Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)☆.

BACKGROUND: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study. PATIENTS AND METHODS: This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used. RESULTS: Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR = 0.71, 95% CI (0.57; 0.89), P = 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR = 0.88, 95% CI (0.65; 1.21), P = 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively. CONCLUSIONS: With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.

Targeting protein kinase C in sarcoma.

Protein kinase C (PKC) is a family of serine/threonine tyrosine kinases that regulate many cellular processes including division, proliferation, survival, anoikis and polarity. PKC is abundant in many human cancers and aberrant PKC signalling has been demonstrated in cancer models. On this basis, PKC has become an attractive target for small molecule inhibition within oncology drug development programmes. Sarcoma is a heterogeneous group of mesenchymal malignancies. Due to their relative insensitivity to conventional chemotherapies and the increasing recognition of the driving molecular events of sarcomagenesis, sarcoma provides an excellent platform to test novel therapeutics. In this review we provide a structure-function overview of the PKC family, the rationale for targeting these kinases in sarcoma and the state of play with regard to PKC inhibition in the clinic.

Dichloroacetate induces autophagy in colorectal cancer cells and tumours.

BACKGROUND: Dichloroacetate (DCA) has been found to have antitumour properties. METHODS: We investigated the cellular and metabolic responses to DCA treatment and recovery in human colorectal (HT29, HCT116 WT and HCT116 Bax-ko), prostate carcinoma cells (PC3) and HT29 xenografts by flow cytometry, western blotting, electron microscopy, (1)H and hyperpolarised (13)C-magnetic resonance spectroscopy. RESULTS: Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo. We observed increased production of reactive oxygen species (ROS) and mTOR inhibition (decreased pS6 ribosomal protein and p4E-BP1 expression) as well as increased expression of MCT1 following DCA treatment. Steady-state lactate excretion and the apparent hyperpolarised [1-(13)C] pyruvate-to-lactate exchange rate (k(PL)) were decreased in DCA-treated cells, along with increased NAD(+)/NADH ratios and NAD(+). Steady-state lactate excretion and k(PL) returned to, or exceeded, control levels in cells recovered from DCA treatment, accompanied by increased NAD(+) and NADH. Reduced k(PL) with DCA treatment was found in HT29 tumour xenografts in vivo. CONCLUSIONS: DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced k(PL) and increased NAD(+)/NADH ratio. The observed cellular and metabolic changes recover on cessation of treatment.

Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Efficacy and safety of sorafenib in a subset of patients with advanced soft tissue sarcoma from a Phase II randomized discontinuation trial.

AIM: Phase II multi-disease randomized discontinuation trial to assess the safety and efficacy of sorafenib including patients with advanced soft tissue sarcoma (STS). METHODS: Sorafenib (400 mg twice daily) was initially administered for 12 weeks. Patients with: ≥25% tumour shrinkage continued sorafenib; ≥25% tumour growth discontinued; other patients were randomized and received sorafenib or placebo. RESULTS: Twenty-six patients (median age 55 years) were enrolled. Common drug-related adverse events, including fatigue, hand-foot skin reaction, rash or gastrointestinal disturbances, were manageable, reversible and generally low grade. Fatigue, skin toxicity, nausea, diarrhoea and hypertension occurred at grade ≥3 in 19% of patients. After 12 weeks eight (31%) patients had not progressed. Three patients who experienced tumour shrinkage and continued on sorafenib, and five (19%) were randomized either to continue sorafenib or to receive placebo. Of the three patients randomized to sorafenib, one achieved a partial response and two had SD. Overall one patient achieved a partial response and three further patients achieved minor responses. CONCLUSIONS: There was evidence of disease activity in STS as defined by tumor regressions including one objective partial response. Further investigation in STS is warranted.

Metabolites of 2'-fluoro-2'-deoxy-D-glucose detected by 19F magnetic resonance spectroscopy in vivo predict response of murine RIF-1 tumors to 5-fluorouracil.

