Cellular and plasma pharmacokinetics of weekly 20-mg 4′-epi-adriamycin bolus injection in patients with advanced breast carcinoma

Summary Weekly low-dose injections of 20 mg 4-epiadriamycin (E-ADM) were given to 12 patients with advanced postmenopausal breast cancer for at least 8 weeks. In advance, all patients were given hormonal therapy and polychemotherapy not containing anthracyclines. E-ADM concentrations in plasma and urine and in blood and bone marrow cells were determined during 8 consecutive weeks. Plasma concentrations in the range of a few nanograms per milliliter were seen up to 72–96 h. Cellular concentrations, and were 190±66 ng/10⁹ cells on day 8, before the next injection was given. Nevertheless, no serious bone marrow toxicity was observed. In two patients with an increased plasma bilirubin concentration, cellular E-ADM concentrations were 20%–40% higher than those observed in the other patients. Plasma concentrations of E-ADM and 4-epi-adriamycinol showed terminal half-lives 2–3 times longer and could be followed throughout the week. In three patients biopsies of skin metastases were examined. In two patients E-ADM could be demonstrated in the tumor tissue up to 7 days after the last injection. Although the number of patients investigated is too small to relate the drug kinetics to clinical response, it is of interest that the two patients with the highest cellular E-ADM concentrations responded better than the others.This work was supported by the Queen Wilhelmina Foundation, The Netherlands Cancer Foundation (KWF) and, in part, by Farmitalia Carlo Erba, Milan, Italy     

Pharmacokinetics and disposition of 4′-O-tetrahydropyranyladriamycin in mice by HPLC analysis

Summary The plasma level of 4-O-tetrahydropyranyladriamycin (THP) declined rapidly after IV injection to mice, with a t_1/2() of 0.453 min. Only 1.2 g/ml THP was detected 2 min after injection of 5 mg/kg. The drug was immediately transferred to various tissues, where the drug levels were much higher than the plasma concentration. In the lung and spleen, 8.26 and 13.6 g/g THP was present, respectively, 2 h after administration. Major metabolites of THP were 13-dihydro-THP, ADM, 7-deoxyadriamycinone, and 7-deoxy-13-dihydro-adriamycinone. Only 1.12% of the dose had been recovered in the urine by 48 h after injection as THP and its metabolites, according to analysis by HPLC fluorospectroscopy. The observed disposition of THP was compared with that of adriamycin (ADM). The plasma disappearance and tissue transfer of THP were faster than those of ADM. THP levels in the spleen and lung were higher and those in the heart and liver were lower than the corresponding ADM levels. Drug levels declined more quickly in most tissues in the case of THP than of ADM. Tissue distributions after single bolus and multiple injections were also compared and discussed.     

Pharmacokinetics and exposure–effect relationships of capecitabine in elderly patients with breast or colorectal cancer

Purpose

The aims of the present study were (1) to investigate the impact of great age on pharmacokinetics of capecitabine and its metabolites and (2) to evaluate the exposure–effect relationship of capecitabine in elderly patients.

Methods

Data collected from 20 elderly patients (75–92 years old) with breast or colorectal cancer who received oral capecitabine were analyzed. In order to study the old age effect on pharmacokinetics, data collected from two phase I studies involving 40 younger adults (<75 years old) with metastatic cancer who received oral capecitabine were added in the database. The population pharmacokinetic analysis was based on a four-compartment model describing the sequence of capecitabine and three of its metabolites.

Results

The absorption rate constant was found lower in the oldest patient group (≥75 years) compared with the youngest group, and the constant rate elimination of the 5-fluorouracil metabolite was found decreased over time (i.e., after 2 consecutive weeks of capecitabine administration). This time effect was not found different between the two age groups. In elderly patients, the exposure-safety analysis showed, from the second cycle of chemotherapy, significantly higher median exposures of capecitabine and its metabolites (5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine and 5-fluorouracil) in patients who experienced hand-foot syndrome compared with patients who did not.

Conclusion

This study puts forward new arguments for the treatment of elderly cancer patients who could benefit from capecitabine chemotherapy with acceptable toxicity.     

Treatment of advanced breast cancer with a metronomic schedule of oral vinorelbine: what is the opinion of Italian oncologists?

