Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer.

PURPOSE: To compare long-term survival in patients with locally advanced and metastatic transitional cell carcinoma (TCC) of the urothelium treated with gemcitabine plus cisplatin (GC) or methotrexate/vinblastine/doxorubicin/cisplatin (MVAC). PATIENTS AND METHODS: Efficacy data from a large randomized phase III study of GC versus MVAC were updated. Time-to-event analyses were performed on the observed distributions of overall survival time and progression-free survival. RESULTS: Four hundred and five patients were randomized, 203 to the GC arm and 202 to the MVAC arm. At the time of this analysis, 347 patients have died (GC 176, MVAC 171). Overall survival was similar in both arms (HR 1.09; 95% confidence interval [CI] 0.88-1.34, P = 0.66) with a median survival of 14.0 months (95% CI 12.3-15.5 months) in the GC, and 15.2 months (95% CI 13.2-17.3 months) in the MVAC arm. The median progression-free survival was 7.7 months with GC (95% CI 6.8-8.8) and 8.3 months with MVAC (95% CI 7.3-9.7) with a HR of 1.09 (95% CI 0.89-1.34). Significant prognostic factors favoring overall survival included performance status (>70), TNM staging (M0 vs. M1), low/normal alkaline phosphatase expression, number of sites of disease <3, and the absence of visceral metastasis. By adjusting for these prognostic factors, the HR was 0.99 for overall survival and 1.01 for progression-free survival. CONCLUSIONS: Long-term overall and progression-free survival following treatment with GC or MVAC are similar. These results strengthen the role of GC as a standard of care in patients with locally advanced and metastatic transitional-cell carcinoma (TCC).

Prophylactic strategies to meet infectious complications in fludarabine-treated CLL.

Fludarabine has emerged as salvage therapy in chlorambucil-resistant CLL. However, encouraging response rates have been compromised by a high incidence of serious infectious complications. Prophylactic measures to reduce the frequency of infections are needed, but up to now, there are no established standards for supportive therapy in fludarabine-treated CLL. Clinicians have observed an increasing frequency of life-threatening opportunistic infections but only some of these may be explained by fludarabine-induced impairment of cell-mediated immunity. Neutrocytopenia commonly found during initial fludarabine treatment may not have been addressed sufficiently as risk factor for infections. Thus, G-CSF supplementation may improve the rate of infectious complications by reducing the duration of fludarabine-induced neutrocytopenia. The changing spectrum of infectious complications should stimulate additional trials on the value of IVIG replacement in fludarabine-treated CLL patients and on the role of low-dose co-trimoxazole in patients at high risk of Pneumocystis carinii infections.

Increases of sICAM-1 during neutropenic pneumonia in leukemic patients.

Aggressive chemotherapy of leukemia increases the risk of severe infections during treatment-induced myelosuppression. However, the assessment of an infectious origin of neutropenic fever is often difficult. Leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are involved in early inflammatory response. We studied plasma concentrations of their soluble isoforms during 48 treatment courses with myeloablative chemotherapy in 32 leukemic patients. There were 35 febrile episodes during neutropenia. Pneumonia was clinically and microbiologically documented in 15 cases, six had proven infections but normal chest radiograph, and 14 were classified as fever of unknown origin. Longitudinal studies revealed a sustained increase of sICAM-1 plasma levels associated with pneumonia. Increase of sICAM-1 plasma levels distinguished patients with pneumonia from those with fever not related to pneumonia (positive predictive value 0.87, negative predictive value 0.94). Plasma levels of sICAM-1 were elevated in both, fungal and non-fungal pneumonia. Increases of sICAM-1 paralleled first radiographic evidence of pulmonary infiltrations in most cases. In contrast, no elevation of sVCAM-1 or sE-selectin was documented during febrile events prior to recovery of leukocyte counts.

Serum erythropoietin concentrations in patients with myelodysplastic syndromes.

Medullary dyserythropoiesis with reduced production of erythrocytes is an early and consistent feature of myelodysplastic syndromes (MDS). The mechanism underlying the disturbed red cell proliferation and maturation is presently unknown. In order to study the role of erythropoietic growth factors, we determined by radioimmunoassay the serum concentrations of immunoreactive erythropoietin (Epo) in 42 non-transfused patients with primary and secondary MDS. Their median hemoglobin concentration at the time of Epo measurement was 9.1 g/dl (range, 5.7-14.6). Compared with the control group, 83% of the MDS patients had increased serum Epo levels, ranging from 26-4530 mU/ml. Although in the entire patient population an inverse relationship between serum Epo and hemoglobin concentrations was noted (r = -0.35; p = 0.02), Epo titers differed markedly between patients at comparable degrees of anemia. In 7 patients presenting with a hemoglobin concentration between 5.9 and 11.9 g/dl, excessive elevations of Epo levels (greater than 500 mU/ml) were found. In contrast to previous observations, serum Epo concentrations were not shown to correlate with the percentage of erythroblasts in the bone marrow. There was, however, a significant relationship between the Epo activity and the degree of medullary dyserythropoiesis, as assessed by morphological criteria (p less than 0.01). From these data we conclude that the anemia in MDS is not due to an endogenous Epo deficiency. The marked variability of Epo production in these disorders is not fully explained by the degree of anemia, but may also reflect inherent abnormalities of the myelodysplastic erythropoiesis.

