Phase II trial and pharmacokinetic study of thalidomide in patients with metastatic colorectal cancer

Introduction. This study was designed to estimate the percentage of objective tumor responses, toxicity profile, and obtain additional information about the plasma pharmacokinetics of thalidomide in patients with refractory and progressing metastatic colorectal cancer. Study design. This phase II clinical trial was conducted according to the two-stage Simon method with the inclusion of consecutive patients. The study protocol was approved by the Institutional Review Board (IRB) of the Academic Hospital (HCPA) of the Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Patients and methods. Seventeen patients with previously treated, refractory progressive metastatic colorectal cancer were eligible. Six patients had prior radiotherapy. The patients had a median of one previous chemotherapy regimen. Patients were initially treated with 200mg/day of thalidomide with an increase in dose by 200mg/day every 2 weeks until a final daily dose of 800mg/day was achieved. Patients were evaluated every 8 weeks for response by radiographic criteria. Plasma pharmacokinetics studies were performed in four patients at 200mg level and in one patient at 600mg during the first 24h. Main outcome measures and results. A total of 17 patients were accrued, all of them being evaluable for toxicity and 14 for response. Thalidomide was well tolerated, with constipation, somnolence, dizziness, and dry mouth being the major toxicities. There were no objective response or stable disease. The median survival was 3.6 months. Single-agent thalidomide is a generally well-tolerated drug that showed no antitumor activity in patients with advanced pretreated metastatic colorectal cancer. Although thalidomide did not show antitumor activity in this patient population, future studies of this agent in patients at initial stages of the disease (when its antiangiogenic properties may be more relevant to disease progression) could be considered.     

A phase II study of rebeccamycin analog (NSC-655649) in metastatic renal cell cancer

Objective: Rebeccamycin analog (NSC-655649) is an antibiotic with antitumor properties demonstrated in preclinical and phase I studies. We conducted a phase II trial to evaluate the efficacy and toxicity of this agent in patients with advanced renal cell cancer (RCC). Methods: Eligible patients had histologically or cytologically confirmed diagnosis of RCC that was either locally advanced unresectable, locally recurrent, or metastatic. Patients had to have measurable disease, no prior chemotherapy, life expectancy of greater than 12 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate-organ function, and be 18 years old. Patients were treated with NSC-655649 at a dose of 165mg/m² daily i.v. over 30–60min for 5 days. Treatment was repeated every 21 days. Response was assessed every two courses. Results: Twenty-four patients were enrolled. There were sixteen males and eight females with a median age of 60.5 years (range 42–76). Nineteen were Caucasians, seventeen had prior nephrectomy, and thirteen had prior immunotherapy. The major toxicity was myelosuppression with grade 3 and 4 neutropenia in 38% of patients and anemia in 33% of patients. There were two partial responses (2/24, 8%) and 11 patients (46%) achieved stable disease (SD). The 6-month progression-free rate for patients with SD was 30%. Of the seventeen patients with progressive disease at registration, one had a PR and eight had SD. The overall median survival time for all 24 patients was 10.0 months (90% CI=5.2, 17.4 months). The 12-month survival rate was 39%, with 90% CI=(0.21, 0.58). Nine patients are still alive with survival times ranging from 3.8 to 24.2 months, at a median follow-up time of 11.9 months. Conclusion: Rebeccamycin analog (NSC-655649) is well tolerated and has modest antitumor activity in patients with advanced RCC.     

Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma

Fifty-five patients with metastatic renal cell carcinoma (RCC) were treated on a multicenter, single-arm Phase II trial. Patients received single-agent Cetuximab (C225) administered by intravenous infusion at a loading dose of 400 or 500mg/m² followed by weekly maintenance doses at 250mg/m². None of the patients treated with C225 achieved either a complete or partial response. The median time to progression was 57 days. The most frequently reported grade 3 or 4 toxicity treatment-related adverse events were acne (17%) and rash or dry skin (4%). The lack of clinical response or suggestion of prolonging time to progression compared to historical data with interferon-alfa supports no further study of single-agent C225 in patients with metastatic RCC.     