Background: The aim of this study was to record the opinions of Italian oncologists about the use of oral vinorelbine administered metronomically in patients with advanced breast cancer.

Methods: A series of meetings were held throughout Italy, and participants were asked how much they agreed with each of the several statements.

Results: The majority of oncologists agreed that the concept of the minimum biologically effective dose should be used for drugs administered metronomically. Over 50% agreed that metronomic vinorelbine is an option in first-line chemotherapy for patients with advanced breast cancer, including those with a terminal illness and the elderly, as well as in young and fit patients. Just over one-third of experts agreed that a combination of two chemotherapy agents instead of one is not desirable in metastatic breast cancer because of increased toxicity. Most experts agreed that the main aim of a first-line therapy is to control the disease over time and to preserve quality of life.

Conclusion: Metronomically administered oral vinorelbine, either as monotherapy or in combination with other drugs, is effective in the long-term treatment of patients with advanced breast cancer. The clinical profiles of patients should be carefully considered to determine the appropriate treatment strategy.     

Phase I–II trial of prolonged gemcitabine infusion plus paclitaxel as a biweekly schedule for advanced breast cancer patients pretreated with anthracyclines

Purpose

Paclitaxel (PACL) plus gemcitabine (GEM) is an effective regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged GEM infusion at a fixed dose rate (FDR) of 10 mg/m²/min produces higher levels of intracellular active metabolites of GEM when compared with a standard 30-min infusion. In the present phase I/II trial, we investigated the association of FDR GEM plus PACL.

Methods

1,200 mg/m² was the dose of GEM recommended for the phase II study, in which patients received PACL at 150 mg/m², followed by FDR GEM at 1,200 mg/m² (total GEM infusion time = 120 min), both drugs administered biweekly.

Results

Forty-two anthracycline-pretreated advanced breast cancer patients with disease recurrence following at least one line of chemotherapy were enrolled. Two (4.8%) and 12 (33.3%) patients experienced a complete and partial response, respectively, for an overall response rate of 38.1% (95% CI 23.4–52.8%). Median progression free survival and overall survival were 5 and 19.9 months, respectively. No statistically significant association was noted between in situ protein expression of RRM1 and BRCA1 (as assessed by immunofluorescence combined with automated quantitative analysis) and response to treatment in 15 patients with tissue available for analysis. Toxicity was mostly mild to moderate, mainly consisting of G3–G4 neutropenia (9.6%) and hypertransaminasemia (9.5%).

Conclusions

Biweekly FDR GEM in combination with PACL is an active and safe regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged infusion regimen of GEM does not seem to improve the efficacy of a standard 30-min infusion.     

Do radiation use disparities influence survival in patients with advanced breast cancer?

BACKGROUND:

The authors previously identified racial/ethnic disparities in the use of radiation therapy (RT) in patients with advanced breast cancer (BC). They hypothesized that disparities in the use of RT were associated with survival differences favoring white patients.

METHODS:

The authors used the Surveillance, Epidemiology, and End Results database to identify white, black, Hispanic, and Asian patients with BC associated with ≥10 metastatic lymph nodes diagnosed between 1988 and 2005. Multivariate analyses of overall survival (OS) and disease‐specific survival (DSS) assessed age, sex, race, tumor size, histology, estrogen receptor status, progesterone receptor status, RT, and type of surgery. The authors further stratified for use of RT and type of surgery. Risk of mortality was reported as hazard ratios (HRs) with 95% confidence intervals (CIs).

RESULTS:

Of 15,895 patients with advanced BC, 12,653 met entry criteria. On multivariate analysis, RT was associated with a decreased risk of all‐cause (HR, 0.78; 95% CI 0.74‐0.83; P < .001) and disease‐specific (HR, 0.81; 95% CI, 0.76‐0.86; P < .001) mortality; black race was associated with an increased risk of all‐cause (HR, 1.54; 95% CI, 1.42‐1.68; P < .001) and disease‐specific (HR, 1.53; 95% CI, 1.39‐1.68; P < .001) mortality. After stratifying by type of surgery and use of RT, blacks demonstrated poorer survival than their white counterparts, regardless of surgery type or receipt of RT.

CONCLUSIONS:

Only black patients had poorer OS and DSS relative to whites. When stratified by type of surgery and use of RT, blacks continued to demonstrate poorer survival. This survival disparity is unlikely to be because of lack of RT. Cancer 2012;. © 2011 American Cancer Society.     

