1990, The British Journal of Radiology, 63, 871-874
Lack of late skin necrosis in man after high-dose irradiation using small field sizes: experiences of grid therapy By * H . Shirato, M D , * N . K. Gupta, FRCR, tT. J . Jordan, PhD and t J . H. Hendry, PhD 'Department of Radiotherapy, tDepartment of Medical Physics and tCancer Research Campaign Department of Radiobiology, Paterson Institute for Cancer Research, The Christie Hospital and Holt Radium Institute, Manchester M20 9BX, UK
(Received April 1990 and in revised form June 1990)
Abstract. Out of a total of 437 patients with superior vena caval syndrome or advanced malignancy, given single-dose grid radiotherapy, four survived to 7 years. The dose to the skin under each of the 77 holes in the grid was approximately 58 Gy. The lack of skin necrosis in the total of 308 skin circles of 1 cm diameter among these survivors, compared with known necrosis rates in larger irradiated areas, implies that there is a marked field-size effect for late necrosis in small areas of irradiated skin.
Knowledge of the influence of field size on late skin reactions is important not only in radiation therapy but also in accidents. Previous studies regarding early skin reactions in man, mouse and pig showed a strong dependence on the area irradiated over a range 1-20 mm in diameter (MacKee et al, 1943; Joyet & Hohl, 1953; von Essen, 1968; Hendry, 1978; Hopewell et al, 1986; Charles et al, 1989; Charles, 1990). However, there are fewer data for late skin reactions. A field-size effect was reported for dermal atrophy in pig skin at 2 years after ^-irradiation using ^Sr/Y or 170Tm when the field diameter was less than 2 mm (Hamlet et al, 1986). A field-size effect for late skin necrosis in man was reported for treatments of superficial skin cancer when the field diameter was varied between 10 and 40 mm (Chan et al, 1988; Chan, 1989). Before the era of megavoltage machines, grid or sieve therapy, using orthovoltage photon beams and a lead sheet with many small holes was one of the most popular techniques employed in order to deliver high doses at depth with avoidance of untoward reactions on the skin surface {e.g. Jolles, 1952; Rode, 1962). We have now reviewed the late skin necrosis rate in patients treated using grid therapy and single exposures. Materials and methods
Irradiation and dosimetry
Grid therapy was performed at Victoria Hospital, Blackpool and at the Christie Hospital, Manchester, UK. The treatment machine at Blackpool is a Marconi 230 kVp X-ray unit with a half-value thickness (HVT) of 1.55 mm Cu. The grid treatment involved placing on the anterior chest wall of the patient a sheet of lead in which there were holes of 10 mm diameter, centred at 14 mm intervals (Fig. 1). The phantom studies and •Present address of Hiroki Shirato, MD: Department of Therapeutic and Diagnostic Radiology, Obihiro Kosei Hospital, West-6 South-8, Obihiro, Hokkaido, Japan 080. Address correspondence to N. K. Gupta. Vol. 63, No. 755
patient treatments were performed at a focus-surface distance of 50 cm. The treatment dosage was fixed at a nominal 45 Gy single exposure (surface dose without backscatter), which required about 50 min continuous irradiation. Details of the measurement of nominal dose in grid therapy are described elsewhere (Massey, 1970). Absolute dosimetry was performed at Blackpool with a 0-6 ml Farmer-type ion chamber, with a calibration traceable back to the National Physical Laboratory (Teddington, Middlesex, UK) primary standard. In addition, for measurements made under the grid, a Farmer thimble chamber with an especially reduced long axis (6 mm x 6 mm diameter) and a volume of 0.15 ml was used. The sensitivity of this chamber was established by direct comparison with the calibrated chamber at 230 kVp on the surface of a Mix D slab phantom (ICRU, 1989) with no grid. Two of the 1 cm Mix D slabs were clamped and drilled with a hole matching the Farmer chamber dimensions. This permitted measurements to be made at depth with minimum air gaps or, by separating the slabs, surface measurements with the ion chamber in "half-sunk" geometry. Using this latter arrangement, the dose rate of the Blackpool unit was measured and the magnitude of the shutter error established. Film dosimetry was also used extensively to investigate the shape of the dose distribution under the grid and as a second method of determining absolute dosimetry with depth. As a preliminary, the film was given a known range of exposures on the surface of the Mix D phantom, and the relationship between absorbed dose and optical density was established. The dose rate at the phantom surface irradiated using a 10 cm circle field without the grid was 109.0 + 0.4 cGy/min. The dose rate at the phantom surface under the central hole of the grid was 108.2+1.6 cGy/min as measured by the 0.15 ml ionization chamber. The total skin dose under the central hole of the grid in the patient treatment was estimated to be 58.0 + 0.9 Gy. The significant difference between the 871
H. Shirato et al Table I. Number of patients at risk, number of 1 cm skin circles at risk (none showing necrosis), and the expected number of 2-3 cm skin circles showing necrosis as a function of time following 22.5 Gy (see text)
mmm0m0 000000 000000
0 mm 0 0 0 0 0
0 0 0 0 0
0 0 0 0 0
0 0 0 0 0
0 0 0 0 0 0 0 0 0 0
Figure 1. Lead sheet (4 mm thick) for use in grid therapy, with holes 10 mm in diameter with centres at 14 mm intervals.