Pharmacokinetic Drug–Drug Interaction of the Novel Anticancer Agent E7070 and Acenocoumarol

E7070 is a novel sulfonamide anticancer agent that arrests cancer cells at the G1/S boundary of the cell cycle. Three patients receiving chronic therapy with the oral anticoagulant acenocoumarol experienced bleeding and/or a prolonged prothrombin time after treatment with E7070 at a dose of 700mg/m² given as a 1-h infusion. In vitro studies have shown that E7070 has the potential to inhibit several cytochrome P450 (CYP)-enzymes, including CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The major enzyme involved in the metabolism of acenocoumarol in man is CYP2C9. This study was performed to investigate the interaction between E7070 and acenocoumarol.Blood samples were obtained from two patients receiving daily oral maintenance treatment with acenocoumarol both prior to and following treatment with E7070. In addition, we incubated acenocoumarol enantiomers with pooled human microsomes with and without E7070 and measured the in vitro plasma protein binding of acenocoumarol after incubation with E7070. Pharmacokinetic parameters of acenocoumarol were calculated by noncompartmental analysis and revealed that in both patients the area under the concentration–time curve up to 24h after the acenocoumarol administration was higher following E7070 (2.56 and 1.58h*mol/L) compared to the systemic exposure in the absence of E7070 (1.87 and 1.23h*mol/l). The formation of acenocoumarol metabolites was retarded by E7070 at already low concentrations (2.1M). The plasma protein binding of acenocoumarol was reduced at higher concentrations of E7070 (259M).These results indicate that E7070 may primarily interact with acenocoumarol by reducing its systemic clearance. Displacement of acenocoumarol's plasma protein binding by E7070 may also occur but to a minor extent. In the absence of careful monitoring this drug–drug interaction may result in hypoprothrombinemia and a hemorrhagic tendency.     

Weekly regimen of irinotecan/docetaxel in previously treated non-small cell lung cancer patients and correlation with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism

Purpose: Inherited variations in drug metabolizing enzymes may influence drug efficacy. This phase II study assesses the impact of second-line weekly irinotecan (CPT-11)/docetaxel in non-small cell lung cancer (NSCLC) patients, and gauges the uridine diphosphate glucuronosyl transferase (UGT1A1) polymorphism influence in toxicity and antitumor activity. Experimental Design: Fifty-one patients with NSCLC treated with at least one prior chemotherapy regimen were enrolled. Patients received irinotecan 70mg/m² followed by docetaxel 25mg/m². Both drugs were given on days 1, 8, and 15 every 28 days. UGT1A1 polymorphism were analyzed in blood samples of 47 patients. The UGT1A1 polymorphism are classified according to the number of TA repeats in the promoter region of this gene. Results: Three patients (6%) achieved a partial response and nineteen patients (37%) had stable disease. Median survival was 8 months (95% CI: 4.8–11.2) and 1-year survival 30%. Grade 3–4 hematologic toxicity was low (less than 10% of patients); 15% of patients had grade 3 asthenia and 25% of patients had grade 3/4 diarrhea. The frequency of UGT1A1 genotypes was as follows: 6/6 49%, 6/7 36%, and 7/7 15%. No differences in toxicity were observed according to UGT1A1 polymorphism. A nonsignificant improvement in time to progression (4 vs. 3 months) and median survival (11 vs. 8 months) was detected in patients with the variant alleles (6/7 and 7/7). Conclusions: This weekly irinotecan/docetaxel regimen has shown an acceptable toxicity profile while encouraging median and 1-year survival in heavily pretreated NSCLC patients. The tendency to better prognosis in patients carrying the variant genotypes 6/7 and 7/7 of UGT1A1 gene requires further validation.     

An open label, non-comparative phase II study of topotecan as salvage treatment for patients with soft tissue sarcoma

Background: The number of effective cytotoxic agents for the treatment of patients with metastatic soft tissue sarcoma (STS) is limited, especially when patients have failed anthracyline-based chemotherapy. Patients and methods: Between 1999 and 2000 a total of 16 patients with histologically proven STS progressing during or after first-line anthracycline-based chemotherapy were entered into this open-label, noncomparative study. Topotecan was administered as a 30-min infusion at a dosage of 1.5mg/m² on five consecutive days every 3 weeks. All patients had received an anthracycline- or ifosfamide-based first-line chemotherapy. Results: None of the 16 included patients achieved an objective response to topotecan. Six patients achieved stable disease (38%), lasting for at least 6 weeks in four patients (25%) and for less than 6 weeks in two patients (13%). Ten patients (62%) had progressive disease. The median time to progression was 79 days calculated from the start of topotecan therapy (range, 28–230). The treatment was well tolerated; however, both anemia and thrombopenia grade III/IV occurred in 25% of the patients as well as severe neutropenia in 69% of the patients. Nonhematologic toxicities grade III/IV such as diarrhea and severe bleeding occurred only in one patient each (6%). Discussion: Topotecan is well tolerated in anthracycline-resistant patients with metastatic STS, but no objective response has been observed in this trial.     

