Cees J. van Groeningen

Predictive Factors for Outcome in a Phase II Study of Gefitinib in Second-Line Treatment of Advanced Esophageal Cancer Patients

PURPOSE The efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib was assessed in a phase II study in patients with advanced esophageal cancer. Several biologic features were investigated as potential markers of gefitinib activity. PATIENTS AND METHODS Patients with advanced esophageal cancer, who had failed one line of prior chemotherapy, were administered gefitinib 500 mg/d. Response was evaluated every 8 weeks. Tumor material obtained before gefitinib treatment was investigated for gene mutations in EGFR, k-ras, and PIK3CA; protein expression levels of EGFR, p-Akt, and p-Erk; and EGFR gene amplification. RESULTS Of the 36 enrolled patients, one (2.8%) achieved a partial response, 10 (27.8%) had stable disease, 17 (47.2%) experienced progression on treatment, and eight (22.2%) were not assessable for response. The progression-free survival time was 59 days, and the median overall survival time was 164 days. Although EGFR or PIK3CA mutations were absent, k-ras mutations were found in two patients with progressive disease. High EGFR gene copy number was identified in two patients experiencing partial response or progressive disease. A higher disease control rate (response plus stable disease) was observed in females (P = .038) and in patients with squamous cell carcinoma (SCC; P = .013) or high EGFR expression (P = .002). CONCLUSION Gefitinib has a modest activity in second-line treatment of advanced esophageal cancer. However, the patient outcome was significantly better in female patients and in patients demonstrating high EGFR expression or SCC histology. The selection of esophageal cancer patients for future studies with EGFR-TKIs based on the level of EGFR expression in their tumors or SCC histology should be considered.

Pharmacokinetics of free and total platinum species after rapid and prolonged infusions of cisplatin

Pharmacokinetic studies were performed in 51 patients who received cisplatin infusions. Two treatment regimens (single‐day or daily for 5 days) and three infusion schedules (for 4 to 15 minutes, 2 to 3 hours, or 24 hours) were used. The daily dose of cisplatin varied from 20 to 120 mg/m2. The kinetics of total platinum studied up to day 5 revealed differences only during the initial period after the infusion. Peak levels were both dose and schedule dependent and initial t½values in the decay curves were only schedule dependent (mean values: 13 minutes for rapid infusions, 40.3 minutes for 2 to 3–hour infusions, and 220.5 minutes for 24‐hour infusion). The t½ values between days 1 and 5 were neither dose nor schedule dependent (mean 5.0 to 7.3 days). Concentrations of free platinum declined biexponentially after the rapid and 2 to 3–hour infusions, but they declined monoexponentially after 24‐hour infusions. Final t½ values ranged from 26.0 to 78.8 minutes. In patients with normal renal and hepatic function, the free platinum AUC was identical for cisplatin infusions of different duration when equal doses were given. Free platinum clearance correlated with creatinine clearance (P = 0.017). The uptake of platinum in red blood cells was rapid, and peak concentrations correlated with the free platinum AUC (P = 0.0006), independent of the infusion schedule. The decay of platinum levels in red blood cells was biphasic. The mean terminal t½for the interval between days 5 and 15 was 29.8 days. This suggests a breakdown of red blood cells that results from cisplatin dosing.

A comparison of 5-fluorouracil metabolism in human colorectal cancer and colon mucosa