There is a clinical need for early detection of tumor response to therapy. This study aimed to determine whether metabolites of fluorodeoxyglucose (FDG) detected in solid mouse tumors in situ by I9F magnetic resonance spectroscopy (19F MRS) correlated with response to 5-fluorouracil chemotherapy. After injection of FDG (1.4 mmol/kg i.p.), uptake and metabolism was monitored for 2 h in RIF-1 tumors. FDG was detectable immediately, and after 10 min, a second broad peak was detected 5-6 ppm upfield. 19F MRS analysis of cell and tumor extracts in vitro showed that the upfield peak (> or =15% of the total detectable 19F signal) consisted of the epimer alpha-fluorodeoxymannose (FDM) and various conjugates. Mice treated with 5-fluorouracil (130 mg/kg) received, 48 h later, a repeat dose of FDG. The change in the rate of FDM formation, but not the FDG or total 19F signal, correlated significantly with the response to 5-fluorouracil (P = 0.032), suggesting that 19F MRS of FDM metabolism in vivo may be a novel means of predicting tumor response.

Idoxifene: report of a phase I study in patients with metastatic breast cancer.

Idoxifene, a novel antiestrogen with reduced estrogenic activity when compared to tamoxifen, has been given to 20 women with metastatic breast cancer, 19 of whom had received tamoxifen previously, in doses between 10-60 mg. Idoxifene had an initial half-life of 15 h and a terminal half-life of 23.3 days. At a maintenance dose of 20 mg, a mean steady-state level of 173.5 ng/ml was achieved. Significant falls in luteinizing hormone and follicle-stimulating hormone were seen, but the falls were not dose related. Idoxifene was well tolerated, with 11 patients complaining of mild symptoms similar to those seen with tamoxifen. Fourteen patients continued idoxifene therapy for 1-56 weeks; 4 patients showed stabilization of disease for 6-56 weeks and 2 patients showed a partial response.

ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study.

N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is a water-soluble, folate-based thymidylate synthase (TS) inhibitor designed to be a less toxic and more potent analogue of the clinically tested N10-propargyl-5,8-dideazafolic acid. Inhibition of isolated L1210 TS by ICI D1694 is mixed noncompetitive (although tending toward competitive), with a Ki of 62 nM (Kies = 960 nM). The synthetic gamma-polyglutamates are up to 2 orders of magnitude more potent as inhibitors of TS; e.g., the tetraglutamate (glu4) has a Ki of 1.0 nM (Kies = 15 nM). Although inhibitory activity of ICI D1694 toward rat liver dihydrofolate reductase was similar to that of TS (Ki = 92 nM; competitive inhibition) the polyglutamate derivatives did not show enhanced activity. ICI D1694 was also a very potent inhibitor of L1210 cell growth (50% inhibitory activity = 8 nM). L1210 growth inhibition was not observed in the presence of thymidine, consistent with TS being the locus of action. Folinic acid antagonized L1210 growth inhibition in a competitive fashion such that the highest folinic acid concentration used (25 microM) increased the 50% inhibitory activity 6000-fold. When given as a 4-h delayed "rescue", folinic acid was much less effective in antagonizing growth inhibition. These observations are consistent with folinic acid competing with ICI D1694 for uptake into the cell and/or intracellular polyglutamation. The L1210:1565 cell line, which has greatly impaired reduced-folate/methotrexate transport and thus is resistant to methotrexate, was significantly cross-resistant to ICI D1694 (121-fold), suggesting that ICI D1694 is dependent on this uptake mechanism for good cytotoxic potency in L1210 cells. L1210 cells that were incubated for 4 h with 0.1 microM 3H-ICI D1694 accumulated approximately 1.5 microM intracellular 3H, and the high performance liquid chromatography analysis of the cell extracts demonstrated that 96% of the 3H was associated with the ICI D1694 polyglutamate fractions (principally glu4). Upon resuspension in drug-free medium for 24 h, approximately 75% of the cellular 3H was retained, this being the higher polyglutamate pool (glu4-6). In mice, after a single bolus injection of 10 mg/kg of ICI D1694, TS was inhibited greater than 80% for 24 h in ascitic L1210:NCI cells (as measured by the rate of 3H release from [5-3H]deoxyuridine). ICI D1694 cured the L1210:ICR ascitic tumor in mice at 0.4 mg/kg daily for 5 days (maximum tolerated dose, approximately 50 mg/kg).(ABSTRACT TRUNCATED AT 400 WORDS)

Carbogen breathing increases 5-fluorouracil uptake and cytotoxicity in hypoxic murine RIF-1 tumors: a magnetic resonance study in vivo.

