1975, British Journal of Radiology, 48, 131-133
FEBRUARY 1975
Radiotherapy by several sessions a day By V. H. J. Svoboda, D.M.R.T., F.F.R. Department of Radiotherapy, St. Mary's General Hospital, Milton Road, Portsmouth {Received January, 1974 and in revised form June, 1974)
ABSTRACT
The early clinical experience with external beam radiotherapy using three treatment sessions a day is briefly reported. Thirty-seven patients suffering from advanced malignant disease, mostly of the breast or neck, were treated. The normal tissues tolerance was similar to the tolerance of daily fractions using the same doses.
Radiotherapy is based on the presumption that normal tissues recover better than do neoplastic. After single exposure of external radiation to a skin carcinoma, normal tissue recovery will occur from the untreated edges and from the stroma, whereas the tumour tissue fails to recover if treatment is successful. Single exposures cannot be used for large volume treatments. Here only fractionation of the dose sufficient to sterilize a tumour of limited sensitivity will ensure adequate normal tissue recovery. For many years, a five-times-a-week regimen was accepted as the standard method of fractionation. Although some of the early moist skin reactions could be avoided by delivering the dose in several courses of conventional radiotherapy, problems of late tissue damage remained. There is now agreement that the curative dose should be delivered in one definitive course. The development of megavoltage radiation made the increase of the dose increments easier and the accustomed six-week course of 30 sessions was sometimes replaced by 12-18 larger fractions. Today, the majority of routine curative radiotherapy courses deliver the tumour dose by identical daily fractions five times a week over a period of 3 to 11 weeks. The only alternative to external beam fractionation is interstitial curie therapy, where the dose is delivered more or less continuously over five to eight days, with a relatively inhomogenous distribution of the dose in the treated volume. It is well known, but less well understood, that the biological effect of one rad differs in these two types of treatment. Some recovery of normal tissue probably occurs during the low dose-rate treatment. Recently experimental work on animals led Hill and Bush (1973) to a conclusion about the possible advantages of frequent fractionation in clinical radiotherapy, and Jakobsson and Littbrand (1973), and Backstrom et al. (1973) tried the split courses
with three sessions of radiotherapy a day with good clinical results. An irradiated malignant tumour behaves in one of three ways: (1) It is resistant, that is, no damage is done to the clonogenic malignant cells. (2) It is sensitive. The cells show minimal or no recovery and fractionation protects the normal tissue. (3) It is semi-sensitive. The tumour is partially destroyed by the radiation fraction, but can recover and repopulate. The presumption that normal soft tissues and tumour recover with the
Dose in rad
45 days overall time
FIG. 1. Normal soft-tissue tolerance. 20 X 20 cm chest wall area, megavoltage radiotherapy. (After L. Cohen, p. 46, in Modern Trends in Radiotherapy, vol. 2, ed. T. J. Deeley, Butterworths, 1972.)
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same speed and efficiency is not substantiated for multifractional treatment. There is some evidence, that recovery for damage occurs soon after the exposure, often within the first one to three hours. It is not unreasonable to expect that the solid tumour tissue, with its disorganized vascular supply and often lazy cell cycling, recovers less rapidly. Twenty-four hours between two fractions should therefore be unnecessary and may even allow the tumour to gain ground, which it has lost in the first few hours after treatment. Cohen (1972) recently published his table of tolerance doses and therapeutic ratios for breast cancer treated by large megavoltage fields. His values agree with clinical experience where available. Figure 1 presents in a graphical form some of Cohen's values of normal tissue tolerance for different types of fractionation. FRACTIONATION TRIAL
This trial was planned to test the clinical validity of Cohen's figures using multiple fractions and short overall time. This poses two basic questions: (1) How will normal soft tissue tolerate more than one daily fraction of radiation exposure? (2) Will the tumour response differ from conventional fractionation ? Hence, will a more favourable therapeutic ratio result?
days. This produced only minimal or mild skin erythema followed in some cases by light pigmentation 6-12 months later. The larynx was treated by 24-28 fractions, 10-13 days overall time, tumour dose to a minimal volume 7 x 7 x 5 cm was 5,0005,500 rads. No treatment was given on Saturdays and Sundays. Skin erythema and confluent fibrinous mucosal reaction readied its maximum one to three weeks after the treatment. This cleared within six to eight weeks and caused little discomfort. The dose of 5,500 rads produced mucosal oedema ten months later, but the patient is symptom free. The recurrence of a vaginal carcinoma after previous radiotherapy was treated by a three fields plan. 4,750 rads tumour dose was delivered over 16 days in 24 fractions (there was a week's interval after the first part of the course). Only mild radiation reaction was observed in the vagina and on the vulva and five months later there is no sign of recurrence. We have never observed any systemic reaction and the tumour failed to respond only in one case of breast carcinoma. SUMMARY OF THE CLINICAL EXPERIENCE
External beam radiotherapy giving doses of up to 4,500 rads in 15 fractions over a period of fourand-a-half days to a large area caused minimal skin reaction and no systemic symptoms.
