Quality-of-life analysis of the MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG study comparing platinum-based versus non-platinum-based chemotherapy in patients with partially platinum-sensitive recurrent ovarian cancer.

Background: MITO-8 showed that prolonging platinum-free interval by introducing non-platinum-based chemotherapy (NPBC) does not improve prognosis of patients with partially platinum-sensitive recurrent ovarian cancer. Quality of life (QoL) was a secondary outcome. Patients and methods: Ovarian cancer patients recurring or progressing 6-12 months after previous platinum-based chemotherapy (PBC) were randomized to receive PBC or NPBC as first treatment. QoL was assessed at baseline, third and sixth cycles, with the EORTC C-30 and OV-28 questionnaires. Mean changes and best response were analysed. Progression-free survival, response rate, and toxicity are also reported for proper interpretation of data. All analyses were based on intention-to-treat. Results: Out of the 215 patients, 151 (70.2%) completed baseline questionnaire, balanced between the arms; thereafter, missing rate was higher in the NPBC arm. At mean change analysis, C30 scores were prevalently worse in the NPBC than PBC arm, statistical significance being attained for emotional functioning, global health status/QoL, fatigue, and dyspnoea (effect sizes ranging from 0.30 to 0.51). Conversely, as for OV28 scale, the other chemotherapy side-effects item was significantly worse with PBC at three and six cycles, with a larger effect size (0.70 and 0.54, respectively). At best response analysis, improvement of emotional functioning and pain and worsening of peripheral neuropathy and other chemotherapy side-effects were significantly more frequent in the PBC arm. Progression-free survival (median 9 versus 5 months, P = 0.001) and objective response rate (51.6% versus 19.4%, P = 0.0001) were significantly better with PBC. Allergy, blood cell count, alopecia, nausea, musculoskeletal, and neurological side-effects were more frequent and severe with PBC; hand-foot skin reaction, rash/desquamation, mucositis, and vascular events were more frequent with NPBC. Conclusion: MITO-8 QoL analysis shows that deterioration of some functioning and symptom scales is lower with PBC, with improvement of emotional functioning and pain, despite worsening of toxicity-related items. ClinicalTrials.gov: NCT00657878.

Prospective phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: the MITO 15 trial.

BACKGROUND: Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype. PATIENTS AND METHODS: A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [single-nucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed. RESULTS: Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1-2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported. CONCLUSIONS: Our data prospectively confirmed that the signature of 'repeated platinum sensitivity' identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum. EUDRACT NUMBER: 2011-001298-17.

A Phase II, randomized, double-blind study of zibotentan (ZD4054) in combination with carboplatin/paclitaxel versus placebo in combination with carboplatin/paclitaxel in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy (AGO-OVAR 2.14).

BACKGROUND: In platinum-sensitive relapsed ovarian cancer, paclitaxel plus carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral, specific ETA-receptor antagonist with demonstrated antitumour activity in xenograft models of human ovarian cancer. METHODS: In this Phase II, randomized, placebo-controlled study, patients with relapsed ovarian cancer sensitive to platinum-based chemotherapy received zibotentan 10mg or placebo once-daily, plus paclitaxel 175 mg/m(2) iv followed by carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of eight cycles. The primary endpoint was progression-free survival (PFS), evaluated by Response Evaluation Criteria In Solid Tumours (RECIST). Secondary and exploratory endpoints included objective tumour response rate, tumour size, CA-125/RECIST progression, and safety and tolerability. RESULTS: A total of 120 patients were randomized (zibotentan: n=59; placebo: n=61). Addition of zibotentan 10mg/day to carboplatin and paclitaxel did not improve PFS compared with placebo (median PFS, 7.6 versus 10.0 months, respectively; HR=1.46, [80% CI: 1.10-1.94]; P=0.0870). No improvements in any of the secondary or exploratory efficacy endpoints were observed for patients receiving zibotentan compared with placebo. Median duration of total treatment exposure was 6.7 months. Total chemotherapy dose received was lower for zibotentan-treated versus placebo-treated patients (carboplatin: -16%; paclitaxel: -14%). The most common adverse events in the zibotentan arm were anaemia, nausea, alopecia, headache and neutropenia (43-48% of patients). CONCLUSIONS: Zibotentan 10mg/day plus carboplatin and paclitaxel did not result in an improvement in PFS compared with chemotherapy alone in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy. No unexpected safety concerns were identified.

