion significantly hastens granulocyte recovery without interfering with platelet recovery.