Joss R

New agents in non-small cell lung cancer

Combination chemotherapy has changed the outlook for patients with a variety of human malignancies, inducing clinically useful tumor responses, prolongation of median survival and, in patients with certain diseases, resulting in long-term disease-free survival. Development of an effective combination chemotherapy regimen depends primarily on the activities of its individual component drugs (12). In 1979 Cohen and Perevodchikova published an extensive review of single-agent chemotherapy of lung cancer (28). The purpose of the present paper is to update this review for non-small cell lung cancer.

A Phase I trial of Cis-diammine-1,1-cyclobutane dicarboxylate platinum II (Carboplatin, CBDCA, JM-8) with a single dose every five week-schedule

SummaryCarboplatin, a new platinum analogue, was administered intravenously on a schedule of a single dose every five weeks to 23 patients with advanced malignant solid tumors. Patients were treated at six dosage levels ranging from 200–550 mg/m2 every five weeks. Thrombocytopenia was dose-limiting. At 550 mg/m2 Carboplatin, the median platelet nadir was 65 000/mm3. Leukopenia was common, but usually of mild to moderate degree. Gastrointestinal upset was commonly seen at all dose levels, but 35% of the patients experienced no vomiting. No significant increase of the serum creatinine following Carboplatin was seen. In 16 patients serial determinations of the creatinine clearance were performed. The median base line creatinine clearance was 87 (50–155) ml/min and dropped to a median lowest creatinine clearance of 69 (23–171) ml/min on day four (p < 0.05). The median creatinine clearance before the next Carboplatin treatment was 89 (42–155) ml/min. No significant proteinuria or electrolyte disturbances were noted. Carboplatin exhibited antitumor activity in ovarian, endometrial, thyroid and gastric carcinomas. The maximally tolerated dose appears to be 550 mg/m2 every five weeks. A starting dose of 450 mg/m2 seems to be appropriate for Phase II studies. In patients with impaired renal function and/or prior cis-Platin chemotherapy, Carboplatin at doses of 200–500

Phase II trial of epirubicin in advanced squamous, adeno- and large cell carcinoma of the lung

Epirubicin , a stereoisomer of doxorubicin with suggested lower potential for cardiotoxicity in animal tumor systems, was evaluated in a disease-oriented phase II trial in non-small cell lung cancer. The drug was given as a direct i.v. injection of 90 mg/m2 repeated every 3 weeks. Four partial remissions were observed among 75 evaluable patients. Forty-two of the 75 patients had received no prior chemotherapy. The predicted true response rate is equal to 5% (0.2-10%). Leucopenia (75% of patients), gastrointestinal disturbances (76% of patients) and alopecia (53% of patients) were common side-effects observed. Four patients had cardiac abnormalities after treatment with epirubicin (one sinustachycardia , two premature beats, one biopsy-proven cardiomyopathy with congestive heart failure). One patient developed a peripheral neuropathy possibly related to epirubicin . We conclude that epirubicin in the present dose and schedule is an inactive agent in patients with non-small cell lung cancer.

Unexpected High Toxicity in a Phase II Study of Teniposide (VM-26) in Elderly Patients with Untreated Small Cell Lung Cancer (SCLC)

Teniposide (VM 26) as a single agent has shown promising results in the treatment of patients with small cell lung cancer. We treated 32 (30 evaluable) non-pretreated elderly and poor prognosis patients with small cell lung cancer with teniposide 100 mg/day (30 min infusion) days 1-5, every 3-4 weeks. Overall initial performance status was poor (WHO 2 or 3 in 62%). Extensive disease (ED) was documented in 50% including five patients with CNS metastases all of whom received simultaneous cranial irradiation. There was an unexpected high early death rate of 30% (9/30) including five patients with early toxic death due to severe bone marrow suppression leading to fatal septicaemia. The overall response rate was only 33% with no complete response. Where appropriate non-responding or relapsing patients received second line treatment with multidrug regimens +/- radiotherapy. The overall median survival was 5.6 months [ED: 1.7, limited disease (LD): 7.5 months]. Median response duration was 5.4 months (ED: 5.1, LD: 6.7 months). For responding patients median survival was 8.8 months (ED) and 11.5 months (LD). We conclude that in elderly and poor performance status patients single agent teniposide as used in this study has an unacceptable high early death rate and that the response rate is inferior to modern standard multidrug regimens.

The antiemetic activity of high‐dose alizapride and high‐dose metoclopramide in patients receiving cancer chemotherapy: A prospective, randomized, double‐blind trial

Alizapride is a new substituted benzamide with suggested superior antiemetic efficacy to and fewer side effects than metoclopramide. High‐dose alizapride (4 mg/kg x five doses) was compared with high‐dose metoclopramide (2 mg/kg x five doses) in a prospective, randomized, double‐blind trial in 62 évaluable patients undergoing strongly emetic cancer chemotherapy. Patients receiving metoclopramide experienced significantly fewer vomiting episodes than patients receiving alizapride (median of three episodes vs. eight episodes; P < 0.001). Metoclopramide was more effective in decreasing the volume of emesis than was alizapride (median of 100 ml vs. 360 ml; P < 0.02). Seventy‐two percent of the patients receiving alizapride and 57% of those receiving metoclopramide experienced side effects. High‐dose metoclopramide is an effective antiemetic in patients receiving cancer chemotherapy. Alizapride is less effective and has more side effects than metoclopramide. We do not recommend the further use of alizapride.

