71
Radiotherapy and Oncology, Suppl. 20 (1991) 71-74 Elsevier
What have we learnt from hyperbaric oxygen? Stanley Dische Marie Curie Research Wing, Regional Centre for Radiotherapy and Oncology, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN England
Keywords." Radiotherapy; Hyperbaric oxygen; Carbogen; Tumour control; Clinical trial
Summary The 15 randomised controlled clinical trials of hyperbaric oxygen in radiotherapy yielded three with highly significant benefit and six with useful margins not reaching statistical significance. The increase in tumour control was partly negated by an increase in normal tissue effect. Now simple carbogen breathing in animal tumour models has shown high efficiency and there is the potential for its use in man as a simple means of hypoxic cell radiosensitisation.
Introduction In 1955 Ian Churchill-Davidson and his colleagues published the first clinical account of their work in the use of hyperbaric oxygen in radiotherapy. The work excited great interest and controversy. The more easily employed Vickers chamber was soon introduced and many explored its use. There were excited reports of great advantage, a series of randomised controlled trials and now, this year, the last remaining practitioner in the United Kingdom is retiring and the method will cease to be used in this country, where it was first introduced. Despite this there is much that we can learn concerning the oxygen effect of human radiobiology, of clinical trials and of what has already been performed.
Randomised controlled clinical trials If we look just at the randomised controlled clinical trials performed in centres throughout the world, we see a most encouraging pattern of result (Table 1). A statistically significant increase in tumour control and in survival has been obtained in some of the studies and good margins are achieved in others where
Table 1. Results of randomised controlled trials of hyperbaric oxygen Therapeutic benefit Significantly improved results Margin in favour (not significant) No difference Margin against (not significant) Adverse response TOTAL
3 0 6 6 0 0 l5
0167-8140/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)
72 numbers did not permit the achievement of the magic P value of 0.05 [3]. Why has this method become disused? Interpretation of some of the trials was made difficult by the use of unconventional fractionation regimes and some control groups did not receive a regime of radiotherapy considered optimal by international standards [4]. In all the hyperbaric oxygen trials in the management of carcinoma of the cervix there was an increased incidence of normal tissue injury. If we just look at those employing for both treatment arms, a conventional daily fraction of about 2 Gy. we find that in all four [1,5,9,10] there was an excess of radiation morbidity in the oxygen treated group though it did not reach statistical significance in all. By putting all four trials together we have 307 controls and 286 patients treated in hyperbaric oxygen. A total of 27 (8.8%) control patients showed moderate or severe morbidity, usually in the bowel but also included were bladder problems. Of the oxygen treated cases 57 (19.9%) showed similar morbidity. There was a statistically significant increase in normal tissue injury ( P ~< 0.0005).
Normal tissue effects - hyperbaric o x y g e n and chemical agents
Why were normal tissue effects increased? If we look at the historic Alper-Flanders curve, we can see that at high oxygen tension the curve flattens but still has a very slight inclination. By this, I believe Dr. Suit predicted many years ago, that trials with hyperbaric oxygen might lead to a slight increase in normal tissue injury. He advocated that the dose used for hyperbaric oxygen should be slightly reduced because of this - an advice which was disregarded. There may also be another explanation. If we look at the work which has been performed with the chemical sensitising agents, we entirely find no significant increase in normal tissue injury and this is so even in those studies where some margin of increased tumour control has been reported. One cannot exclude, of course, a very small margin of increase in normal tissue injury, but if present this was obviously at a very low level, much below that seen in the hyperbaric oxygen studies [4]. The difference between the findings in the hyperbaric oxygen trials and in the chemical sensitising ones may relate to the distribution of oxygen through the tissues. Following a study of the histological pattern seen in human bronchial carcinoma Thomlinson and Gray [8] described their model in which there was a steep fall in oxygen tension at a distance from the capillary. Severely hypoxic cells, unless rescued by their radioresistance and subsequent reoxygenation, would soon pass into necrosis. This model has formed the basis for work with hypoxic cell radiosensitisation, but is the model true of all parts of all tumours and also generally of normal tissues? We have seen the work of Dr. MueUer-Klieser and the wide range of oxygen saturation levels in normal tissues and in tumours. The direct