nominal and the actual dose is attributed mainly to the contribution from backscatter in the Mix D phantom. At orthovoltage energies, the unflattened beam centre is the most intense point. The dose estimated by film densitometry under each hole of the grid gave the following distribution: four holes (5%) received doses between 47.0 and 49.9 Gy, 18 (23%) between 50.0 and 52.9 Gy, 18 (23%) between 53.0 and 55.9 Gy, and 37 (48%) between 56.0 and 58.9 Gy. The skin dose under the lead sheet was estimated to be 12.3 ± 1.5 Gy. The grid technique used in Manchester was similar to that used in Blackpool except that it used 300 kVp X rays with HVL = 1.7 mm (Holmes, 1963). As the prescribed doses and the type and size of the grid used in the two hospitals were identical, it can be assumed that the surface doses received by the two sets of patients were similar. Patient treatment and follow-up
Four hundred and thirty-seven patients received orthovoltage therapy using the grid technique, to the anterior mediastinum. Two hundred and sixty-eight patients had treatment for superior vena caval syndrome and 169 patients received treatment for gross dyspnoea/stridor, persistent haemoptysis and/or chest wall pain due to advanced malignancy. Three hundred and nine (70%) were male and the mean age of the 872
Months Number of Number of 1 cm Expected number patients skin circles of 2-3 cm skin at risk at risk circles having necrosis at 22.5 Gy
0 12 24 36 48 60 84
437 (127) 19 7 5 5 4(3) 4(3)
33 649 1463 539 385 385 308 308
0 3 10 25 63 59 27"
Values in brackets refer to the Blackpool patients only. "Crude rate; other values are actuarial rates (see text).
group was 58 years (range 26-80). Three hundred and ten patients in this study had treatment in Manchester (1956-1959) and 127 patients were treated in Blackpool (1970-1985). All were in poor general condition with distressing symptoms and were considered unsuitable for protracted fractionation. In view of this and the urgency of institution of palliative therapy, histological diagnoses were not sought and were available only in 66 patients (15%). Of those where histology was available, 57 had squamous cell carcinoma of the bronchus, three with metastatic breast cancer, two with oesophageal cancer and four patients with miscellaneous tumours. There are no survivors. One of the authors (N.K.G.) was involved in the treatment and subsequent follow-up of all his patients at Blackpool. The information about the Manchester patients was collected from the hospital case notes and via postal enquiries from their general practitioners. Late skin necrosis was defined as necrosis existing at or after 3 months following radiotherapy, which either healed or was excised surgically and histologically proven (Dutreix, 1986). Follow-up of patients was at intervals of at least 2-3 months during the first year, 3-4 months during the second year, and then every 6 months from 3 years. Results
The poor long-term survival of these patients was expected. All were in poor general condition with advanced cancer and had a simple palliative radiotherapy merely to alleviate the distressing symptoms. All patients had relief of vena caval obstruction within the first week after irradiation, and 75% of these had benefit lasting 2-9 months. Only 19 patients were alive at the end of the first year, seven patients survived for 2 years,fivepatients lived 3 years and a mere four patients lived for more than 4 years (Table I). Of the seven who were alive more than 2 years, five had treatment in Blackpool (total 127 treated), and three of these The British Journal of Radiology, November 1990
Field size and grid radiotherapy
survived to 7 years. In one patient, a post-mortem examination 10 years after grid therapy showed radiation fibrosis around the retrosternal thyroid, but there was no evidence of cutaneous or bone necrosis (nor of tumour). However, in all long-surviving patients, deep permanent skin pigmentation matching the grid pattern was evident. No skin necrosis has been detected. Regarding the previous Manchester patients, the annotation on the case notes was not always precise about the status of the skin but a statement of moist desquamation in the treated site was frequently noted at 3 months after therapy (as also observed in the Blackpool patients). Further comments specific to the skin condition were rarely made thereafter, and usually referred to skin atrophy. As auscultation of the chest was done during follow-up visits, it is not unreasonable to assume that a degree of inspection of the chest wall was inevitable. It is unlikely that a clinician could overlook skin necrosis which is painful and takes several weeks to heal. With an observation of (0/19) patients as a skin necrosis rate at 12 months, the 95% confidence interval of probability of skin necrosis at 1 year is 0-18% assuming a binominal distribution. The number of patients after 24 months was too small to analyse on an individual basis. However, if the