XH1--a new cervical carcinoma cell line and xenograft model of tumour invasion, 'metastasis' and regression.

A new cell line, XH1, has been derived from an invasive focally keratinising adenosquamous carcinoma of the cervix in a 32 year old patient. It has been maintained in long term monolayer culture for 26 months, and passaged over 100 times (much greater than 300 population doublings). It is aneuploid with a mean chromosome number of 78. Examination using two minisatellite hypervariable DNA probes has shown it to be different from other cell lines maintained in this laboratory and from HeLa. Two sublines, XH1a and XH1b, show marked differences in monolayer culture, growth in soft agar, and xenograft formation. XH1 and XH1a cells readily form subcutaneous xenografts, and lung colonies can be established by their intravenous injection. Subcutaneous injection of XH1b cells results in rapid cell growth for a few days after which the tumour undergoes degeneration and then regresses completely. The XH1 karyotype has many rearranged chromosomes. Parental XH1 cells and both sublines show integration of HPV16 into the genome.

Final report on the second British Institute of Radiology fractionation study: short versus long overall treatment times for radiotherapy of carcinoma of the laryngo-pharynx.

The second British Institute of Radiology trial of dose fractionation in radiotherapy compared two groups of prospectively randomized patients with squamous carcinoma of the laryngo-pharynx; one group was treated in a short (less than or equal to 4 weeks) and the other in a long (greater than 4 weeks) overall time. Treatment in any one centre could be given, with no planned gap in the course of treatment, either as a conventional, daily (5 fractions per week regime) or as 3 fractions per week. A total of 611 patients were allocated to treatment, of whom nine have had to be excluded from the analysis for a lack of information. Patients were admitted to the trial from January 1976 to December 1985 and were followed up for a maximum of 10 years and a minimum of 3 years. A reduction in total dose was made for use in the short compared with the long treatment regime. This reduction in total dose varied between 18% and 22% depending on whether 5 fractions or 3 fractions per week regimes were used. Overall, no statistically significant differences have been found between the two arms of the trial. The patients treated with 5 fractions per week in a short overall treatment time showed fewer late normal tissue effects. An analysis based on stratification by age, stage and anatomical site gave a relative risk (short/long overall treatment time) for deaths of 1.23 with a 95% confidence interval from 0.96 to 1.59. Analyses stratified for stage and site gave relative risks with 95% confidence intervals of 1 x 10 (0.84-1.44) for local recurrences/tumour persistence, and 1.01 (0.70-1.45) for laryngectomies.

The immunoperoxidase localization of tumour markers in ovarian cancer: the value of CEA, EMA, cytokeratin and DD9.

Primary tumours from 40 patients with epithelial ovarian cancer, treated at St Thomas's Hospital over a 10-year period, were studied for the immunocytochemical expression of the following tumour markers in formalin-fixed paraffin embedded material: carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), cytokeratin (CAM 5.2), and DD9. An indirect immunoperoxidase staining technique was used. All of the tumours were positive for EMA and CAM 5.2, and 30% of them were positive for both CEA and DD9. The absence of CEA and DD9 may be of value in differentiating between metastatic abdominal adenocarcinomas of ovarian origin and those of gastrointestinal origin, but no indication of prognosis was obtained using these epithelial markers. The strong and widespread staining of all the tumours for EMA suggests that this may be a useful marker for detecting metastatic or recurrent disease by immunoscintigraphy.

Final report of the general clinical results of the British Institute of Radiology fractionation study of 3F/wk versus 5F/wk in radiotherapy of carcinoma of the laryngo-pharynx.

The 10 year follow-up of a clinical trial involving the comparison of 3F/wk versus 5F/wk in radiotherapy of squamous cell carcinoma of the larynx and hypopharynx has now been completed. The trial involved an intake of 734 patients between 1966 and 1975. The classification of all patients has been revised to conform with the latest TNM publication. A reduction in total dose was made for 3F/wk compared with 5F/wk. This varied between 13% and 11% in centres treating over 3 weeks and 6 weeks, respectively. No statistically significant differences have been found between the two arms (3F/wk versus 5F/wk) of the trial in any of the main group analyses. A number of sub-group analyses relating to survival, tumour-free and laryngectomy-free rates and to the comparison of acute or late normal-tissue radiation damage have also been performed. No differences have been found that could be considered to be statistically significant in relation to the particular sub-group. Previous interim reports suggested minor differences in sub-group analyses between the 3F/wk and 5F/wk regimes in this trial; these have diminished now that the full follow-up data are available. This trial has provided evidence on which clinicians may base their choice between either a 3F/wk fractionation regime or a conventional 5F/wk treatment protocol in the treatment of carcinoma of the laryngo-pharynx.