Pharmacokinetics of high-dose cytarabine and its deamination product--a reappraisal.

Cytarabine is intracellularly activated and correlations have been established between the pharmacokinetic behaviour of active metabolites and their antileukemic effect. Recently, a good response to high-dose treatment of leukemias has additionally been attributed to a so-called low deamination phenotype of cytarabine inactivation. Consequently, these findings would support plasma level monitoring of cytarabine and its metabolite uracil arabinoside in high-dose cytarabine regimens. This pharmacokinetic study presents data attempting to reevaluate these observations. Thirty-seven patients were treated by 3-h high-dose cytarabine infusions (9 patients 1000 mg/m2, 28 patients 3000 mg/m2) as part of their treatment for acute leukemia. Serial blood samples during and post infusion were analysed for cytarabine (araC) and its deamination product uracil arabinoside (araU) using HPLC with UV-detection. Considerable interindividual variation was observed in end-infusion plasma concentrations of araC (1000 mg/m2: 2.1-fold, 3000 mg/m2: 5.5-fold) and araU (1000 mg/m2: 2.7-fold, 3000 mg/m2: 2.9-fold). The median ratio of end infusion concentrations araU/araC (on a molar basis) was 5.6 (S.D. 3.0), extreme ratio values were 2 and 14. No differences of the araU/araC ratio were found between the two dosages used. Minimum plasma araC concentrations at the end of infusion were 10.5 micromol/l and 22.0 micromol/l at a dose of 1000 and 3000 mg/m2, respectively. In our European study population a "fast" deamination phenotype of cytarabine (araU/araC ratio > 14) was not be observed.

Monitoring of multiple myeloma patients by simultaneously measuring marker substances of bone resorption and formation.

Fifteen patients (13 males and two females; mean age, 63 years; age range, 46-84 years) with multiple myeloma were studied prospectively (range of follow-up period, 2-6 months) to elucidate the diagnostic validity of biochemical markers of bone formation (bone alkaline phosphatase and the C-terminal propeptide of type I procollagen) and bone resorption (urinary excretion of pyridinium cross-links) for monitoring these patients. Eleven of 15 patients received melphalan i.v. and prednisone p.o. every 4 weeks. All patients were given pamidronate i.v. for inhibition of bone resorption. The mean values of the urinary excretion of pyridinium cross-links were significantly higher in the patients fulfilling the criteria of 'progression' or 'relapse' than in those showing 'response' and those in the 'plateau phase' (P < 0.05). In contrast, neither bone alkaline phosphatase nor C-terminal propeptide serum values differed significantly between these two groups (P > 0.05). The concentrations of both bone formation markers were significantly lower in the patients than in the samples obtained from apparently healthy persons (P < 0.001). There was a significant inverse correlation between the number of pamidronate courses and the serum concentrations of bone alkaline phosphatase (P < 0.05). A lack of correlation was observed between the urinary excretion of pyridinium cross-links and all other laboratory parameters measured (serum concentrations of total protein, calcium, creatinine and (beta 2-microglobulin). In conclusion, the urinary excretion of pyridinium cross-links might be a useful parameter for monitoring multiple myeloma patients. Decreased values of bone formation markers may be due to a suppressive effect of the bisphosphonate agents administered or reflect the severity of osteolytic lesions which have been described as being associated with unbalanced bone remodelling.

The influence of gemcitabine on the CD4/CD8 ratio in patients with solid tumours.

