Factors influencing catheter-related infections in the Dutch multicenter study on high-dose chemotherapy followed by peripheral SCT in high-risk breast cancer patients.

Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate. Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated. Median catheter dwell time was 25 days (range 1-141). Catheter-related infections were seen in 28.3% of patients (11 infections per 1000 catheter-days). Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Cox regression analysis showed that duration of neutropenia >10 days (P=0.04), using the catheter for both stem-cell apheresis and high-dose chemotherapy (P= <0.01), and use of total parenteral nutrition (TPN, P=0.04) were predictive for catheter-related infections. In conclusion, a high incidence of catheter-related infections after high-dose chemotherapy was seen related to duration of neutropenia, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.

Antitumor effect, cardiotoxicity, and nephrotoxicity of doxorubicin in the IgM solid immunocytoma-bearing LOU/M/WSL rat.

Antitumor activity, cardiotoxicity, and nephrotoxicity induced by doxorubicin were studied in LOU/M/WSL inbred rats each bearing a transplantable solid IgM immunocytoma. Animals with a tumor (diameter, 15.8 +/- 3.3 mm) were treated with iv injections of doxorubicin on 5 consecutive days, followed by 1 weekly injection for 7 weeks (dose range, 0.015-4.0 mg/kg body wt). Tumor regression was observed with 0.5 mg doxorubicin/kg. Complete disappearance of the tumor was induced with 1.0 mg doxorubicin/kg. Histologic evidence of cardiotoxicity scored as grade III was only observed at a dose of 1.0 mg doxorubicin/kg. Light microscopic evidence of renal damage was seen above a dose of 0.5 mg doxorubicin/kg, which resulted in albuminuria and very low serum albumin levels. In the group that received 1.0 mg doxorubicin/kg, the serum albumin level decreased from 33.6 +/- 4.1 to 1.5 +/- 0.5 g/liter. Ascites and hydrothorax were observed simultaneously. The same experiments were performed with non-tumor-bearing rats, in which no major differences were observed. In conclusion, antitumor activity, cardiotoxicity, and nephrotoxicity were studied simultaneously in the same LOU/M/WSL rat. Albuminuria due to renal damage led to extremely low serum albumin levels, so ascites and hydrothorax were not necessarily a consequence of the observed cardiomyopathy.

Time-course study on doxorubicin-induced nephropathy and cardiomyopathy in male and female LOU/M/Wsl rats: lack of evidence for a causal relationship.

In a previous study on doxorubicin-induced cardiotoxicity in LOU/M/Wsl rats, severe nephropathy has been observed; therefore, the question was raised whether nephropathy adds to or even might be responsible for doxorubicin-induced cardiomyopathy in rats. For elucidation of this question, the temporal relationship between the onset of doxorubicin-induced cardiomyopathy and nephropathy was studied. In addition, examination was made of whether modifications of the treatment schedule could circumvent nephrotoxicity. Because preliminary studies had shown that female LOU/M/Wsl rats developed less doxorubicin-induced albuminuria, both male and female LOU/M/Wsl rats were treated with an iv dose of 1 mg doxorubicin/kg (body wt)/rat on five consecutive days and then weekly. Saline-treated animals served as controls. Albuminuria, serum albumin, and serum creatine levels were assessed weekly. For histologic examination, 5 male and 5 female rats were killed weekly. At day 14 and thereafter, doxorubicin-treated male rats showed albuminuria greater than or equal to 10 g/liter. Albuminuria of greater than or equal to 10 g/liter was not avoided by modifications of the treatment schedule. Female rats had on day 14 a urinary albumin level of 1.0-3.0 g/liter, yet reaching the level of greater than or equal to 10 g/liter at day 49. In male rats serum albumin levels decreased to levels below 10 g/liter (p less than .001 vs. finding for day 0); in contrast female rats maintained constant serum albumin levels till day 49. Serum creatine levels showed a tendency to rise, the values of male rats not being measured after day 28 due to hyperlipidemia; the levels of female rats increased from 37.8 +/- 3.0 mumol/liter to 53.7 +/- 2.5 mumol/liter on day 49 (P less than .001). At day 10 in male and female rats a grade 1-1.5 cardiomyopathy score, assessed according to the modified Billingham scoring system, was found, gradually increasing to grade 2.5-3 cardiomyopathy, both in males and females, on day 49. In male LOU/M rats the nephropathy developed steadily from day 14 and thereafter, whereas in females the rate of development of kidney damage was slower and at the end point of the study the severity of kidney lesions was less in comparison to that of the males. The onset of cardiomyopathy and nephropathy was simultaneous. It was concluded that cardiomyopathy observed in LOU/M rats is a phenomenon independent of nephropathy.

