JULY 1962 Dose, time and volume parameters in irradiation therapy of Kaposi's sarcoma by Lionel Cohen, Ph.D., M.B., B.Ch., D.M.R.T. Radiation Therapy Department, Johannesburg Hospital, Johannesburg, S. Africa (Received September, 1961) In a recent review on the treatment of Kaposi's sarcoma (Cohen, Palmer and Nickson, 1962), it appeared that there was relatively little information published on its radiosensitivity, and that reported methods of management varied widely and were often contradictory. It has, however, become possible, since the disease is of extraordinary fre- quency in Africa, to present the following analysis of a comparatively large irradiated series from which appropriate data can be extracted. The patho- logical and clinical features of this African series are described in detail by a number of investigators (U.I.C.C. Symposium on Kaposi's Sarcoma, 1962, in press); the present report deals with the radio- sensitivity of the individual lesions and the tolerance limits of the associated normal tissues. Between 1949 and 1960, 58 cases of typical Kaposi's sarcoma were referred to the Radiation Therapy Department of the Johannesburg Hospital for therapy. Of these, 16 were lost to follow-up yielding no information on the length of remission, three cases received no more than minimal palliative treatment shortly before death from widespread cutaneous or visceral dissemination, and one patient was killed in a street accident after an initial re- mission, thus leaving 38 definitive cases available for analysis. All but three of these patients were males, the average age being 40 years (range five to 80). Individual lesions were identical in appearance with Kaposi's original description of the disease, presenting as small, usually tender or itchy, intra- dermal or subcutaneous nodules, almost invariably multiple and often becoming confluent to form plaques or regionally infiltrating masses with the characteristic pigmentary and fibrotic changes. Generally starting in the extremities (feet, legs, hands, forearms, thighs being the sites most com- monly affected in order of frequency), the di- sease slowly progresses centripetally and affects the trunk or viscera only in the late stages or in fulminating cases. Characteristic of the rather more florid African cases, however, is the extensive tumour formation in the subcutaneous connective tissues and fascial planes, usually associated with regional oedema and demonstrable on soft tissue radiography. Large ulcerated masses were also present in the majority of patients in this series. The tumours appear to be intimately associated with vascular structures, often showing evidence of a hyperkinetic local circulation, apparently attribu- table to opening of arterio-venous shunts. Lymph- oedema and gross abnormalities of lymph flow are also evident. Lesions examined after irradiation show markedly diminished vascularity, often to the point of ischaemia, and a greatly increased tendency to fibrosis. Following treatment, 12 cases were apparently "cured" without complications; in five others the tumours were eradicated with evident high-dose effects; eight cases were locally cured but had proximal extension of the disease (four with wide- spread dissemination); and 13 had persistent or locally recurrent tumours (five associated with high- dose effects to be described below). Radiosensitivity in relation to dosage and fractionation In the absence of any satisfactory standard radiotherapeutic procedure for Kaposi's sarcoma, a wide variety of techniques had been used. In general, medium-voltage "superficial" radiation (135 kV, 2 mm Al filter) was applied to the earlier localised lesions, and ortho-voltage therapy (240 kV H.V.L. 1-5 mm Cu) for more advanced disease. Both dosage and time factors varied considerably, thus rendering the material amenable to dose-time studies after Strandqvist's (1944) method. Among the 38 patients reviewed, many having received treatment to more than one affected area, 65 distinct dose-time combinations were delivered, and the response observed for a follow-up ranging from two to 12 years. Considering the local response alone, irrespective of extension or dissemination beyond the treated area, there were 36 "cured" lesions and 29 "recurrences". The dose and time factors for each lesion were accordingly charted on logarithmic co-ordinates after Strandqvist's method (Fig. 1). For those cases treated with ortho-voltage therapy, when one or more opposed pairs of fields were used, dosage is expressed in terms of the calculated minimum tissue dose at the centre of the limb (ignoring bone absorption). 485
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Dose, Time and Volume Parameters in Irradiation Therapy of Kaposi's SarcomaJULY 1962
Dose, time and volume parameters in irradiation therapy of Kaposi's sarcoma
by Lionel Cohen, Ph.D., M.B., B.Ch., D.M.R.T.