measurement of oxygen tension in an affected lymph node of patients with head and neck tumours has revealed low concentrations and these have been associated with poor response and survival [6]. However, tumour cells may not survive at such low levels and the findings may be an indication of the extent of hypoxia prevailing through the rest of the tumour. This may give it its prognostic power. The distribution of oxygenation through a tumour may have a particular relevance for the effectiveness of oxygen compared with chemical agents as hypoxic cell sensitisers. The relationship between radiosensitivity and oxygen concentration shown in Fig. 1 is based on the data of Denekamp et al. [2]. Radiosensitivity is expressed in a linear form but oxygen concentration on a log scale. It can be seen that in severely hypoxic cells with oxygen concentrations below 1% the maximum effect is obtained with a sensitiser. However, as the oxygen tension rises, the effect diminishes. With moderate levels of hypoxia there is still considerable radioresistance compared with that of the fully oxic cell, but very little sensitisation is achieved with a chemical agent. These agents are not metabolised in the oxic cells and so do become uniformly distributed throughout the tumour. The sensitising efficiency of 1.6 is the maximum likely to be achieved by the sensitising drugs presently being employed. The pattern, however, will be different with the use of oxygen, carbogen or hyperbaric oxygen. The cells most likely to show an elevation of oxygen tension will be those showing a modest hypoxia. These cells will metabolise the oxygen so denying it to the more severely hypoxic cells placed more peripherally. This, then, may well be the cause of the increased /
73 0 r-< Iw w 0
z< 2 III
,
O( >"SmZx
,
SENSITIZERJ
I N2
,
I 1
I I0
I 100
OXYGEN CONCENTRATION mmHg
Fig. 1. The relationship between oxygen enhancement ratio and oxygen concentration is shown and is based upon the data of
Denekamp et al. [2]. The enhancement ratio is expressed in a linear form, but oxygenconcentration on a log scale. The effect of the addition of an hypoxiccell radiosensitiser such as a nitroimidazole, at a clinically achievable concentration, is also shown. normal tissue effect observed in the hyperbaric oxygen trials. If moderate hypoxia is the major problem of radioresistance of tumours caused by oxygen deprivation then oxygen will be the effective agent. Chemical sensitisers will be more effective under severely hypoxic conditions.
Normobaric carbogen breathing re-visited Recent laboratory experiments using carbogen breathing performed by Rojas [7] in the Gray Laboratory have shown sensitisation superior to that obtained using chemical agents. Due to these experiments we have to take a further look at carbogen breathing in the clinic. A most interesting feature of her work has been the rapidity with which increased oxygen concentration in respired air is reflected in increased radiosensitivity - less than 2 minutes appears appropriate in the animal system. We have looked at more effective oxygen delivery systems in the original clinical work using carbogen than were used 30 years ago. Our work suggests that equally short intervals between the commencement of oxygen breathing and increase in radiosensitivity may occur in man as in the animals, so suggesting a regime of management very different from that used previously. It is possible that simple carbogen breathing which we have shown to be very easily applied, gives a method which may lead to the most effective hypoxic cell sensitisation using a non-toxic technique, free of all the problems associated with the use of chemical agents in clinical practice.
Conclusions We can summarise by saying that in the hyperbaric oxygen trials greater tumour control was obtained, but this was at the expense of an increase in normal tissue injury. We have learned that control groups must be treated by an internationally acceptable scheme of radiotherapy, otherwise the trial will be given little or no significance. Normal tissue effects must be observed and measured as closely as those of turnout. In the design of the study the level of morbidity should, if possible, be equal in both control and experiment arms - a very difficult situation to plan in advance. We must recognise that a complex and demanding technique must give an obviously large benefit to justify a continuation of the effort and adoption of practice. Finally, we have learnt that oxygen is a potent radiosensitiser and that we may give, with simple normobaric carbogen breathing, effective hypoxic cell radiosensitisation. We must still look at it carefully to seek advantage to our patients.
74
Acknowledgements I w i s h to t h a n k Dr. M . I . S a u n d e r s for h e r a d v i c e u p o n t h e m a n u s c r i p t a n d M r s . E. D a v i e s for h e r h e l p in its p r e p a r a t i o n . I a m also g r a t e f u l to t h e C a n c e r R e s e a r c h C a m p a i g n f o r t h e i r c u r r e n t s u p p o r t a n d the M e d i c a l R e s e a r c h C o u n c i l for t h e s u p p o r t g i v e n p r e v i o u s l y .