MATERIALS AND METHODS
DISCUSSION
From October 16, 1972 to June 7, 1974, 37 patients were treated by different regimens, but three daily sessions were always used every working day. The spacing was usually at 9.00, 13.00 and 16.00 hours. There was never less than three hours between the treatments. All the patients had an advanced malignant lesion, confirmed by histology or cytology, either metastatic or inoperable. Thirty-seven patients were treated by 42 courses. Sixteen of them had previous radiotherapy, usually to the area under consideration. Twenty-six patients had breast cancer, six patients a squamous carcinoma of the larynx or hypopharynx, one had a generalized melanoma, one a generalized malignant lymphoma, one recurrence of squamous carcinoma of the vagina and two had carcinoma of the bronchus. Out of 42 courses, 40 used cobalt treatment, one 250 keV and one 100 keV. Mostly two fields were used and all the fields were treated in each session. In the breast cases, the maximum treated volume was 2 4 x 2 8 x 8 cm and the dose delivered in 15 fractions was 3,750-4,500 rads over four-and-a-half
Cohen's prediction of normal tissue tolerance for unusual fractionation regimens was confirmed in this group of patients. The normal soft tissues reaction is related more to the number of fractions than to the overall time. Fifteen fractions do not produce much more reaction when applied in four-and-a-half days than over 21 days. The mucosal reaction in the treatment of the hypopharynx and larynx by 24 fractions over ten days was comparable to only a slightly higher dose delivered to the same volume over five-and-ahalf weeks by the same number of fractions. The course of 15 fractions required only four nights hospitalization in patients who do not live locally. The intervals between sessions were three to four hours during the day and 15 hours overnight. It is likely, that most of the normal soft tissue recovery occurs within less than three hours after the exposure. It would be interesting to know, if a similar dose could be delivered in 15 fractions in 48 hours overall time,- keeping the spacing between the sessions always three hours. This would be near
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to the tolerance of curie therapy and the tumour would be denied long periods of no treatment. Some of the tumours treated by our new fractionation responded very well, some only partially and at least one patient out of 26 breast lesions has shown no objective response. This is a situation to which we are accustomed from conventional radiotherapy. It was interesting to see an early response of a fungating malignant melanoma and complete disappearance of a poorly differentiated carcinoma of the hypopharynx and aryepiglottic fold. It could be expected, that the squamous lesions are more predictable in their radiation response. The therapeutic ratio has not been assessed. It depends on the tumour biology, treated volume, type of beam and fractionation. It is, however, unlikely that frequent fractions treatment would alter it in favour of the tumour. Our experience certainly does not demonstrate such a situation. But even if the response and the ratio are the same as with conventional fractionation, frequent fractions treatment provides an administrative advantage with less discomfort. If on the other hand, the therapeutic ratio can be in this way changed to react against the tumour, as Cohen predicts in his table, and if the tumour is really more slow to recover in the first three hours after the exposure, than is the normal tissue, then
we shall have to think again about many of our current treatment regimens in radiotherapy. Even if each exposure causes the same original damage to both the tumour and normal tissue, the character of recovery can differ: normal tissues recover relatively quickly in the first three hours, but after this period, further recovery is minimal or at least slows down considerably. In the case of neoplasm, the rapid early phase is less pronounced, but after three hours the residual tumour repopulates steadily and faster, than does the normal tissue. In extreme situations this could make it impossible to destroy the tumour with acceptable level of normal tissues damage— unless we use more frequent fractions. REFERENCES BACKSTROM, A., JAKOBSSON, P. A., LITTBRAND, B., and
WERSALL, J., 1973. Fractionation scheme with low individual doses in irradiation of carcinoma of the mouth. Ada Radiologica {Therapy), 12, 401-406. COHEN, L., 1972. Cell Population Kinetic Models in Radiotherapy. Modern Trends in Radiotherapy, 2, 31-50 (Butterworths, ed. Deeley). HILL, R. P., and BUSH, R. S., 1973. The effect of contin-
uous or fractionated irradiation on a murine sarcoma. British Journal of Radiology, 46, 167-174. JAKOBSSON, P. A., and LITTBRAND, B., 1973. Fractionation
scheme with low individual tumour doses and high total dose. Ada Radiologica (Therapy), 12, 337-346. PIERQUIN, B., 1970. L'effet differentiel de l'irradiation continue ou semi-continue a faible debit des carcinomes epidermoides. Journal de Radiologie, d'Eledrologie et de Medezine nucleaire, 51, 533-536.