Gemcitabine (dFdC) is a novel pyrimidine antimetabolite with documented antineoplastic activity against metastatic non-small cell lung cancer (NSCL), pancreatic carcinoma, ovarian and breast cancer. The side effects of gemcitabine are generally mild; severe infections are reported in less than Ilo of patients. In contrast, other new nucleoside analogues such as the purine antimetabolite fludarabine lead to a significant alteration of the CD4/CD8 lymphocyte ratio associated with an increased risk for opportunistic infections. This study investigates the effect of gemcitabine on different lymphocyte subsets during consecutive applications. 16 patients with solid rumours (3 non-small cell lung cancer, 3 pancreas, 3 testicular, 2 breast, ovarian germ-cell, 1 ovarian, 1 small cell lung, 1 gastric cancer, 1 carcinoma of unknown primary); 15 patients were previously treated, received at least 3 applications of gemcitabine (1,000 mg/m(2) as a 30 min infusion, at days 1, 8, 15; q 4 weeks). Lymphocytes surface antigens were analysed by standard technique flow cytometry prior to every infusion. The median number of leukocytes before therapy was 7823/mu l, with lymphocytes 875/mu l, including 68% T-cells (CD3(+)), 9% B-cells (CD19(+); CD20(+)) and 15% NK-cells (CD56(+); CD16(+); CD3(-)), the CD4/CD8 ratio was 1.7. After gemcitabine therapy the median number of leukocytes was 5136/mu l, with lymphocytes 1012/mu l, including 77% T-cells, 8% B-cells and 10% NK-cells and a CD4/CD8 ratio of 2.2. Severe complications or opportunistic infections were not seen in these 16 patients. No significant change of CD4/CD8 ratios and NK-ccll numbers was seen in our patients with solid tumours during weekly treatment with gemcitabine. A severely increased risk for opportunistic infections following treatment with the new antimetabolite gemcitabine appears unlikely.

A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer.

BACKGROUND: This randomized phase III study compared the overall survival (OS) of pemetrexed plus gemcitabine (PG) versus standard gemcitabine (G) in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Patients with unresectable locally advanced or metastatic pancreatic cancer and no prior systemic therapy (including 5-fluorouracil as a radiosensitizer) were randomized to receive either 1,250 mg/m(2) gemcitabine on days 1 and 8 plus pemetrexed 500 mg/m(2) after gemcitabine on day 8 (PG arm) of each 21-day cycle, or gemcitabine 1,000 mg/m(2) on days 1, 8 and 15 of each 28-day cycle (G arm). RESULTS: Five hundred and sixty-five patients with well-balanced baseline characteristics were randomly assigned (283 PG, 282 G). OS was not improved on the PG arm (6.2 months) compared with the G arm (6.3 months) (P=0.8477). Progression-free survival (3.9 versus 3.3 months; P=0.1109) and time to treatment failure (3 versus 2.2 months; P=0.2680) results were similar. Tumor response rate (14.8% versus 7.1%; P=0.004) was significantly better on the PG arm. Grade 3 or 4 neutropenia (45.1% versus 12.8%), thrombocytopenia (17.9% versus 6.2%), anemia (13.9% versus 2.9%), febrile neutropenia (9.9% versus 0.4%; all P <0.001) and fatigue (15% versus 6.6%; P=0.002) were significantly more common on the PG arm. Four treatment-related deaths occurred on the PG arm and none in the G arm. CONCLUSIONS: Pemetrexed plus gemcitabine therapy did not improve OS. Single-agent gemcitabine remains the standard of care for advanced pancreatic cancer.

[Prophylaxis against mycoses in neutropenic patients]. / Mykose-Prophylaxe bei neutrozytopenischen Patienten.

During the last years, the proportion of cancer patients who develop systemic fungal infections has increased steadily. These infections are characterised by high mortality, especially in patients with persistent granulocytopenia and in those receiving allogeneic bone marrow transplants. The most important pathogens in neutropenic patients are Candida and Aspergillus spp. Usually, Candida infections arise from overgrowth in the gastrointestinal tract, while Aspergillus infections are acquired by inhalation of spores. Prophylaxis of systemic fungal infections seems mandatory since optimal strategies for diagnosis and treatment of these infections are lacking. Treatment with the non-absorbable polyenes nystatin and amphotericin B is useful for prophylaxis of superficial fungal infections, provided that compliance of the patients is optimal. The imidazoles ketoconazole and miconazole can reduce the incidence of superficial fungal infections, but there are conflicting data regarding their value for prevention of systemic mycoses. There are several studies indicating that prophylactic use of fluconazole reduces the incidence of mucosal and systemic fungal infections, especially in patients receiving allogeneic bone marrow transplants. Fluconazole shows reduced activity against several Non-albicans spp. and is not active against Aspergillus spp. Itraconazole has in vitro and in vivo activity against several Aspergillus spp. but high serum and tissue levels are necessary. However, bioavailability of itraconazole is reduced in patients with raised gastric pH and no i.v. formulation is available. Although there is some evidence for its prophylactic activity against Aspergillus infections in neutropenic patients, more studies are necessary to confirm these findings. Intravenous amphotericin B cannot be recommended for routine prophylactic use because of its toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)