The purpose of this study was to examine the effect of carbogen gas (95% O2-5% CO2) on uptake and metabolism of 5-fluorouracil (5FU) in murine RIF-1 tumors and their growth in vivo. In addition, we have explored the mechanisms by which carbogen can transiently affect the physiology of RIF-1 tumors. After i.p. injection of 1 mmol/kg 5FU into C3H mice, the uptake and metabolism of the drug by s.c. RIF-1 tumors was followed for 2 h noninvasively using 19F-magnetic resonance spectroscopy (MRS). In all animals, irrespective of tumor size, carbogen caused a significant increase in the half-life (t(1/2)) of the elimination of 5FU by the tumor and a significant increase in growth inhibition. In 2-3-g tumors (group II), carbogen also caused increased 5FU uptake and metabolism to the cytotoxic 5-fluoronucleotides, whereas in 0.8-1.5-g tumors (group I), only the t(1/2) was slightly increased. These results suggested that tumor size was an important factor in the effect of carbogen on tumor physiology. Measurements of RIF-1 tumor vascular and necrotic volume showed no significant differences between group I and group II tumors. However, 1H-MR images of RIF-1 tumors showed that carbogen caused a transient decrease in signal intensity, which correlated positively (P = 0.02) with tumor size, suggesting that larger tumors responded to carbogen by transiently increasing O2 uptake from the blood. 19F-MRS was used to measure RIF-1 tumor retention of the fluorinated nitroimidazole SR-4554. These studies also showed a positive correlation (P = 0.001) with tumor size, implying greater hypoxia in larger tumors. We propose that carbogen may transiently open nonfunctional blood vessels in the tumor, allowing increased leakage of 5FU from the plasma into the extracellular space. 5FU transport is known to be pH dependent. Intra- and extracellular tumor pH was measured using 31P- and 19F-MRS, which showed that carbogen caused a significant decrease in the extracellular pH of 0.1 unit in group II tumors and a consequent increase in the negative pH gradient across the tumor plasma membrane, which can cause increased 5FU uptake. The pH gradient was unaffected in group I tumors. We conclude that carbogen breathing can increase tumor uptake of 5FU by two independent mechanisms involving changes in tumor blood flow and pH, which consequently cause increased formation of 5-fluoronucleotides and cytotoxicity. The effect seems more pronounced in hypoxic tumors, implying that carbogen would be a valuable aid in clinical chemotherapy.

Phase I trial and pharmacokinetics of trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine).

Trimelamol is an analogue of hexamethylmelamine and pentamethylmelamine which does not require metabolic activation and is sufficiently soluble to allow parenteral administration. A Phase I trial has been performed at the Royal Marsden Hospital in which two schedules of administration have been evaluated, a single i.v. infusion repeated every 3 weeks and 3 daily doses repeated every 3 weeks. Pharmacokinetic analysis was performed at all dose levels on both schedules and a linear correlation was demonstrated between dose and area under the curve. Myelosuppression was dose limiting for single dose administration with a maximum tolerated dose of 2400 mg/m2. Median leukocyte nadirs at 1800, 2100, and 2400 mg/m2 were 3.2, 2.6, and 1.5 x 10(9)/liter. Thrombocytopenia and anemia also occurred but were not dose limiting. Doses greater than 1500 mg/m2 caused WHO grade 3 nausea and vomiting but no acute sedation. Three day administration appeared to be less myelosuppressive, giving a maximum tolerated dose of 1000 mg/m2. Median leukocyte nadirs at 800, 900, and 1000 mg/m2 daily for 3 days were 3.0, 2.3, and 1.5 x 10(9)/liter. Nonhematological toxicities were also less marked on the fractionated schedule. Antitumor effects were observed including 1 complete and 9 partial responses. Demonstration of activity in ovarian cancer has led to further evaluation in this disease using the 3-day schedule at a dose of 800 mg/m2 daily for 3 days.

Ewing's sarcoma and primitive neuroectodermal tumor in adults: are they different from Ewing's sarcoma and primitive neuroectodermal tumor in children?