probability of late skin necrosis is assumed to be independent of patient characteristics and if there is no interaction between circles, it is possible to use each 1 cm circle as an independent observation (Table I, third column). In this case, the 95% confidence interval would be 0-1.2%, i.e. an upper limit of only four events (necroses) in 308 sites even at 7 years. Discussion Late radiation morbidity from grid therapy has not been well documented. The technique has only been used for patients with poor prognosis and hence there have been only a few long-term survivors. The first report on the use of grid technique was by Kohler (1909). This form of therapy was developed further (for example: Liberson, 1933; Haring, 1934; Grynkraut, 1945; Jolles 1949, 1952), and individual experiences were reported (for example: Marks, 1952; Tenzel, 1952; Jolles, 1962; Rode, 1962; Aliev 1976). Anecdotal incidences of skin necrosis after fractionated grid technique were reported by Jolles (1952) and Tenzel (1952), but this seems to have been due to technical errors in grid placement or as a consequence of previous irradiation. Although fractionated therapy has its potential problems with reproducibility of grid placement, the low incidence of skin damage is striking. Our results are very similar to those in an extensive series reported by Rode (1962) who found no evidence of tissue necrosis occurring in 1200fieldsof 800 patients who received 30 Gy in a single (nominal) dose for a mixed group of tumours treated over a period of 7 years. This dose and other doses referred to in the literature do not include the contribution from backscatter, and are in fact 10-30% higher than their prescribed nominal doses. Jolles (1962) Vol. 63, No. 755
reported five small necrotic skin patches in 83 patients with advanced bladder cancer treated with 110 and 120 Gy in 20-25 fractions using an anterior field and a further 90 Gy delivered to the skin by a posteriorfieldin the same overall time. Aliev (1976) noted 19 cases of late skin necrosis in 251 patients who had received doses between 150 and 200 Gy using fractionated grid therapy with a daily dose of between 6 and 10 Gy/fraction. The results can be compared with those for larger field sizes. A previous study from this Institute has shown that the actuarial skin necrosis rate after a 22.5 Gy single dose for the treatment of skin cancer using a 2.0-3.0 cm diameter field was 0.2%, 1.9%, 6.6%, 16.4% and 19.2% at 1, 2, 3, 4 and 5 years respectively (Chan et al, 1988). The value at 7 years was quoted as a crude rate (8.9%). Using these percentages, Table I (last column) shows the expected number of necroses as a function of time after 22.5 Gy using a 2.0-3.0 cm diameter field. In spite of the large difference in dose between 22.5 Gy and 47-59 Gy, the necrosis rate in the present study (0/308) was significantly lower than for a 2-3 cm diameter field. Chan et al (1988) have also shown that the crude skin necrosis rate at 7 years was 2.3%, 3.0% and 8.9% after 18 Gy, 20 Gy and 22.5 Gy single dose for the treatment of skin cancer using a 2.0-3.0 cm diameter field. Using those data, a dose-response curve calculated by probit analysis predicts 50% risk of skin necrosis at 29 + 1 Gy and 99% incidence at about 40 Gy (Chan, 1989). The corresponding dose for 50% incidence in 3-4 cm diameter fields was 28±4Gy. This is consistent with other data where 50% incidence of necrosis was produced by 24.5 Gy using a field more than 3 cm in diameter and where virtually 100% necrosis was predicted at >30 Gy (Trott et al, 1984). The difference between this and the lack of skin necrosis (0/308) using 58 Gy and 1 cm diameter fields in grid therapy is thus highly significant. This difference occurred in spite of the probability of interaction effects between the neighbouring 1 cm fields which may have increased, not decreased, their response. It was shown by Jolles (1950) that there was no interaction regarding acute skin reactions on the leg when 2 areas each of 1.56 cm2 were separated by not less than 2 cm of unirradiated skin. In the present studies the holes were separated by a minimum of only 0.4 cm of (shielded) skin. Another possibility, which would apparently decrease the differential in responses between the different field sizes, is that the 1 % of patients who survived to 5 years in the present study were inherently radioresistant. However, there was no evidence for a lack of acute skin reactions in these four individuals compared with the majority. Also, at 2 yearsfiveout of the seven survivors were part of the original number of 127 treated in Blackpool, and 4% of individuals more resistant than the other 96% by a factor of as much as 2-3 in terms of tolerance dose is contrary to common radiotherapeutic experience. It is also noted that the dose as high as 12 Gy to the skin between the high-dose circles did not increase the 873