133
FEBRUARY 1975
Radiotherapy by several sessions a day By V. H. J. Svoboda, D.M.R.T., F.F.R. Department of Radiotherapy, St. Mary's General Hospital, Milton Road, Portsmouth {Received January, 1974 and in revised form June, 1974)
ABSTRACT
The early clinical experience with external beam radiotherapy using three treatment sessions a day is briefly reported. Thirty-seven patients suffering from advanced malignant disease, mostly of the breast or neck, were treated. The normal tissues tolerance was similar to the tolerance of daily fractions using the same doses.
Radiotherapy is based on the presumption that normal tissues recover better than do neoplastic. After single exposure of external radiation to a skin carcinoma, normal tissue recovery will occur from the untreated edges and from the stroma, whereas the tumour tissue fails to recover if treatment is successful. Single exposures cannot be used for large volume treatments. Here only fractionation of the dose sufficient to sterilize a tumour of limited sensitivity will ensure adequate normal tissue recovery. For many years, a five-times-a-week regimen was accepted as the standard method of fractionation. Although some of the early moist skin reactions could be avoided by delivering the dose in several courses of conventional radiotherapy, problems of late tissue damage remained. There is now agreement that the curative dose should be delivered in one definitive course. The development of megavoltage radiation made the increase of the dose increments easier and the accustomed six-week course of 30 sessions was sometimes replaced by 12-18 larger fractions. Today, the majority of routine curative radiotherapy courses deliver the tumour dose by identical daily fractions five times a week over a period of 3 to 11 weeks. The only alternative to external beam fractionation is interstitial curie therapy, where the dose is delivered more or less continuously over five to eight days, with a relatively inhomogenous distribution of the dose in the treated volume. It is well known, but less well understood, that the biological effect of one rad differs in these two types of treatment. Some recovery of normal tissue probably occurs during the low dose-rate treatment. Recently experimental work on animals led Hill and Bush (1973) to a conclusion about the possible advantages of frequent fractionation in clinical radiotherapy, and Jakobsson and Littbrand (1973), and Backstrom et al. (1973) tried the split courses
with three sessions of radiotherapy a day with good clinical results. An irradiated malignant tumour behaves in one of three ways: (1) It is resistant, that is, no damage is done to the clonogenic malignant cells. (2) It is sensitive. The cells show minimal or no recovery and fractionation protects the normal tissue. (3) It is semi-sensitive. The tumour is partially destroyed by the radiation fraction, but can recover and repopulate. The presumption that normal soft tissues and tumour recover with the
Dose in rad
45 days overall time
FIG. 1. Normal soft-tissue tolerance. 20 X 20 cm chest wall area, megavoltage radiotherapy. (After L. Cohen, p. 46, in Modern Trends in Radiotherapy, vol. 2, ed. T. J. Deeley, Butterworths, 1972.)
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48, No. 566 V. H. J. Svoboda
same speed and efficiency is not substantiated for multifractional treatment. There is some evidence, that recovery for damage occurs soon after the exposure, often within the first one to three hours. It is not unreasonable to expect that the solid tumour tissue, with its disorganized vascular supply and often lazy cell cycling, recovers less rapidly. Twenty-four hours between two fractions should therefore be unnecessary and may even allow the tumour to gain ground, which it has lost in the first few hours after treatment. Cohen (1972) recently published his table of tolerance doses and therapeutic ratios for breast cancer treated by large megavoltage fields. His values agree with clinical experience where available. Figure 1 presents in a graphical form some of Cohen's values of normal tissue tolerance for different types of fractionation. FRACTIONATION TRIAL
This trial was planned to test the clinical validity of Cohen's figures using multiple fractions and short overall time. This poses two basic questions: (1) How will normal soft tissue tolerate more than one daily fraction of radiation exposure? (2) Will the tumour response differ from conventional fractionation ? Hence, will a more favourable therapeutic ratio result?
days. This produced only minimal or mild skin erythema followed in some cases by light pigmentation 6-12 months later. The larynx was treated by 24-28 fractions, 10-13 days overall time, tumour dose to a minimal volume 7 x 7 x 5 cm was 5,0005,500 rads. No treatment was given on Saturdays and Sundays. Skin erythema and confluent fibrinous mucosal reaction readied its maximum one to three weeks after the treatment. This cleared within six to eight weeks and caused little discomfort. The dose of 5,500 rads produced mucosal oedema ten months later, but the patient is symptom free. The recurrence of a vaginal carcinoma after previous radiotherapy was treated by a three fields plan. 4,750 rads tumour dose was delivered over 16 days in 24 fractions (there was a week's interval after the first part of the course). Only mild radiation reaction was observed in the vagina and on the vulva and five months later there is no sign of recurrence. We have never observed any systemic reaction and the tumour failed to respond only in one case of breast carcinoma. SUMMARY OF THE CLINICAL EXPERIENCE
External beam radiotherapy giving doses of up to 4,500 rads in 15 fractions over a period of fourand-a-half days to a large area caused minimal skin reaction and no systemic symptoms.