Effects of Aniline–An Aromatic Amine to Some Freshwater Organisms

We determined the acute and chronic toxicity of aniline to tilapia (Oreochromis mossambicus), cladoceran crusatcea (Moina micrura) and oligochaete worm (Branchiura sowerbyi) using static bioassay tests. The 96h LC₅₀ values of aniline for O. mossambicus, M. micrura and B. sowerbyi were 69.4, 0.6 and 586mg l^–1 respectively. Tilapia responded to even low concentrations of aniline: the fish lost appetite at aniline concentrations as low as 0.02mg l^–1. A 90 d outdoor bioassay with tilapia showed that 0.02mg l^–1 aniline reduced fish yield, specific growth rate and food conversion efficiency. Reproductive functions of fish were affected by aniline at a concentration of 0.5mg l^–1 and above. Dissolved oxygen, primary productivity and plankton population of the test medium also were significantly reduced at 2.65 and 6.94mg l^–1 aniline.     

A study of a different dose-intense infusion schedule of phenylacetate in patients with recurrent primary brain tumors

Purpose: To compare two different infusion schedules of phenylacetate (PA) in patients with primary brain tumors and to assess the feasibility of the administration in a multi-institutional setting. Patients and methods: Adult patients with recurrent primary brain tumors were treated with PA on two different schedules. The first schedule (I) consisted of a 2-week continuous, intravenous infusion followed by a 2-week rest period (14 days on, 14 days off) at a dose of 400mg/kg/day based on ideal body weight. This was repeated once and the 8-week period defined as a cycle. The second schedule (II) consisted of a 12-day continuous infusion at a dose of 400mg/kg/day based on IBW with a 2-day rest period. This was repeated four times for a duration of 8 weeks which defined one cycle of therapy. Cycles were repeated until tumor progression, unacceptable toxicity, or a delay of more than 28 days from the last day of the preceding infusion. Tumor response was assessed every 8 weeks. The National Cancer Institute toxicity criteria were used to assess toxicity. Dose adjustments were specified for toxicities. Plasma concentrations achieved during the patients' first cycle of therapy were assessed. Results: The clinical results of the phase II study of patients treated on schedule I were previously reported [8]. Of the nine eligible patients treated on schedule II, seven were assessable for radiographic response. There were no objective responses. One patient had stable disease and six had progressive disease. The median survival was 9 months (95% confidence intervals of 3–12 months). The steady state plasma concentrations of PA and phenylacetylglutamine were comparatively the same between the two dosing schedules. However a 1.7-fold greater amount of PA was delivered by schedule II. Conclusion: The infusions were well tolerated. Despite the feasibility of administering this agent in an outpatient setting, there were no responses seen with the more intensive schedule of PA.     

Toxicity of Lithium to Three Freshwater Organisms and the Antagonistic Effect of Sodium

Lithium (Li) is the lightest metal and occurs primarily in stable minerals and salts. Concentrations of Li in surface water are typically <0.04mg l^–1 but can be elevated in contaminated streams. Because of the general lack of information concerning the toxicity of Li to common toxicity test organisms, we evaluated the toxicity of Li to Pimephales promelas (fathead minnow), Ceriodaphnia dubia, and a freshwater snail (Elimia clavaeformis). In the laboratory, the concentration of Li that inhibited P. promelas growth or C. dubia reproduction by 25% (IC25) was dependant upon the dilution water. In laboratory control water containing little sodium (2.8mg l^–1), the IC25s were 0.38 and 0.32mg Li l^–1 and in ambient stream water containing 17mg Na l^–1, the IC25s were 1.99 and 3.33, respectively. A Li concentration of 0.15mgl^–1 inhibited the feeding of E. clavaeformis in laboratory tests. Toxicity tests conducted to evaluate the effect of sodium on the toxicity of Li were conducted with fathead minnows and C. dubia. The presence of sodium greatly affected the toxicity of Li. Fathead minnows and Ceriodaphnia, for example, tolerated concentrations of Li as great as 6mg l^–1 when sufficient Na was present. The interaction of Li and Na on the reproduction of Ceriodaphnia was investigated in depth and can be described using an exponential model. The model predicts that C. dubia reproduction would not be affected when animals are exposed to combinations of lithium and sodium with a log ratio of mmol Na to mmol Li equal to at least 1.63. The results of this study indicate that for most natural waters, the presence of sodium is sufficient to prevent Li toxicity. However, in areas of historical disposal or heavy processing or use, an evaluation of Li from a water quality perspective would be warranted.     