References 1. Brady, L.W., Plenk, H.P., Hanley, J.A., Glassburn, J.R., Kramer, S. and Parker, R.G. Hyperbaric oxygen therapy for carcinoma of the cervix - Stages liB, IliA, IIIB and IVA: results of a randomized study by the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys., 7, 991-998, 1981. 2. Denekamp, J., Rojas, A. and Stevens, G. Redox competition and radiosensitivity: implications for testing radioprotective compounds. Pharmacol. Ther., 39, 59-66, 1988. 3. Dische, S. The clinical use of hyperbaric oxygen and chemical hypoxic cell sensitizers - an overview. In: The Biological Basis of Radiotherapy pp. 225-237. Editors: G.G. Steel, G.E. Adams and M. Peckham. Elsevier Science Publishers, B.V, 1983. 4. Dische, S. A review of hypoxic cell radiosensitization. Int. J. Radiat. Oncol. Biol. Phys. (Awaiting publication). 5. Fletcher, G.L., Lindberg, R.D., Caderao, J.N. and Taylor Wharton, J. Hyperbaric oxygen as a radiotherapeutic adjuvant in advanced carcinoma of the uterine cervix. Preliminary results of a randomized trial. Cancer, 39, 617-623, 1977. 6. Gatenby. R.A., Kessler, H.B., Rosenblum, J.S., Coia, L.R., Moldofsky, P.J., Hartz, W.H. and Broder, G.J. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys., 14, 831-838, 1988. 7. Rojas, A. Oxygen: a clinical reality or a mirage? In: BIR Report 19, The Scientific. Basis of Modem Radiotherapy, pp. 86-90. Editor: N.J. McNally, Butterworth & Co. Kent. 1989. 8. Thomlinson R.H. and Gray, L.H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer, 9, 539-549, 1955. 9. Sealy, R. Hyperbaric oxygen and radiotherapy. In: Advances in Medical Oncology, Research and Education, Vol. 6. Basis for Cancer Therapy II, pp. 223-233. Editor: M. Moore, Pergamon Press, Oxford and New York, 1979. 10. Watson, E.R., Halnan, K.E., Dische, S., Saunders, M.I., Cade, I.S., McEwen, J.B., Wiemik, G., Perrins, D.J.D. and Sutherland, I. Hyperbaric oxygen and radiotherapy. A Medical Research Council trial in carcinoma of the cervix. Br. J. Radiol., 51, 879-887, 1978.
Radiotherapy and Oncology, Suppl. 20 (1991) 71-74 Elsevier
What have we learnt from hyperbaric oxygen? Stanley Dische Marie Curie Research Wing, Regional Centre for Radiotherapy and Oncology, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN England
Keywords." Radiotherapy; Hyperbaric oxygen; Carbogen; Tumour control; Clinical trial
Summary The 15 randomised controlled clinical trials of hyperbaric oxygen in radiotherapy yielded three with highly significant benefit and six with useful margins not reaching statistical significance. The increase in tumour control was partly negated by an increase in normal tissue effect. Now simple carbogen breathing in animal tumour models has shown high efficiency and there is the potential for its use in man as a simple means of hypoxic cell radiosensitisation.
Introduction In 1955 Ian Churchill-Davidson and his colleagues published the first clinical account of their work in the use of hyperbaric oxygen in radiotherapy. The work excited great interest and controversy. The more easily employed Vickers chamber was soon introduced and many explored its use. There were excited reports of great advantage, a series of randomised controlled trials and now, this year, the last remaining practitioner in the United Kingdom is retiring and the method will cease to be used in this country, where it was first introduced. Despite this there is much that we can learn concerning the oxygen effect of human radiobiology, of clinical trials and of what has already been performed.
Randomised controlled clinical trials If we look just at the randomised controlled clinical trials performed in centres throughout the world, we see a most encouraging pattern of result (Table 1). A statistically significant increase in tumour control and in survival has been obtained in some of the studies and good margins are achieved in others where
Table 1. Results of randomised controlled trials of hyperbaric oxygen Therapeutic benefit Significantly improved results Margin in favour (not significant) No difference Margin against (not significant) Adverse response TOTAL
3 0 6 6 0 0 l5
0167-8140/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)
72 numbers did not permit the achievement of the magic P value of 0.05 [3]. Why has this method become disused? Interpretation of some of the trials was made difficult by the use of unconventional fractionation regimes and some control groups did not receive a regime of radiotherapy considered optimal by international standards [4]. In all the hyperbaric oxygen trials in the management of carcinoma of the cervix there was an increased incidence of normal tissue injury. If we just look at those employing for both treatment arms, a conventional daily fraction of about 2 Gy. we find that in all four [1,5,9,10] there was an excess of radiation morbidity in the oxygen treated group though it did not reach statistical significance in all. By putting all four trials together we have 307 controls and 286 patients treated in hyperbaric oxygen. A total of 27 (8.8%) control patients showed moderate or severe morbidity, usually in the bowel but also included were bladder problems. Of the oxygen treated cases 57 (19.9%) showed similar morbidity. There was a statistically significant increase in normal tissue injury ( P ~< 0.0005).
