Hyperbaric oxygen and radiotherapy: a Medical Research. Council trial in carcinoma of the bladder. By I. S. Cade, M.S., F.R.C.S., F.R.C.R. and J. B. McEwen, ...
1978, British Journal of Radiology, 51, 876-878
Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the bladder By I. S. Cade, M.S., F.R.C.S., F.R.C.R. and J. B. McEwen, M.B., F.R.C.R., Department of Radiotherapy and Oncology, St. Mary's General Hospital, Portsmouth PO3 6AD S. Dische, M.D., F.R.C.R., and M. I. Saunders, M.B., F.R.C.R., Marie Curie Research Wing for Oncology, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN E. R. Watson, M.B., F.R.C.R., and K. E. Hainan, F.R.C.P., F.R.C.R., F.R.S.E., Glasgow Institute of Radiotherapeutics, Western Infirmary, Glasgow G11 6NT G. Wiernik, M.D., F.R.C.R., and D. J. D. Perrins, M.D., F.R.C.S., Research Institute, The Churchill Hospital, Headington, Oxford 0X3 7LJ and I. Sutherland, M.A., D.Phil. MRC Statistical Research and Services Unit, University College Hospital Medical School, 115 Gower Street, London WC1E6AS {Received April, 1978) ABSTRACT
In a randomized controlled clinical trial of hyperbaric oxygen in the radiotherapy of carcinoma of the bladder a total of 241 cases were contributed by four radiotherapy centres in the United Kingdom. In this trial where in each centre identical radiotherapy was employed for both oxygen and air cases, no benefit was shown with the use of hyperbaric oxygen.
During the past 20 years patients with carcinoma of the bladder have received treatment in hyperbaric oxygen in an effort to demonstrate a process of radiosensitization by this method of treatment. For patients with advanced carcinoma of the bladder radiotherapy is probably the best method of radical treatment available, but five-year survival rates are only of the order of 30%, indicating that there is an urgent need to improve the method of treatment. The working party on radiotherapy and hyperbaric oxygen decided to include bladder carcinoma in its clinical trials. THE FIRST TRIAL
This trial was initiated at a time when the cooperating centres were already pursuing their own studies, so it was agreed that each centre should continue to employ its own radiotherapy regimen. The irradiation schedule in each centre was similar for cases in both arms of the trial but the patients were randomized to treatment in air or hyperbaric oxygen. Four radiotherapy centres collaborated: Portsmouth, Mount Vernon, Glasgow and Oxford. Method Preliminary investigations of all patients included: chest X ray; full blood count; blood urea estimation;
intravenous pyelography; examination under anaesthesia; bacterial culture of urine. Patients were included in the trial if: 1. They had carcinoma of the bladder of any histological type and were considered suitable for an attempt to cure by radiotherapy using an external beam of high energy radiation. 2. The primary tumour had not extended to infiltrate the skin, the rectal wall or another segment of the intestine. Involvement of the vagina and uterus was allowed, provided there was no fistula. 3. Lymph node involvement was confined to the external iliac nodes. Patients were excluded if: (a) there was impaired renal function, a blood urea greater than 100 mg-% (16.7 mmol/litre); (b) they were unable to enter the chamber because (i) they were unable to lie flat for any reason (ii) they had a past history of fits or convulsions; (c) they were unlikely or unable to co-operate in pressurization or in setting up for treatment inside the chamber; (d) they resided abroad or co-existing disease made it unlikely that a course of treatment or followup could be completed; (e) they had reached their 75th birthday. (f) total cystectomy or urinary diversion had been performed. If patients were accepted into the trial they were allocated to treatment in oxygen or in air by opening a sealed envelope containing instructions prepared by the Medical Research Council Statistical Research and Services Unit.
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NOVEMBER 1978
Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the bladder Radiotherapy techniques Table I summarizes the protocols adopted by each of the centres. The patients who received treatment in oxygen were placed in a Vickers transparent chamber and the oxygen pressure was raised to three atmospheres absolute. Radiotherapy was delayed until 15 minutes after full pressure had been reached in order to allow time for the tumour to become
saturated with oxygen. A correction was made for radiation absorbed in the chamber wall, Results From 1964 to 1971, 241 patients were entered into the trial and of these 236 patients were available for assessment. The actuarial survival rates are given in Table II.
TABLE I PROTOCOLS ADOPTED BY THE COLLABORATING CENTRE
Number of cases
Centre
Period of entry to trial
Ti& T2
T3& T4
Radiotherapy
Total
No. of fractions
Overall time (days)
Dose
Machine used
Portsmouth
May 64-Dec. 67 Jan. 68-Dec. 71
33 34
32 23
65 57
40 6
56 18
*6000 R |3600 rad
Cobalt 60
Oxford
Dec. 68-Dec. 71
—
25
25
10
31
|4250 rad
Cobalt 60
Glasgow
Nov. 66-Feb. 70
18
9
27
24
34
J6000 rad
4 MV
Mount Vernon
Apr. 66-May 71
21 7
20 19
41 26
30 15
42 33
6000 R 4725 R
4MV
*Minimum tumour dose.
