A. van der Gaast

Disposition of docetaxel in the presence of P-glycoprotein inhibition by intravenous administration of R101933

Recently, a study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made. Here, we assessed the feasibility of combining docetaxel with intravenously (i.v.) administered R101933, and determined the disposition of docetaxel with and without the P-gp inhibitor. Patients received i.v. R101933 alone at a dose escalated from 250 to 500 mg on day 1 (cycle 0), docetaxel 100 mg/m(2) as a 1-h infusion on day 8 (cycle 1) and the combination every 3 weeks thereafter (cycle 2 and further cycles). 12 patients were entered into the study, of whom 9 received the combination treatment. Single treatment with i.v. R101933 was associated with minimal toxicity consisting of temporary drowsiness and somnolence. Dose-limiting toxicity consisting of neutropenic fever was seen in cycles 1 and 2 or in further cycles at both dose levels. The plasma pharmacokinetics of docetaxel were not changed by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 22.5+/-6.2 l/h/m(2) and 24.2+/-7.4 l/h/m(2) (P=0.38) in cycles 1 and 2, respectively. However, the faecal excretion of unchanged docetaxel decreased significantly after the combination treatment from 2.5+/-2.1% to less than 1% of the administered dose of docetaxel, most likely due to inhibition of the intestinal P-gp by R101933. Plasma concentrations of R101933 were not different in cycles 0 or 2 and the concentrations achieved in the first 12-h period after i.v. infusion were capable of inhibiting P-gp in an ex vivo assay. We conclude that the combination of 100 mg/m(2) i.v. docetaxel and 500 mg i.v. R101933 is feasible, lacks pharmacokinetic interaction in plasma, and shows evidence of P-gp inhibition both in an ex vivo assay and in vivo as indicated by the inhibition of intestinal P-gp.

Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours

A single-agent dose-escalating phase I study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile and recommended dose for phase II studies. Plasma pharmacokinetics were determined as well as the SCH 66336-induced inhibition of farnesyl protein transferase in vivo. SCH 66336 was given orally once daily (OD) without interruption to patients with histologically-confirmed solid tumours. Routine antiemetics were not prescribed. 12 patients were enrolled into the study. Dose levels studied were 300 mg (6 patients) and 400 mg (6 patients) OD. Pharmacokinetic sampling was performed on days 1 and 15. Although at 400 mg OD only 1 patient had a grade 3 diarrhoea, 3 out of 6 patients interrupted treatment early due to a combination of various grade 1-3 toxicities (diarrhoea, uremiacreatinine, asthenia, vomiting, weight loss) indicating that this dose was not tolerable for a prolonged period of time. At 300 mg OD, the same pattern of toxicities was observed, but all were grade 1-2. Therefore, this dose can be recommended for phase II studies. Pharmacokinetic analysis showed that peak plasma concentrations as well as the AUCs were dose-related, with increased parameters at day 15 compared with day 1, indicating some accumulation upon multiple dosing. Plasma half-life ranged from 5 to 9 h and appeared to increase with increasing dose. Steady state plasma concentrations were attained by day 14. A large volume of distribution at steady state suggested extensive distribution outside the plasma compartment. There is evidence of inhibition of protein prenylation in some patients after OD oral administration of SCH 66336. SCH 66336 can be safely administered using a continuous oral OD dosing regimen. The recommended dose for phase II studies using this regimen is 300 mg OD.

The addition of pravastatin to chemotherapy in advanced gastric carcinoma: A randomised phase II trial

PURPOSEnStatins have for long been considered to play a potential role in anticancer treatment based upon their ability to inhibit the mevalonate synthesis pathway. This randomised phase II trial compared the efficacy and safety of pravastatin added to epirubicin, cisplatin and capecitabine (ECC versus ECC+P) in patients with advanced gastric carcinoma.nnnMETHODSnPatients were randomised to receive up to six cycles of 3-weekly ECC with or without pravastatin (40 mg, once daily from day 1 of the first cycle until day 21 of the last cycle). Primary end-point was progression-free rate at 6 months (PFR(6 months)). Secondary end-points were response rate (RR), progression-free survival (PFS), overall survival (OS) and safety. For early termination in case of futility, a two-stage design was applied (P(0) = 50%; P(1) = 70%; α = 0.05; β = 0.10).nnnRESULTSnThirty patients were enrolled. PFR(6 months) was 6/14 patients (42.8%) in the ECC+P arm, and 7/15 patients (46.7%) in the control arm, and therefore the study was terminated after the first stage. In the ECC and ECC+P arm, RR was 7/15 (46.7%) and 5/15 (33.3%), median PFS was 5 and 6 months and median OS was 6 and 8 months, respectively. Toxicity data showed no significant differences, although there was a trend towards more gastrointestinal side-effects such as diarrhoea and stomatitis in the ECC+P arm.nnnCONCLUSIONnIn this randomised phase II trial the addition of pravastatin to ECC did not improve outcome in patients with advanced gastric cancer. Therefore, further testing of this combination in a randomised phase III trial cannot be recommended.