Normal tissue effects - hyperbaric o x y g e n and chemical agents
Why were normal tissue effects increased? If we look at the historic Alper-Flanders curve, we can see that at high oxygen tension the curve flattens but still has a very slight inclination. By this, I believe Dr. Suit predicted many years ago, that trials with hyperbaric oxygen might lead to a slight increase in normal tissue injury. He advocated that the dose used for hyperbaric oxygen should be slightly reduced because of this - an advice which was disregarded. There may also be another explanation. If we look at the work which has been performed with the chemical sensitising agents, we entirely find no significant increase in normal tissue injury and this is so even in those studies where some margin of increased tumour control has been reported. One cannot exclude, of course, a very small margin of increase in normal tissue injury, but if present this was obviously at a very low level, much below that seen in the hyperbaric oxygen studies [4]. The difference between the findings in the hyperbaric oxygen trials and in the chemical sensitising ones may relate to the distribution of oxygen through the tissues. Following a study of the histological pattern seen in human bronchial carcinoma Thomlinson and Gray [8] described their model in which there was a steep fall in oxygen tension at a distance from the capillary. Severely hypoxic cells, unless rescued by their radioresistance and subsequent reoxygenation, would soon pass into necrosis. This model has formed the basis for work with hypoxic cell radiosensitisation, but is the model true of all parts of all tumours and also generally of normal tissues? We have seen the work of Dr. MueUer-Klieser and the wide range of oxygen saturation levels in normal tissues and in tumours. The direct measurement of oxygen tension in an affected lymph node of patients with head and neck tumours has revealed low concentrations and these have been associated with poor response and survival [6]. However, tumour cells may not survive at such low levels and the findings may be an indication of the extent of hypoxia prevailing through the rest of the tumour. This may give it its prognostic power. The distribution of oxygenation through a tumour may have a particular relevance for the effectiveness of oxygen compared with chemical agents as hypoxic cell sensitisers. The relationship between radiosensitivity and oxygen concentration shown in Fig. 1 is based on the data of Denekamp et al. [2]. Radiosensitivity is expressed in a linear form but oxygen concentration on a log scale. It can be seen that in severely hypoxic cells with oxygen concentrations below 1% the maximum effect is obtained with a sensitiser. However, as the oxygen tension rises, the effect diminishes. With moderate levels of hypoxia there is still considerable radioresistance compared with that of the fully oxic cell, but very little sensitisation is achieved with a chemical agent. These agents are not metabolised in the oxic cells and so do become uniformly distributed throughout the tumour. The sensitising efficiency of 1.6 is the maximum likely to be achieved by the sensitising drugs presently being employed. The pattern, however, will be different with the use of oxygen, carbogen or hyperbaric oxygen. The cells most likely to show an elevation of oxygen tension will be those showing a modest hypoxia. These cells will metabolise the oxygen so denying it to the more severely hypoxic cells placed more peripherally. This, then, may well be the cause of the increased /
73 0 r-< Iw w 0
z< 2 III
,
O( >"SmZx
,
SENSITIZERJ
I N2
,
I 1
I I0
I 100
OXYGEN CONCENTRATION mmHg
Fig. 1. The relationship between oxygen enhancement ratio and oxygen concentration is shown and is based upon the data of
Denekamp et al. [2]. The enhancement ratio is expressed in a linear form, but oxygenconcentration on a log scale. The effect of the addition of an hypoxiccell radiosensitiser such as a nitroimidazole, at a clinically achievable concentration, is also shown. normal tissue effect observed in the hyperbaric oxygen trials. If moderate hypoxia is the major problem of radioresistance of tumours caused by oxygen deprivation then oxygen will be the effective agent. Chemical sensitisers will be more effective under severely hypoxic conditions.
