Stephen W. Banham

Phase II clinical and pharmacological study of oral 4-demethoxydaunorubicin in advanced non-pretreated small cell lung cancer

Summary4-Demethoxydaunorubicin (4-DMDNR) is an oral anthracycline with antitumour activity demonstrated in a number of clinical studies. We have assessed the usefulness of 4-DMDNR in 16 patients with advanced small cell lung cancer, none of whom had received previous chemotherapy. There were no complete or partial responders among the 14 evaluable patients, but 9 patients showed a minor radiographic improvement and 6 reported transient symptomatic improvement. Side effects were mostly minor or moderate, although one patient succumbed to septicaemia during neutropenia following treatment. There was no evidence of cardiotoxicity in any patient. Pharmacological studies were undertaken in 8 patients. A previously undescribed metabolite, identified as the 7-deoxyaglycone of 4-demethoxydaunorubicinol, was detected in 3 patients and these 3 patients all showed some anti-tumor response.

High-dose cyclophosphamide and VP 16 as late dosage intensification therapy for small cell carcinoma of lung.

SummaryThis study investigated the use of late dose intensification therapy (LDIT) with cyclophosphamide (180 mg/kg) and VP 16 (1 g/m2) plus autologous bone marrow rescue in 22 patients with small cell lung cancer (SCLC). These patients were selected from a group of 95 patients who received three courses of a five-drug induction regimen comprising cyclophosphamide (750–1000 mg/m2), adriamycin (40 mg/m2), VP 16 (100 mg/m2) for 3 days, methotrexate (50 mg/m2) and vincristine (2 mg) (CAVMO). There were 16 patients with limited disease, 8 of whom were in complete remission (CR) and 8 in partial remission (PR) after the induction therapy. The other 6 patients had extensive disease; 3 of these achieved CR and 3 PR after induction therapy. Of the 11 patients in PR, 5 responded to LDIT; 3 had a further PR, and 2 CR. Subsequent to LDIT radiotherapy 4000 cGy was given to the primary site in 10 of the 22 patients. Since the start of the study, 19 of the 22 patients have relapsed and died (median survival 11 months), while 3 remain alive and in remission at 11, 11, and 24 moths. Comparison of the survival of patients receiving LDIT with that of an equivalent group (with respect to staging and response to induction chemotherapy) of patients who received induction chemotherapy alone showed no significant difference. In this study, LDIT following conventional induction therapy in patients with chemosensitive tumours did not improve survival.

Metacognitive beliefs in primary insomnia: developing and validating the Metacognitions Questionnaire--Insomnia (MCQ-I).

Patients with Primary insomnia often experience intrusive, worrisome cognitive activity in the pre-sleep period. Metacognitive beliefs may explain this yet no valid reliable scale exists. The present study, therefore, developed the Metacognitions Questionnaire--Insomnia (MCQ-I). Following initial metacognitive insomnia profiling interviews, item refinement produced a preliminary 60-item MCQ-I. This was administered to 34 primary insomniacs and 37 normal sleepers. Psychometric data indicate primary insomniac patients score significantly higher than normal sleepers on MCQ-I. Test-retest reliability is good. Face, concurrent, construct and discriminant validity, scale sensitivity and specificity are all acceptable. Further research with larger primary insomnia and normal sleeper samples is now required.

The pharmacokinetics of high dose cyclophosphamide and high dose etoposide

We have studied the pharmacokinetics of single agent high dose cyclophosphamide (HDC) (160–240 mg kg−1) given as repeated intravenous (i.v.) infusions to six patients with small cell lung cancer (SCLC), and HDC (180 mg kg−1) combined with ctoposide (750–1000 mg m−2) as repeated i.v. infusions to five patients with SCLC and two patients with teratoma.HDC has a similar pharmacokinetic profile to low dose cyclophosphamide, with a half-life of 4.83 ± 1.3 h. Repeated administration of HDC produced a small but significant shortening of the half life (P =0.02). The terminal half-life of high dose ctoposide was 7.7 ± 2 h which is similar to our previous results with low dose etoposide (50–300 mg m−2),but the volume of distribution which was 35.5 ± 11.61. was significantly increased (P < 0.001). Plasma steady state concentrations of 26.2 ± 11.7 μ ml−1 were achieved. The possible mechanism for the alteration of volume of distribution of etoposide will be discussed.

Small cell lung cancer: results of a phase II study of 1,2,4 triglycidylurazol.

SummaryFourteen patients with small cell lung cancer (SCLC) received treatment with 1,2,4 triglycidylurazol (TGU) 600 mg/m2 or 800 mg/m2 as an IV bolus every 4 weeks. Twelve patients had received previous chemotherapy consisting of a five-drug regimen given for the short duration of only 9 weeks. All had measurable disease. Following TGU 11 patients had progressive disease and 3 patients had stable disease. The most frequent toxicity was nausea and vomiting, which occurred in all patients but was generally mild. Myelosuppression was common with a median white blood count nadir of 2.5×109/l (range 0.9–7.4×109/l) and median platelet count nadir of 76×109/l (range 5–173×109/l). Alopecia, thrombophlebitis, and hepatic or renal toxicity were not observed.In this study, TGU had no activity in SCLC, and the dose-limiting toxicity was myelosuppression.

Short duration combination chemotherapy in the treatment of small cell lung cancer.

Ninety five patients (57 with limited disease and 38 with extensive disease) with previously untreated small cell lung cancer were entered into a study of short duration combination chemotherapy with intravenous cyclophosphamide (750 mg/m2) on day 1, adriamycin (40 mg/m2) on day 1, and etoposide VP-16 (100 mg/m2) on days 1, 2, and 3, with the addition on day 10 of methotrexate 50 mg/m2 with folinic acid rescue and vincristine 2 mg. The treatment was repeated on day 22 and only three courses were given. No maintenance chemotherapy was given, though patients with a complete response received radiotherapy (30-40 Gy (3000-4000 rads] to the primary site in most cases. Forty nine patients (86%) with limited disease achieved a response, with 26 (46%) complete remissions. Twenty five patients (66%) with extensive disease had a response, but only eight (21%) had a complete response. Actuarial survival analysis for the whole patient population showed a median survival of 13 months for patients with limited disease and seven months for those with extensive disease. The median survival was 14 months for those patients with limited disease who achieved a complete response, but only 10 months for non-responders. Myelosuppression was the major expression of toxicity. There were three deaths related to treatment and seven patients had febrile episodes during neutropenia that required antibiotics. Mucositis, which was usually mild, occurred in 49% of patients. The primary site was the main site of initial relapse in 56% of the patients who relapsed. Among patients with limited disease who achieved a complete response, relapses at the primary site were less common in those who received radiotherapy (five out of 12) than in those who did not (all eight). The results indicate that this short duration chemotherapy in small cell lung cancer gives response rates and the potential for long term survival similar to those obtained in other series while allowing patients the maximum time free from treatment.

Gallium scintigraphy in small cell lung cancer.

We have undertaken gallium imaging studies in 49 patients with histologically proven small cell lung cancer. Tracer uptake in the primary tumour was seen in 98% of cases. Twenty five patients underwent repeat scanning after induction chemotherapy and a correlation was demonstrated between conventional parameters of response and gallium scan changes (P<0.01). There was no correlation between initial gallium activity and subsequent chemoresponse (which was evaluated in 32 patients) or survival (measured in 42 patients). Ten patients who had shown a complete response to induction treatment were followed up with gallium scans repeated at three monthly intervals. Such longitudinal studies were particularly helpful in excluding tumour activity when the appearance of the chest radiographs were difficult to interpret.