Ellen Bork

Teniposide (VM-26), an overlooked highly active agent in small-cell lung cancer. Results of a phase II trial in untreated patients.

Teniposide, VM-26 (Vumon), was administered in a dose of 60 mg/m2 on days 1 to 5 every third week to 36 patients with histologically confirmed small-cell lung cancer. None had previously received chemotherapy or radiotherapy. The median age was 73 years (range, 52 to 79). Thirty-three patients were evaluable; 21 of these had local disease. Five patients had bone marrow metastases, four had liver involvement, and one CNS metastases. All patients had a performance status less than or equal to 2 before the start of treatment. Thirty patients obtained a response (90%), ten of whom had a complete remission (30%). The median duration of remission was 8+ months (range, 1.1 to 17+ months), whereas the median survival was 8.7 months (range, 1.9 to 20 months). Toxicity was primarily hematologic, with leukopenia the only dose-limiting effect. Besides alopecia, all other side effects were minimal including nausea and vomiting. We find these results provocative in regard to the response rate and the duration of response obtained as well as in reference to the dismal results that prior investigations in previously treated patients have shown. These data may indicate the need for reconsideration of the usual strategy for performing phase II trials.

Teniposide and etoposide in previously untreated small-cell lung cancer: a randomized study.

A randomized study comparing teniposide (VM-26) and etoposide (VP-16) was performed to investigate whether there are any differences in the activity and toxicity of these two analogs in small-cell lung cancer (SCLC). Only previously untreated patients with SCLC were included; 46 and 48 patients receiving VP-16 and VM-26, respectively, are assessable for response. There were no differences between the two groups with respect to extent of disease, median age, and performance status (PS). The initial doses were for both compounds 70 mg/m2 intravenously (IV) daily for 5 days every 3 weeks. After inclusion of 25 patients in the study, the doses were increased to 80 mg/m2 for VM-26 and 90 mg/m2 for VP-16 because of differences in toxicity. VM-26 caused more hematologic toxicity than VP-16 throughout the study. The overall responses (complete response [CR] plus partial response [PR]) were 65% for VP-16 and 71% for VM-26, with CR occurring in 24% and 23%, respectively, for the two compounds. Median survival was 8.5 months for VP-16-treated patients versus 11.3 months for VM-26-treated patients (P = .58). It is concluded that both VP-16 and VM-26 are highly active single agents in SCLC.

Early detection of response in small cell bronchogenic carcinoma by changes in serum concentrations of creatine kinase, neuron specific enolase, calcitonin, ACTH, serotonin and gastrin releasing peptide

Creatine kinase (CK-BB), neuron specific enolase (NSE), ACTH, calcitonin, serotonin and gastrin releasing peptide (GRP) were measured in serum or plasma before and immediately after initiation of treatment in patients with small cell lung cancer (SCC). Pretherapeutic elevated concentrations of CK-BB were found in 82% of extensive disease patients and in 50% of patients with local disease. NSE was raised in 72% with extensive disease versus 14% of patients with local disease. Calcitonin and ACTH were raised in 27% and 28%, respectively, in all patients without significant difference between extensive and local disease patients. Serotonin was generally overall elevated in 10% and GRP in 7% but elevations were seen only in patients with extensive disease. Out of the four most frequently elevated substances at least one marker was elevated in 80% of all the patients, including 91% in extensive stage patients and 71% in limited stage patients. Frequent initial monitoring of the substances showed an increase in the concentrations of pretherapeutic elevated CK-BB and NSE on day 1 or 2 followed by a sharp decrease within 1 week. These changes were correlated to objective clinical response determined within 4-8 weeks. The results indicate that serum CK-BB and NSE are potential markers for SCC at the time of diagnosis and that changes in the concentrations during the first course of cytostatic therapy are promising as biochemical tests for early detection of response to chemotherapy.

Double-blind, placebo-controlled, randomized study of chlorhexidine prophylaxis for 5-fluorouracil-based chemotherapy-induced oral mucositis with nonblinded randomized comparison to oral cooling (cryotherapy) in gastrointestinal malignancies.

The purpose was to evaluate prevention of oral mucositis (OM) using chlorhexidine compared with placebo and with oral cooling (cryotherapy) during fluorouracil (5‐FU)‐based chemotherapy in gastrointestinal (GI) cancer.

Chemotherapy for adenocarcinoma of the lung (WHO III): A randomized study of vindesine versus lomustine, cyclophosphamide, and methotrexate versus all four drugs

Two hundred seventy-nine patients with previously untreated nonresectable adenocarcinoma of the lung (ACL) entered a prospective randomized trial, comparing vindesine (VDS) to a combination of lomustine (CCNU), cyclophosphamide (CTX), and methotrexate (MTX), and to a regimen including all four drugs. Response assessment was possible in 218 patients, while 259 were evaluable for survival. Response rates were similar (22%, 23%, and 27%, respectively) as were median durations of response (15 weeks overall) and survival (29 weeks overall). Patients with dose-limiting toxicity had significantly higher response rate and longer survival than patients without toxicity. The major toxicity was peripheral neuropathy with VDS treatment and myelosuppression with the other two regimens. The VDS single-agent activity in ACL was confirmed, but addition of VDS to the three-drug regimen did not increase activity. Future studies of VDS in combination with other active agents, and comparison to a matched control group on supportive care, are indicated.

Elevated plasma concentrations of C-flanking gastrin-releasing peptide in small-cell lung cancer.

