Angela Harvey

Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial

BACKGROUND AND METHOD A randomised controlled trial in locally advanced non-small cell lung cancer (NSCLC), compared CHART which employs 36 fractions of 1.5 Gy 3 times per day to give 54 Gy in 12 consecutive days with conventional radiotherapy-30 fractions of 2 Gy to a total dose of 60 Gy in 6 weeks. A total of 563 patients were entered between April 1990 and April 1995. This report is based upon the data updated to 1 April 1998. RESULTS The analysis of the mature data shows that the benefits previously reported have been maintained. Overall there was a 22% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 9% from 20 to 29% (P = 0.008) and a 21% reduction in the relative risk of local progression (P = 0.033). In the large subgroup of patients with squamous cell cancer which accounted for 81% of the cases, there was a 30% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 13% from 20 to 33% (P = 0.0007) and a 27% reduction in the relative risk of local progression (P = 0.012). Furthermore, in squamous carcinoma there was a 25% reduction in the relative risk of local and/or distant progression (P = 0.025) and 24% reduction in the relative risk of metastasis (P = 0.043). There was no evidence that CHART gave more or less benefit in any other subgroup. CONCLUSION This analysis of mature data confirms that CHART is superior to conventional radiotherapy in achieving local tumour control and survival in locally advanced NSCLC. This demonstrates the importance of cellular repopulation as a cause of failure in the radiotherapy of NSCLC. The reduction in the risk of metastasis confirms that improved local tumour control, even in lung cancer, can reduce the incidence of metastasis. This trial shows that control of local tumour can lead to an improvement in long term survival.

Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial

BACKGROUND Human tumour cells can proliferate rapidly, and giving radiotherapy in many small fractions may reduce long-term normal-tissue morbidity. In response to these observations, we developed the CHART (continuous hyperfractionated accelerated radiotherapy) regimen, which uses thirty-six small fractions of 1.5 Gy given three times per day, to give 54 Gy in only 12 consecutive days. We report the long-term follow-up of a trial of CHART versus conventional radiotherapy in patients with locally advanced non-small-cell lung cancer (NSCLC). METHODS 563 patients were entered by thirteen centres between April, 1990, and March, 1995. We included patients with NSCLC localised to the chest with a performance status of 0 or 1 in whom radical radiotherapy was chosen as the definitive management. Patients were randomly allocated in a 3:2 ratio to CHART or conventional radiotherapy. The latter was thirty fractions of 2 Gy to a total dose of 60 Gy in 6 weeks. RESULTS The groups were well matched for possible prognostic factors. Overall there was a 24% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2-year survival of 9% from 20% to 29% (p = 0.004, 95% CI 0.63-0.92). Subgroup analyses (predefined) suggest that the largest benefit occurred in patients with squamous cell carcinomas (82% of the cases), in whom there was a 34% reduction in the relative risk of death (an absolute improvement at 2 years of 14% from 19% to 33%). During the first 3 months, severe dysphagia occurred more often in the CHART group than in the group on conventional radiotherapy (19 vs 3%). Otherwise, there were no important differences in short-term or long-term morbidity. INTERPRETATION CHART compared with conventional radiotherapy gave a significant improvement in survival of patients with NSCLC. Further improvement may be achieved with dose escalation in conformal radiotherapy, by the addition of cytotoxic chemotherapy, and by hypoxic cell radiosensitisation.