First interim progress report on the second British Institute of Radiology Fractionation Study: short versus long overall treatment times for radiotherapy of carcinoma of the laryngopharynx.

Preliminary data from a second British Institute of Radiology Fractionation Trial comparing short (less than or equal to 4 weeks) and long (greater than 4 weeks) overall treatment times are reported. The intake of patients ran from January, 1975 to December, 1985 when 611 patients with carcinoma of the laryngo-pharynx were registered in this prospective, randomized, multicentre clinical trial. No significant differences have, so far, been demonstrated between the two arms of the trial with respect to observed survival rates, tumour-free or laryngectomy-free rates. Further long-term follow-up is continuing.

The 10-year results of a prospective trial of post-operative radiotherapy delivered in 3 fractions per week versus 2 fractions per week in breast carcinoma.

The 10-year results are presented of a prospective trial of 411 patients with breast carcinoma treated by mastectomy and post-operative radiotherapy given in either 2 or 3 fractions per week (i.e. a comparison of 6 fractions in 18 days with 12 fractions in 28 days). The early radiation effects on the normal tissues were similar and acceptable. The late skin changes in the chest wall (treated with 70 kV X rays) were progressive and by 10 years were slightly more marked with 6 fractions. Late subcutaneous fibrosis in the axilla (treated with cobalt-60 teletherapy), however, was much less in the 6-fraction group. Twelve fractions resulted in greater restriction of shoulder movement and an increased incidence of lymphoedema of the arm. Doses were selected on the basis of past clinical experience. The dose used to treat the axilla in 6 fractions was 35 Gy, 14.99% less than that predicted by NSD. The dose predicted by alpha:beta, using a value of 2 Gy for late reactions, is 38.14 Gy. Thus simple theory, which omits time, still predicts too high a dose for 6 fractions, although it is closer than NSD. In this trial, the 6-fraction technique showed an advantage over the 12-fraction technique. It was equally effective in controlling local recurrence and had fewer late sequelae. It was also convenient for patients and economic in the use of radiotherapy resources.

Primary adenocarcinoma of the cervix: treatment and results.

Between 1972 and 1983, 49 patients with adenocarcinoma of the cervix were treated in four ways: (i) radiotherapy alone, (ii) pre- or postoperative radiotherapy and a total abdominal hysterectomy and bilateral salpingo-oophorectomy, (iii) Wertheim's hysterectomy, and (iv) pre- or postoperative pelvic radiotherapy and Wertheim's hysterectomy. The 5-year survival results for patients with FIGO Stage I disease was 90%; with Stage II disease 60%; with Stage III disease 11% and none survived with Stage IV disease. All the patients, except one (Stage III), with well-differentiated tumours are alive and disease-free, irrespective of the type of treatment they received whereas only one patient out of the 13 who had poorly differentiated tumour is alive and disease-free. Three patients had bowel damage, one after radiotherapy alone and two after Wertheim's hysterectomy and postoperative radiotherapy. No major surgical complications occurred in this series.

A randomized, prospective, comparative, multicentre trial of a single combination versus alternating combinations of antitumour drugs in advanced breast cancer.

A prospective, multicentre trial was conducted in 262 patients with advanced breast cancer randomized to receive every 3 weeks either: (i) a single five-drug combination of adriamycin (50 mg), vincristine (1.5 mg) and 5-fluorouracil (750 mg) given intravenously; with methotrexate (50 mg) intramuscularly and chlorambucil (10 mg) orally all at time zero, followed by three further doses of chlorambucil (10 mg) at 6-h intervals, or (ii) one course of two alternating three-drug combinations consisting of regimen A--vincristine (1.5 mg), adriamycin (70 mg) and methotrexate (50 mg) and regimen B--5-fluorouracil (750 mg) and vindesine (5 mg) intravenously with cyclophosphamide (50 mg) orally at time zero, followed by three further doses of cyclophosphamide (50 mg) at 6-h intervals. Results show that overall response rates to chemotherapy were comparable in the two arms of this study being 63% (83 of 131 patients) for the single combination and 64% (84 of 131 patients) for the alternating combinations. Response rates according to menopausal status indicate no significant difference for the two arms of this study. However overall, combining all patients treated with either the single or the alternating combinations, post-menopausal patients had a significantly lower response rate (57%) compared with pre-menopausal patients (76%), P less than 0.05. Overall serious side-effects were minimal and were similar in both treatment groups. Response durations and overall survival data, which are essentially similar for the two treatment groups, proved disappointing with a median response duration of only approx. 6 months and overall median survival only slightly in excess of 1 year. Alternative treatment approaches are needed to maintain the remissions initially achieved in metastatic breast cancer.