Pharmacokinetics and safety of ILX23-7553, a non-calcemic-vitamin D3 analogue, in a phase I study of patients with advanced malignancies

Purpose: Differentiation therapy is an alternative to chemotherapy with potentially less toxicity, improved quality of life, and survival. We conducted a phase I trial of ILX23-7553, a formulation of 1,25-dihydroxy-16-ene-23-yne-vitamin D₃, a 1,25-dihydroxyvitamin D₃ analog with preclinically demonstrated antitumor and differentiating effects and diminished hypercalcemic effects. Patients and methods: The protocol consisted of five daily oral treatments during 14-day cycles at 15 dose levels from 1.3 to 45.0g/m²/day. We treated 42 heavily pretreated patients who had a variety of malignancies with 162 treatment cycles, and obtained pharmacokinetics from three patients at the two highest dose levels. Results: There were no grade 3 or 4 toxicities. Grade 1–2 toxicities included diarrhea, nausea, fatigue, constipation, and one grade 1 hypercalcemia. Average day 6 calcium was 9.26 ± 0.55mg/dl in cycle 1 and 9.30 ± 0.67mg/dl in cycle 2. Pharmacokinetics at dose levels 14 (40g/m²/day) (1 patient) and 15 (45g/m²/day) (2 patients) demonstrated an average C _max of 30.4 ± 7.8pg/ml (0.07nM) and 104 ± 38.2pg/ml (0.25nM), and AUCs of 222.5 ± 225.2pg·h/ml and 855 ± 536pgh/ml, respectively. Eight patients (19%) had stable disease. While in vitro effects have been reported at these concentrations, they were at least 10-fold lower than ED₅₀s, and the study was terminated before an MTD was reached. Conclusion: The drug is safe and has potential benefits at serum concentrations where effects begin to be noted in vitro. Further study is needed with a reformulated higher unit dose compound to determine the safety and efficacy of higher serum concentrations.     

Phase II study of single agent paclitaxel in adult patients with relapsed acute lymphocytic leukemia

Background: A phase II study of paclitaxel in patients with relapsed adult acute lymphocytic leukemia (ALL) was conducted. Methods: Patients with relapsed ALL, no more than one prior salvage regimen, and no overt hepatic, renal, or cardiac dysfunction were eligible. Patients received paclitaxel 250mg/m² given as a continuous 24 -h intravenous infusion repeated every 3–4 weeks. Results: Eight patients received 13 courses of paclitaxel. One transient partial response was observed. The only severe extramedullary toxicities observed were Grade 3 myalgias and arthralgias. Conclusion: The study paclitaxel regimen was ineffective in refractory adult ALL.     