A RANDOMISED MULTICENTRE TRIAL OF CHART VERSUS CONVENTIONAL RADIOTHERAPY IN HEAD AND NECK CANCER

BACKGROUND AND PURPOSE Continuous, hyperfractionated, accelerated radiotherapy (CHART) has shown promise of improved tumour control and reduced late morbidity in pilot studies and has now been tested in a multicentre randomised controlled clinical trial. MATERIAL AND METHODS Patients with squamous cell cancer in the main sites within the head and neck region with the general exception of early T1 N0 tumours were entered into the study by 11 centres. There was a 3:2 randomisation to either CHART, where a dose of 54 Gy was given in 36 fractions over 12 days, or to conventional therapy where 66 Gy was given in 33 fractions over 6.5 weeks. A total of 918 patients were included over a 5 year period from March 1990. RESULTS ACUTE MORBIDITY: Acute radiation mucositis was more severe with CHART, occurred earlier but settled sooner and was in nearly all cases healed by 8 weeks in both arms. Skin reactions were less severe and settled more quickly in the CHART treated patients. TUMOUR CONTROL AND SURVIVAL: Life table analyses of loco-regional control, primary tumour control, nodal control, disease-free interval, freedom from metastasis and survival showed no evidence of differences between the two arms. In exploratory subgroup analyses there was evidence of a greater response to CHART in younger patients (P = 0.041) and poorly differentiated tumours appeared to fare better with conventional radiotherapy (P = 0.030). In the larynx there was evidence of a trend towards increasing benefit with more advanced T stage (P = 0.002). LATE TREATMENT RELATED MORBIDITY: Osteoradionecrosis occurred in 0.4% of patients after CHART and 1.4% of patients after conventional radiotherapy. The incidence of chondritis or cartilage necrosis was similar in both arms. Life table analysis showed evidence of reduced severity in a number of late morbidities in favour of CHART. These were most striking for skin telangiectasia, superficial and deep ulceration of the mucosa and laryngeal oedema. CONCLUSION Similar local turnout control was achieved by CHART as compared with conventional radiotherapy despite the reduction in total dose from 66 to 54 Gy supporting the importance of repopulation as a cause of radiation failure. The effects seen in advanced laryngeal cancer and those related to histological differentiation need further study. Reduced late morbidity is a factor which together with patient preference should be considered in the decision as to the programme of radiotherapy to employ in the curative treatment of head and neck cancer.

Quality of life assessment in clinical trials—guidelines and a checklist for protocol writers: the U.K. Medical Research Council experience

Many clinical trials groups now routinely consider including Quality of Life (QoL) assessment in trials. Indeed, several have policies stating that QoL should be considered as a potential endpoint in all new trials and that if it is not to be evaluated the applicants should justify not doing so. However, inclusion of QoL in clinical trials presents a number of difficult organisational issues, and serious problems in compliance have frequently been reported. Thus, in multicentre clinical trials many of the expected QoL questionnaires fail to be successfully completed and returned, although a few groups have claimed high success rates. However, it is well recognised that if questionnaires are missing, there may be bias in the interpretation of trial results, and the estimates of treatment differences and the overall level of QoL may be inaccurate and misleading. Hence it is important to seek methods of improving compliance, at the level of both the participating institution and the patient. We describe a number of methods for addressing these issues, which we suggest should be considered by all those writing clinical trial protocols involving QoL assessment. These are based upon over a decade of experience with assessing QoL in Medical Research Council (MRC) cancer clinical trials. In particular, we provide a checklist for points that should be covered in protocols. Examples are given from a range of current MRC Cancer Trials Office protocols, which it is proposed might act as templates when writing new protocols.

Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and minimal thoracic symptoms: randomised controlled trial