The metabolism of 5‐fluorouracil (5‐FU) was studied in biopsy specimens of primary colorectal cancer and healthy colonic mucosa obtained from previously untreated patients immediately after surgical removal. The conversion of 5‐FU to anabolites was measured under saturating substrate (5‐FU) and cosubstrate concentrations. For all enzymes, the activity was about threefold higher in tumor tissue compared with healthy mucosa of the same patient. The activity of pyrimidine nucleoside phosphorylase with deoxyribose‐1‐phosphate (dRib‐1‐P) was about tenfold higher (about 130 and 1200 nmol/hr/mg protein in tumors) than with ribose‐1‐phosphate (Rib‐1‐P), both in tumor and mucosa. Synthesis of the active nucleotides (5‐fluoro‐uridine‐5′‐monophosphate [FUMP] and 5‐fluoro‐2′deoxyuridine‐5′‐monophosphate [FdUMP]) was studied by adding physiologic concentrations of adenosine triphosphate (ATP) to the reaction mixture; the rate of FdUMP synthesis was 50% of that of FUMP (about 4 and 7 nmol/hr/mg protein in tumors). Direct synthesis of FUMP from 5‐FU in the presence of 5‐phosphoribosyl‐1‐pyrophosphate (PRPP) was about 2 nmol/hr/mg protein. With the natural substrate for this reaction, orotic acid, the activity was about 14‐fold higher. To obtain insight into the recruitment of precursors for these cosubstrates, the authors also tested the enzyme activity of pyrimidine nucleoside phosphorylase with inosine and ribose‐5‐phosphate (Rib‐5‐P, as precursors for Rib‐1‐P) and deoxyinosine (as a precursor for dRib‐1‐P); enzyme activities were approximately 7%, 7%, and 3%, respectively, of that with the normal substrates, both in tumors and mucosa. However, when ATP and Rib‐5‐P were combined, the synthesis of FUMP was about 70% of that with PRPP, but only in tumors. In normal tissues no activity was detectable. These data suggest a preference of colon tumor over colon mucosa for the conversion of 5‐FU to active nucleotides by a direct pathway; a selective antitumor effect of 5‐FU may be related to this difference.

Imatinib Mesylate in Patients with WHO B3 Thymomas and Thymic Carcinomas

Thymic malignancies are rare tumors of the mediastinum. c-KIT is highly expressed in thymic carcinomas (TC) but infrequently in thymomas. Anecdotal experience suggests activity of imatinib mesylate in TC. Patients with unresectable World Health Organization B3 thymomas or TC, performance status 0 to 2, good organ function, and measurable disease were enrolled in this study. Imatinib was administered at 600 mg PO daily. Seven patients were recruited at one institution: two World Health Organization B3 thymomas and five TC. Imatinib treatment was generally well tolerated. Two patients had stable disease and five progressed. Median survival was 4 months, and median time to progression was 2 months. c-KIT expression was found in one of four samples by immunohistochemistry. No mutations were detected in the c-KIT or PDGFRA genes in three samples analyzed. Imatinib has no major activity in this rare tumor. Given the small number of patients treated in this study, selection based on presence of c-KIT mutations might be warranted.

Thymidylate synthase from untreated human colorectal cancer and colonic mucosa: Enzyme activity and inhibition by 5-fluoro-2′-deoxyuridine-5′-monophosphate

Inhibition of thymidylate synthase (TS) by the 5-fluorouracil (5-FU) metabolite FdUMP is considered to be the main mechanism of action of 5-FU. TS from colorectal tumours and normal colon mucosa from 10 untreated patients was studied. There was a large variation in the activity of tumour TS both at 1 and 10 mumol/l of its substrate dUMP; in normal mucosa this variation was less. Inhibition by 10 nmol/l FdUMP in tumours varied from 80 to 90% at 1 mumol/l dUMP; in normal mucosa, inhibition varied from 10 to 80%. The number of FdUMP binding sites ranged from 0.1 to 1 in tumours but such binding sites were not detectable in normal mucosa. The ratio between TS activity and FdUMP binding sites varied considerably in tumours but not in normal mucosa. The deviations from normal kinetics may represent a mutant TS form. Alterations in TS may partly account for differences in response to 5-FU.

Severe acute lung injury induced by gemcitabine.