H. Shirato et al risk of necrosis. These results are consistent with clinical observations using interstitial treatments, which give ultrahigh doses around the radioactive needles but which result in no tissue necrosis. The sharp increase in iso-effect dose for areas decreasing to 1.0 cm diameter is similar to data for early skin reactions using single fields previously reviewed (Hopewell & Young, 1982). Although skin reactions are no longer dose limiting in conventional radiotherapy, these dosage increases for both early and late skin reactions are probably applicable to treatment of other tissues as well, such as the use of charged particles in the treatment of occular melanomas and of chordomas and chondrosarcomas abutting the central nervous system, where high doses can be delivered safely to small volumes. Also, it has been suggested that grid therapy may still have a role in treatments involving "seriestype" tissues such as the spinal cord where each of a series of critically sized elements is essential for the function of the whole organ (Maruyama et al, 1989). The sparing of single elements due to the field-size effect (e.g. Hopewell & van der Kogel, 1988) would enable much higher regional doses to be tolerated. Acknowledgment We thank Mr R. Swindell for his help with the statistical aspects of this study. References ALIEV, E. M., 1976. Moglichkeiten dun Perspektiven einer ungleichmassigen Bestrahlung von malignen Geschwulsten. Radiobiology-Radiotherapy, 2, 223-234. CHAN, S., 1989. The effect of field size on late skin necrosis in man following single-exposure radiotherapy. British Journal of Radiology, 62, 770. CHAN, S., LIM, J. & HUNTER, R. D., 1988. Single fraction
radiotherapy for carcinoma of the skin. British Journal of Cancer, 55, 520-521. CHARLES, M. W., 1990. General considerations of the choice of dose limits, averaging areas and weighting factors for the skin in the light of revised skin cancer risk figures and experimental data on non-stochastic effects. International Journal of Radiation Biology, 57, 841-858. CHARLES, M. W., HOPEWELL, J. W., WELLS, J. & COGGLE, J. E.,
1989. Recent trends in radiobiology of the skin and repercussions for dose limitation and personal dosimetry. Radiation protection theory and practice. In Proceedings of the Fourth International Symposium of the Society for Radiological Protection, Malvern, 1989 (Institute of Physics, Bristol), pp. 419^124. DUTREIX, J., 1986. Human skin: early and late reactions in relation to dose and its time distribution. In Radiation Damage to Skin (British Journal of Radiology Supplement 19, British Institute of Radiology, London), pp. 22-28. VON ESSEN, C. F., 1968. Radiation tolerance of the skin. Acta Radiologica, Therapy, Physics, Biology, 8, 311-330. GRYNKRAUT, B., 1945. Direct and indirect radiotherapy. American Journal of Roentgenology, 53, 491-499.
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HAMLET, R., HERYET, J. D., HOPEWELL, J. W., WELLS, J. &
CHARLES, M. W., 1986. Late changes in pig skin after irradiation from beta-emitting sources of different energy. In Radiation Damage to Skin (British Journal of Radiology Supplement 19, British Institute of Radiology, London), pp. 51-53. HARING, W., 1934. Siebstrahlung. Strahlentherapie, 51, 154-163. HENDRY, J. H., 1978. Radionecrosis of normal tissue: studies on mouse tails. International Journal of Radiation Biology, 33, 47-55. HOLMES, K. S., 1963. The treatment of superior vena caval syndrome by high-dose grid technic. Radiology, 81, 402-405. HOPEWELL, J. W. & YOUNG, C. M. A., 1982. Letter to the
Editor. British Journal of Radiology, 55, 936-937. HOPEWELL, J. W. & VAN DER KOGEL, A. J., 1988. Volume
effects in the spinal cord. British Journal of Radiology, 61, 973-975. HOPEWELL, J. W., COGGLE, J. E., WELLS, J., HAMLET, R.,
WILLIAMS, J. P. & CHARLES, M. W., 1986. The acute effects
of different energy beta-emitters on pig and mouse skin. In Radiation Damage to Skin (British Journal of Radiology Supplement 19, British Insititute of Radiology, London), pp. 47-51. ICRU, 1989. Report 44: Tissue Substitutes in Radiation Dosimetry and Measurement (ICRU, Bethesda), p. 189. JOLLES, B., 1949. Radiotherapy of accessible malignant tumors by alternating chess-board method. Lancet, 2, 603-606. JOLLES, B., 1950. The reciprocal vicinity of irradiated tissues on a 'diffusible substance' in irradiated tissues. British Journal of Radiology, 23, 18-24. JOLLES, B., 1952. The sieve in radiotherapy. British Journal of Radiology, 25, 395^05. JOLLES, B., 1962. X-ray sieve therapy of pelvic tumors. Proceedings of the Royal Society of Medicine, 55, 493^98. JOYET, G. & HOHL, K., 1953. Die Biologische Hautreaktion in
der Tiefentherapie als Function der Feldgrosse. Ein Gesetz der Strahlentherapie. Fortschritte auf dem gebiete der Rontgenstrahlung, 82, 387-400. KOHLER, A., 1909. Zur Rontgentieftherapie mit massendosen. Munchen med. Wochenschrift, 56, 2314-2316. LIBERSON, F., 1933. The value of a multi-perforated screen in deep X-ray therapy. Radiology, 20, 186-195. MACKEE, G. M., MUTSCHELLER, A. & CIPOLLARO, A. C , 1943.