PURPOSE: To determine whether age at diagnosis influences the behavior of Ewing's sarcoma and primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS: We reviewed the clinical features, treatment, and outcome of 59 consecutive patients with Ewing's sarcoma and PNET treated on the Adult Sarcoma Unit at our institution from 1980 to 1995. RESULTS: The 37 male and 22 female patients had a median age of 24 years. Lower limb was the most common primary tumor site. Fifteen patients had nonmetastatic tumor less than 100-mL volume, 27 had nonmetastatic disease greater than 100-mL volume, and 17 had evidence of metastatic disease at presentation. The origin of the primary tumor was soft tissue in 28 cases, bone in 30, and uncertain in one. The Kaplan-Meier estimate of 5-year overall survival (OS) in all patients was 38% and of progression-free survival (PFS), 27%. When patients with metastatic disease at presentation were excluded, these figures increased to 52% and 34%, respectively. Bulk of disease at presentation and response to primary treatment were statistically highly significant predictors of both PFS and OS. Age and tissue of origin of the tumor did not influence outcome. CONCLUSION: The behavior of Ewing's sarcoma and PNET in adults is no different from its behavior in children. We feel the way forward in the treatment of adults with Ewing's sarcoma and PNET is for them to be included in the current multicenter trials of multidisciplinary treatment directed at children.

Synovial sarcoma: a clinicopathologic, staging, and prognostic assessment.

PURPOSE: Synovial sarcoma (SS) is a common soft tissue sarcoma (STS) with a propensity for young adults and notable sensitivity to chemotherapy (CT). This study provides a current clinicopathologic, staging, and prognostic assessment for SS. The problems with the current American Joint Committee for Cancer (AJCC) Staging System in relation to SS are discussed. METHODS: Review of a prospective database supplemented by retrospective data. RESULTS: One hundred fifty patients were assessed; median age was 30 years and median follow-up was 52 months. Overall actuarial 5-year survival rate was 57%. Size trend, but not a cutoff of less than 5 cm versus > or = 5 cm, was a prognostic indicator (P <.001). The current AJCC/International Union Against Cancer Staging System differentiated prognosis less well than the recently proposed Royal Marsden Hospital Staging System. Age greater than 20 years at diagnosis implied worse prognosis. A local recurrence event was associated with a worse survival (P <.001). Therapeutic CT was administered to 55 patients. Eleven of 19 patients had an objective response to a combination of ifosfamide and doxorubicin. Four cases had complete response after CT. Twenty-one patients had pulmonary metastasectomy, with an actuarial 5-year survival rate of 23%. CONCLUSION: SS tends to affect young people. In this subtype of STS, size trend is the most significant influence on stage and hence survival; however, smaller SSs have an unexpectedly poor prognosis. Adequate local control may affect survival. SS is often chemosensitive, and given its poor prognosis, multicenter trials of adjuvant therapy are warranted.

Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer.

PURPOSE: We aimed to determine the maximum-tolerated dose (MTD) clinical toxicities, pharmacokinetics, and pharmacodynamics of oral JM216 given once daily for 5 days to cancer patients. PATIENTS AND METHODS: Patients who fulfilled standard phase I trial criteria were enrolled. Oral JM216 was given at doses based on patient body-surface area, on an empty stomach, once daily for 5 consecutive days, as 10-, 50-, and 200-mg hard gelatin capsules and with oral antiemetics. The pharmacokinetics of platinum were studied on days 1 and 5 of the first treatment course using atomic absorption spectrophotometry (AAS). RESULTS: Thirty-two patients received 94 courses of oral JM216 at doses that ranged from 30 to 140 mg/m2 body-surface area for 5 consecutive days. The MTD was 140 mg/m2/d. The dose-limiting toxicities were thrombocytopenia and neutropenia. Hematotoxicity was reversible (nadir, 17 to 21 days; recovery, 28 days), noncumulative, and dependent on the dose and history of previous therapy. There were two instances of neutropenic sepsis. Two-thirds of patients experienced mild nausea, vomiting, or diarrhea. There was no ototoxicity, neurotoxicity, nephrotoxicity, or objective tumor responses. There was a significant correlation between JM216 dose and the day 1 and 5 plasma ultrafiltrate area under the concentration-time curve (AUC; r = .78), which indicates linear pharmacokinetics. There was considerable intersubject pharmacokinetic and pharmacodynamic variability, but a significant sigmoidal relationship between the plasma ultrafiltrate AUC and severity of thrombocytopenia (R2 = .83). CONCLUSION: We recommend JM216 doses of 100 and 120 mg/m2/d x 5 for previously treated and untreated patients, respectively, for phase II trials.

Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors.

PURPOSE: To perform a phase I clinical and pharmacologic study of ZD1694 (Tomudex, Alderley Park, United Kingdom), a new folate-based thymidylate synthase (TS) inhibitor, in patients with advanced malignancy. PATIENTS AND METHODS: From February 1991 to January 1993, 61 patients with a range of solid tumor received 161 courses of ZD1694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.5 mg/m2. Pharmacokinetic (PK) analysis was performed with the first two courses of treatment. There were 33 men and 28 women with a median age of 53 years (range, 21 to 73). Fifty-five patients (90%) had previously received chemotherapy. RESULTS: Reversible liver toxicity and dose-related gastrointestinal (GI) and bone marrow toxicity occurred at > or = 1.6 mg/m2. Liver function usually returned to normal with repeated treatment, but GI and bone marrow toxicities generally became more severe. No renal toxicity was observed. The maximum-tolerated dose (MTD) was 3.5 mg/m2, at which, in addition to antiproliferative toxicities, four of six patients (67%) developed severe malaise that consisted of anorexia, nausea, and asthenia, with rapidly decreasing performance status that limited re-treatment. Abnormal liver function was also seen in four patients (67%). At 3.0 mg/m2, grades III and IV diarrhea were seen in six of 23 patients (26%) and grade IV myelosuppression in two others. Liver toxicity was self-limiting and not associated with severe malaise. Two patients had a partial response to treatment. PK analysis showed that plasma elimination was triexponential, with pronounced variability in the mean terminal half-life (t1/2gamma) for a given dose ranging from 8.2 to 105 hours. There was a linear relationship between dose and both the area under the concentration-time curve (AUC) and maximum concentration (Cmax), but no clear association between these parameters and response or toxicity. CONCLUSION: The dose of ZD1694 recommended for phase II trials is 3.0 mg/m2.

Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: a study of the european organization for research and treatment of cancer soft tissue and bone sarcoma group.

PURPOSE: To assess antitumor response and time to progression (TTP) with docetaxel compared with doxorubicin in first-line treatment of advanced and/or metastatic soft tissue sarcoma. PATIENTS AND METHODS: Patients with measurable soft tissue sarcoma lesions and adequate bone marrow, liver, and renal function were entered onto the study. They were randomized to either docetaxel 100 mg/m(2) given as a 1-hour intravenous infusion every 3 weeks or doxorubicin 75 mg/m(2) given as a bolus injection every 3 weeks. A maximum of seven cycles of treatment were scheduled. The study was designed as a randomized phase III study evaluating TTP by log-rank model. There was a clause for premature closure of the trial if fewer than five responses were observed among the first 25 assessable patients in the docetaxel treatment arm. RESULTS: Eighty-six patients were entered onto the study; 85 were assessable for toxicity and 83 for response. The rate of severe granulocytopenia was not significantly different between the two arms. Nausea (P =.001), vomiting (P <.001), and stomatitis (P =.005) were more common with doxorubicin therapy, whereas neurotoxicity was more frequent with docetaxel treatment. The response rate to doxorubicin therapy was 30% (95% confidence interval, 17% to 46%), whereas no responses to docetaxel therapy were seen (P <.001). In view of this, the trial was closed prematurely and the phase III study part was not conducted. CONCLUSION: Docetaxel is inactive in soft tissue sarcomas and cannot be recommended for further use in treatment of this disease.

Investigations in vivo of the effects of carbogen breathing on 5-fluorouracil pharmacokinetics and physiology of solid rodent tumours.