Gemcitabine is a nucleoside analog that is active in the treatment of various solid tumors. In general it is well tolerated and has few side effects. Pulmonary toxicity reported with gemcitabine use is usually mild and self-limiting. We present a case of severe pulmonary dysfunction after intravenous administration of a single dose of gemcitabine in a 58-year-old female patient with metastatic carcinoma of the pancreas. She developed tachypnea, marked hypoxemia, and an interstitial infiltrate on chest radiograph consistent with pulmonary edema, 4 days after receiving this drug. Diuretics and corticosteroids were beneficial in treating the acute respiratory failure. Pulmonary damage was completely resolved by means of clinical and radiological assessment. Because of the severity of this side effect, no further treatment with gemcitabine was given. Eventually, the patient died because of obstruction of the bowel due to progression of tumor growth. Publications concerning severe pulmonary toxicity due to gemcitabine are sparse. Pathophysiology and treatment are considered and a review of the literature is presented.

Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma.

SummaryThe effect of leucovorin (LV) given in various doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil (5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous administration of 5FU and LV nor 5FU combined with delayed administration of LV potentiated the antitumor activity of 5FU. LV given twice — 1 hr before (50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) — gave significantly better delay of tumor growth of both tumor lines than 5FU did alone (100 mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg. Delayed administration of uridine (3500 mg/kg) allowed the use of higher 5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity led to moderate weight loss in treated mice, but was comparable for mice treated with 5FU alone or combined with LV. Hematological toxicity consisted of moderate leukopenia (nadir 40%), which was observed with the most active schedule and was less severe than with 5FU alone. This schedule did not cause thrombocytopenia, but after discontinuation the thrombocyte count showed an overshoot. Addition of uridine to this schedule reduced hematological toxicity only slightly. It is concluded that LV potentiated the antitumor activity of 5FU against two solid tumor lines, i.e., a relatively resistant and a sensitive murine colon carcinoma, and that toxicity was moderate.

Effect of pyrimidine nucleosides on body temperatures of man and rabbit in relation to pharmacokinetic data.

The effect of high-dose uridine on body temperatures of rabbits and man has been studied in relation to plasma concentrations of uridine and its catabolite uracil. Uridine induced fever in both rabbits and man. High-dose cytidine had no influence on body temperature in rabbits. Plasma concentrations of uridine were between 1 and 1.5 mM at 30 min after an iv bolus injection of 400 mg uridine/kg in rabbits and reached peak levels of 2 mM after a 1-hr infusion of 12 g uridine/m2 in man. The plasma concentration of cytidine in rabbits was about 0.5 mM and that of uridine was 0.30 mM at 30 min after an iv bolus injection of 400 mg cytidine/kg. The mean residence time for uridine in patients and rabbits varied between 80 and 195 min. The area under the plasma concentration–time curve (AUC) for uridine in rabbits was 2.0 mmol · hr/liter, and that for cytidine was 0.6 mmol · hr/liter. A large AUC for uridine indicates a prolonged exposure of tissues to uridine, which might lead to extensive formation of degradation products. The administration of some of these catabolites, dihydrouracil (at 20–40 mg/kg), carbamyl-β-alanine (at 60 mg/kg), and β-alanine (at 300–400 mg/kg), resulted in a significant increase in body temperature. It is concluded that the change in body temperature associated with uridine administration was not due to bacterial pyrogens but that one of the degradation products might be involved in thermoregulation.

Hepatic Arterial Chemotherapy for Colorectal Cancer Metastatic to the Liver

In advanced colorectal cancer, liver metastases are a major problem. In patients with liver metastases as the major site of disease hepatic arterial chemotherapy is a valid alternative to systemic treatment. In this review about hepatic arterial chemotherapy we will discuss the theoretical and practical aspects, the results and complications, the selection of patients for hepatic arterial chemotherapy, and its future developments.

Palliative chemotherapy in advanced gastrointestinal cancer

In this review, the role of chemotherapy in the palliative treatment of advanced gastrointestinal cancer is discussed. Emphasis is placed on chemotherapy-related problems, current chemo-therapy options, and new developments.