The area factor in roentgen irradiation. Archives of Dermatology and Syphilology (Chicago), 47, 657-664. MARKS, H., 1952. Clinical experience with irradiation through a grid. Radiology, 58, 338-341. MARUYAMA,
Y.,
YAES,
R.
J.,
URANO
M.,
PATEL,
P. &
HERNANDEZ, J. D., 1989. Stem-cell depletion and grid therapy. British Journal of Radiology, 62, 386-387. MASSEY, J. B., 1970. In Manual of Dosimetry in Radiotherapy (International Atomic Energy Agency, Vienna), pp. 59-60. RODE, I., 1962. Clinical and economic significance of massive grid irradiation in the therapy of breast cancer. Acta Chirurgica Acad. Sci. Hungarica, 3, viii-xx. TENZEL, W. V., 1952. Experience with grid therapy. Radiology, 59, 399-408. TROTT,
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SKOLYSZEWSKI, J., 1984. Dose-response curve and split-dose recovery in human skin cancer. Radiotherapy and Oncology, 2, 123-129.
The British Journal of Radiology, November 1990
Lack of late skin necrosis in man after high-dose irradiation using small field sizes: experiences of grid therapy By * H . Shirato, M D , * N . K. Gupta, FRCR, tT. J . Jordan, PhD and t J . H. Hendry, PhD 'Department of Radiotherapy, tDepartment of Medical Physics and tCancer Research Campaign Department of Radiobiology, Paterson Institute for Cancer Research, The Christie Hospital and Holt Radium Institute, Manchester M20 9BX, UK
(Received April 1990 and in revised form June 1990)
Abstract. Out of a total of 437 patients with superior vena caval syndrome or advanced malignancy, given single-dose grid radiotherapy, four survived to 7 years. The dose to the skin under each of the 77 holes in the grid was approximately 58 Gy. The lack of skin necrosis in the total of 308 skin circles of 1 cm diameter among these survivors, compared with known necrosis rates in larger irradiated areas, implies that there is a marked field-size effect for late necrosis in small areas of irradiated skin.
Knowledge of the influence of field size on late skin reactions is important not only in radiation therapy but also in accidents. Previous studies regarding early skin reactions in man, mouse and pig showed a strong dependence on the area irradiated over a range 1-20 mm in diameter (MacKee et al, 1943; Joyet & Hohl, 1953; von Essen, 1968; Hendry, 1978; Hopewell et al, 1986; Charles et al, 1989; Charles, 1990). However, there are fewer data for late skin reactions. A field-size effect was reported for dermal atrophy in pig skin at 2 years after ^-irradiation using ^Sr/Y or 170Tm when the field diameter was less than 2 mm (Hamlet et al, 1986). A field-size effect for late skin necrosis in man was reported for treatments of superficial skin cancer when the field diameter was varied between 10 and 40 mm (Chan et al, 1988; Chan, 1989). Before the era of megavoltage machines, grid or sieve therapy, using orthovoltage photon beams and a lead sheet with many small holes was one of the most popular techniques employed in order to deliver high doses at depth with avoidance of untoward reactions on the skin surface {e.g. Jolles, 1952; Rode, 1962). We have now reviewed the late skin necrosis rate in patients treated using grid therapy and single exposures. Materials and methods
Irradiation and dosimetry
Grid therapy was performed at Victoria Hospital, Blackpool and at the Christie Hospital, Manchester, UK. The treatment machine at Blackpool is a Marconi 230 kVp X-ray unit with a half-value thickness (HVT) of 1.55 mm Cu. The grid treatment involved placing on the anterior chest wall of the patient a sheet of lead in which there were holes of 10 mm diameter, centred at 14 mm intervals (Fig. 1). The phantom studies and •Present address of Hiroki Shirato, MD: Department of Therapeutic and Diagnostic Radiology, Obihiro Kosei Hospital, West-6 South-8, Obihiro, Hokkaido, Japan 080. Address correspondence to N. K. Gupta. Vol. 63, No. 755