Phase I study of a weekly schedule of a fixed dose of cisplatin and escalating doses of paclitaxel in patients with advanced oesophageal cancer

The objective of this study was to determine the toxicities and maximum tolerated dose (MTD) of a dose-dense schedule with a fixed dose of cisplatin and escalating doses of paclitaxel in patients with metastatic or irresectable squamous cell-, adeno-, or undifferentiated carcinoma of the oesophagus. Patients received paclitaxel over 3 h followed by a 3-h infusion of a fixed dose of cisplatin of 70 mg/m(2) on days 1, 8, 15, 29, 36 and 43. The starting dose of paclitaxel was 80 mg/m(2). Patients were re-treated if white blood cell count (WBC) was >/=1 x 10(9) cells/l, except for day 29 when the WBC had to be >/=3 x 10(9) cells/l. Six patients were treated at each dose level. The dose of paclitaxel was increased by 10 mg/m(2) per level. Of the 24 patients enrolled, 13 had adenocarcinoma, 10 had squamous cell carcinoma and one had an undifferentiated carcinoma. All patients were evaluable for toxicity and 22 of 24 patients were evaluable for response. The paclitaxel dose could be escalated to 110 mg/m(2). At this dose, 3 out of 6 patients developed dose-limiting toxicity (DLT) including neutropenic enterocolitis with sepsis, vomiting and diarrhoea. Diarrhoea grades 3 and 4 was seen in 4 (17%) patients. Two of these patients died of neutropenic enterocolitis. Neutropenia grades 3 or 4 was seen in 20 (83%) patients, but apart from the two patients with neutropenic enterocolitis no other infectious complications were seen. Mild to moderate sensory neurotoxicity was seen in 11 (46%) patients (grade 1 in 8 patients and grade 2 in 3 patients). Other toxicities were mild and easily manageable. Of the 22 evaluable patients, 11 (50%) patients achieved a partial or complete response with a median duration of 13 months. Ten patients with either locally advanced disease or supraclavicular or celiac lymph nodes received additional local treatment after response to chemotherapy, seven patients are still without evidence of disease after a median follow-up of 32 months. Paclitaxel at a dose 100 mg/m(2) infused over 3 h followed by a 3-h infusion of 70 mg/m(2) cisplatin can be recommended for further studies in patients with metastatic or unresectable oesophageal cancer. Occurring diarrhoea should be handled with caution because it may be a sign of neutropenic enterocolitis. The response rate of this dose-dense schedule seems encouraging.

Disease Monitoring by the Tumour Markers Cyfra 21.1 and TPA in Patients with Non-small Cell Lung Cancer

We evaluated the use of two tumour markers Cyfra 21.1 and tissue polypeptide antigen (TPA) for disease monitoring. Assessment of response to WHO criteria was compared to response assessment according to changes in the tumour marker levels. The criteria defined for marker response were a 65% decrease for a partial response and a 40% increase for progressive disease. When response evaluations with a positive lead time were included, 72% of 115 evaluations for Cyfra 21.1 and 59% of 107 evaluations for TPA yielded the same result. Most discordant evaluations were caused by those evaluations whereby the patient achieved a partial response according to the WHO criteria and had normalisation of the marker. Less cases with a positive lead time, more negative lead times, and more patients with progressive disease without an increase of the marker were seen with TPA compared to Cyfra 21.1. In conclusion, Cyfra 21.1 follows the changes in the tumour load better than TPA. Rising levels of both markers nearly always indicate disease progression, and such knowledge easily obtained may prevent the continuation of ineffective treatment.

Prognostic significance of tissue polypeptide-specific antigen (TPS) in patients with advanced non-small cell lung cancer

In this study, we evaluated the prognostic value of the tumour marker, tissue polypeptide-specific antigen (TPS), in 203 patients with non-small cell lung cancer (NSCLC), and related this to several other known prognostic factors. TPS was significantly correlated with lactate dehydrogenase (LDH), gamma-glutamyltranspeptidase and alkaline phosphatase, and the median level of TPS in patients with stage 4 disease was significantly higher as compared to stage 3A and 3B disease. In the univariate analysis, performance status, stage of disease, LDH, alkaline phosphatase, a histology of undifferentiated large cell carcinoma and TPS all had a statistically significant association with survival. Multivariate analysis showed that stage of disease, performance status, histology and TPS were the most important prognostic factors. TPS has prognostic significance for survival in patients with advanced NSCLC, independent from performance status and stage of disease.

Chemotherapy followed by surgery in patients with carcinoma of the distal esophagus and celiac lymph node involvement

Patients with carcinoma of the distal esophagus and metastatic celiac lymph nodes (M1a) have a poor prognosis and are often denied surgery. In this study, we evaluated our treatment strategy of chemotherapy followed by surgery in patients with M1a disease.

Correlation between changes in the tumour markers CA-M26 and CA-M29 and standard response evaluation in patients with metastatic breast cancer

In this study we correlated response evaluated by standard WHO criteria to strict defined criteria of tumour marker response in 63 patients with metastatic breast cancer. Pretreatment sensitivity at first evaluation was 71% and 85% for CA-M26 and CA-M29, respectively. Of the 156 evaluations for CA-M26 and 178 for CA-M29 in 26 and 30 patients with evaluable lesions 72% and 67% were concordant with the results of the clinical evaluations. When the discordant evaluations due to lead time were included the concordances were 87% for CA-M26 and 83% for CA-M29. Of the 70 evaluations for CA-M26 and 92 for CA-M29 in 19 and 24 patients with non-evaluable lesions 59% and 72% were concordant with the results of the clinical evaluations. Most importantly, progressive disease according to the changes in the marker level nearly always predicted disease progression. Such knowledge obtained in a simple way may prevent continuation of ineffective treatment in patients with metastatic breast cancer.