Abstract Objective: To determine whether patients with locally advanced non-small cell lung cancer unsuitable for resection or radical radiotherapy, and with minimal thoracic symptoms, should be given palliative thoracic radiotherapy immediately or as needed to treat symptoms. Design: Multicentre randomised controlled trial. Setting: 23 centres in the United Kingdom, Ireland, and South Africa. Participants: 230 patients with previously untreated, non-small cell lung cancer that is locally too advanced for resection or radical radiotherapy with curative intent, with minimal thoracic symptoms, and with no indication for immediate thoracic radiotherapy. Interventions: All patients were given supportive treatment and were randomised to receive palliative thoracic radiotherapy either immediately or delayed until needed to treat symptoms. The recommended regimens were 17 Gy in two fractions one week apart or 10 Gy as a single dose. Main outcome measures: Primary—patients alive and without moderate or severe cough, chest pain, haemoptysis, or dyspnoea six months from randomisation, as recorded by clinicians. Secondary—quality of life, adverse events, survival. Results: From December 1992 to May 1999, 230 patients were randomised. 104/115 of the patients in the immediate treatment group received thoracic radiotherapy (90 received one of the recommended regimens). In the delayed treatment group, 48/115 (42%) patients received thoracic radiotherapy (29 received one of the recommended regimens); 64 (56%) died without receiving thoracic radiotherapy; the remaining three (3%) were alive at the end of the study without having received the treatment. For patients who received thoracic radiotherapy, the median time to start was 15 days in the immediate treatment group and 125 days in the delayed treatment group. The primary outcome measure was achieved in 28% of the immediate treatment group and 26% of patients from the delayed treatment group (27/97 and 27/103, respectively; absolute difference 1.6%, 95% confidence interval -10.7% to 13.9%). No evidence of a difference was observed between the two treatment groups in terms of activity level, anxiety, depression, and psychological distress, as recorded by the patients. Adverse events were more common in the immediate treatment group. Neither group had a survival advantage (hazard ratio 0.95, 0.73to 1.24; P=0.71). Median survival was 8.3 months and 7.9 months, and the survival rates were 31% and 29% at 12 months, for the immediate and delayed treatment groups, respectively. Conclusion: In minimally symptomatic patients with locally advanced non-small cell lung cancer, no persuasive evidence was found to indicate that giving immediate palliative thoracic radiotherapy improves symptom control, quality of life, or survival when compared with delaying until symptoms require treatment.

Is double data entry necessary? The CHART trials

There is some controversy over the need for double data entry in clinical trials. In particular, does the number and types of errors identified with this approach justify the extra effort involved? We report the results of a study carried out to address this question. Our main outcome measure was the frequency and types of errors involved in the entry of data for the CHART (continuous, hyperfractionated, accelerated radiotherapy) trials. Data were reentered for a sample of 44 patients by a data manager other than the one making the initial entry. The second entry was then compared with the first entry. The error rate for the two entries combined was 14 per 10,000 data items (fields) (95% confidence interval 10, 19). The error rate for the initial entry alone was 15 per 10,000 fields (95% confidence interval 9.5, 22), and the vital/important error rate (defined as any error on a principal outcome measure or a major error on any other endpoint or variable) was 2.5 per 10,000 fields (95% confidence interval 0.68, 6.4). On this evidence double data entry is not performed for the CHART trials.

Survey of the administration of quality of life (QL) questionnaires in three multicentre randomised trials in cancer

We surveyed centres collaborating in two trials in lung cancer (LU12, LU13) and one in lung and head and neck cancer (CHART) to find out how QL questionnaires were being administered, with the aim of standardising procedures and improving compliance. Dedicated local trials staff were funded for CHART but not for the other trials. In all three trials, patients completed a Rotterdam Symptom Checklist (RSCL) and a Hospital Anxiety and Depression Scale (HADS) at specified times. 17 of 22 LU12 centres, 9 of 11 LU13 and all 10 CHART centres returned survey forms. In LU12 and LU13, the category of staff responsible for questionnaires varied widely; in CHART, only research staff were involved. This led to more consistency in CHART centres in the administration and collection of questionnaires, and more frequent checking of forms. However, even the CHART administration, although better than in the other two trials, could not be regarded as standardised. All centres were equally affected by logistical problems. These embraced organisational deficits (e.g. unavailability of staff, lack of questionnaires) and patient-related factors (e.g. patient deemed to be too ill, had difficulty reading or left before completing the form). Patient refusals were an uncommon reason for non-compliance and patients were considered to be generally in favour of QL assessment. As a result of these findings, a number of measures have been put in place to increase standardisation of procedures and improve compliance. These include publishing guidelines for protocol writing, providing centres with guidelines for QL administration and information leaflets for patients, together with introducing staff training.