Search

The role of post-operative radiotherapy for patients with non-small-cell lung cancer (NSCLC) is unclear despite five previous randomised trials. One deficiency with these trials was that they did not include adequate TNM staging, and so the present randomised trial was designed to compare surgery alone (S) with surgery plus post-operative radiotherapy (SR) in patients with pathologically staged T1-2, N1-2. M0 NSCLC. Between July 1986 and October 1993, 308 patients (154 S, 154 SR) were entered from 16 centres in the UK. The median age of the patients was 62 years, 74% were male, > 85% had normal or near normal levels of general condition, activity and breathlessness, 68% had squamous carcinoma, 52% had had a pneumonectomy, 63% had N1 disease and 37% N2 disease. SR patients received 40 Gy in 15 fractions starting 4-6 weeks post-operatively. Overall there was no advantage to either group in terms of survival, although definite local recurrence and bony metastases appeared less frequently and later in the SR group. In a subgroup analysis, in the N1 group no differences between the treatment groups were seen, but in the N2 group SR patients appeared to gain a one month survival advantage, delayed time to local recurrence and time to appearance of the bone metastases. There is, therefore, no clear indication for post-operative radiotherapy in N1 disease, but the question remains unresolved in N2 disease.

A total of 458 eligible patients, from 21 centres, with histologically or cytologically confirmed SCLC were allocated at random to three chemotherapy regimens, each given at 3-week intervals. In two regimens, etoposide, cyclophosphamide, methotrexate and vincristine were given for a total of either three courses (ECMV3) or six courses (ECMV6). In the third regimen, etoposide and ifosfamide were given for six courses (EI6). Patients with limited disease (56% of the total) also received radiotherapy to the primary site after the third course of chemotherapy in all three groups. A partial response occurred in 45% of 144 ECMV3 patients, 48% of 141 ECMV6, and 53% of 141 EI6 patients assessed, and a complete response in a further 15%, 9%, and 13% respectively, giving total response rates of 60%, 57%, and 67%, respectively. There was no overall survival advantage to any of the three regimens. At 1 year, 24%, 29%, and 30% of patients were alive, and at 2 years 7%, 8%, and 9%, respectively. The median survival time was 7.4 months in the ECMV3 group, 8.6 months in the ECMV6 group and 8.8 months in the EI6 group. The individual factors: poor performance status, extensive disease, the presence of dysphagia and a raised white blood cell count on admission adversely affected prognosis. The results do not exclude the possibility of a minor survival advantage with the two 6-course regimens. The findings on quality of life are presented in the companion paper (MRC Lung Cancer Working Party, 1993b).

A total of 458 eligible patients, from 21 centres, with microscopically confirmed SCLC were allocated at random to three chemotherapy regimens, each given at 3-week intervals. In two regimens, etoposide, cyclophosphamide, methotrexate and vincristine were given for a total of either three courses (ECMV3) or six courses (ECMV6). In the third regimen, etoposide and ifosfamide were given for six courses (E16). Patients with limited disease also received radiotherapy to the primary site after the third course of chemotherapy in all three groups. As reported by clinicians, 59% of the ECMV3, 67% of the ECMV6 and 63% of the EI6 patients experienced moderate or severe adverse reactions to their chemotherapy. The major symptoms of disease, cough, haemoptysis, chest pain, anorexia, and dysphagia, were palliated in 63% or more of patients and the median duration of palliation was 63% or more of survival, the results being similar in the three groups. Among patients with poor overall condition, physical activity and breathlessness on admission, the proportions who improved were higher in the EI6 group but the differences were small. In all three groups, levels of anxiety fell substantially during treatment. Levels of depression were lower and showed little change. As assessed by patients using a daily diary card, the patterns of nausea, vomiting, activity and mood, associated with courses of chemotherapy were very similar in the three groups. In the EI6 group there was less dysphagia and better overall condition between courses, but these advantages need to be weighed against the inconvenience of the 24-h infusions required, compared with the 30-min infusions of the other two regimens. As reported in the companion paper (MRC Lung Cancer Working Party, 1993a) there was no statistically significant survival advantage to any of the three regimens, although the results do not exclude the possibility of a minor survival advantage with the two six-course regimens. In conclusion, there was no major clinical gain from continuing chemotherapy beyond three courses or from using the ifosfamide regimen.

A total of 474 adult patients with malignant glioma (astrocytoma) grade 3 or 4 were randomised into an MRC study (BR2) comparing 45 Gy (in 20 fractions over 4 weeks) with 60 Gy (in 30 fractions over 6 weeks) of radiotherapy given post-operatively. Using 2:1 randomisation, 318 patients were allocated the 60 Gy course and 156 the 45 Gy course. Adjuvant chemotherapy was not given. The results show that a 60 Gy course produces a modest lengthening of progression-free and overall survival. They suggest a statistically significant prolongation of median survival from 9 months in the 45 Gy group to 12 months in the 60 Gy group (hazard ratio = 0.75, chi 2 = 7.36, d.f. = 1, P = 0.007). Over 80% of patients reported no morbidity from the radiotherapy, and there was no evidence of increased short-term morbidity in the higher dose group. Late morbidity was not assessed. A prognostic index defined in a previous MRC study was validated in this new cohort. It identifies a group of patients (20% of the total) with a 2 year survival rate of 28% (95% confidence interval 19% to 38%). It was apparent that the survival advantage to the higher dose was maintained even in the poorest prognostic groups defined by this index.

Transient plugging of microcapillaries by leucocytes is a possible reason for the occurrence of acute hypoxia in tumours. We compared the abilities of nicotinamide at 1000 micrograms ml-1 and 150 micrograms ml-1 and pentoxifylline at 300 micrograms ml-1 to increase the filterability of normal and artificially activated human leucocytes through 8 microns pores, as a model for the capillary bed. Using a St George's filtrometer, filterability of treated leucocyte suspensions was compared with control for three to six sequential 60 microliters samples, normalising control values to unity. Pentoxifylline at 300 micrograms ml-1 halved the ratio of treated to control value to 0.47 +/- 0.13 (2 s.e.), P = 0.001 (i.e. an increase in filterability), and nicotinamide at 1000 micrograms ml-1 reduced it to 0.69 +/- 0.22, P = 0.04, but the clinically achievable 150 micrograms ml-1 was ineffective (0.82 +/- 0.25, P = 0.24). Filterability of artificially activated leucocytes was reduced (3.9 +/- 1.20) but was restored to control values of unity by 1000 micrograms ml-1 nicotinamide and 300 micrograms ml-1 pentoxifylline and partially restored by 150 micrograms ml-1 nicotinamide (1.2 mM), which was isoeffective with 100 micrograms ml-1 pentoxifylline (0.37 mM). Pentoxifylline is therefore more effective on a molar basis and was shown to affect both polymorphonuclear leucocytes and lymphocytes, while nicotinamide only affects lymphocytes. The data are consistent with the hypothesis that both agents modify acute hypoxia by increasing leucocyte filterability.