Carboplatin-paclitaxel-induced leukopenia and neuropathy predict progression-free survival in recurrent ovarian cancer.

BACKGROUND: We assess the prognostic value of chemotherapy-induced leukopenia and sensory neuropathy in the CALYPSO trial patients treated with carboplatin-paclitaxel (CP) or carboplatin-liposomal doxorubicin (CPLD). METHODS: We performed a landmark analysis at first month after randomisation to correlate leukopenia (nadir white blood cell <4.0 × 10(9) per litre or severe infection) during cycle 1 of chemotherapy with progression-free survival (PFS). Using time-dependent proportional-hazards models, we also investigated the association between neuropathy and PFS. RESULTS: Of 608 patients with nadir blood and did not receive growth factors, 72% (CP=70%, CPLD=73%) had leukopenia. Leukopenia was prognostic for PFS in those receiving CP (adjusted hazard ratio (aHR) 0.66, P=0.01). Carboplatin-liposomal doxorubicin was more effective than CP in patients without leukopenia (aHR 0.51, P=0.001), but not those experiencing leukopenia (aHR 0.93, P=0.54; interaction P=0.008).Of 949 patients, 32% (CP=62%, CPLD=28%) reported neuropathy during landmark. Neuropathy was prognostic for PFS in the CP group only (aHR 0.77, P=0.02). Carboplatin-liposomal doxorubicin appeared to be more effective than CP among patients without neuropathy (aHR 0.70, P<0.0001), but not those with neuropathy (aHR 0.96, P=0.81; interaction P=0.15). CONCLUSION: First-cycle leukopenia and neuropathy were prognostic for patients treated with CP. Efficacy of CP treatment was similar to CPLD in patients who developed leukopenia. These findings support further research to understand the mechanisms of treatment-related toxicity.

Carboplatin and pegylated liposomal doxorubicin for advanced ovarian cancer: preliminary activity results of the MITO-2 phase III trial.

BACKGROUND: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. PATIENTS AND METHODS: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m(2) or PLD 30 mg/m(2) every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). CONCLUSIONS: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.

Gemcitabine and anthracyclines in platinum-resistant ovarian cancer.

BACKGROUND: Most of the patients with advanced ovarian cancer will recur after first-line platinum-based chemotherapy and need additional treatment. Gemcitabine (G) and Anthracyclines are active in this setting and their combination has shown synergistic antiproliferative activity in vitro, due to different mechanisms of action and non-overlapping toxicities. PATIENTS AND METHODS: In 2002 we began a phase II study with G 1000 mg/m(2) (day 1,8) combined to Epirubicin (E) 60 mg/m(2) (day 1), every 3 weeks for 6 cycles, in Platinum resistant/refractory ovarian carcinoma patients. RESULTS: Among 30 patients enrolled so far (27 evaluable), receiving 149 cycles (median 6), 1 complete and 12 partial responses (48%), 9 stabilizations (33%) and 5 progressions (18%) were observed, with a good correlation with serological responses. Median time to progression was 8 months, while median time to response was 10 weeks and median duration 8 months. Grade 3-4 toxicities consisted of neutropenia (58%), thrombocytopenia (3%), anemia (10%), liver toxicity (13%), and mucositis (7%). Eight patients (27%) received G-CSF and 3 (10%) blood transfusions. No febrile neutropenia nor cardiotoxicity were observed. CONCLUSIONS: Although our results are preliminary, G/E combination appears particularly effective and safe in these platinum resistant/refractory patients.

A study from the EORTC new drug development group: open label phase II study of sabarubicin (MEN-10755) in patients with progressive hormone refractory prostate cancer.