Many small-cell lung cancers (SCLCs) produce gastrin-releasing peptides (GRPs) (mammalian bombesin) but the plasma concentration of GRP is rarely elevated, possibly because of its rapid elimination. We developed a radioimmunoassay for the C-terminal flanking peptide of proGRP and measured its concentration in plasma from 71 patients with SCLC, in 27 healthy subjects and in 49 patients with other diseases including lung carcinomas. In addition, we studied the molecular size of immunoreactive C-flanking peptide in two SCLC cell lines and in plasma from SCLC patients. The concentration of immunoreactive C-flanking peptide in normal subjects and in control patients did not exceed 10 pmol/L and 26 pmol/L, whereas 72% of the SCLC patients had C-flanking peptide concentrations above 10 pmol/L. In patients with extensive disease (n = 35) the median concentration was 71 pmol/L (range, 10 to 940). ProGRP C-flanking peptide levels paralleled the clinical course in 12 patients. The molecule(s) responsible for the immunoreactivity had a molecular size of about 8 to 10 kd in both patient plasma and tumor cell lines, suggesting that the measured peptide(s) represented major fragment(s) if not the entire C-flanking peptide of proGRP. Thus this peptide(s) seems to be a useful marker for SCLC.

A phase I clinical evaluation of 1-(2-chloroethyl)-3-[2-(dimethylaminosulphonyl)ethyl]-1-nitrosourea (TCNU)

TCNU (1-(2-chloroethyl)-3-[2-(dimethylaminosulphonyl)ethyl]-1-nitrosour ea) is a newly developed water-soluble nitrosourea based on the endogenous aminoethanesulphonic acid taurine. TCNU was in an extended phase I trial given orally every 4-8 weeks using a stepwise dose escalation from 20 to 170 mg/m2. One hundred and thirty-nine patients received a total of 323 courses. Minor haematologic toxicity was observed in 12 patients treated at dose levels less than 70 mg/m2. Thrombocytopenia WHO grades 1-4 occurred in 43% (55/127) and leucopenia WHO grades 1-3 in 45% (57/127) of the patients treated at dose levels greater than or equal to 70 mg/m2. Nausea and vomiting was recorded in about half the patients despite the use of metoclopramide. At the initial dose level 41 patients received greater than or equal to 3 courses of TCNU. Cumulative leucopenia and thrombocytopenia occurred in 3/41 and in 12/41 patients, respectively, while reversible hepatotoxicity was observed in two patients. Antitumour activity was observed in patients with advanced squamous cell, adeno- and large cell carcinoma of the lung. The recommended starting doses for phase II trials with TCNU are as follows: heavily pretreated patients 90 mg/m2, minimally/-moderately pretreated patients 110 mg/m2 and previously untreated patients 130 mg/m2 with TCNU given every 4-5 weeks, the repeated doses and intervals being adjusted to individual tolerance.

A phase I clinical and pharmacokinetic study of brequinar sodium, DUP 785 (NSC 368390), using a weekly and a biweekly schedule

Brequinar, DUP 785, is a substituted 4-quinoline carboxylic acid derivative which in preclinical studies has shown broad antitumor activity. It is a novel antimetabolite blocking pyrimidine nucleotide synthesis. In a clinical phase I study, 83 patients were treated on a weekly schedule and 18 patients on a biweekly schedule. The drug was given intravenously as a short infusion. Three patients were entered on each dose level from a starting dose of 6 mg/m2 up to 2600 mg/m2 weekly. The dose ranges on a biweekly schedule were 500-850 mg/m2. There was no dose escalation in individual patients. Pharmacokinetic studies were performed in 19 patients on a weekly schedule and in two patients on a biweekly schedule. A biphasic decay in plasma was observed with a median half life of 10 h (5.1-23.4). The main dose-limiting toxicity was thrombocytopenia. Of non-hematologic side-effects, stomatitis/mucositis occurred frequently. Skin eruptions occurred rarely, but were a major problem when found. All side-effects were fully reversible; there were no signs of cumulative toxicity. Antitumor activity was observed in one patient with a lung metastasis from a bladder cancer and in a patient with an unknown primary tumor. The recommended doses for phase II trials with DUP 785 are: 1500-2000 mg/m2 on a weekly schedule and 500-750 mg/m2 on a biweekly schedule dependent on status before treatment.

A phase I evaluation of N10-propargyl-5,8-dideazafolic acid

The quianazoline antifolate N10-propargyl-5,8-dideazafolic acid (ICI 155,387), an inhibitor of thymidylate synthetase (TS), was evaluated for clinical toxicity in a phase I trial. The compound was given once every week as a bolus injection. Fourteen patients with advanced cancer were treated at doses of 10-30 mg/m3. Four patients from the lowest to the highest dose developed severe renal toxicity, detected by a reversible decrease in the Cr-EDTA clearance. Hepatotoxicity was observed with transient elevations of alanine aminotransferase (ALT) in 10 patients and alkaline phosphatase in nine patients. Neither the incidence nor the severity of these toxicities was dose related. Two patients developed feelings of fatigue, which in one patient coincided with a decrease in Cr-EDTA clearance. No myelotoxicity, dermatological, gastrointestinal toxicity or mucositis was seen. No tumour responses due to ICI 155,387 occurred. The severity and the erratic nature of the renal side-effects suggest that this schedule cannot be recommended for further development of this compound in Phase II trials.

Calcitonin gene-related peptide in small cell lung carcinomas

OBJECTIVE Calcitonin gene‐related peptide (CGRP) is a regulatory peptide encoded by the calcitonin gene. CGRP is expressed in increased amounts by the cells of medullary thyroid carcinomas and has been demonstrated by immunohistochemistry to occur in neuroendocrine cells and nerve fibres of lung tissue.