Radiation Therapy Department, Johannesburg Hospital, Johannesburg, S. Africa (Received September, 1961)
In a recent review on the treatment of Kaposi's sarcoma (Cohen, Palmer and Nickson, 1962), it appeared that there was relatively little information published on its radiosensitivity, and that reported methods of management varied widely and were often contradictory. It has, however, become possible, since the disease is of extraordinary fre- quency in Africa, to present the following analysis of a comparatively large irradiated series from which appropriate data can be extracted. The patho- logical and clinical features of this African series are described in detail by a number of investigators (U.I.C.C. Symposium on Kaposi's Sarcoma, 1962, in press); the present report deals with the radio- sensitivity of the individual lesions and the tolerance limits of the associated normal tissues.
Between 1949 and 1960, 58 cases of typical Kaposi's sarcoma were referred to the Radiation Therapy Department of the Johannesburg Hospital for therapy. Of these, 16 were lost to follow-up yielding no information on the length of remission, three cases received no more than minimal palliative treatment shortly before death from widespread cutaneous or visceral dissemination, and one patient was killed in a street accident after an initial re- mission, thus leaving 38 definitive cases available for analysis. All but three of these patients were males, the average age being 40 years (range five to 80).
Individual lesions were identical in appearance with Kaposi's original description of the disease, presenting as small, usually tender or itchy, intra- dermal or subcutaneous nodules, almost invariably multiple and often becoming confluent to form plaques or regionally infiltrating masses with the characteristic pigmentary and fibrotic changes. Generally starting in the extremities (feet, legs, hands, forearms, thighs being the sites most com- monly affected in order of frequency), the di- sease slowly progresses centripetally and affects the trunk or viscera only in the late stages or in fulminating cases. Characteristic of the rather more florid African cases, however, is the extensive tumour formation in the subcutaneous connective tissues and fascial planes, usually associated with regional oedema and demonstrable on soft tissue
radiography. Large ulcerated masses were also present in the majority of patients in this series. The tumours appear to be intimately associated with vascular structures, often showing evidence of a hyperkinetic local circulation, apparently attribu- table to opening of arterio-venous shunts. Lymph- oedema and gross abnormalities of lymph flow are also evident. Lesions examined after irradiation show markedly diminished vascularity, often to the point of ischaemia, and a greatly increased tendency to fibrosis.
Following treatment, 12 cases were apparently "cured" without complications; in five others the tumours were eradicated with evident high-dose effects; eight cases were locally cured but had proximal extension of the disease (four with wide- spread dissemination); and 13 had persistent or locally recurrent tumours (five associated with high- dose effects to be described below).
Radiosensitivity in relation to dosage and fractionation In the absence of any satisfactory standard
radiotherapeutic procedure for Kaposi's sarcoma, a wide variety of techniques had been used. In general, medium-voltage "superficial" radiation (135 kV, 2 mm Al filter) was applied to the earlier localised lesions, and ortho-voltage therapy (240 kV H.V.L. 1-5 mm Cu) for more advanced disease. Both dosage and time factors varied considerably, thus rendering the material amenable to dose-time studies after Strandqvist's (1944) method. Among the 38 patients reviewed, many having received treatment to more than one affected area, 65 distinct dose-time combinations were delivered, and the response observed for a follow-up ranging from two to 12 years. Considering the local response alone, irrespective of extension or dissemination beyond the treated area, there were 36 "cured" lesions and 29 "recurrences".
The dose and time factors for each lesion were accordingly charted on logarithmic co-ordinates after Strandqvist's method (Fig. 1). For those cases treated with ortho-voltage therapy, when one or more opposed pairs of fields were used, dosage is expressed in terms of the calculated minimum tissue dose at the centre of the limb (ignoring bone absorption).
485
VOL. 35, No. 415 L. Cohen
With superficial therapy, the dosage given is that estimated at the skin surface. For the purpose of this analysis, the time factor chosen is the overall treat- ment time in days; almost all patients were treated daily for five days a week.