Adjuvant chemotherapy in the treatment of breast cancer: results of a multicentre study.

248 patients with locally radically treated early breast cancer (196 node-positive) were randomized post-operatively between 6 courses of a 'CMF like' chemotherapy and no further treatment. Results (with a minimum of 5 years follow-up on every patient) favour chemotherapy with a significant increase in the median time to recurrence from 31 to 50 months for all patients (P = 0.04) and from 26 to 49 months for node-positive patients (P = 0.023). No significant effect on survival is seen although there is a trend towards longer survival in the treated group. The regimen used was relatively non-toxic when compared to the traditional CMF with 34% of patients experiencing mild nausea and vomiting immediately post-injection and only 11% complaining of more severe nausea and vomiting. Because of this lower toxicity the treatment was found to be amenable to administration in both regional hospitals and specialized centres.

A clinician's view on palliative care, terminal care and quality of life.

No more than 20-25% of cancer patients are cured and 55% need palliative treatment from the time of diagnosis. Medical and nurse training in palliative care, and pain control in particular, is poor and there is a great shortage of doctors trained in terminal care. Palliative care is detailed, complex care and includes many services both in the hospital and in the community. It should be available to all patients wherever they live. We need a network of Home Care and Hospital Support Teams throughout the country, and a limited number of specialist hospice inpatient units to deal with the difficult problems, research and training in terminal care. These services need to be co-ordinated and monitored and will require funding by governmental bodies.

Seventh interim progress report of the british institute of radiology fractionation study of 3F/week versus 5F/week in radiotherapy of the laryngo-pharynx.

A fresh analysis of the data entered into the multicentre BIR fractionation trial of 3F/week versus 5F/week in radiotherapy of the laryngopharynx has been undertaken. Completed records of the 732 patients initially entered into the trial have now risen from 687 at the last report to 706. The data have been analysed in a manner similar to that adopted previously so as to measure the effects of the two regimes on both tumour and normal tissues, and some additional analyses have now also been made. There have been some modifications in the results in the various sub-groups which may be due to an inadequate number of patients having been followed up for long enough at the time of the previous analyses. More data for late radiation damage to normal tissues and new radiobiological findings have suggested possible explanations for the differences which have emerged between the two groups. The apparent differences between the sub-groups containing patients with highly localized tumours, which were reported in our previous report, are now less marked and not statistically significant.

Comparison of 5-day, 1-day, and 2-day cyclical combination chemotherapy in advanced breast cancer.

The results of 5-day cyclical combined chemotherapy for advanced breast cancer were compared in two trials with the less demanding 1-day and 2-day regimens. At all stages, except at 3 months, 5-day treatment was significantly more successful in providing regression and remission of tumours than the 1-day regimen. However, although the differences are not statistically significant, data from the second trial indicated that the 2-day regimen tended to be more effective than the 5-day regimen. The lower 95% confidence limit for the success of the 2-day treatment was 56.2% at 3 months.

A prospective clinical trial of post-operative radiotherapy delivered in three fractions per week versus two fractions per week in breast carcinoma.

The results are presented of a five-year prospective trial of 411 patients with breast carcinoma treated by mastectomy and post-operative radiotherapy. Twice or thrice weekly dose-fractionation techniques were used, i.e. 12 fractions in 28 days and six fractions in 18 days. The results show that, in terms of survival and control of local disease, the two techniques are very similar. The early and late radiation effects on the normal tissues up to five years are similar and acceptable. Dose levels thought to be biologically equivalent on the basis of experience at St Thomas's Hosiptal were selected. It is stressed that there is a narrower margin of normal tissue tolerance when six fractions over 18 days are used, that it is essential to treat all fields on each treatment occasion and that the total maximum tissue dose of 3600 R is not exceeded. Attention is drawn to the fact that the dose for six fractions, derived from the NSD formula which would be predicted to be equivalent to the 12-fraction dose is, in fact, over 10% higher than the dose used here and likely to produce unacceptable late radiation changes.