Normobaric carbogen breathing re-visited Recent laboratory experiments using carbogen breathing performed by Rojas [7] in the Gray Laboratory have shown sensitisation superior to that obtained using chemical agents. Due to these experiments we have to take a further look at carbogen breathing in the clinic. A most interesting feature of her work has been the rapidity with which increased oxygen concentration in respired air is reflected in increased radiosensitivity - less than 2 minutes appears appropriate in the animal system. We have looked at more effective oxygen delivery systems in the original clinical work using carbogen than were used 30 years ago. Our work suggests that equally short intervals between the commencement of oxygen breathing and increase in radiosensitivity may occur in man as in the animals, so suggesting a regime of management very different from that used previously. It is possible that simple carbogen breathing which we have shown to be very easily applied, gives a method which may lead to the most effective hypoxic cell sensitisation using a non-toxic technique, free of all the problems associated with the use of chemical agents in clinical practice.
Conclusions We can summarise by saying that in the hyperbaric oxygen trials greater tumour control was obtained, but this was at the expense of an increase in normal tissue injury. We have learned that control groups must be treated by an internationally acceptable scheme of radiotherapy, otherwise the trial will be given little or no significance. Normal tissue effects must be observed and measured as closely as those of turnout. In the design of the study the level of morbidity should, if possible, be equal in both control and experiment arms - a very difficult situation to plan in advance. We must recognise that a complex and demanding technique must give an obviously large benefit to justify a continuation of the effort and adoption of practice. Finally, we have learnt that oxygen is a potent radiosensitiser and that we may give, with simple normobaric carbogen breathing, effective hypoxic cell radiosensitisation. We must still look at it carefully to seek advantage to our patients.
74
Acknowledgements I w i s h to t h a n k Dr. M . I . S a u n d e r s for h e r a d v i c e u p o n t h e m a n u s c r i p t a n d M r s . E. D a v i e s for h e r h e l p in its p r e p a r a t i o n . I a m also g r a t e f u l to t h e C a n c e r R e s e a r c h C a m p a i g n f o r t h e i r c u r r e n t s u p p o r t a n d the M e d i c a l R e s e a r c h C o u n c i l for t h e s u p p o r t g i v e n p r e v i o u s l y .
References 1. Brady, L.W., Plenk, H.P., Hanley, J.A., Glassburn, J.R., Kramer, S. and Parker, R.G. Hyperbaric oxygen therapy for carcinoma of the cervix - Stages liB, IliA, IIIB and IVA: results of a randomized study by the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys., 7, 991-998, 1981. 2. Denekamp, J., Rojas, A. and Stevens, G. Redox competition and radiosensitivity: implications for testing radioprotective compounds. Pharmacol. Ther., 39, 59-66, 1988. 3. Dische, S. The clinical use of hyperbaric oxygen and chemical hypoxic cell sensitizers - an overview. In: The Biological Basis of Radiotherapy pp. 225-237. Editors: G.G. Steel, G.E. Adams and M. Peckham. Elsevier Science Publishers, B.V, 1983. 4. Dische, S. A review of hypoxic cell radiosensitization. Int. J. Radiat. Oncol. Biol. Phys. (Awaiting publication). 5. Fletcher, G.L., Lindberg, R.D., Caderao, J.N. and Taylor Wharton, J. Hyperbaric oxygen as a radiotherapeutic adjuvant in advanced carcinoma of the uterine cervix. Preliminary results of a randomized trial. Cancer, 39, 617-623, 1977. 6. Gatenby. R.A., Kessler, H.B., Rosenblum, J.S., Coia, L.R., Moldofsky, P.J., Hartz, W.H. and Broder, G.J. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys., 14, 831-838, 1988. 7. Rojas, A. Oxygen: a clinical reality or a mirage? In: BIR Report 19, The Scientific. Basis of Modem Radiotherapy, pp. 86-90. Editor: N.J. McNally, Butterworth & Co. Kent. 1989. 8. Thomlinson R.H. and Gray, L.H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer, 9, 539-549, 1955. 9. Sealy, R. Hyperbaric oxygen and radiotherapy. In: Advances in Medical Oncology, Research and Education, Vol. 6. Basis for Cancer Therapy II, pp. 223-233. Editor: M. Moore, Pergamon Press, Oxford and New York, 1979. 10. Watson, E.R., Halnan, K.E., Dische, S., Saunders, M.I., Cade, I.S., McEwen, J.B., Wiemik, G., Perrins, D.J.D. and Sutherland, I. Hyperbaric oxygen and radiotherapy. A Medical Research Council trial in carcinoma of the cervix. Br. J. Radiol., 51, 879-887, 1978.