The solid black circles in Fig. 1 represent locally recurrent or persistent disease, while the open circles indicate locally cured lesions. The oblique
DOSE. »6OOO • sooo
dence of 65 irradiated lesions.
line, fitted by eye so as to give the best separation between the two groups, demarcates the majority (30/36) of successfully eradicated lesions above, from the bulk (24/29) of the failures below it, thus giving an estimate of median effective dosage for the tumour as a function of time.
The line describes a parabolic function D — E.Tn, D being the dose in rads delivered in T days, where E, the intercept on the "single exposure" axis, corresponds to a median dose of 850 rads, and n the recovery exponent equals 0-25. With respect to the effective single dose (E), the radiosensitivity of this tumour resembles that estimated for the malignant lymphomata (Scott, 1961), while the recovery factor (n) is practically identical to that derived for epidermoid cancer (Cohen, 1960). The approximate fiducial limits are given by the broken lines, corresponding roughly to a coefficient of variation of the order of 10 per cent, and including virtually the whole of the zone in which successes and failures overlap. The upper limit thus represents the minimum curative (LD95) dose-time combi- nation for the Kaposi lesion. It will be noted that this line ranges from a single exposure of 1,000 rads up to nearly 2,500 rads for a one month's course of therapy.
Tolerance limits and high-dose effects As in all radical radiation therapy, the value of
treatment for Kaposi's sarcoma has to be weighed against the risks of high-dose effects and other complications arising from irradiation of adjacent normal structures. This is particularly difficult, since all the tissues at risk are affected in the natural course of Kaposi's disease in a manner closely resembling the appearance of late radiation changes. Indolent ulceration of the skin, progressive vascular obliteration, fibrous contracture of the subcutaneous and musculo-skeletal tissues, as well as bone atrophy and osteolytic lesions are all common features of the untreated disease.
The incidence of complications probably attri- butable at least in part to irradiation may be esti- mated from the fact that ten patients in our series of 38 definitive cases developed presumptive high- dose effects in the treated areas. These are shown as crossed circles in Fig. 1, and it will be noted that in five instances the effects appeared in locally cured areas and five more were associated with local recurrence of the lesions. The reason for these complications is not obvious from the diagram, and although ten cases are insufficient for any but the most superficial analysis of contributing factors, examination of their protocols revealed some suggestive influences. In only two cases was necrosis attributable to overdosage; these showed skin necrosis of the sole of the foot affecting small areas which had been re-treated for recurrence following wide-field irradiation. Of the remaining eight patients, four had progressive sclerosis with fibrous contractures and flexion deformities, and four others developed extensive gangrene necessi- tating amputation. Histological examination of the amputated limbs revealed well-marked endarteritis characteristic of late radiation damage. In these cases dosage ranged from 1,400 to 1,900 rads in six days up to 2,200 rads over 11 days, all manifestly within accepted tolerance limits even for large fields. It seemed significant, however, that all eight cases showing these high-dose effects were treated through portals exceeding 20 cm in length, while only four of the 31 uncomplicated cured lesions had equally large fields treated to similar dose levels.
The foregoing observations suggested that the tolerance of extremities to irradiation with large portals is substantially lower than the levels generally accepted for other situations. In the following para- graphs a biophysical explanation for this apparent discrepancy is proposed. This will also provide for some revision of tolerance limits, affording a wider margin of safety in irradiating extremities, and
486
JULY 1962
Dose, Time and Volume parameters in Irradiation Therapy of Kaposi's Sarcoma
perhaps obviating most of the complications arising after treatment of Kaposi's sarcoma in these situations.
Biophysical factors affecting tolerance of extremities The relatively poor tolerance of limbs observed
in our series of cases of Kaposi's sarcoma may, of course, be a specific feature of the disease. On the other hand, there is practically no experience of any other condition necessitating this type of blanket irradiation of limbs, so that it may be argued with equal justification, that, owing to anatomical peculiarities, the normal tissues of extremities are exceptionally sensitive to wide-field irradiation. The latter hypothesis is supported by the observation that the dose required to produce a given skin reaction varies inversely with the cube-root of the ratio of the treated volume with its bounding sur- face (Jolles and Mitchell, 1947). When the treated volume is reasonably symmetrical and surrounded on all sides by unirradiated tissue (as on the trunk), the latter ratio is proportional to the field diameter. In the case of an irradiated extremity, however, the volume is disproportionately large and the bounding surface virtually restricted to the area of the cross- section of the limb.
