Longevity in small cell lung cancer. A report to the Lung Cancer Subcommittee of the United Kingdom Coordinating Committee for Cancer Research.

An analysis of the long-term results of treatment of 3,681 patients with small cell lung cancer (SCLC) is presented. The data were obtained from major centres in the UK who were conducting treatment trials during the period 1978-1986 and for whom complete computer records and follow-up were available. A total of 217 (5.9%) survived 2 years or more. Two year survival for patients presenting with limited disease (LD) was 8.5% and for extensive disease (ED) 2.2%. Death from SCLC continued until 7 years after diagnosis but not thereafter. At this point overall survival was 3% (3.6% LD, 1.1% ED). Survival after 2 years was not affected by initial disease extent, sex, thoracic radiotherapy or prophylactic cranial irradiation. Death from causes other than SCLC continued throughout the period of observation. Vascular disease, respiratory failure and second tumours were the main other causes of death. The better survival in younger patients was mainly attributable to few deaths from these other causes. These results indicate that only a small proportion of patients with SCLC are cured by current treatment. Although shorter term improvement in survival has been obtained with current treatment, the poor overall long-term results support studies exploring new approaches to cure and to palliation

The cytostatic activity of cultured Kupffer cells.

The cytostatic activity of a population of cultured syngeneic and allogeneic Kupffer cells against the K31 tumour cell line has been studied in vitro. The addition of purified populations if Kupffer cells to the tumour cell line resulted in a reduction in the uptake of 125IUdR by the tumour cells. This cytostatic activity was not due to a non-labile supernatant effect. There was a progressive loss of the cytostatic activity of the Kupffer cells as their time in culture increased. The experiments show that Kupffer cells, like other macrophages, possess cytostatic activity in vitro which is not genetically restricted

Cautionary tales of survival analysis: conflicting analyses from a clinical trial in breast cancer.

Data from a completed randomized trial in breast cancer are used to demonstrate and quantify the variation in estimated survival curves and log-rank statistics at different times throughout a trial. False 'plateaux' are common, as are wide fluctuations in chi2 values obtained from the log-rank test when there are few events. We show how analyses conducted at different times can demonstrate different effects. Long follow-up is often necessary to allow correct interpretation of results. We discuss the assumption of proportional hazards and the consequences of making that assumption inappropriately. We show how checking whether hazards are proportional can help in avoiding erroneous conclusions

Adjuvant chemotherapy for soft-tissue sarcoma: review and meta-analysis of the published results of randomised clinical trials.

Fifteen published randomised trials comparing adjuvant chemotherapy with no chemotherapy in soft-tissue sarcoma (STS) were identified (1546 patients). A qualitative review and a meta-analysis of this published literature were performed. With the qualitative review it was not possible to synthesise the apparently conflicting results of individual trials. The meta-analysis of the published data suggests an improvement in survival at 2 years (OR = 0.73, 95% CI = 0.53-0.99, P = 0.044) and at 5 years (OR = 0.59, 95% CI = 0.45-0.78, P = 0.0002) in favour of chemotherapy. However, the assumptions and approximations required to conduct this quantitative summary demand that the results are interpreted with caution. The only reliable means of assessing the current evidence on whether adjuvant chemotherapy has a role in the treatment of patients with STS, is to collect, check and reanalyse individual patients data (IPD) from each trial centrally, and formally combine the results in a stratified time-to-event analysis. Such an IPD analysis is currently being undertaken by an international collaborative group

Cellular pharmacology of novel C8-linked anthramycin-based sequence-selective DNA minor groove cross-linking agents.

The cellular pharmacology of a series of C8-linked pyrrolobenzodiazepine dimers with polymethylene linkers of n = 3-6 (compounds 1-4) has been studied in a range of human tumour cell lines. The four compounds showed the same pattern of relative activity in five ovarian carcinoma cell lines and one cervical carcinoma cell line with the order of IC50 values of 1 < or = 3 < 4 < 2, which correlated with the previously demonstrated DNA interstrand cross-linking ability of the compounds in plasmid DNA. In human leukaemic K562 cells the agents produced a block in the G2/M phase of the cell cycle characteristic of cross-linking drugs, and extensive interstrand cross-linking was observed in cells by alkaline elution with no evidence of single-strand breaks. Cross-links continued to increase up to 24 h following a 1 h exposure to drug, and no repair was evident by 48 h. In a series of ovarian and cervical carcinoma cell lines with acquired resistance to cisplatin no cross-resistance to the most potent compound 1 was observed in two lines whose major mechanism of resistance to cisplatin was reduced platinum transport. Cross-resistance to 1 was observed in a cell line (A2780cisR) possessing elevated glutathione, and depletion of intracellular glutathione using D,L-buthionine-S,R-sulphoximine (BSO) from 10.25 nmol to 2.8 nmol 10(-6) cells reduced the level of resistance from 11-fold to 2-fold compared with sensitive cells. Cross-linking in the resistant cells was restored to 80% of the level in the parent line by BSO pretreatment. There was also a correlation between glutathione levels and sensitivity to 1 measured in several other ovarian cell lines. Compound 1 also showed cross-resistance in the doxorubicin-resistant cell line 41MdoxR and partial cross-resistance in CH1doxR cells. Both these lines possess elevated levels of p170 glycoprotein. Following treatment with 6 microM verapamil, the resistance in these lines decreased almost 2-fold and 8-fold respectively

DNA interstrand crosslinking and sequence selectivity of dimethanesulphonates.