Sabarubicin (MEN-10755), a new synthetic anthracycline analogue, was evaluated for safety and efficacy in a multicentre phase II study in patients with advanced hormone refractory prostate cancer (HRPC). Thirty seven patients were included, of which 34 were evaluable for PSA response according to Bubley's criteria. Sabarubicin was administered as a short (30 min) intravenous infusion at a dose of 80 mg/m(2) every 3 weeks. The main toxicity consisted of grade 3/4 neutropenia in 24 patients (64.9%), with grade 3/4 febrile neutropenia occurring in one patient only. Grade 3/4 cardiotoxicity was observed in 4 patients including one ineligible. Other toxicities were mild. Nine patients achieved a PSA response (26.5%), 10 patients had stable disease (29.4%) and 14 patients disease progression (41.2%). One patient (2.9%) had a PSA response that was not confirmed by repeat PSA testing. The objective response rate according to RECIST criteria was 6.7% in 15 patients with measurable disease. The median duration of PSA responses was relatively long 7.1 months (95% CI 4.9-20.7) as was the median time to treatment progression in patients with stable disease. The median overall survival was 18.7 months (95% CI 9.1-N), comparable to results recently observed in taxotere-containing regimens. To confirm and extend these results, further testing of sabarubicin in larger trials is warranted.

Oral etoposide in elderly patients with advanced non small cell lung cancer: a clinical and pharmacological study.

Seventeen elderly patients with advanced progressive non small cell lung cancer (NSCLC) were treated with oral etoposide at the daily dose of 100 mg for 14 days every 3-4 weeks with pharmacokinetic monitoring. One partial response and 6 stabilizations were documented with a median overall duration of 13 weeks (range 8-32). The median survival was 24 weeks with an apparent advantage for non-progressive patients (40 weeks vs. 18 weeks). The treatment was well tolerated especially by those patients without concomitant illness, suggesting the crucial role of a careful selection of the geriatric population. Toxicity was not related to the etoposide plasma level, but was clearly dependent on comorbidity. A geriatric assessment rather than chronological age therefore appears to be more reliable in the selection of elderly patients for clinical trials. The easy self-management, favorable toxicity profile and synergy with other compounds makes oral etoposide suitable for further clinical-pharmacological studies in elderly patients.

Increasing 4'-epidoxorubicin and fixed ifosfamide doses plus granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a pilot study.

PURPOSE: To determine the maximum-tolerated dose (MTD) of 4'-epidoxorubicin (EPI) in combination with full dose of ifosfamide (IFO) when granulocyte-macrophage colony-stimulating factor (GM-CSF) was used, to estimate its clinical efficacy, and to evaluate the mobilization of hematopoietic progenitors. PATIENTS AND METHODS: Previously untreated advanced patients were treated with fixed doses of IFO at 1.8 g/m2/d for 5 days and escalating doses of EPI. The starting dose level of EPI was 50 mg/m2 bolus on days 1 and 2; subsequent levels were 60 mg/m2 and 70 mg/ m2 given on days 1 and 2. GM-CSF (5 micrograms/kg/d) was administered from days +6 to +19. Clinical evaluation of response was performed after three consecutive cycles. Mobilization of hematopoietic progenitors was evaluated as day 14 CFU-GM after the first cycle only. RESULTS: Overall, six, 18, and 13 assessable patients were entered onto each EPI dose level, respectively. The first and the second EPI level were considered feasible. Conversely, at the third level, only six of 13 patients [46%] tolerated full EPI doses at the scheduled time. Therefore, the dose-intensity of the three levels was 100%, 99.7%, and 86.1%, respectively. Overall, 20 of 37 patients (54%) obtained an objective response. The response rates for the three EPI dose levels were significantly different [17%, 33%, and 100%, respectively; test for trend, P < .001]. Considering only lung metastases, the overall response rate was 72% (20%, 66%, and 100% for the three EPI levels, respectively). The most relevant mobilization effect was obtained at the third EPI level, when both GM-CSF and IL-3 were used as in vitro-stimulating factors. CONCLUSION: The third EPI level (70 mg/m2 on days 1 and 2) is the MTD of this program, since it was administered, without dose reduction or treatment delay, for three consecutive cycles in less than half of the patients. Nevertheless, this level proved to be interesting with regard to response rate (13 of 13 objective responses) and in mobilization of the hematopoietic progenitors.

Phase II study of sequential administration of docetaxel followed by doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer.