PURPOSE: We have shown previously that carbogen (95% 0(2), 5% CO(2)) breathing by rodents can increase uptake of anticancer drugs into tumours. The aim of this study was to extend these observations to other rodent models using the anticancer drug 5-fluorouracil (5FU). 5FU pharmacokinetics in tumour and plasma and physiological effects on the tumour by carbogen were investigated to determine the locus of carbogen action on augmenting tumour uptake of 5FU. METHODS: Two different tumour models were used, rat GH3 prolactinomas xenografted s.c. into nude mice and rat H9618a hepatomas grown s.c. in syngeneic Buffalo rats. Uptake and metabolism of 5FU in both tumour models with or without host carbogen breathing was studied non-invasively using fluorine-19 magnetic resonance spectroscopy ((19)F-MRS), while plasma samples from Buffalo rats were used to construct a NONMEM pharmacokinetic model. Physiological effects of carbogen on tumours were studied using (31)P-MRS for energy status (NTP/Pi) and pH, and gradient-recalled echo magnetic resonance imaging (GRE-MRI) for blood flow and oxygenation. RESULTS: In both tumour models, carbogan-induced GRE-MRI signal intensity increases of approximately 60% consistent with an increase in tumour blood oxygenation and/or flow. In GH3 xenografts, (19)F-MRS showed that carbogen had no significant effect on 5FU uptake and metabolism by the tumours, and (31)P-MRS showed there was no change in the NTP/Pi ratio. In H9618a hepatomas, (19)F-MRS showed that carbogen had no effect on tumour 5FU uptake but significantly ( p=0.0003) increased 5FU elimination from the tumour (i.e. decreased the t(1/2)) and significantly ( p=0.029) increased (53%) the rate of metabolism to cytotoxic fluoronucleotides (FNuct). The pharmacokinetic analysis showed that carbogen increased the rate of tumour uptake of 5FU from the plasma but also increased the rate of removal. (31)P-MRS showed there were significant ( p

Understanding anticancer drug resistance: opportunities for modulation and impact on new drug design.

As our understanding of the mechanisms of cytotoxic drug resistance improves, it becomes feasible to circumvent this resistance through the rational design of non cross-resistant analogues or modulation of existing agents. Although this knowledge has yet to make a major impact on the success of cancer therapy, there are good reasons to be optimistic that this increased knowledge will be translated into more effective therapy in the future.

Stable analogues of the antitumour agent trimelamol retain in vitro cytotoxicity in drug-sensitive and resistant rodent and human cell lines.

In spite of clinical activity in heavily-pretreated ovarian cancer, the antitumour s-triazine trimelamol [TM; tris(hydroxymethyl)-tris(methyl)melamine] had to be withdrawn from further clinical studies due to formulation difficulties related to instability. A synthetic programme has produced tris(hydroxymethyl) analogues containing electron-withdrawing groups in place of methyl-triscyanomethyl CB 7669, tristrifluoroethyl CB 7639, CB 7529 and trispropargyl CB 7547, all showing markedly superior stability to TM. Chemosensitivity testing of analogues (MTT assay, continuous exposure) using a panel of rodent and human cell lines showed activity close to that of TM, e.g. for the CH1 human ovarian cancer cell line. IC50 values were TM 23.4 microM, CB 7639 30.5 microM, CB 7529 29.5 microM, CB 7547 28.5 microM and CB 7669 27.3 microM. CB 7669 and CB 7639 required prolonged exposure (> 12 h) in order to exhibit equivalent cytotoxicity to a 2-h exposure to TM. Thus, rather than administration as a single daily dose, the stable analogues may be more suited to prolonged infusion, which was suggested as being a more beneficial regimen in clinical trials with TM. In line with clinical observations indicating the efficacy of TM in platinum-refractory ovarian cancer, we saw no significant cross-resistance to TM or CB 7529 in a range of platinum-sensitive and acquired-resistant cell line pairs or in an alkylating-agent resistant cell line, despite TM's ability to crosslink DNA. Data obtained using cell lines with acquired resistance to TM, CB 7669 and formaldehyde (released in the breakdown of TM) suggest a pivotal role for formaldehyde and a more minor role for alkylating activity in the mechanism of action of the N-(hydroxymethyl)melamines in vitro. Further clinical trials of these compounds are eagerly awaited, and their usefulness as second-line chemotherapy for heavily pretreated ovarian cancer deserves further investigation.