Members of the homologous series of alkanediol dimethanesulphonates of general formula H3C.SO2O.(CH2)n.O.SO2.CH3 have been tested for their ability to produce DNA interstrand crosslinking and DNA sequence selectivity of guanine-N7 alkylation. In a sensitive crosslinking gel assay the efficiency of DNA interstrand crosslink formation, dependent on the ability of the alkylating moiety to span critical nucleophilic distances within the DNA, was found at 6 h to be 1,6-hexanediol dimethanesulphonate (Hexa-DMS) (n = 6) greater than methylene dimethanesulphonate (MDMS) (n = 1) greater than 1,8-octanediol dimethanesulphonate (Octa-DMS) (n = 8) greater than Busulphan (n = 4). The DNA interstrand crosslinking produced by MDMS was not due to either of its hydrolysis products, formaldehyde or methanesulphonic acid (MSA). In contrast the extent of monoalkylation at guanine-N7 as determined by a modified DNA sequencing technique was found to be Busulphan much greater than Hexa-DMS = Octa-DMS, with a sequence selectivity somewhat less than that of other chemotherapeutic alkylating agents such as nitrogen mustards. MDMS at high levels induced a non-specific depurination as a result of the reduction in pH resulting from MSA release. More strikingly MDMS (and MSA) produced a single strong site of guanine reaction (depurination) in a guanine-rich 276 base pair fragment of pBR322 DNA in the sequence of 5'-ATGGTGG-3'. This was observed when non-specific depurination was negligible and was not seen with formic acid. Thus structurally similar alkylating agents can differ in their type and extent of DNA monoalkylation and interstrand crosslinking, and in some cases (e.g. MDMS/MSA) produce reactions with a high degree of selectivity

Patient compliance with prolonged low-dose oral etoposide for small cell lung cancer.

Using an 'intelligent' tablet bottle which, unknown to the patient, electronically records the times of opening we have assessed the compliance of patients with prescribed oral medication. The compliance pattern of 12 patients receiving low dose etoposide for small cell lung cancer was monitored over 25 treatment periods, representing a total of 298 days. The data were expressed as overall compliance (OC), defined as the observed number of bottle openings as a percentage of the prescribed number of doses, and as two indices representing daily and hourly irregularities in the times of opening. The OC had a mean (+/- s.d.) value of 93.2% (+/- 12%) over the 25 treatment periods, and is similar to that which we have reported in a group of lymphoma patients (Lee et al., 1992). By means of a self assessed diary card we monitored the physical and mental state of the patients. Although we found significant associations between the compliance measures and some of the diary card measures, the magnitude of the observed effects would be of little practical consequence. We conclude that, in our group of patients, inadequate compliance with oral chemotherapy would not account for any significant lack of clinical response

Neutrophil function during chemotherapy for Hodgkin's disease.

Simultaneous measurement of neutrophil migration, phagocytic activity, candidacidal and bactericidal activity were made during quadruple chemotherapy of advanced Hodgkin's disease (HD). Measurements were also made in normal individuals, hospital patients not on chemotherapy, untreated patients with advanced HD and patients off chemotherapy for over a year. Neutrophil migratory activity was usually normal in untreated HD patients and those on chemotherapy, but less than 20% of all tests showed depressed values, some of which were corrected by plasma. Similar results were found with neutrophil phagocytosis. Abnormalities in these functions were found in both early and late cycles, but there was a tendency for migration to deteriorate during later chemotherapy cycles. Neutrophil candidacidal and bactericidal activity were frequently depressed in patients on treatment and there was deterioration in candidacidal activity during the chemotherapy cycle. These abnormalities of killing activity were frequently corrected in control plasma. Neutrophil function is normal in most patients with advanced HD and in patients in remission. In a minority of patients on treatment there are marked functional defects, especially in killing activity. These defects are partly cell-associated and partly plasma-related. Susceptibility to infection during chemotherapy of HD may be partly due to defective neutrophil function

An immunohistochemical investigation of diagnostic biopsy material taken from short and long term survivors with small cell lung cancer.

An immunohistochemical study has been carried out on fibre optic-biopsy specimens from patients with small cell lung cancer (SCLC) who had either died within 3 months, or who had survived more than 2 years. Long term survivors (LTS) were identified from completed clinical trials at major UK centres and were matched for age and sex within the trial with short term survivors (STS). The panel of immunohistochemical markers included those previously reported to be associated with prognosis, and reagents representative of both neuroendocrine and epithelial differentiation. A preliminary screen of 17 antibodies identified 11 as consistently reactive on paraffin-embedded material using streptavadin-biotin immunoperoxidase. Of 186 identified patients, 110 biopsy samples were retrieved. Of these, 70 gave sufficient material for analysis. All sections were scored by three observers without knowledge of the prognosis. The analysis failed to identify any antigen whose expression was correlated with prognosis. We conclude that, in fibre-optic biopsy specimens, immunohistochemical analysis does not add prognostic information in SCLC