Phase II trial of fenretinide in advanced renal carcinoma

Summary Purpose: Fenretinide, a synthetic form of retinoid, induced apoptosis even in chemotherapy resistant cell lines. A phase II study was hence conducted to evaluate toxicity and efficacy of fenretinide in metastatic renal cancer. Methods: Eligibility included unresectable or metastatic renal cell carcinoma (RCC), adequate organ function and Zubrod performance status 2. Prior immunotherapy and a maximum of one prior chemotherapy regimen were allowed. Fenretinide was administered at a dose of 900 mg/m² twice daily orally for 7 days in a 21-day cycle. Toxicity was assessed at the start of each cycle, and response every 2 cycles. Results: Nineteen eligible patients enrolled of which fifteen had visceral/bone metastases. Seventeen patients had prior nephrectomy and 11 had prior immunotherapy. 76 cycles of therapy were delivered. Therapy was very well tolerated with few severe toxicities consisting of thrombosis in 1 individual and grade 3 fatigue, nausea and diarrhea in 1 patient. 5 patients had grade 2 nyctalopia and 3 patients had transient grade 2 visual toxicity. No objective responses were noted. Stable disease was seen in seven of nineteen cases (37%, 90% C.I. 0.21–0.59). Median time to progression was 1.5 months and median duration of stable disease was 5.8 months (90% C.I. 3.0–8.4). Median survival was 10 months. Tumor fenretinide levels were obtained in three patients and were in the lower end of the therapeutic range. Conclusion: Fenretinide was well tolerated but demonstrated minimal activity that was consistent with results of intratumoral drug measurements. Strategies are needed that will increase systemic and tumor levels of fenretinide.Supported in part by NCI Cancer Center Support Grant CA-22453.     

A phase II study of rebeccamycin analog NSC 655649 in patients with metastatic colorectal cancer

The analog, rebeccamycin tartrate salt (NSC 655649, Cancer Therapy Evaluation Program, National Cancer Institute) has broad preclinical anti-neoplastic activity. Preliminary data from phase I study demonstrated anti-tumor activity in colorectal carcinoma. This phase II trial evaluates its efficacy in patients with minimally treated metastatic colorectal cancer. Eligibility included Karnofsky performance status 70%, age 18 years and bidimensionally measurable disease. Thirteen patients were treated with NSC 655649 at 500mg/m² by central venous catheter once every 3 weeks by bolus injection. Thirty-four cycles (median [range] 2 [1–6]) of therapy were administered. Twelve patients are eligible for response assessment. No major objective responses were seen using the RECIST criteria; however stable disease was observed in three patients with mean duration of 15 weeks. The median time to progression was 8 weeks. There was no toxic death. Four patients received only one cycle of treatment, and three had disease progression. Toxicities were tolerable and hematologic toxicity was the most common. The median (range) granulocyte and platelet nadir counts were 2043/l (116–16,374/l) and 276×10³/l (5–769), respectively. Non-hematologic toxicities were moderate, including generalized weakness/fatigue, nausea/vomiting, diarrhea and anorexia. One patient required dose reduction; three patients required dose delays. NSC 655649 at this dose and schedule is inactive against advanced previously minimally treated metastatic colorectal cancer and further study of this drug as a single agent in this disease using an every three-week schedule is not warranted.     

Phase II trial of perillyl alcohol (NSC 641066) administered daily in patients with metastatic androgen independent prostate cancer

Objective. We conducted a phase II multicenter trial of perillyl alcohol in patients with advanced hormone refractory prostate cancer (HRPC). The primary endpoint was to evaluate the 6-month progression-free survival given the potential cytostatic nature of the drug. Secondary objectives included assessing acute and chronic toxicities, as well as measuring objective response rates. Methods. Patients with metastatic androgen-independent prostate cancer that failed at least one prior chemotherapeutic or experimental regimen were eligible. Perillyl alcohol was administered orally at 1200mg/m²/dose four times daily and continued until disease progression or development of unacceptable toxicity. Results. Fifteen patients were eligible. Six patients received less than one cycle (4 weeks) of drug, four of which stopped because of drug intolerance. Only six patients received more than two cycles of therapy and were considered evaluable for response. Main toxicity included grade 1–2 gastrointestinal intolerance (nausea/vomiting in 60% of the patients) and fatigue (47%). One patient developed a grade 4 hypokalemia that was felt likely attributable to the drug. No objective responses were seen. All patients either progressed or withdrew from the study secondary to drug intolerance before the 6-month time period. Conclusion. Perillyl alcohol administered at this dose and formulation did not have any objective clinical activity in this patient population.     