Skin tolerance limits, usually given as functions of radiation quality, treatment time, and irradiated volume, are strictly applicable only in the case of reasonably symmetrical volumes. In this regard, the volume factor is a function of the average diameter (L) of the treated field, which has been shown to be a convenient variate for the purpose of analysis (Cohen and Kerrich, 1951). Applying Jolles and Mitchell's volume : surface relationship, and con- sidering an irradiated cube of volume V and bounding surface S with one face on the skin, the "diameter" L' = 5.V/S. The same relationship could be derived for other symmetrical shapes. In the case of an extremity, homogeneously irradiated over a length L, we may consider the bounding surface S to be the cross-sectional area of the limb at the level of the proximal edge of the skin field, in which case V = L.S, so that the parameter L' (corresponding to 5.V/S) = 5.L. That is, the toler- ance of an irradiated extremity approaches that of a field diameter five times greater than the actual length of limb treated, and hence, applying the cube- root rule, is lower by a factor of 3 \ /5 = 1-7. In other words, in order to obtain an equivalent reac- tion in treating an extremity, dosage must be reduced by about 40 per cent below the level tolerated by a corresponding field on the trunk.
In Fig. 2, the dose-time curve for "cure" of the
DOSE •5OOO
PIELD SIZE
TIME FIG. 2.
Tolerance of limbs to irradiation of segments of given length (thin lines) compared with the curative dose for Kaposi's sarcoma (heavy line) in relation to the overall treatment
time.
Kaposi lesion (heavy line) is superimposed on the limb tolerance limits for the corresponding periods. The positions and slopes of these lines are estimated after the writer's (1960) method, and corrected by the factor proposed for tolerance of extremities. The field sizes shown represent the lengths of irradiated limb segments in centimetres. It will be noted that for small areas, say under 10 cm in size, single exposures of 1,000 rads are theoretically both safe and effective, while progressively longer courses of therapy and correspondingly higher doses become necessary with larger fields.
Optimal dosage and treatment policy for Kaposi's sarcoma
Examining the data from which Fig. 1 was com- piled reveals nothing to suggest that "successes" and "failures" came from different populations. Indeed the even distribution around the median line indicates an essentially homogeneous population in which success or failure in eradicating the indi- vidual lesion was largely determined by differences in dosage. It seems possible, therefore, to devise treatment procedures which are consistently safe and effective by taking into account the observed radiosensitivity of the lesions as well as the limita- tions of tissue tolerance in the extremities as de- scribed previously.
The following treatment policy is accordingly suggested, and takes into account all the foregoing considerations together with recently collated data on the distribution and progression of the lesions. In the exceptional case, a single small nodule may be treated by superficial therapy with a dose of 1,000 rads in a single exposure. More usually,
487
L. Cohen
however, the tumour is multicentric in origin and tends to spread centripetally, requiring regional rather than local treatment. When the disease is obviously localised to one or a contiguous group of nodules, extending no deeper than the skin itself, and there is no oedema, no radiological evidence of deep soft-tissue or bone involvement, and no palpable lymph nodes, treatment may be given by medium-voltage superficial therapy to an area of skin extending well beyond the palpable edge of the disease. In such cases, radiation in the 100 kV range is probably adequate. Electron-beam irradiation of appropriate energy (4 to 10 MeV) is, as exemplified in the cases reported by Ronchese and Kern (1957), likely to prove the ideal modality for cutaneous involvement at this stage. With either modality, single doses of the order of 1,000 rads, or higher doses over longer periods as indicated in Fig. 2, should be given.