patient treatments were performed at a focus-surface distance of 50 cm. The treatment dosage was fixed at a nominal 45 Gy single exposure (surface dose without backscatter), which required about 50 min continuous irradiation. Details of the measurement of nominal dose in grid therapy are described elsewhere (Massey, 1970). Absolute dosimetry was performed at Blackpool with a 0-6 ml Farmer-type ion chamber, with a calibration traceable back to the National Physical Laboratory (Teddington, Middlesex, UK) primary standard. In addition, for measurements made under the grid, a Farmer thimble chamber with an especially reduced long axis (6 mm x 6 mm diameter) and a volume of 0.15 ml was used. The sensitivity of this chamber was established by direct comparison with the calibrated chamber at 230 kVp on the surface of a Mix D slab phantom (ICRU, 1989) with no grid. Two of the 1 cm Mix D slabs were clamped and drilled with a hole matching the Farmer chamber dimensions. This permitted measurements to be made at depth with minimum air gaps or, by separating the slabs, surface measurements with the ion chamber in "half-sunk" geometry. Using this latter arrangement, the dose rate of the Blackpool unit was measured and the magnitude of the shutter error established. Film dosimetry was also used extensively to investigate the shape of the dose distribution under the grid and as a second method of determining absolute dosimetry with depth. As a preliminary, the film was given a known range of exposures on the surface of the Mix D phantom, and the relationship between absorbed dose and optical density was established. The dose rate at the phantom surface irradiated using a 10 cm circle field without the grid was 109.0 + 0.4 cGy/min. The dose rate at the phantom surface under the central hole of the grid was 108.2+1.6 cGy/min as measured by the 0.15 ml ionization chamber. The total skin dose under the central hole of the grid in the patient treatment was estimated to be 58.0 + 0.9 Gy. The significant difference between the 871
H. Shirato et al Table I. Number of patients at risk, number of 1 cm skin circles at risk (none showing necrosis), and the expected number of 2-3 cm skin circles showing necrosis as a function of time following 22.5 Gy (see text)
mmm0m0 000000 000000
0 mm 0 0 0 0 0
0 0 0 0 0
0 0 0 0 0
0 0 0 0 0
0 0 0 0 0 0 0 0 0 0
Figure 1. Lead sheet (4 mm thick) for use in grid therapy, with holes 10 mm in diameter with centres at 14 mm intervals.
nominal and the actual dose is attributed mainly to the contribution from backscatter in the Mix D phantom. At orthovoltage energies, the unflattened beam centre is the most intense point. The dose estimated by film densitometry under each hole of the grid gave the following distribution: four holes (5%) received doses between 47.0 and 49.9 Gy, 18 (23%) between 50.0 and 52.9 Gy, 18 (23%) between 53.0 and 55.9 Gy, and 37 (48%) between 56.0 and 58.9 Gy. The skin dose under the lead sheet was estimated to be 12.3 ± 1.5 Gy. The grid technique used in Manchester was similar to that used in Blackpool except that it used 300 kVp X rays with HVL = 1.7 mm (Holmes, 1963). As the prescribed doses and the type and size of the grid used in the two hospitals were identical, it can be assumed that the surface doses received by the two sets of patients were similar. Patient treatment and follow-up
Four hundred and thirty-seven patients received orthovoltage therapy using the grid technique, to the anterior mediastinum. Two hundred and sixty-eight patients had treatment for superior vena caval syndrome and 169 patients received treatment for gross dyspnoea/stridor, persistent haemoptysis and/or chest wall pain due to advanced malignancy. Three hundred and nine (70%) were male and the mean age of the 872
Months Number of Number of 1 cm Expected number patients skin circles of 2-3 cm skin at risk at risk circles having necrosis at 22.5 Gy
0 12 24 36 48 60 84
437 (127) 19 7 5 5 4(3) 4(3)
33 649 1463 539 385 385 308 308
0 3 10 25 63 59 27"
Values in brackets refer to the Blackpool patients only. "Crude rate; other values are actuarial rates (see text).