PURPOSE: To evaluate the feasibility and efficacy of a sequential administration of four cycles of docetaxel (100 mg/m(2) every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m(2) every 3 weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-eight patients received 443 cycles of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of 267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation therapy was given to 33 patients (29 with docetaxel). RESULTS: Grade 4 neutropenia was the most frequent toxicity (83% of patients). This was not cumulative and was rarely complicated by febrile neutropenia or severe infection. The nonhematologic safety profile was favorable: there were no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific toxicities were generally not severe. With a median cumulative doxorubicin dose of 397 mg/m(2) (range, 150 to 543 mg/m(2)), two incidences of unrelated congestive heart failure after further treatment with anthracyclines and two of asymptomatic left ventricular ejection fraction decrease were observed. Among the 42 assessable patients, five (12%) had complete and 25 (60%) had partial responses, for an overall response rate of 71% (95% confidence interval, 55% to 84%). Median duration of response was 53 weeks (range, 12 to 72 weeks), and median time to progression was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median survival was 32 months (range, 2 to 55 months). CONCLUSION: This docetaxel-based sequential schedule is safe and effective in first-line therapy for MBC, without incurring cumulative toxicity, and provides a feasible chemotherapeutic option in this clinical setting.

Dose-finding and pharmacologic study of chronic oral idarubicin therapy in metastatic breast cancer patients.

Oral idarubicin (IDA) is an active drug in metastatic breast cancer, but its role in the management of this tumor is yet not established completely. To investigate a new modality of IDA administration, a dose-finding study was designed with hyperfractionated doses. The purpose was to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetics of this schedule. IDA was administered twice daily as outpatient therapy in cycles of 3 weeks followed by a 1-week rest. Thirty-one patients with progressive metastatic breast cancer and pretreated with chemotherapy (including epirubicin and doxorubicin) were enrolled. DLT was defined as G4 hematological toxicity or any other toxicity G3 or higher (Bloom and Richardson grading). Inter- and intrapatient dose increases were studied. Pharmacokinetics of IDA and its metabolite idarubicinol (IDOL) were evaluated. IDA dose was increased from 2 mg/day to 10 mg/day, by steps of 1 mg/day, with the larger dose given in the evening. MTD was reached at 10 mg/day. Overall, the therapy cycles were 69 (median/patient, 2; range, 1-6). DLTs were G4 neutropenia associated with leukopenia and thrombocytopenia in one patient and G3 diarrhea in another of the 5 patients in the 10 mg/day cohort. The two patients developing DLT at the daily dose of 10 mg received a dose normalized for body surface of 6.85 and 5.65 mg/m2/day, respectively. We considered 5.5 mg/m2/day to be the MTD. Other toxicities were nausea, vomiting, neutropenia, and diarrhea, grades G1 to G2. By univariate analysis, significant correlations were observed between absolute neutrophil count at nadir and IDA area under the curve (P = 0.022; r = -0.33), IDA Cmax (P = 0.0067; r = -0.38), IDOL area under the curve (P = 0.0009; r = -0.43), and IDOL Cmax (P = 0.0016; r = -0.41), respectively. By multivariate analysis, IDA Cmax was the strongest determinant for neutropenia (R2 = 0.14; P = 0.01). Among the 21 patients evaluable for response, 3 (14.3%) had partial response (lasting 3, 6, and 8 months, respectively), and 6 (28.6%) had a complete arrest of disease progression (lasting 2-6 months). In conclusion, the MTD of this schedule is 10 mg/day and the DLTs are neutropenia and diarrhea. Tolerance was good, and the treatment is feasible as home therapy. Some objective measurable responses were documented in this group of anthracycline-pretreated patients. IDOL could have a role for the pharmacological effect. Further evaluation of this schedule is warranted to assess the activity and toxicity of prolonged oral IDA administration.

Pharmacokinetics of vinorelbine in patients with liver metastases.

