Michael A. Cornbleet

Mitoxantrone for the treatment of advanced breast cancer: Single-agent therapy in previously untreated patients

Mitoxantrone (dihydroxyanthracenedione) is a substituted anthraquinone with a similar spectrum of activity to adriamycin in experimental tumours. One hundred and thirty-four patients with advanced breast cancer and no prior chemotherapy for advanced disease were treated with mitoxantrone (14 mg/m2 i.v. q 3 weeks), of whom 99 are presently evaluable for response and all for toxicity. Six patients achieved a complete response and 29 a partial response, the overall response rate being 35% (95% confidence limits, 25-45%). Median time to treatment failure was greater than 46 weeks. Mitoxantrone was well tolerated, myelosuppression being the dose-limiting toxicity. The most frequent nonhaematological toxicities were nausea and vomiting (40%), but these were rarely severe. Total alopecia occurred in only 6 patients. Four patients developed clinically significant evidence of cardiotoxicity after cumulative mitoxantrone doses of 174-256 mg/m2. Mitoxantrone offers comparable efficacy and less acute toxicity than the most active currently available single agents in advanced breast cancer.

Adult neuroblastoma: report of three cases and review of the literature

Adult neuroblastoma is an uncommon malignancy. The authors report three additional cases and review the 39 reported cases in the world literature. Presentation in the abdomen is the most common; a high rate of lower limb presentation is also observed. Incidence is equal between sexes with a median age of presentation of 34 years. Survival is greatest after surgical intervention (median, 20.5 months) compared with no surgery (median, 12.5 months). Chemotherapy may benefit individual patients but does not have a major impact on survival. Radiotherapy is indicated for localized, inoperable primaries or painful metastases. The survival rates of this group of patients parallels that of childhood neuroblastoma, Stage III‐IV. Cancer 57:2419–2421, 1986.

Prognosis at presentation of small cell carcinoma of the lung

Prognostic factors in 411 patients with small cell lung carcinoma have been retrospectively analysed. Univariate analysis of continuous variables showed that prognosis was worse with deteriorating performance status, extensive disease, positive bone scan, increasing age, elevated total white cell count, alkaline phosphatase, lactate dehydrogenase, and decreased serum chloride and albumin. Low serum sodium was less clearly associated with poor survival. Cox multivariate regression showed that performance status, disease extent, age and raised lactate dehydrogenase and white cell count were independent prognostic factors. When disease extent was excluded from analysis, performance status, age, total white cell count, lowered serum chloride and raised lactate dehydrogenase were significant independent prognostic variables.

Phase II trial of vindesine and VP16-213 in the palliation of poor-prognosis patients and elderly patients with small cell lung cancer

SummaryForty-three previously untreated patients, all of whom had poor-prognosis small cell lung cancer and/or were >65 years old, received treatment with vindesine and VP16-213. Thirteen patients had limited disease and 30 extensive disease. Response rates (CR+PR) of 86% (CR 29%) and 66% (CR 17%) were seen in patients with limited and extensive disease, respectively. Time to relapse was short in those responding (4–4.5 months), and most responders required additional treatments. The overall toxicity was minimal and patient compliance was high. This combination is useful for the palliative treatment of small cell lung cancer when aggressive chemotherapy is inappropriate.

Phase I study of TCNU, a novel nitrosourea

TCNU is a chloroethyl nitrosourea based on the endogenous amino acid taurine. This paper reports its first evaluation in man. Eighty-four patients with refractory cancer received 12 dose escalations from 10-150 mg/m2 TCNU administered orally every 6 weeks. Clinical side-effects were predominantly gastro-intestinal but dose-limiting toxicity was thrombocytopenia. Pharmacokinetic monitoring with an HPLC assay sensitive to the nanogram range demonstrated unchanged TCNU in plasma for up to 8 h following administration. The mean half-life was 60 min. Clinical responses were seen in melanoma (four patients), lung cancer (two squamous, one small cell) and one patient each with renal and stomach cancer. These responses, together with the unusual pharmacokinetic profile of TCNU, warrant exploration in disease-orientated phase II studies at a recommended dose of 130 mg/m2 p.o. q 5 weeks.