Effects of Endocrine Disruptors on Prosobranch Snails (Mollusca: Gastropoda) in the Laboratory. Part III: Cyproterone Acetate and Vinclozolin as Antiandrogens

The effects of suspected endocrine disrupting chemicals on freshwater and marine prosobranch species were analysed in laboratory experiments. In this last of three publications, the responses of the fresh water snail Marisa cornuarietis and of two marine prosobranchs (Nucella lapillus, Nassarius (Hinia) reticulatus) to the antiandrogenic model compounds cyproterone acetate (CPA) and vinclozolin (VZ) are presented. The snails were exposed to nominal CPA concentrations of 1.25mg/L alone and simultaneously to a potent synthetic estrogen (ethinylestradiol), androgen (methyltestosterone) or an indirectly acting xeno-androgen (tributyltin) in experiments with adult specimens and in a life cycle test for 12 months. Marisa and Nucella were furthermore exposed to nominal concentrations of 0.03–1.0µg VZ/L for up to 5 months. The antiandrogens induced a number of biological responses in all three species. The length of the penis and of accessory male sex organs (e.g., penis sheath, prostate) were significantly reduced. For Marisa, this effect occurred only in sexually immature specimens and was reversible as the males attained puberty. Typical androgen-mediated responses (imposex development, delayed spermatogenesis, tubulus necrosis of the testis with orchitis and Leydig cell hyperplasia) were partially or totally suppressed by a simultaneous administration of CPA. In the two marine species even adult, sexually mature males responded to antiandrogens with a reduction of the male sex organs and an advancement of the sexual repose phase. The results for CPA and VZ are compared with the effects of an exposure to xeno-estrogens (bisphenol A, octylphenol) and xeno-androgens (triphenyltin, tributyltin) in the same species. Each group of endocrine disruptors induces a characteristic set of toxicological effects in prosobranch snails which can be used as endpoints in an organismic invertebrate test for the identification of endocrine mimetic test compounds. Estrogens cause primarily an induction of superfemales resulting in an increased female mortality by the enhancement of spawning mass and egg production. The main effects of androgens are a virilization of females by imposex development and a marked decrease of the fecundity. Compared with estrogens and androgens, the antiandrogen responses seem to be less drastic and might have–in contrast to the two other disruptor classes–no biologically significant effects at the population level.     

Phase II study of XR5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with advanced ovarian cancer*

Background. XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of the present study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with ovarian cancer who had relapsed within 1 year after first-line chemotherapy with taxanes and platinum for advanced disease. Patients and methods. Patients received XR5000 at the dose of 3010mg/m² through a 120-h central venous infusion every 3 weeks. Toxicity was graded according to the Common Toxicity Criteria (CTC), version 2.0. An independent panel assessed response every two cycles according to the World Health Organization (WHO) criteria. Gehan's rule was used for sample size determination. Results. Sixteen patients were enrolled; one patient was ineligible because of prior melphalan single agent treatment. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (eight patients), 1 (five patients), or 2 (two patients). The 15 eligible patients received 43 cycles of XR5000 (median 2, range 1–8). Hematological toxicity was mild with only one grade 3 anemia in one patient. Other drug-related toxicities never exceeded grade 3 and included fatigue (four patients), thrombosis (one patient), nausea (one patient), stomatitis (one patient) as well as dyspnea/cough (one patient). One patient who had refused further therapy and controls after the first cycle was not assessable for response evaluation. No objective responses were observed. Four patients experienced stable disease and 10 patients progressive disease. The median time to progression was 42 days (CI 95% 40; 54). Conclusions. The complete lack of any objective response does not justify further evaluation of XR5000 in patients with advanced ovarian cancer using this dose and schedule, although the therapy was generally well tolerated.     

Environmental Impacts of Diesel Fuel on Bacteria and Phytoplankton in a Tropical Estuary Assessed Using <Emphasis Type="BoldItalic">In Situ</Emphasis> Mesocosms.

Dissolved or dispersed petroleum hydrocarbon concentrations (DDPH) were monitored in Ponggol estuary, Singapore, fortnightly from July 1999 to June 2000. DDPH concentrations ranged from 4.4 to 248.9gl^–1 and 0.4 to 1099.7gl^–1 for surface and subsurface waters, respectively and with mean concentrations of 41.01gl^–1 in the water column. Absorbed or adsorbed petroleum hydrocarbon (AAPH) concentrations measured in sediments ranged from 20.6 to 541.0 mg kg^–1, with mean concentrations of 148.23 mgkg^–1. In situ mesocosm studies of bacteria and phytoplankton were based on field monitoring ofenvironmentally measured concentrations of petroleum hydrocarbons, using diesel fuel as the source of contaminant. The mesocosm comprised of 25 L clear polycarbonate carboys incubated in situ for 6 days. Water and sediments from a clean site with undetectable levels of petroleum hydrocarbons were used in controls. The treatment mesocosms comprised of mean and highest concentrations of DDPH and AAPH. The study revealed signs of acute toxicity to autotrophs viz., phytoplankton and autotrophic bacteria in treatments simulating concentrations of diesel fuel found in the sediments. A stimulatory effect was seen at lower concentrations. Bacterial heterotrophs responded positively to all concentrations of diesel fuel because of the abundance of a carbon source, reduced grazing pressure and reduced competition for nutrients from phytoplankton.     