BACKGROUND: The main elimination pathway of vinorelbine is hepatic metabolism, and the clearance of vinorelbine could be reduced in patients with liver metastases. OBJECTIVES: To study the pharmacokinetics of vinorelbine in patients who have advanced breast cancer with or without liver metastases and to study the relationship between hepatic function and vinorelbine clearance. PATIENTS AND METHODS: We studied 29 patients with advanced breast cancer: 19 with liver metastases and 10 control patients with extrahepatic metastases (mean age, 61 years; age range, 38 to 81 years). The vinorelbine dose was 30 mg/m2 as a short intravenous infusion; the dose was reduced by 50% in patients with bilirubin > 2 mg/dl. Patients were classified by ultrasonographic estimation of the liver volume replaced by tumor (%LVRT). Standard liver function tests and a monoethylglycinexylidide test (a quantitative liver function test based on lidocaine metabolite formation) were performed. Vinorelbine was assayed in plasma by HPLC with fluorescence detection. Vinorelbine determination was impossible in two patients with more than 75% LVRT because of interferences. Pharmacokinetic parameters were calculated with a noncompartimental method and compared by means of the Kruskal-Wallis test. RESULTS: A lower vinorelbine clearance rate was observed in the five patients with more than 75% LVRT (22.9 L/hr/m2) compared with the 10 patients with no liver metastases (48.0 L/hr/m2) and the 12 patients with 25% to 75% LVRT (45.3 L/hr/m2). Terminal elimination half-life and apparent volume of distribution were not significantly different among groups. The monoethylglycinexylidide test had a significant correlation with vinorelbine clearance. (r2 = 0.70; p = 10(-4). CONCLUSIONS: These results support vinorelbine dose reduction in patients with severe liver failure but not in patients with moderate secondary liver involvement. The monoethylglycinexylidide test may prove to be useful for vinorelbine dose individualization.

Treatment of older breast cancer patients with high recurrence risk.

Adjuvant treatment of elderly women affected by breast cancer who have a high risk of recurrence is one of the most questionable issues in clinical oncology. The use of tamoxifen in women with hormone receptor-positive tumors is a relatively simple therapeutic option considering the favourable toxicity profile, whereas the administration of adjuvant chemotherapy is more complicated and a variety of aspects need to be considered. The estimated life expectancy, the presence and degree of comorbid conditions, the geriatric assessment and estimated benefit from treatment should be taken into account. Due to the lack of data from clinical trials in women over the age of 70, the approach is still experimental. Clinical trials evaluating the role of adjuvant chemotherapy in high risk patients are currently being developed and hopefully in the near future, more convincing data on the best drugs, regimens and benefits for the treatment of elderly breast cancer patients will become available.

The treatment of metastatic renal cell carcinoma by continuous intravenous infusion of recombinant interleukin-2.

Between March 1989 and June 1990, 133 patients were treated with interleukin 2 (rIL-2) for metastatic renal cell carcinoma (RCC) in a multicentre open non-randomised study. The results show an objective response rate of 14% (95% confidence interval 8-21) with 4 patients achieving a complete remission. This is in keeping with the data from previous studies using rIL-2 by continuous infusion. It is of interest that 87% of objective responses occurred in hospitals that entered 5 or more patients.

Pharmacokinetics and tolerance of vinorelbine in elderly patients with metastatic breast cancer.

25 patients older than 65 years with metastatic breast cancer were treated with vinorelbine 30 mg/m2 i.v. days 1 and 8 every 3 weeks; the pharmacokinetics were studied in 10 of them. Vinorelbine showed a large apparent volume of distribution (mean 23.4 l/kg), a long terminal half-life (mean 26.2 h) and a large systemic clearance rate (mean 1.2 l/kg). These results are similar to those reported in younger patients. No correlation has been found between toxicity, age and drug exposure. We observed 6 partial responses out of 20 evaluable patients despite a relatively low mean dose intensity (67%). Severe neutropenia occurred in 37% of the patients; other side-effects were acceptable. This study does not provide a pharmacokinetic rationale for reducing the dosage of vinorelbine in selected elderly patients.

EO9 phase II study in advanced breast, gastric, pancreatic and colorectal carcinoma by the EORTC Early Clinical Studies Group.

In a phase II trial, the activity of EO9, a new bioreductive alkylating agent, was assessed. EO9 was used as second-line chemotherapy in breast cancer patients and as first-line chemotherapy for patients with gastric, pancreatic and colorectal cancer. EO9 was given as a 5 min i.v. infusion at a weekly dose of 12 mg/m2. 92 patients were entered; 22 with breast cancer, 26 with colon cancer, 24 with pancreatic cancer and 20 with gastric cancer. In general, the drug was well tolerated with nausea and vomiting occurring in 26.42 and 13.3% of courses, respectively. Reversible proteinuria was the main toxicity occurring in 45% of courses. Antitumour activity was not observed. At this dose and schedule, EO9 is not an active drug in the type of tumour studied.