Continuous infusion of high-dose metoclopramide for the prevention of nausea and vomiting in patients receiving cancer chemotherapy.

SummaryFourteen patients undergoing strongly emetic cancer chemotherapy received a total of 33 continuous infusions of high-dose metoclopramide to prevent nausea and vomiting. Metoclopramide 2 mg/kg was given as an i.v. infusion over 15 min followed by continuous infusion over 13 h of 5 mg/kg. The antiemetic response could be evaluated in 12 patients receiving their first continuous metoclopramide infusion. Six patients were partly or completely protected from acute gastrointestinal disturbances. Three patients experienced a short-lived extrapyramidal syndrome during the continuous metoclopramide infusions. Other side effects observed were mild. Thus, high-dose metoclopramide given as a continuous infusion is an effective antiemetic treatment in patients receiving cancer chemotherapy.

Clinical studies with granisetron, a new 5-HT3 receptor antagonist for the treatment of cancer chemotherapy-induced emesis

Granisetron (BRL 43694A) is a novel, selective 5-hydroxytryptamine-3 (5-HT3) receptor antagonist developed for the prophylaxis and treatment of cytostatic drug-induced emesis. After a brief review of the preclinical evaluation of granisetron the clinical findings with this novel compound are summarised. From the data of large randomised trials one can conclude that granisetron is an active antiemetic, both as a prophylactic and an intervention agent, to an extent which is superior or at least equal to the best available antiemetic combination regimens, having a major efficacy ranging from 74 to 92%. Granisetron may be given as a single, 5-min infusion before chemotherapy and is thus more convenient to administer than many antiemetic regimens. The adverse event profile of granisetron is favourable with a wide therapeutic margin. The only consistent side-effects attributable to granisetron are headache in about 14% of the patients and constipation in about 4% of the patients. Headache induced by granisetron was generally mild and resolved spontaneously or was promptly relieved with standard analgesics. No extrapyramidal side-effects were observed with granisetron.

Alizapride, a new substituted benzamide, as an antiemetic during cancer chemotherapy

SummaryIn early clinical trials alizapride showed a better antiemetic activity with fewer side effects than metoclopramide. Alizapride has now been evaluated in an open dose — ranging study in 24 patients receiving strongly emetic chemotherapy. Alizapride 4–8 mg/kg was given as a 15 min infusion 0.5 h before and 1.5, 3.5, 5.5 and 8.5 h after the chemotherapy. At the dose levels of 6 and 8 mg/kg × 5, respectively 6 out-of 9 and 4 of 4 patients experienced side effects (hypotension, dizziness, profuse sweating, general malaise and diarrhoea). At 4 mg/kg × 54 of 15 patients experienced side effects due to alizapride (dyspnoea 1, diarrhoea 2, extrapyramidal syndrome 1 patient). Overall, 9 of 24 patients were partially or completely protected from nausea and vomiting. Based on this experience alizapride has antiemetic activity and few side effects in the dose of 4 mg/kg × 5.

Phase II study of continuous subcutaneous interferon-alfa combined with cisplatin in advanced malignant melanoma

Interferon-alfa (IFN-alpha) and cisplatin have shown synergism in vitro against tumour cell lines and optimal effects were observed with continuous and high IFN concentration. 20 patients with advanced malignant melanoma were treated with 10 MU IFN subcutaneously continuously, daily, plus cisplatin 50 mg/m2 intravenously on days 8 and 9. Cisplatin was repeated every 4 weeks. The main toxic effects were myelosuppression, fatigue and weight loss. Toxicities always resolved completely after reduction/interruption of IFN and no life-threatening infection was observed. There were 1 complete and 6 partial responses. 6 patients had stable disease. Median time to progression was 7 months with a range of 16 to 2 months. The combined regimen of IFN-alpha and cisplatin is active in patients with multiple visceral and skeletal sites.

Negative phase II trial of menogaril in advanced squamous, adeno- and large cell carcinoma of the lung

RUDOLF A. JOSS,* SILVIO MONFARDINI,t MOGENS HANSEN,; PER DOMBERNOWSKY,§ JOSETTE RENARDfl and HERBERT M. PINED07 for the EORTC Early Clinical Trials Group** *Institute for Medical Onzology, lJniversi@ of Bern, Inselspital, Bern, Switzerland, TCentro di Rifcrimtnto Oncologico, Aviano, Itab,