Superficial therapy is, of course, inadequate for the purpose of controlling oedema, bone involve- ment, lymphadenopathy, or other manifestations of deeper extension of the disease. In these cases it is advisable to use more penetrating radiation gene- rated at 200 to 250 kV with copper or other heavy composite filters. In general, two opposing fields up to 20 cm in length are directed through the affected part. When necessary, several contiguous pairs of fields may be made to include longer seg- ments. Dosage depends on portal size (Fig. 2), and may approach 2,500 rads in four weeks with the larger portals. With the very wide fields necessi- tated by involvement of the whole or major part of a limb, and particularly in the presence of bone lesions, it is probably advisable to use high-energy radiation from cobalt 60 teletherapy or other megavoltage sources, in order to ensure safe and effective homo- geneous irradiation of bone and intra-osseous roft tissues. Whether any correction factor is required to compensate for the difference in relative bio- logical efficiency between megavoltage qualities and
the 100 to 250 kV radiations from which our empirical dose-time data were obtained, remains to be determined.
CONCLUSIONS
With the exception of those patients in whom the disease becomes widely disseminated, it appears that the lesions of Kaposi's sarcoma may be cured by radiation therapy provided that the quality, time, area and dosage factors are judiciously selected. A time-dose analysis indicates that the effective dose is of the order of 1,000 rads at a single exposure, and increases with fractionation by a factor of T 0-25, where T is the overall time in days. The incidence of complications, mainly vascular and attributable at least in part to irradiation, approaches 25 per cent, and leads to ischaemic gangrene in 10 per cent, of patients treated radically without regard to the peculiar tolerance limits of extermities. It is estimated that, in treating extremi- ties, a reduction in tissue dosage by about 40 per cent below that permissible in other areas is required, which necessitates prolonged fractionation (up to 2,500 rads in four weeks) for the larger portals.
Taking the foregoing factors into account, it appears that a substantial proportion of patients could be "cured" in the sense that the disease may be permanently eradicated from the treated areas, without either high-dose complications or evidence of local, regional or distant recurrence.
REFERENCES COHEN, L., Amer.J. Roentgenol., 1960, 84, 741. COHEN, L., and KERRICH, J. E., Brit. J. Cancer, 1951, 5,
180. COHEN, L., PALMER, P. E. S., and NICKSON, J. J., 1962,
in press. JOLLES, B., and MITCHELL, R. G., Brit. J. Radiol, 1947,
20, 405. RONCHESE, F., and KERN, A. B., Arch, dermatol., 1957,
75, 418. SCOTT, R. N., Radiology, 1961, 76, 276. STRANDQVIST, M., Acta radiol. Suppl. 55, 1944.
488
Dose, time and volume parameters in irradiation therapy of Kaposi's sarcoma
by Lionel Cohen, Ph.D., M.B., B.Ch., D.M.R.T.
Radiation Therapy Department, Johannesburg Hospital, Johannesburg, S. Africa (Received September, 1961)
In a recent review on the treatment of Kaposi's sarcoma (Cohen, Palmer and Nickson, 1962), it appeared that there was relatively little information published on its radiosensitivity, and that reported methods of management varied widely and were often contradictory. It has, however, become possible, since the disease is of extraordinary fre- quency in Africa, to present the following analysis of a comparatively large irradiated series from which appropriate data can be extracted. The patho- logical and clinical features of this African series are described in detail by a number of investigators (U.I.C.C. Symposium on Kaposi's Sarcoma, 1962, in press); the present report deals with the radio- sensitivity of the individual lesions and the tolerance limits of the associated normal tissues.
Between 1949 and 1960, 58 cases of typical Kaposi's sarcoma were referred to the Radiation Therapy Department of the Johannesburg Hospital for therapy. Of these, 16 were lost to follow-up yielding no information on the length of remission, three cases received no more than minimal palliative treatment shortly before death from widespread cutaneous or visceral dissemination, and one patient was killed in a street accident after an initial re- mission, thus leaving 38 definitive cases available for analysis. All but three of these patients were males, the average age being 40 years (range five to 80).
Individual lesions were identical in appearance with Kaposi's original description of the disease, presenting as small, usually tender or itchy, intra- dermal or subcutaneous nodules, almost invariably multiple and often becoming confluent to form plaques or regionally infiltrating masses with the characteristic pigmentary and fibrotic changes. Generally starting in the extremities (feet, legs, hands, forearms, thighs being the sites most com- monly affected in order of frequency), the di- sease slowly progresses centripetally and affects the trunk or viscera only in the late stages or in fulminating cases. Characteristic of the rather more florid African cases, however, is the extensive tumour formation in the subcutaneous connective tissues and fascial planes, usually associated with regional oedema and demonstrable on soft tissue
radiography. Large ulcerated masses were also present in the majority of patients in this series. The tumours appear to be intimately associated with vascular structures, often showing evidence of a hyperkinetic local circulation, apparently attribu- table to opening of arterio-venous shunts. Lymph- oedema and gross abnormalities of lymph flow are also evident. Lesions examined after irradiation show markedly diminished vascularity, often to the point of ischaemia, and a greatly increased tendency to fibrosis.
