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

Conservative treatment of invasive bladder cancer

The concept of organ-preserving therapies is a trend in modern oncology, and several tumour types are now treated in this fashion. Trimodality therapy consisting of as thorough a transurethral resection of the bladder tumour as is judged safe, followed by concomitant chemoradiation therapy, is emerging as an attractive alternative for bladder preservation in selected patients with muscle-invasive bladder cancer. Long-term data from multiple institutional and cooperative group studies have shown that this approach is safe and effective and that it provides patients with the opportunity to maintain an intact and functional bladder with a survival rate similar to that for modern radical cystectomy

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

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

Multi-Focal, Multi-Centric Angiosarcoma of Bone

A multi-focal multi-centric, malignant tumour of vascular origin arising in bone in a 55-year-old man is described. The presenting symptoms were pain and weight loss. Radiologically, multiple lytic lesions were demonstrated in the long bones of both legs and throughout the pelvis. Histological examination demonstrated an angiosarcoma which was predominantly low grade in nature but with focal areas of intermediate grade. Turnout cells expressed the endothelial markers CD31, CD34 and von Willebrand's factor. There was rapid radiological progression of disease with no response to radiotherapy. Pain abated within a few days of institution of doxorubicin, 75 mg m-2, but the patient died of massive pulmonary thromboembolism 14 days later, 11 months after the first symptoms

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

Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life

BACKGROUND: In 1995 a meta-analysis of randomised trials investigating the value of adding chemotherapy to primary treatment for non-small cell lung cancer (NSCLC) suggested a small survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings. However, the metaanalysis included many small trials and trials with differing eligibility criteria and chemotherapy regimens. METHODS: The aim of the Big Lung Trial was to confirm the survival benefits seen in the meta-analysis and to assess quality of life and cost in the supportive care setting. A total of 725 patients were randomised to receive supportive care alone (n = 361) or supportive care plus cisplatin-based chemotherapy (n = 364). RESULTS: 65% of patients allocated chemotherapy (C) received all three cycles of treatment and a further 27% received one or two cycles. 74% of patients allocated no chemotherapy (NoC) received thoracic radiotherapy compared with 47% of the C group. Patients allocated C had a significantly better survival than those allocated NoC: HR 0.77 (95% CI 0.66 to 0.89, p = 0.0006), median survival 8.0 months for the C group v 5.7 months for the NoC group, a difference of 9 weeks. There were 19 (5%) treatment related deaths in the C group. There was no evidence that any subgroup benefited more or less fromchemotherapy. No significant differences were observed between the two groups in terms of the pre-defined primary and secondary quality of life end points, although large negative effects of chemotherapy were ruled out. The regimens used proved to be cost effective, the extra cost of chemotherapy being offset by longer survival. CONCLUSIONS: The survival benefit seen in this trial was entirely consistent with the NSCLC meta-analysis and subsequent similarly designed large trials. The information on quality of life and cost should enablepatients and their clinicians to make more informed treatment choices