A phase II study of topotecan in patients with anaplastic oligodendroglioma or anaplastic mixed oligoastrocytoma

To determine the efficacy and toxicity of a novel chemotherapeutic approach with topotecan, a camptothecin analog, for progressive or recurring anaplastic oligodendroglioma or mixed oligoastrocytoma.Patients from seven centers with recurrent or progressive disease were treated with topotecan, 1.5mg/m² intravenously (i.v.), 30min daily×5 days every 3 weeks. Efficacy and toxicity were assessed clinically and radiologically. The study was planned to accrue up to 30 evaluable patients if there was at least one response among the first 15 patients treated.Sixteen eligible patients entered the study. No response was documented in 14 evaluable patients. Eleven patients had stable disease of a median of 3.8 months and three had progressive disease. Sixteen patients were evaluable for toxicity. The most significant toxic effect was myelosuppression. Grade 3 or 4 granulocytopenia was experienced by 15 of 16 patients and led to dose reduction in nearly half of the cycles delivered. Other adverse effects were fatigue, nausea, stomatitis, alopecia, and vomiting.Topotecan, delivered in the daily×5 regimen, is relatively well tolerated. We could not demonstrate significant activity among the population studied to justify completing accrual to 30 patients. Topotecan did not demonstrate, with this small sample size, efficacy as a salvage chemotherapy monotherapy after exposure to procarbazine, CCNU and vincristine. Further trials with different agents in this indication are certainly warranted.     

Activity of weekly irinotecan (CPT-11) in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes

Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is active in the treatment of non-small cell lung cancer (NSCLC). In this report we describe our experience with this drug when used as a single agent in patients with advanced NSCLC refractory to chemotherapy with platinum and taxanes. Nineteen NSCLC patients (thirteen males and six females; 53% adenocarcinoma and 26% squamous cell carcinoma) with a median age of 52 years (range 34–71) and a Karnofsky performance status of 60% (60–80%) were included in the study. At baseline, the patients had a median of two disease sites and had been treated with a median of two prior regimens. Irinotecan was given at a dose of 100mg/m² i.v.) weekly for 4 weeks followed by 1 week of rest. A total of 123 weekly infusions were administered, and each patient received a median of 4 weeks of treatment (range 1–32). All patients were evaluated by intention-to-treat analysis for efficacy and safety. Main toxicities reported were grade 3 neutropenia (10% of patients), diarrhea (10% of patients), and grade 4 thrombocytopenia (5% of patients). The overall clinical response rate was 16% (95% CI: 8–24) with three partial responses and 9 (47%) patients with stable disease. The median time to progression and the median survival time were 7 and 15 weeks, respectively. In conclusion, weekly irinotecan showed antitumoral activity and minimum toxicity in NSCLC patients refractory to platinum and taxanes.     

Slow replenishment of carnitine deficiency after cessation of long-term treatment with pivaloyl-containing antibiotics

Long-term treatment with pivampicillin and pivmecillinam for 6–24 months in five adults and one child reduced the total serum carnitine concentration to 3.7–14 mol/l (reference value: 25–66 mol/l). Muscle carnitine was reduced to 0.3–0.7mol/g wet weight (reference value: 3–5mol/g) in two cases. All patients had muscle symptoms with weakness, asthenia and pains. One showed signs of carnitine depletion in the liver with increased secretion of dicarboxylic acids (C6, C8, C10) in urine and limited ketone body formation during prolonged fasting. Serum carnitine increased slowly after cessation of therapy and reached normal concentrations after 6–12 months. All symptoms caused by carnitine depletion disappeared. This was achieved on a normal diet without carnitine supplementation.