Following treatment, 12 cases were apparently "cured" without complications; in five others the tumours were eradicated with evident high-dose effects; eight cases were locally cured but had proximal extension of the disease (four with wide- spread dissemination); and 13 had persistent or locally recurrent tumours (five associated with high- dose effects to be described below).
Radiosensitivity in relation to dosage and fractionation In the absence of any satisfactory standard
radiotherapeutic procedure for Kaposi's sarcoma, a wide variety of techniques had been used. In general, medium-voltage "superficial" radiation (135 kV, 2 mm Al filter) was applied to the earlier localised lesions, and ortho-voltage therapy (240 kV H.V.L. 1-5 mm Cu) for more advanced disease. Both dosage and time factors varied considerably, thus rendering the material amenable to dose-time studies after Strandqvist's (1944) method. Among the 38 patients reviewed, many having received treatment to more than one affected area, 65 distinct dose-time combinations were delivered, and the response observed for a follow-up ranging from two to 12 years. Considering the local response alone, irrespective of extension or dissemination beyond the treated area, there were 36 "cured" lesions and 29 "recurrences".
The dose and time factors for each lesion were accordingly charted on logarithmic co-ordinates after Strandqvist's method (Fig. 1). For those cases treated with ortho-voltage therapy, when one or more opposed pairs of fields were used, dosage is expressed in terms of the calculated minimum tissue dose at the centre of the limb (ignoring bone absorption).
485
VOL. 35, No. 415 L. Cohen
With superficial therapy, the dosage given is that estimated at the skin surface. For the purpose of this analysis, the time factor chosen is the overall treat- ment time in days; almost all patients were treated daily for five days a week.
The solid black circles in Fig. 1 represent locally recurrent or persistent disease, while the open circles indicate locally cured lesions. The oblique
DOSE. »6OOO • sooo
dence of 65 irradiated lesions.
line, fitted by eye so as to give the best separation between the two groups, demarcates the majority (30/36) of successfully eradicated lesions above, from the bulk (24/29) of the failures below it, thus giving an estimate of median effective dosage for the tumour as a function of time.
The line describes a parabolic function D — E.Tn, D being the dose in rads delivered in T days, where E, the intercept on the "single exposure" axis, corresponds to a median dose of 850 rads, and n the recovery exponent equals 0-25. With respect to the effective single dose (E), the radiosensitivity of this tumour resembles that estimated for the malignant lymphomata (Scott, 1961), while the recovery factor (n) is practically identical to that derived for epidermoid cancer (Cohen, 1960). The approximate fiducial limits are given by the broken lines, corresponding roughly to a coefficient of variation of the order of 10 per cent, and including virtually the whole of the zone in which successes and failures overlap. The upper limit thus represents the minimum curative (LD95) dose-time combi- nation for the Kaposi lesion. It will be noted that this line ranges from a single exposure of 1,000 rads up to nearly 2,500 rads for a one month's course of therapy.
Tolerance limits and high-dose effects As in all radical radiation therapy, the value of
treatment for Kaposi's sarcoma has to be weighed against the risks of high-dose effects and other complications arising from irradiation of adjacent normal structures. This is particularly difficult, since all the tissues at risk are affected in the natural course of Kaposi's disease in a manner closely resembling the appearance of late radiation changes. Indolent ulceration of the skin, progressive vascular obliteration, fibrous contracture of the subcutaneous and musculo-skeletal tissues, as well as bone atrophy and osteolytic lesions are all common features of the untreated disease.