Reduced cardiotoxicity and nephrotoxicity with preservation of antitumor activity of doxorubicin entrapped in stable liposomes in the LOU/M Wsl rat.

LOU M/Wsl rats inoculated s.c. with 10(4) immunoglobulin immunocytoma cells have a palpable tumor at Day 17. Doxorubicin (DXR) has been entrapped in negatively charged liposomes (lip- DXR) composed of egg phosphatidylcholine, cholesterol, and phosphatidylserine and in positively charged liposomes (lip+ DXR) composed of phosphatidylcholine, cholesterol, and stearylamine. DXR, lip- DXR, and lip+ DXR were administered i.v. (0, 0.25, 0.5, 1.0, and 2.0 mg/kg) at Day 17 for 5 consecutive days and then weekly. Control animals showed progressive tumor growth leading to death 27 days after inoculation. Antitumor activity for all three preparations was dose dependent. DXR and lip- DXR showed the same antitumor activity; lip+ DXR had less antitumor activity. The overall survival of tumor-bearing animals treated with 2.0-mg/kg lip- DXR was significantly prolonged (p less than 0.05) in comparison to the animals treated with 2.0-mg/kg free DXR. Grade III cardiomyopathy was observed 47 days after treatment with free DXR; treatment with lip- DXR resulted in Grade I cardiomyopathy. In animals treated with 1.0-mg/kg and 2.0-mg/kg free DXR urinary albumin concentrations of 10 g/liter were observed. Treatment with 1.0-mg/kg lip- DXR and 1.0-mg/kg lip+ DXR resulted in urinary albumin concentration of less than 3.0 and less than 1.0 g/liter, respectively. Free DXR, 1.0 mg/kg, resulted in a decline of serum albumin concentration from 27.8 +/- 3.2 g/liter to 9.6 +/- 4.2 g/liter. No such decline was observed after treatment with lip- DXR and lip+ DXR. Treatment with a 1.0-mg/kg dose of free DXR resulted in severe glomerular and tubular lesions which were not found after treatment with 1.0-mg/kg lip- DXR and 1.0 mg/kg lip+ DXR. Administration of lip- DXR resulted in lower DXR levels in cardiac and renal tissue compared to administration of free DXR. After administration of lip+ DXR, very low tissue and tumor DXR levels were found. In conclusion, treatment with lip- DXR or lip+ DXR resulted in a prolonged survival, less albuminuria, and higher serum albumin levels. Also, fewer lesions in heart and kidney were found, correlating with lower DXR levels in these organs. Only lip- DXR had the same antitumor effect as free DXR.

Dose intensity of chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil in the elderly with advanced breast cancer.

Toxicity and results of two different dose levels of chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in older (greater than 70 years) patients with advanced breast cancer were evaluated in a prospective (non-randomised) study. During the first three courses of chemotherapy dose reduction for haematological toxicity was necessary in all of 10 and 8 of 13 patients treated with an intended dose of 100% and 75% of standard dose CMF, respectively. The median percentages of CMF, administered during the first three courses were about 75% in both groups of patients corresponding with a median dose intensity of 72% (range 49-87%) and 64% (range 36-78%) for patients of the 100% and 75% dose group, respectively. In 34 younger postmenopausal women (mean age 57 years) treated in our institution for advanced breast cancer the median percentages of CMF in the second and third course were 86% and 84%, respectively with a median dose intensity during the three courses of 82%. Dose reductions of CMF and bone marrow toxicity, though interdependent, were statistically significantly correlated with the endogenous creatinine clearance, but not with age. 1 patient died during severe leukopenia and thrombocytopenia. Non-haematological side effects were most pronounced in the 100% group. Results of therapy in both groups of patients were about equal and compared well with those of CMF therapy in general. It is advised that the dose of CMF in patients above 70 years should not exceed 75% of standard dose. Further dose reduction of methotrexate in case of severe renal failure is required.

Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group.

Gemcitabine (2'-deoxy-2'-difluorocytidine monohydrochloride) at a dose of 1250 mg/m(2) was given as a 30-min intravenous (i.v.) infusion on days 1 and 8 in a 3-weekly schedule to 32 patients with advanced soft-tissue sarcoma (STS) failing first-line chemotherapy. One patient was ineligible due to a delay between the previous chemotherapy and the start of treatment. Of the eligible patients, median age was 53 years (range 23-73 years). The predominant histological subtype was leiomyosarcoma in 12 patients (38%). The median number of cycles was three (range 1-8 cycles) with a median total dose of gemcitabine of 6.25 g/m(2) (range 1.25-19.97 g/m(2)). The relative dose intensity of gemcitabine was 96% (range 50-103%). Treatment was tolerated very well with non-complicated haematological toxicity as the most frequently observed side-effect. Only one partial tumour response was documented, giving a response rate of 3.23% (95% Confidence Interval (CI): 0.08-16.2%). The median overall survival was 268 days (95% CI: 129-377) and the median time to progression was 45 days (95% CI: 41-79). These results indicate that gemcitabine given at this dose and schedule is not active as second-line therapy in advanced STS.

Clinical pharmacokinetics of doxorubicin.

Doxorubicin (adriamycin) has a very wide antitumour spectrum, compared with other anticancer drugs; however, except for Hodgkin's disease, it is not associated with curative chemotherapy. Doxorubicin has been in clinical use for more than 2 decades, and only recently has it been recognised that the cytotoxic effect is produced at the cellular level by multiple mechanisms which have not yet been conclusively identified. Key factors are a combination of doxorubicin-induced free radical formation due to metabolic activation, deleterious actions at the level of the membrane, and drug-intercalation into DNA. Multiple aspects of the clinical pharmacokinetics of this drug have been described. Wide interpatient variations in plasma pharmacokinetics have been noted, but without firm relation to clinical outcome. An apparent volume of distribution of approximately 25 L/kg points to extensive uptake by tissues. Up to several weeks after administration, significant concentrations of doxorubicin have been found in haematopoietic cells and in several other tissues. The maximum cellular doxorubicin concentrations reached in vivo remain significantly below those at which all clonogenic leukaemic cells are killed in vitro. Doxorubicin has been administered as frequent (weekly) low doses, single high doses, and as a continuous infusion. The optimal schedule with respect to tumour cytotoxicity and dose-limiting side effects such as myelosuppression or cardiotoxicity, has never been investigated in a prospective, randomised manner. Clinical trials large enough to study optimal, and possibly individualised, doxorubicin chemotherapy need to be performed. This review summarises pharmacological and pharmacodynamic data of doxorubicin, and discusses these in relation to possible improvement of its therapeutic index. Furthermore, drug interactions, dose-response relationships, mechanisms of action, multidrug resistance, and treatment scheduling are discussed in the perspective of the development of novel treatment strategies.

Phase II trial of 5-fluorouracil, adriamycin and cisplatin (FAP) followed by radiation and 5-fluorouracil in locally advanced pancreatic cancer.