Pharmacokinetics of 7-con-O-methylnogarol in patients with solid tumors.

The pharmacokinetics of 7-con-O-methylnogarol were investigated by HPLC assay with fluorometric detection in nine cancer patients with normal hepatic and renal function, after a 2-h infusion of 160 or 200 mg/m2. The drug disappeared from plasma biexponentially with a mean elimination half-life of 38 +/- 3 h; the mean apparent volume of distribution and the plasma clearance were 805 +/- 91 1/m2 and 14 +/- 2 1/h per m2. Within 48 h of administration, urinary excretion of the drug and its metabolite 7-con-O-methyl-N-demethylnogarol accounted for 2%-15% and 0.1%-6% of the dose, respectively. Neither 7-con-O-methylnogarol nor its N-demethyl derivative was conjugated with glucuronic acid or sulfate in detectable amounts.

Pharmacokinetics of VM 26 given intrapericardially or intravenously in patients with malignant pericardial effusion.

Three patients with lung cancer (1 SCLC, 2 NSCLC) and pericardial malignant effusion received 100 mg/m2 Teniposide (VM 26) i.v. and, 1 week later, 50 mg/m2 intrapericardially. Plasma, pericardial, and urine levels of the drug were measured in all patients after the two treatments by a HPLC assay. After intrapericardial administration, a high VM 26 concentration was found in the pericardial cavity and slow systemic drug absorption was observed. Since the drug AUC after intrapericardial administration was approximately 15-21 times that after i.v. administration, it could be that this treatment is more effective against neoplastic deposits localized in the pericardium. Even though this small series does not permit conclusions to be drawn on the efficacy of VM 26 given intrapericardially, the lack of local toxicity, minimal systemic toxicity, and the response observed in two out of three patients given intrapericardial VM 26 suggest that further investigation should be carried out on this method of VM 26 administration.

Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma.

Etoposide dosage in patients with liver dysfunction remains controversial. Since etoposide has a hepatic component to its clearance (CL) and shows a high degree of protein binding, hepatic impairment could affect etoposide disposition. However, the empiric recommendation that the dose of etoposide be decreased in such patients may reduce systemic exposure and be detrimental to its antitumor activity. To address these issues we studied the pharmacokinetics (PK) of etoposide in patients with hepatocellular carcinoma (HCC) and underlying cirrhosis (n = 17) treated with daily oral etoposide. Unbound etoposide was obtained by ultrafiltration. Etoposide concentrations (total and free drug) were measured by high-performance liquid chromatography (HPLC) and analyzed by noncompartmental equations. The patients had mild or moderate liver dysfunction. Albuminemia was in the normal range for all the patients. Creatininemia was normal in all but two patients. PK results (mean and range) showed that etoposide disposition was unchanged in patients with liver dysfunction. We found slightly high etoposide bioavailability [F, 61% (17-95%)] and clearance [CL, 1.1 (0.7-2.3)l h(-1) m(-2)] resulting in a normal degree of systemic exposure (AUC(oral) 27 microg h ml(-1)). Normal protein binding [PB 93.2% (84.4-98.1%)] contributed to a normal level of exposure to free drug (AUC(f, oral) 1.9 microg h ml(-1)). The distribution volume [V(SS) 8.4 (6.1-13.2) l/m2] and the effective half-life [t1/2eff, 5.1 (3.0-9.6) h] were normal. Median CL and protein binding did not differ in the seven patients with total bilirubin value of > 1.2 mg/dl as compared with the ten patients with total bilirubin levels of < or = 1.2 mg/dl (1.3 versus 1.01 h(-1) m(-2) and 92.5% versus 93.4%, respectively). In agreement with this PK finding, we observed no clinical evidence of increased toxicity in patients with hyperbilirubinemia as compared with patients with normal bilirubinemia (mean WBC decrease 38% versus 47%). The only case of severe (grade 4) hematological toxicity was observed in one patient with reduced glomerular filtration. Since the pharmacological effects of etoposide correlate with the level of systemic exposure to the free drug, our data suggest that no dose reduction is needed in patients with HCC. It is even possible to increase the dose intensity in patients with favorable PK parameters under appropriate hematological and therapeutic drug monitoring.