Bevacizumab in the treatment of patients with advanced breast cancer: where have we landed?

Vast preclinical and clinical evidence has made angiogenesis one of the hallmarks of cancer. In many human tumours, vascular endothelial growth factor (VEGF) has been identified as the crucial mediator of this process. Initial studies suggested that angiogenesis, and VEGF in particular, could be inhibited without the risk of major side effects. After the pivotal data in first-line studies in patients with colorectal cancer, numerous clinical trials have been undertaken in patients with breast cancer. This review attempts to update these investigations and define the role of anti-VEGF antibody treatment in advanced breast cancer.     

Safety and efficacy of weekly nab®-paclitaxel in combination with carboplatin as first-line therapy in elderly patients with advanced non-small-cell lung cancer

BackgroundThis analysis evaluates safety and efficacy in elderly (≥70 years old) versus younger patients enrolled in a phase III advanced non-small-cell lung cancer (NSCLC) trial.Patients and MethodsUntreated stage IIIB/IV patients with PS 0/1 were randomly assigned (1:1) to carboplatin AUC6, day 1 every 3 weeks, and either nab-paclitaxel (Abraxane) 100 mg/m² weekly (nab-P/C) or solvent-based paclitaxel (Taxol) 200 mg/m² day 1 every 3 weeks (sb-P/C). The primary end-point was overall response rate (ORR).ResultsFifteen percent of 1052 enrolled patients were elderly: nab-P/C, n = 74; sb-P/C, n = 82. In both age cohorts, the ORR was higher with nab-P/C versus sb-P/C (age ≥70: 34% versus 24%, P = 0.196; age <70: 32% versus 25%, P = 0.013). In elderly patients, progression-free survival (PFS) trended in favor of nab-P/C (median 8.0 versus 6.8 months, hazard ratio (HR) 0.687, P = 0.134), and overall survival (OS) was significantly improved (median 19.9 versus 10.4 months, HR 0.583, P = 0.009). In younger patients, PFS (median 6.0 versus 5.8 months, HR 0.903, P = 0.256) and OS (median 11.4 versus 11.3 months, HR 0.999, P = 0.988) were similar in both arms. Adverse events were similar in both age groups, with less neutropenia (P = 0.015), neuropathy (P = 0.001), and arthralgia (P = 0.029), and increased anemia (P = 0.007) with nab-P/C versus sb-P/C.ConclusionsIn elderly NSCLC patients, nab-P/C as first-line therapy was well tolerated and improved the ORR and PFS, with substantially longer OS versus sb-PC.     

Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-na?ve patients with advanced non-small-cell lung cancer

Background:Gemcitabine (GEM) and paclitaxel (TAX) are active,non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performeda phase I study to determine the maximum-tolerated dose (MTD), antitumoractivity and pharmacokinetics of GEM and TAX given weekly in chemo-naïvepatients with advanced NSCLC. Patients and methods:Escalating doses of GEM (800–2000mg/m²) and TAX (60–100 mg/m²) were administeredon days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasmapharmacokinetics of TAX and GEM was assessed at the three higher dose-levels. Results:Dose-escalation was discontinued in absence of MTDbecause of increased cumulative toxicity leading to dose modification ortreatment delay at levels 6 and 7 (TAX 100 mg/m² plus GEM 1750 and,respectively, 2000 mg/m²). Hematological toxicity included grade4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycleand febrile neutropenia in three cycles. Maximal non-hemathological toxicitywas grade 3 elevation in serum transaminases and grade 2 neuro-sensorytoxicity in 8% and 5% of cycles, respectively. At the two higherdose-levels a non-linear pharmacokinetics of GEM was observed with aremarkable variability of C_max and AUC. No pharmacokineticinteractions were reported. Objectives responses were seen at all dose levels,with an overall response rate of 43% (95% confidence interval(95% CI): 25.5%–62.6%) in 30 evaluable patients. Conclusions:The weekly administration of GEM and TAX is very welltolerated, and has shown promising antitumor activity in NSCLC. In view of thecumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500mg/m² of GEM and 100 mg/m² of TAX are recommended forphase II studies.     

Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol™), a novel isoflav-3-ene, in patients with advanced cancer

Background: We wished to define the maximum tolerated dose (MTD), toxicity, and pharmacokinetics of the novel isoflav-3-ene, NV06 (Phenoxodiol™), a compound with a diphenolic structure related chemically and biologically to genistein and flavopiridol. Patients and Methods: Twenty-one patients with advanced cancers were treated with weekly intravenous administration of NV06 at escalating dose levels with 1–4 patients at each dose cohort. Plasma sampling was undertaken to characterize the pharmacokinetic (PK) profile of the compound. Results: Toxicity was minimal, with asymptomatic Grade 3 lymphocytopenia occurring in nine patients. Nine patients developed Grade 1 nausea, six patients developed Grade 1 increases in alkaline phosphatase, and six patients developed Grade 1 increases in transaminases. Two patients experienced hypersensitivity reactions. The MTD was not reached. Most patients had progressive disease on treatment but eight completed 12 weeks and two completed 24 weeks of treatment. The best response was stable disease of 6 months duration. The plasma half-life (T1/2), clearance (Cl), and volume of distribution (V _D) were 304 (±91) min, 82 (±19) ml/min and 32,663 (±7,199) ml, respectively, for total NV06. Conclusions: NV06 is well tolerated and can be given safely as an intravenous infusion over 1–2 h at a dose of at least 30 mg/kg.     

Inability to escalate vinorelbine dose intensity using a daily × 3 schedule with and without filgrastim in patients with metastatic breast cancer

Purpose: Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid with documented activity in breast cancer. The major dose-limiting toxicity (DLT) when given weekly is myelosuppression with minimal neurologic toxicity. This phase I study attempted to define the maximally tolerated dose (MTD) and the DLT of vinorelbine on a daily ×3 schedule with and without filgrastim support. Methods: A total of 19 patients with stage IV breast cancer were enrolled in separate studies at Duke University Medical Center (DUMC) and the Dana-Farber Cancer Institute (DFCI). Eligible patients could have received up to two prior chemotherapy regimens in the metastatic setting and had to have an ANC >1500/mm², PLT >100 000 m³, creatinine <2.0 mg/dl, bilirubin <2.0 mg/dL, SGOT not more than three times normal, and performance status 0–1. Vinorelbine was administered using a daily ×3 schedule every 3 weeks. The protocols were designed to study dose escalation with and without growth factor support. At DUMC, in the initial phase of the study, the starting dose was 15 mg/m² per day and dose escalations of 5 mg/m² were planned until DLT developed and the MTD was defined. DLT was defined as granulocytopenia <500/mm³ for >7 days, grade IV thrombocytopenia, febrile neutropenia, or grade III or greater nonhematologic toxicity. In the second phase of the study, growth factor support was given with vinorelbine at the MTD. Filgrastim at a dose of 5 g/kg was started on day 4 of the 21-day cycle and was continued until the neutrophil count exceeded 10 000 cells/mm³. At DFCI, all patients received growth factor starting on day 4 and the starting dose of vinorelbine was 25 mg/m². Results: At DUMC, DLT was seen at 20 mg/m² in three of three patients and included febrile neutropenia, grade IV neutropenia >7 days, grade III neurotoxicity, and grade III vomiting. Despite the addition of filgrastim, DLT was again seen at 20 mg/m² and included grade III neurotoxicity (jaw pain, abdominal pain, constipation, ileus) and grade IV mucositis. Three patients at DFCI were treated with vinorelbine at a dose of 25 mg/m² with growth factor support, and two developed DLT including febrile neutropenia, neutropenia >7 days, and grade III stomatitis. Conclusions: Our effort to escalate the dose intensity of vinorelbine on this schedule was not successful and was complicated by hematologic and nonhematologic toxicity. A daily ×3 schedule of vinorelbine should not be pursued as an alternative treatment regimen in patients with previously treated metastatic breast cancer. Received: 27 October 1997 / Accepted: 16 April 1998     

Presence of HER4 associates with increased sensitivity to Herceptin™ in patients with metastatic breast cancer

Introduction  

HER2 overexpression, or rather HER2 gene amplification, is indicative for Herceptin therapy in both metastatic and pre-metastatic breast cancer patients. Patient's individual sensitivity to Herceptin treatment, however, varies enormously and spans from effectual responsiveness over acquired insensitivity to complete resistance from the outset. Thus no predictive information can be deduced from HER2 determination so that molecular biomarkers indicative for Herceptin sensitivity or resistance need to be identified. Both ErbB receptor-dependent signalling molecules as well as HER2-related ErbB receptor tyrosine kinases, known to mutually interact and to cross-regulate each other are prime candidates to be involved in cellular susceptibility to Herceptin.     

Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer

BackgroundA nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in several markets, including the United States, Canada, and European Union, as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure–response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen.Patients and methodsNivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials.ResultsCompared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grades 3–4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified.ConclusionsThe time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care.Clinical trial numbersNCT01721772, NCT01668784, NCT01673867, NCT01642004     

Clinical observation of Endostar? combined with chemotherapy in advanced colorectal cancer patients

Objective: Endostar® (Rh-endostatin injection) is a new recombinant human endostatin developed by Shandong Simcere-Medgenn Bio-Pharmaceutical Co., Ltd in China. This study was performed to evaluate the efficacy and safety of Endostar plus leucovorin calcium/ 5-fluorouracil/oxaliplatin (FOLFOX4) in treating patients with advanced colorectal cancer. Methods: Thirty-six patients with advanced colorectal cancer were retrospectively assigned to one of two treatment groups: FOLFOX4 (control) or FOLFOX4 plus Endostar (Endostar) according to patient accreditation. The observational end points were overall response rate, overall survival, progression-free survival and toxicity. Results: The response rate and progression-free survival of Endostar were significantly better than those of control group (P <0.05), but significance was not observed for median survival. In addition, gastrointestinal side effects and incidence of leucopenia were not lower than in the control group (P<0.05). Conclusions: The addition of Endostar to FOLFOX4 resulted in a higher objective response rate and longer time to disease progression. Hypertension and cardiac ischemia were the principal safety concerns, but were manageable. Endostar deserves to be further investigated by randomized controlled clinical trails.     

Mitoxantrone in advanced breast cancer—a phase II study with special attention to cardiotoxicity

Thirty-four patients with advanced breast cancer, who had not received previous chemotherapy for metastatic disease, were treated with mitoxantrone 14 mg/m² i.v. every 21 days. Eleven of 33 evaluable patients (33%) achieved a partial response: there were no complete responders. Before commencing mitoxantrone, and 3-monthly thereafter, radionuclide assessment of ventricular performance was obtained at rest and in response to stress. Ten patients showed a deterioration in ejection fraction, two of whom developed congestive cardiac failure. Dose-limiting toxicity was myelosuppression. Nausea and vomiting were generally mild and transient. Alopecia was minimal in most patients. Mitoxantrone is an active, well-tolerated new drug in the treatment of advanced breast cancer, but cardiotoxicity may occur in a proportion of patients. Further investigation is required to determine the precise nature, incidence and prognosis of cardiotoxicity encountered with mitoxantrone.     

Impact of prophylactic pyridoxine on occurrence of hand–foot syndrome in patients receiving capecitabine for advanced or metastatic breast cancer

Background

Capecitabine, an oral fluoropyrimidine, has shown consistently high efficacy in anthracycline- and/or taxane-pretreated advanced and metastatic breast cancer. The safety profile of capecitabine is characterized by hand–foot syndrome (HFS), which, although not life threatening, can impair patients’ quality of life if it is not managed promptly and effectively. We conducted a study to assess the impact of prophylactic pyridoxine on HFS.

Methods

Prophylactic pyridoxine was given to 38 patients receiving capecitabine (alone or in combination with cyclophosphamide) for metastatic breast cancer and compared with historical data from 40 patients receiving capecitabine without pyridoxine in our clinic. The impact of urea ointment on HFS was also assessed.

Results

HFS developed in 20 patients (52.6%) receiving pyridoxine compared with historical data showing an 82.5% rate in patients receiving no pyridoxine prophylaxis (p < 0.01). A nonsignificant trend towards less severe HFS was seen among patients who received urea ointment at first appearance of symptoms. In addition, nonsignificant trends towards higher rates of HFS were seen among those who were ≥61 years and those who derived clinical benefit (clinical response or stable disease).

Conclusions

Prophylactic pyridoxine and urea ointment at first appearance of symptoms appears to reduce the risk of severe capecitabine-induced HFS. However, randomized data are required to determine the true effect of these measures.     