MATERIALS AND METHODS
DISCUSSION
From October 16, 1972 to June 7, 1974, 37 patients were treated by different regimens, but three daily sessions were always used every working day. The spacing was usually at 9.00, 13.00 and 16.00 hours. There was never less than three hours between the treatments. All the patients had an advanced malignant lesion, confirmed by histology or cytology, either metastatic or inoperable. Thirty-seven patients were treated by 42 courses. Sixteen of them had previous radiotherapy, usually to the area under consideration. Twenty-six patients had breast cancer, six patients a squamous carcinoma of the larynx or hypopharynx, one had a generalized melanoma, one a generalized malignant lymphoma, one recurrence of squamous carcinoma of the vagina and two had carcinoma of the bronchus. Out of 42 courses, 40 used cobalt treatment, one 250 keV and one 100 keV. Mostly two fields were used and all the fields were treated in each session. In the breast cases, the maximum treated volume was 2 4 x 2 8 x 8 cm and the dose delivered in 15 fractions was 3,750-4,500 rads over four-and-a-half
Cohen's prediction of normal tissue tolerance for unusual fractionation regimens was confirmed in this group of patients. The normal soft tissues reaction is related more to the number of fractions than to the overall time. Fifteen fractions do not produce much more reaction when applied in four-and-a-half days than over 21 days. The mucosal reaction in the treatment of the hypopharynx and larynx by 24 fractions over ten days was comparable to only a slightly higher dose delivered to the same volume over five-and-ahalf weeks by the same number of fractions. The course of 15 fractions required only four nights hospitalization in patients who do not live locally. The intervals between sessions were three to four hours during the day and 15 hours overnight. It is likely, that most of the normal soft tissue recovery occurs within less than three hours after the exposure. It would be interesting to know, if a similar dose could be delivered in 15 fractions in 48 hours overall time,- keeping the spacing between the sessions always three hours. This would be near
132
FEBRUARY 1975
Radiotherapy by several sessions a day
to the tolerance of curie therapy and the tumour would be denied long periods of no treatment. Some of the tumours treated by our new fractionation responded very well, some only partially and at least one patient out of 26 breast lesions has shown no objective response. This is a situation to which we are accustomed from conventional radiotherapy. It was interesting to see an early response of a fungating malignant melanoma and complete disappearance of a poorly differentiated carcinoma of the hypopharynx and aryepiglottic fold. It could be expected, that the squamous lesions are more predictable in their radiation response. The therapeutic ratio has not been assessed. It depends on the tumour biology, treated volume, type of beam and fractionation. It is, however, unlikely that frequent fractions treatment would alter it in favour of the tumour. Our experience certainly does not demonstrate such a situation. But even if the response and the ratio are the same as with conventional fractionation, frequent fractions treatment provides an administrative advantage with less discomfort. If on the other hand, the therapeutic ratio can be in this way changed to react against the tumour, as Cohen predicts in his table, and if the tumour is really more slow to recover in the first three hours after the exposure, than is the normal tissue, then
we shall have to think again about many of our current treatment regimens in radiotherapy. Even if each exposure causes the same original damage to both the tumour and normal tissue, the character of recovery can differ: normal tissues recover relatively quickly in the first three hours, but after this period, further recovery is minimal or at least slows down considerably. In the case of neoplasm, the rapid early phase is less pronounced, but after three hours the residual tumour repopulates steadily and faster, than does the normal tissue. In extreme situations this could make it impossible to destroy the tumour with acceptable level of normal tissues damage— unless we use more frequent fractions. REFERENCES BACKSTROM, A., JAKOBSSON, P. A., LITTBRAND, B., and
WERSALL, J., 1973. Fractionation scheme with low individual doses in irradiation of carcinoma of the mouth. Ada Radiologica {Therapy), 12, 401-406. COHEN, L., 1972. Cell Population Kinetic Models in Radiotherapy. Modern Trends in Radiotherapy, 2, 31-50 (Butterworths, ed. Deeley). HILL, R. P., and BUSH, R. S., 1973. The effect of contin-
uous or fractionated irradiation on a murine sarcoma. British Journal of Radiology, 46, 167-174. JAKOBSSON, P. A., and LITTBRAND, B., 1973. Fractionation
scheme with low individual tumour doses and high total dose. Ada Radiologica (Therapy), 12, 337-346. PIERQUIN, B., 1970. L'effet differentiel de l'irradiation continue ou semi-continue a faible debit des carcinomes epidermoides. Journal de Radiologie, d'Eledrologie et de Medezine nucleaire, 51, 533-536.
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