The incidence of complications probably attri- butable at least in part to irradiation may be esti- mated from the fact that ten patients in our series of 38 definitive cases developed presumptive high- dose effects in the treated areas. These are shown as crossed circles in Fig. 1, and it will be noted that in five instances the effects appeared in locally cured areas and five more were associated with local recurrence of the lesions. The reason for these complications is not obvious from the diagram, and although ten cases are insufficient for any but the most superficial analysis of contributing factors, examination of their protocols revealed some suggestive influences. In only two cases was necrosis attributable to overdosage; these showed skin necrosis of the sole of the foot affecting small areas which had been re-treated for recurrence following wide-field irradiation. Of the remaining eight patients, four had progressive sclerosis with fibrous contractures and flexion deformities, and four others developed extensive gangrene necessi- tating amputation. Histological examination of the amputated limbs revealed well-marked endarteritis characteristic of late radiation damage. In these cases dosage ranged from 1,400 to 1,900 rads in six days up to 2,200 rads over 11 days, all manifestly within accepted tolerance limits even for large fields. It seemed significant, however, that all eight cases showing these high-dose effects were treated through portals exceeding 20 cm in length, while only four of the 31 uncomplicated cured lesions had equally large fields treated to similar dose levels.
The foregoing observations suggested that the tolerance of extremities to irradiation with large portals is substantially lower than the levels generally accepted for other situations. In the following para- graphs a biophysical explanation for this apparent discrepancy is proposed. This will also provide for some revision of tolerance limits, affording a wider margin of safety in irradiating extremities, and
486
JULY 1962
Dose, Time and Volume parameters in Irradiation Therapy of Kaposi's Sarcoma
perhaps obviating most of the complications arising after treatment of Kaposi's sarcoma in these situations.
Biophysical factors affecting tolerance of extremities The relatively poor tolerance of limbs observed
in our series of cases of Kaposi's sarcoma may, of course, be a specific feature of the disease. On the other hand, there is practically no experience of any other condition necessitating this type of blanket irradiation of limbs, so that it may be argued with equal justification, that, owing to anatomical peculiarities, the normal tissues of extremities are exceptionally sensitive to wide-field irradiation. The latter hypothesis is supported by the observation that the dose required to produce a given skin reaction varies inversely with the cube-root of the ratio of the treated volume with its bounding sur- face (Jolles and Mitchell, 1947). When the treated volume is reasonably symmetrical and surrounded on all sides by unirradiated tissue (as on the trunk), the latter ratio is proportional to the field diameter. In the case of an irradiated extremity, however, the volume is disproportionately large and the bounding surface virtually restricted to the area of the cross- section of the limb.
Skin tolerance limits, usually given as functions of radiation quality, treatment time, and irradiated volume, are strictly applicable only in the case of reasonably symmetrical volumes. In this regard, the volume factor is a function of the average diameter (L) of the treated field, which has been shown to be a convenient variate for the purpose of analysis (Cohen and Kerrich, 1951). Applying Jolles and Mitchell's volume : surface relationship, and con- sidering an irradiated cube of volume V and bounding surface S with one face on the skin, the "diameter" L' = 5.V/S. The same relationship could be derived for other symmetrical shapes. In the case of an extremity, homogeneously irradiated over a length L, we may consider the bounding surface S to be the cross-sectional area of the limb at the level of the proximal edge of the skin field, in which case V = L.S, so that the parameter L' (corresponding to 5.V/S) = 5.L. That is, the toler- ance of an irradiated extremity approaches that of a field diameter five times greater than the actual length of limb treated, and hence, applying the cube- root rule, is lower by a factor of 3 \ /5 = 1-7. In other words, in order to obtain an equivalent reac- tion in treating an extremity, dosage must be reduced by about 40 per cent below the level tolerated by a corresponding field on the trunk.
In Fig. 2, the dose-time curve for "cure" of the
DOSE •5OOO
PIELD SIZE
TIME FIG. 2.
Tolerance of limbs to irradiation of segments of given length (thin lines) compared with the curative dose for Kaposi's sarcoma (heavy line) in relation to the overall treatment
time.