group was 58 years (range 26-80). Three hundred and ten patients in this study had treatment in Manchester (1956-1959) and 127 patients were treated in Blackpool (1970-1985). All were in poor general condition with distressing symptoms and were considered unsuitable for protracted fractionation. In view of this and the urgency of institution of palliative therapy, histological diagnoses were not sought and were available only in 66 patients (15%). Of those where histology was available, 57 had squamous cell carcinoma of the bronchus, three with metastatic breast cancer, two with oesophageal cancer and four patients with miscellaneous tumours. There are no survivors. One of the authors (N.K.G.) was involved in the treatment and subsequent follow-up of all his patients at Blackpool. The information about the Manchester patients was collected from the hospital case notes and via postal enquiries from their general practitioners. Late skin necrosis was defined as necrosis existing at or after 3 months following radiotherapy, which either healed or was excised surgically and histologically proven (Dutreix, 1986). Follow-up of patients was at intervals of at least 2-3 months during the first year, 3-4 months during the second year, and then every 6 months from 3 years. Results
The poor long-term survival of these patients was expected. All were in poor general condition with advanced cancer and had a simple palliative radiotherapy merely to alleviate the distressing symptoms. All patients had relief of vena caval obstruction within the first week after irradiation, and 75% of these had benefit lasting 2-9 months. Only 19 patients were alive at the end of the first year, seven patients survived for 2 years,fivepatients lived 3 years and a mere four patients lived for more than 4 years (Table I). Of the seven who were alive more than 2 years, five had treatment in Blackpool (total 127 treated), and three of these The British Journal of Radiology, November 1990
Field size and grid radiotherapy
survived to 7 years. In one patient, a post-mortem examination 10 years after grid therapy showed radiation fibrosis around the retrosternal thyroid, but there was no evidence of cutaneous or bone necrosis (nor of tumour). However, in all long-surviving patients, deep permanent skin pigmentation matching the grid pattern was evident. No skin necrosis has been detected. Regarding the previous Manchester patients, the annotation on the case notes was not always precise about the status of the skin but a statement of moist desquamation in the treated site was frequently noted at 3 months after therapy (as also observed in the Blackpool patients). Further comments specific to the skin condition were rarely made thereafter, and usually referred to skin atrophy. As auscultation of the chest was done during follow-up visits, it is not unreasonable to assume that a degree of inspection of the chest wall was inevitable. It is unlikely that a clinician could overlook skin necrosis which is painful and takes several weeks to heal. With an observation of (0/19) patients as a skin necrosis rate at 12 months, the 95% confidence interval of probability of skin necrosis at 1 year is 0-18% assuming a binominal distribution. The number of patients after 24 months was too small to analyse on an individual basis. However, if the probability of late skin necrosis is assumed to be independent of patient characteristics and if there is no interaction between circles, it is possible to use each 1 cm circle as an independent observation (Table I, third column). In this case, the 95% confidence interval would be 0-1.2%, i.e. an upper limit of only four events (necroses) in 308 sites even at 7 years. Discussion Late radiation morbidity from grid therapy has not been well documented. The technique has only been used for patients with poor prognosis and hence there have been only a few long-term survivors. The first report on the use of grid technique was by Kohler (1909). This form of therapy was developed further (for example: Liberson, 1933; Haring, 1934; Grynkraut, 1945; Jolles 1949, 1952), and individual experiences were reported (for example: Marks, 1952; Tenzel, 1952; Jolles, 1962; Rode, 1962; Aliev 1976). Anecdotal incidences of skin necrosis after fractionated grid technique were reported by Jolles (1952) and Tenzel (1952), but this seems to have been due to technical errors in grid placement or as a consequence of previous irradiation. Although fractionated therapy has its potential problems with reproducibility of grid placement, the low incidence of skin damage is striking. Our results are very similar to those in an extensive series reported by Rode (1962) who found no evidence of tissue necrosis occurring in 1200fieldsof 800 patients who received 30 Gy in a single (nominal) dose for a mixed group of tumours treated over a period of 7 years. This dose and other doses referred to in the literature do not include the contribution from backscatter, and are in fact 10-30% higher than their prescribed nominal doses. Jolles (1962) Vol. 63, No. 755