A total of 19 patients (7 men, 12 women) with locally advanced pancreatic adenocarcinoma were treated with six cycles of FAP (5-fluorouracil, 300 mg/m2 i.v. on days 1-5; Adriamycin, 50 mg/m2 i.v. on day 1; cisplatin, 20 mg/m2 i.v. on days 1-5). Each course was repeated every 28 days. After six cycles, the treatment was followed by irradiation amounting to 4,000 cGy (split course) in combination with 5-FU (500 mg/m2) on days 1-3 of the two irradiation periods. The median age of our patients was 55 years (range, 40-64 years). The median WHO performance status was 1, with a range of 0-2. Three (16%) complete (CR) and six (31%) partial responses (PR) were observed, as were six cases of stable disease (SD) and four of progressive disease (PD). The median duration of response was 11 months, with a range of 4-24 months, and the median survival was 14 months (range, 5-27 + months). FAP toxicity was tolerated fairly poorly. The dose-limiting toxic effect was myelosuppression, with a mean WBC nadir of WHO grade 1.6 (range, 0-3) and a mean platelet count of WHO grade 1.1 (range, 0-4). Nausea and vomiting were not dose-limiting. Complete alopecia was seen in 14/19 patients. Neuropathy was mild (WHO grade 1) in seven and moderate (grade 2) in four. Irradiation in combination with 5-FU was generally well tolerated. Due to several reasons, only ten patients could be treated with all six cycles of FAP. We conclude that in future combined modality studies, irradiation should be given after three cycles of chemotherapy, and that combined modality treatment for locally advanced pancreatic cancer is feasible and warrants further testing.

A comparative study on the antitumor effect, cardiotoxicity and nephrotoxicity of doxorubicin given as a bolus, continuous infusion or entrapped in liposomes in the Lou/M Wsl rat.

Liposome encapsulation of doxorubicin (DXR) has been shown to increase the therapeutic index of the drug in several animal systems. The prevention of peak plasma concentrations of free drug might be a major factor contributing to the beneficial effects resulting from liposome encapsulation. If so, the administration of DXR as a continuous infusion should also lead to an improved therapeutic index. In the present paper, the administration of liposome-encapsulated DXR is compared with the infusion of DXR with regard to their potential to preserve antitumor activity, enhance survival and reduce cardiomyo- and nephropathy in IgM immunocytoma-bearing Lou/M Wsl rats. Plasma concentrations of DXR were determined to correlate the biological results with pharmacokinetic parameters. Liposomes containing phosphatidylcholine, phosphatidylserine and cholesterol (extrusion-multilamellar vesicles) were used. Bolus injections of free DXR (free DXR) and DXR liposomes (lip-DXR) in a multiple-dose regimen were compared with 24-h infusions of the same cumulative doses of DXR (inf-DXR). The antitumor activity of inf-DXR equalled that of free DXR as well as that of lip-DXR at doses of greater than 0.25 mg/kg. The overall survival of tumor-bearing animals treated with 2.0 mg/kg lip-DXR was significantly prolonged (P less than 0.01) in comparison with that of animals treated with 2.0 mg/kg free DXR; however, treatment with 2.0 mg/kg inf-DXR did not induce a significant prolongation of survival. At a cumulative dose of 12 mg/kg, inf-DXR appeared to be as effective as lip-DXR in reducing the severity of cardiomyopathy induced by free DXR. However, for the reduction of nephropathy, only therapy with lip-DXR was effective. Inf-DXR induced high nephropathy scores comparable with those obtained with free DXR. For the first 24 h after an injection of 2.0 mg/kg or after the start of a continuous infusion of 2.0 mg/kg given over 24 h, similar areas under the plasma concentration-time curves (AUC) were calculated for free DXR and inf-DXR. However, for lip-DXR a much higher value was calculated. The higher plasma levels of lip-DXR did not result in higher cardiac levels. After five daily doses of 2.0 mg/kg, a much lower DXR concentration was found in cardiac tissue after the administration of lip-DXR than after the administration of free DXR or inf-DXR. This suggests that an important parameter to be determined and correlated with biological results is the free (i.e. not bound to liposomes) circulating fraction of DXR in lip-DXR-injected animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Liposomes as drug carrier system for cis-diamminedichloroplatinum (II). II. Antitumor activity in vivo, induction of drug resistance, nephrotoxicity and Pt distribution.