Kaposi lesion (heavy line) is superimposed on the limb tolerance limits for the corresponding periods. The positions and slopes of these lines are estimated after the writer's (1960) method, and corrected by the factor proposed for tolerance of extremities. The field sizes shown represent the lengths of irradiated limb segments in centimetres. It will be noted that for small areas, say under 10 cm in size, single exposures of 1,000 rads are theoretically both safe and effective, while progressively longer courses of therapy and correspondingly higher doses become necessary with larger fields.
Optimal dosage and treatment policy for Kaposi's sarcoma
Examining the data from which Fig. 1 was com- piled reveals nothing to suggest that "successes" and "failures" came from different populations. Indeed the even distribution around the median line indicates an essentially homogeneous population in which success or failure in eradicating the indi- vidual lesion was largely determined by differences in dosage. It seems possible, therefore, to devise treatment procedures which are consistently safe and effective by taking into account the observed radiosensitivity of the lesions as well as the limita- tions of tissue tolerance in the extremities as de- scribed previously.
The following treatment policy is accordingly suggested, and takes into account all the foregoing considerations together with recently collated data on the distribution and progression of the lesions. In the exceptional case, a single small nodule may be treated by superficial therapy with a dose of 1,000 rads in a single exposure. More usually,
487
L. Cohen
however, the tumour is multicentric in origin and tends to spread centripetally, requiring regional rather than local treatment. When the disease is obviously localised to one or a contiguous group of nodules, extending no deeper than the skin itself, and there is no oedema, no radiological evidence of deep soft-tissue or bone involvement, and no palpable lymph nodes, treatment may be given by medium-voltage superficial therapy to an area of skin extending well beyond the palpable edge of the disease. In such cases, radiation in the 100 kV range is probably adequate. Electron-beam irradiation of appropriate energy (4 to 10 MeV) is, as exemplified in the cases reported by Ronchese and Kern (1957), likely to prove the ideal modality for cutaneous involvement at this stage. With either modality, single doses of the order of 1,000 rads, or higher doses over longer periods as indicated in Fig. 2, should be given.
Superficial therapy is, of course, inadequate for the purpose of controlling oedema, bone involve- ment, lymphadenopathy, or other manifestations of deeper extension of the disease. In these cases it is advisable to use more penetrating radiation gene- rated at 200 to 250 kV with copper or other heavy composite filters. In general, two opposing fields up to 20 cm in length are directed through the affected part. When necessary, several contiguous pairs of fields may be made to include longer seg- ments. Dosage depends on portal size (Fig. 2), and may approach 2,500 rads in four weeks with the larger portals. With the very wide fields necessi- tated by involvement of the whole or major part of a limb, and particularly in the presence of bone lesions, it is probably advisable to use high-energy radiation from cobalt 60 teletherapy or other megavoltage sources, in order to ensure safe and effective homo- geneous irradiation of bone and intra-osseous roft tissues. Whether any correction factor is required to compensate for the difference in relative bio- logical efficiency between megavoltage qualities and
the 100 to 250 kV radiations from which our empirical dose-time data were obtained, remains to be determined.
CONCLUSIONS
With the exception of those patients in whom the disease becomes widely disseminated, it appears that the lesions of Kaposi's sarcoma may be cured by radiation therapy provided that the quality, time, area and dosage factors are judiciously selected. A time-dose analysis indicates that the effective dose is of the order of 1,000 rads at a single exposure, and increases with fractionation by a factor of T 0-25, where T is the overall time in days. The incidence of complications, mainly vascular and attributable at least in part to irradiation, approaches 25 per cent, and leads to ischaemic gangrene in 10 per cent, of patients treated radically without regard to the peculiar tolerance limits of extermities. It is estimated that, in treating extremi- ties, a reduction in tissue dosage by about 40 per cent below that permissible in other areas is required, which necessitates prolonged fractionation (up to 2,500 rads in four weeks) for the larger portals.
Taking the foregoing factors into account, it appears that a substantial proportion of patients could be "cured" in the sense that the disease may be permanently eradicated from the treated areas, without either high-dose complications or evidence of local, regional or distant recurrence.
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20, 405. RONCHESE, F., and KERN, A. B., Arch, dermatol., 1957,
75, 418. SCOTT, R. N., Radiology, 1961, 76, 276. STRANDQVIST, M., Acta radiol. Suppl. 55, 1944.
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