reported five small necrotic skin patches in 83 patients with advanced bladder cancer treated with 110 and 120 Gy in 20-25 fractions using an anterior field and a further 90 Gy delivered to the skin by a posteriorfieldin the same overall time. Aliev (1976) noted 19 cases of late skin necrosis in 251 patients who had received doses between 150 and 200 Gy using fractionated grid therapy with a daily dose of between 6 and 10 Gy/fraction. The results can be compared with those for larger field sizes. A previous study from this Institute has shown that the actuarial skin necrosis rate after a 22.5 Gy single dose for the treatment of skin cancer using a 2.0-3.0 cm diameter field was 0.2%, 1.9%, 6.6%, 16.4% and 19.2% at 1, 2, 3, 4 and 5 years respectively (Chan et al, 1988). The value at 7 years was quoted as a crude rate (8.9%). Using these percentages, Table I (last column) shows the expected number of necroses as a function of time after 22.5 Gy using a 2.0-3.0 cm diameter field. In spite of the large difference in dose between 22.5 Gy and 47-59 Gy, the necrosis rate in the present study (0/308) was significantly lower than for a 2-3 cm diameter field. Chan et al (1988) have also shown that the crude skin necrosis rate at 7 years was 2.3%, 3.0% and 8.9% after 18 Gy, 20 Gy and 22.5 Gy single dose for the treatment of skin cancer using a 2.0-3.0 cm diameter field. Using those data, a dose-response curve calculated by probit analysis predicts 50% risk of skin necrosis at 29 + 1 Gy and 99% incidence at about 40 Gy (Chan, 1989). The corresponding dose for 50% incidence in 3-4 cm diameter fields was 28±4Gy. This is consistent with other data where 50% incidence of necrosis was produced by 24.5 Gy using a field more than 3 cm in diameter and where virtually 100% necrosis was predicted at >30 Gy (Trott et al, 1984). The difference between this and the lack of skin necrosis (0/308) using 58 Gy and 1 cm diameter fields in grid therapy is thus highly significant. This difference occurred in spite of the probability of interaction effects between the neighbouring 1 cm fields which may have increased, not decreased, their response. It was shown by Jolles (1950) that there was no interaction regarding acute skin reactions on the leg when 2 areas each of 1.56 cm2 were separated by not less than 2 cm of unirradiated skin. In the present studies the holes were separated by a minimum of only 0.4 cm of (shielded) skin. Another possibility, which would apparently decrease the differential in responses between the different field sizes, is that the 1 % of patients who survived to 5 years in the present study were inherently radioresistant. However, there was no evidence for a lack of acute skin reactions in these four individuals compared with the majority. Also, at 2 yearsfiveout of the seven survivors were part of the original number of 127 treated in Blackpool, and 4% of individuals more resistant than the other 96% by a factor of as much as 2-3 in terms of tolerance dose is contrary to common radiotherapeutic experience. It is also noted that the dose as high as 12 Gy to the skin between the high-dose circles did not increase the 873
H. Shirato et al risk of necrosis. These results are consistent with clinical observations using interstitial treatments, which give ultrahigh doses around the radioactive needles but which result in no tissue necrosis. The sharp increase in iso-effect dose for areas decreasing to 1.0 cm diameter is similar to data for early skin reactions using single fields previously reviewed (Hopewell & Young, 1982). Although skin reactions are no longer dose limiting in conventional radiotherapy, these dosage increases for both early and late skin reactions are probably applicable to treatment of other tissues as well, such as the use of charged particles in the treatment of occular melanomas and of chordomas and chondrosarcomas abutting the central nervous system, where high doses can be delivered safely to small volumes. Also, it has been suggested that grid therapy may still have a role in treatments involving "seriestype" tissues such as the spinal cord where each of a series of critically sized elements is essential for the function of the whole organ (Maruyama et al, 1989). The sparing of single elements due to the field-size effect (e.g. Hopewell & van der Kogel, 1988) would enable much higher regional doses to be tolerated. Acknowledgment We thank Mr R. Swindell for his help with the statistical aspects of this study. References ALIEV, E. M., 1976. Moglichkeiten dun Perspektiven einer ungleichmassigen Bestrahlung von malignen Geschwulsten. Radiobiology-Radiotherapy, 2, 223-234. CHAN, S., 1989. The effect of field size on late skin necrosis in man following single-exposure radiotherapy. British Journal of Radiology, 62, 770. CHAN, S., LIM, J. & HUNTER, R. D., 1988. Single fraction
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1989. Recent trends in radiobiology of the skin and repercussions for dose limitation and personal dosimetry. Radiation protection theory and practice. In Proceedings of the Fourth International Symposium of the Society for Radiological Protection, Malvern, 1989 (Institute of Physics, Bristol), pp. 419^124. DUTREIX, J., 1986. Human skin: early and late reactions in relation to dose and its time distribution. In Radiation Damage to Skin (British Journal of Radiology Supplement 19, British Institute of Radiology, London), pp. 22-28. VON ESSEN, C. F., 1968. Radiation tolerance of the skin. Acta Radiologica, Therapy, Physics, Biology, 8, 311-330. GRYNKRAUT, B., 1945. Direct and indirect radiotherapy. American Journal of Roentgenology, 53, 491-499.
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The British Journal of Radiology, November 1990