‘Tablet burden’ in patients with metastatic breast cancer

The implications for patients with cancer, of the ‘tablet burden’ resulting from increasing use of oral anticancer drugs and medication for co-morbidities have not previously been well explored.AimWe sought to (i) quantify tablet burden in women with metastatic breast cancer (MBC), (ii) establish which groups of drug contribute most to this burden and (iii) gain insight into patients' attitudes towards oral anti-cancer treatment.MethodsOne hundred patients with MBC anonymously completed a questionnaire describing their medication histories and attitudes towards their tablets.ResultsThe patients (mean age 60, range 31–95) were all female and taking a median of six tablets (range 0–31) daily; 37 patients were taking >10 tablets. Oral anticancer treatment constituted the category of treatment taken by the highest proportion of patients, followed by symptomatic cancer treatments, proton pump inhibitors and cardiovascular medication. Numerically, however, symptomatic drugs accounted for 44% of all tablets and specific anti-cancer treatment for 15%; medication not directly related to the cancer accounted for the remaining 40% of tablets. A quarter of patients reported inconvenience in taking their tablets, the main reason being tablet size and one third reported forgetting their tablets at least once a week. Nearly two thirds of patients expressing a preference favoured oral anticancer treatment, the commonest reason being greater convenience.ConclusionTablet burden is considerable for many patients with MBC and can be problematic. A significant proportion of tablets represent treatment for co-morbidities, the significance of which may be questionable in women with MBC.     

Individual radiosensitivity in a breast cancer collective is changed with the patients’ age

Background

Individual radiosensitivity has a crucial impact on radiotherapy related side effects. Our aim was to study a breast cancer collective for its variation of individual radiosensitivity depending on the patients’ age.

Materials and methods

Peripheral blood samples were obtained from 129 individuals. Individual radiosensitivity in 67 breast cancer patients and 62 healthy individuals was estimated by 3-color fluorescence in situ hybridization.

Results

Breast cancer patients were distinctly more radiosensitive compared to healthy controls. A subgroup of 9 rather radiosensitive and 9 rather radio-resistant patients was identified. A subgroup of patients aged between 40 and 50 was distinctly more radiosensitive than younger or older patients.

Conclusions

In the breast cancer collective a distinct resistant and sensitive subgroup is identified, which could be subject for treatment adjustment. Preliminary results indicate that especially in the range of age 40 to 50 patients with an increased radiosensitivity are more frequent and may have an increased risk to suffer from therapy related side effects.     

Metabolism of trabectedin (ET-743, Yondelis™) in patients with advanced cancer

Purpose Trabectedin (ET-743, Yondelis™) is a novel anti-cancer drug currently undergoing phase II–III evaluation, that has shown remarkable activity in pre-treated patients with soft tissue sarcoma. Despite extensive pharmacokinetic studies, the human disposition and metabolism of trabectedin remain largely unknown. We aimed to determine the metabolic profile of trabectedin and to identify its metabolites in humans. Methods We analysed urine and faeces (the major excretory route) from eight cancer patients after a 3 or 24 h intravenous administration of [¹⁴C]trabectedin. Using liquid chromatography with tandem quadrupole mass spectrometric detection (LC-MS/MS) and radiochromatography with off-line radioactivity detection by liquid scintillation counting (LC-LSC), we characterised the metabolic profile in 0–24 h urine and 0–120 h faeces. Results By radiochromatography, a large number of trabectedin metabolites were detected. Incubation with β-glucuronidase indicated the presence of a glucuronide metabolite in urine. Trabectedin, ET-745, ET-759A, ETM-259, ETM-217 (all available as reference compounds) and a proposed new metabolite coined ET-731 were detected using LC-MS/MS. The inter-individual differences in radiochromatographic profiles were small and did not correlate with polymorphisms in drug-metabolising enzymes (CYP2C9, 2C19, 2D6, 2E1, 3A4, GST-M1, P1, T1 and UGT1A1 2B15) as determined by genotyping. Conclusions Trabectedin is metabolically converted to a large number of compounds that are excreted in both urine and faeces. In urine and faeces we have confirmed the presence of trabectedin, ET-745, ET-759A, ETM-259, ETM-217 and ETM-204. In addition we have identified a putative new metabolite designated ET-731. Future studies should be aimed at further identification of possible metabolites and assessment of their activity.