Mitoxantrone as first-line chemotherapy in advanced breast cancer: results of a collaborative European study

SummaryMitoxantrone (Novantrone®; dihydroxyanthracenedione) is a substituted anthraquinone with a spectrum of activity similar to doxorubicin in experimental tumors.One hundred and seventy three patients with advanced breast cancer and no prior cytotoxic therapy for advanced disease entered a phase II study of mitoxantrone, 14 mg/m2 i.v. repeated every 3 weeks. At the time of this analysis 116 patients were evaluable. Eight patients achieved a complete response and 27 a partial response, the overall response rate being 30% (95% confidence limits: 22–39%). The median time until response was recorded was 15 weeks. The median duration of response was 74+ weeks and the median time to progression or death for all 116 patients was 22+ weeks.Mitoxantrone was well tolerated with myelosuppression as the dose-limiting toxicity. The most frequent non-haematological toxicities were nausea and vomiting (65%) but they were rarely severe. Total alopecia occurred in only 6% of the patients. Four patients developed clinically significant evidence of cardiotoxicity after cumulative mitoxantrone doses of 174–256 mg/m2.Thus, mitoxantrone offers comparable efficacy and less acute toxicity than the most active single agents currently available in the treatment of advanced breast cancer.

Emesis due to cancer chemotherapy: Results of a prospective, randomised, double-blind trial of varying doses of metoclopramide in the management of cis-platinum-induced vomiting

A randomised, double-blind prospective trial was conducted to determine the relative anti-emetic efficacy of three dose levels of metoclopramide in cancer patients receiving combination chemotherapy including cis-platinum. With consecutive courses of chemotherapy, 60 patients received doses of either 3,5 or 10 mg/kg metoclopramide (50, 54 or 55 courses respectively) in a randomly assigned sequence. Major control of emesis (less than or equal to 2 vomits) was achieved in 38% of 159 patient treatments. There were no significant differences in either anti-emetic efficacy or the incidence of side-effects between the three doses used. It is concluded that while metoclopramide is an effective anti-emetic for patients receiving cisplatinum therapy, no advantage accrues to the use of doses in excess of 3 mg/kg (total dose).

Randomised trial comparing prednimustine with combination chemotherapy in advanced ovarian carcinoma

SummaryA total of 76 patients with advanced epithelial ovarian carcinoma were randomised to receive 6 months of treatment with either a combination of hexamethylmelamine, 5-fluorouracil, cisplatin and prednimustine or prednimustine alone following initial surgery. Pathologically confirmed response rates were 35% for combination chemotherapy and 28% for prednimustine, and the overall survival was identical for the two groups. Seven patients achieved a pathologically defined complete response, one of whom relapsed at 8 months; the others remain disease-free 18–36 months (median, 23 months) after presentation. The extent of initial surgery significantly affected the survival of patients receiving prednimustine but not of those receiving combination chemotherapy. Prednimustine can produce durable responses in advanced ovarian cancer using a schedule that results in negligible toxicity.

The late results of consolidation treatment following induction chemotherapy for small cell lung cancer

Abstract 33 106 (32%) patients with limited disease (LD) small cell lung cancer (SCLC) achieved a bronchoscopically confirmed complete response (CR) following 4 courses of induction chemotherapy. These patients were offered ‘late intensification’ with high dose melphalan (HDM) (140 mg/m 2 ) and autologous bone marrow support. LDCR patients were advised also to receive radiotherapy to the primary site and prophylactic cranial irradiation (PCI). After a minimum follow-up of 3 years, the LDCR patients who received HDM ( n =13) have had a median disease-free survival (DFS) of 15 months and a median overall survival (OS) of 16 months, compared with a DFS of 9 months ( P =0.06) and OS of 11 months ( P =0.23) for patients who did not receive late intensification ( n =20). Chest radiotherapy and PCI reduced the frequency of recurrence at these sites. Only patients who had received both chest radiotherapy and PCI were disease-free at 18 months. In this non-randomised study it is not possible to state with certainty the contribution of consolidation treatment in SCLC. Nevertheless, in patients with chemosensitive limited disease, late intensification chemotherapy, chest radiotherapy and PCI all appear to have a positive effect on DFS.

A phase I and pharmacology study of GR63178A, a water-soluble analogue of mitoquidone

SummaryGR63178A is a water-soluble analogue of mitoquidone, a pentacyclic pyrroloquinone. This group of drugs exhibit a novel structure and activity against several murine solid tumours and xenografts. In the present phase I study the toxicity and pharmacokinetics of GR63178A given on 5 consecutive days of a 21-day cycle were examined. A total of 24 patients presenting with a wide range of tumours were treated at 5 doses escalated to reach the maximal tolerated dose (MTD). Linear pharmacokinetics was documented over the dose range studied, and there was no difference in parent drug handling between day 1 and day 4 of dosing. A number of metabolites were detected. The toxicity profile was unusual in that pain occurred in 20/24 patients, most often at the site of known disease. This was the dose-limiting toxicity. Other side effects included nausea and vomiting (23/24), phlebitis at the infusion site (6/24) and headache (7/24). No treatment response was seen in this study. The MTD was demonstrated to be 160 mg/m2 daily (total, 800 mg/m2 per treatment cycle). the drug has now entered phase II trials at 120 mg/m2 daily x 5, repeated every 21 days.