^Maximum tissue dose.
JModal dose.
TABLE II ACTUARIAL SURVIVAL RATES
Survival by years since entry to trial Total
1
2
3
4
5
Oxygen
118
75 (64%)
50 (42%)
42 (36%)
37(31%)
33 (28%)
Air
118
76 (64%)
55 (47%)
44 (37%)
41 (35%)
36 (30%)
Probability of difference between curves arising by chance P=0.72.
TABLE III ACTUARIAL SURVIVAL RATES ACCORDING TO HISTOLOGY
Percentage surviving by years since entry to trial Histology
Treatment
Total patients
1
2
3
4
5
38 40
33 35
0.61
—
0.62
—
0.32
Transitional
Oxygen Air
84 91
70 69
46 53
42 42
Anaplastic
Oxygen Air
22 16
50 44
36 (19)
(27)
Oxygen Air
12 11
(42) 54
36
Other
Probability of difference between curves due to chance
— —
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At none of the individual centres, nor when the cases were gathered together, was any significant improvement in survival achieved by the use of hyperbaric oxygen, there being 28% survivors at five years among those treated in hyperbaric oxygen and 30% survivors among those treated in air (P=0.88). An analysis of the results according to the different histological types of tumour (Table III) revealed no significant improvement of survival from either treatment regime. In this trial data as to morbidity and local tumour control were not gathered centrally. In none of the reports from individual centres was any improvement in local control shown and no significant difference in morbidity was found (Dische, 1973; Wiernik and Perrins, 1974; Kirk et al, 1976; Cade and McEwen, 1978). This information has been collected in all subsequent trials including the second bladder trial. THE SECOND TRIAL
treatment given in a small number of fractions in hyperbaric oxygen with a treatment schedule suitable for conventional radiotherapy in air where a greater number of fractions are usually employed. Although 165 patients have so far been entered into this trial not enough time has elapsed yet for conclusions to be reached. CONCLUSIONS
In this study which has involved the treatment of 241 patients, with an intake period of six to seven years and a follow-up period of over 13 years, oxygen has not given any improvement in survival. Local control and morbidity was not recorded centrally but with both no important differences between cases treated in oxygen and air were noted at each centre. These results suggest either than hypoxic tumour cells do not significantly contribute to failure to cure in carcinoma of bladder, or that in this situation hyperbaric oxygen does not significantly contribute to the eradication of hypoxic tumour cells.
By 1971, it appeared that the best results for treatment given in hyperbaric oxygen followed the use of REFERENCES a relatively few (up to ten) fractions. This was con- CADE, I. S., and MCEWEN, J. B., 1978. Clinical trials of radiotherapy in hyperbaric oxygen at Portsmouth (1964sistent with the radiobiological data then being 1976). Clinical Radiology 29, 333-338. reported. Withers and Scott (1964) showed that the DISCHE, S., 1973. The hyperbaric oxygen chamber in the radiotherapy of carcinoma of the bladder. British Journal oxygen enhancement ratio (OER) on normal mouse of Radiology, 45, 13-17. skin is dependent on radiation dose. Revesz and KIRK, J., WINGATE, W. H., and WATSON, E. R., 1976. HighLittbrand (1974) concluded from studies on irradidose effects in the treatment of carcinoma of the bladder under air and hyperbaric oxygen conditions. Clinical ated Chinese hamster cells that the sensitivity of Radiology, 27, 137-144. anoxic and oxic populations will vary with the radiaREVESZ, I., and LITTBRAND, B., 1974. Variation of the oxygen tion dose delivered and that the OER of a 400 rad enhancement ratio at different X-ray dose levels and its possible significance. In Advances in Radiation Research fraction is approximately 2.07, whereas it is negliBiology and Medicine, 3, eds. J. F. Duplan and A. gible for fractions of less than 200 rad. Meanwhile, Chapiro, pp. 1215-1224 (Gordon and Breach, London). Rubin et al. (1969) had pointed out that the OER RUBIN, P., POULTER, C. A., and QUICK, R. S., 1969. Changwas more likely to be impioved by a few fractions ing perspectives in oxygen breathing and radiation therapy. American Journal of Roentgenology, 105, 665-681. each with a large dose since the differential destrucG., and PERRINS, D. J. D., 1974. Hyperbaric tion between aerobic and anoxic cells occurs on the WIERNIK, oxygen and radiotherapy in advanced carcinoma of the slope rather than the shoulder of a cell survival curve. cervix and bladder. In Fifth International Hyperbaric Congress Proceedings, II, pp. 820-829 (Vancouver, B.C.). These considerations, amongst others, led to the WITHERS, H. R., and SCOTT, O. C. A., 1964. British Empire working party initiating further studies to compare Cancer Campaign Report, p. 233.
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