In this study we have investigated the use of liposomes as a drug carrier system for cis-diamminedichloroplatinum(II) (cis-DDP) in order to reduce the nephrotoxicity with preservation of antitumor activity. Liposomes (PC/PS/Chol 10:1:4) were prepared using hydration media containing no or a relatively low concentration of NaCl. It was found that cis-DDP containing liposomes (lip cis-DDP) injected i.v. to IgM immunocytoma-bearing LOU/M rats at a dose of 1 mg cis-DDP/kg (cumulative dose 7 mg cis-DDP/kg) showed less antitumor activity than the free drug. The optimal cumulative dose of free cis-DDP for induction of antitumor activity in this tumor system is 7 mg/kg (7 X 1 mg/kg). At a dose of 2 mg lip cis-DDP/kg (cumulative dose 14 mg cis-DDP/kg) the antitumor activity could not be increased by choosing another phospholipid composition of the liposomes [DPPC/DPPG/Chol (10:1:10)]. cis-DDP incorporated in DPPC/DPPG/Chol liposomes showed a similar antitumor activity to cis-DDP incorporated in PC/PS/Chol liposomes. After an i.v. dose of 2 mg lip cis-DDP/kg (PC/PS/Chol) kidney damage was less compared to the treatment with free cis-DDP (1 mg/kg). However, after a single dose of 2 mg cis-DDP/kg or a cumulative dose of 8 or 16 mg cis-DDP/kg, kidneys of rats treated with lip cis-DDP contained twice as much Pt as after treatment with free cis-DDP. Moreover, after treatment with lip cis-DDP, a twofold increase of the amount of Pt in tumor tissue was measured. In vitro studies with Pt recovered from spleens obtained from rats treated with lip cis-DDP i.v. showed that based on the equal amounts of Pt recovered the antitumor activity of the recovered Pt was reduced, indicating inactivation of cis-DDP in vivo. As during treatment with free cis-DDP, recurrence of the tumor was observed during the continued treatment with lip cis-DDP. It was found that these recurrent tumors were resistant to further therapy with cis-DDP. In conclusion, cis-DDP encapsulation into liposomes decreased the nephrotoxicity. The antitumor activity of cis-DDP is preserved by liposome encapsulation when it was used at a dose of 2 mg/kg, but it was reduced in terms of earlier onset of regrowth.

Synovial sarcoma: oncological and functional results.

AIM: To evaluate the oncological and functional result of the treatment of patients with a synovial sarcoma. This paper gives a retrospective review of 20 patients (15 male and five female) treated for synovial sarcoma at the Nijmegen University Hospital, The Netherlands. METHODS: The median age of the patients was 30 years (range: 14-71, mean 37 years). RESULTS: The tumour locations were: lower extremity in 12 patients; upper extremity in three; pelvic and groin region in four; and the retroperitoneal space in one. Surgical stages according to Enneking (Clin Orthop 1986; 204: 9-24) were IIA in five cases; IIB in seven; and IIIB in eight. The surgical margin was intralesional in three cases; marginal in three; wide in six; and radical in six. In one case the surgical margin could not be assessed and one patient was not operated. One patient developed a recurrent tumour and one developed nodal metastases. Eight patients who did not have metastases at the time of diagnosis developed metastase during follow-up. Fourteen patients died of metastatic disease; one patient died of diabetes; one is alive with disease; and four presently do not have evidence of disease. CONCLUSIONS: The outcome was poor, especially due to the occurrence of pulmonary metastases. The functional result according to the MSTS was 100% in four patients; in one the result was 93% because of the scar and venous insufficiency.

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.

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.

Interleukin-2 therapy for human cancer.

The concept of immunotherapy is evolving from nonspecific, haphazard stimulation of the immune apparatus to more specific and controlled manipulation of the immune system. IL-2 gives the opportunity to exert influence on the cellular immune system. Why LAK cells are able to lyse tumor cells and leave normal cells intact is not known. How LAK cells behave after reinfusion is not known; are they able to migrate to tumor sites? Can improvements be made in scheduling in order to decrease toxicity and to enhance efficacy? But first of all, the question arises whether the tremendous efforts required by adoptive transfer, in terms of toxicity, logistics, and money, are outweighed by the therapeutic results. For clinical practice inside the frontier of oncology, continuous infusion of IL-2 at an intermediate dose is a quite attractive option in finding a balance between efforts and results.