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Response and cosmetic outcome of two fractionation regimens for AIDS-related Kaposi's sarcoma
Radiotherapy and Oncology 46 (1998) 23–28
Response and cosmetic outcome of two fractionation regimens for AIDS-related Kaposi’s sarcoma Mark Harrison a , b ,*, Kevin J. Harrington c, David R. Tomlinson d, J. Simon W. Stewart a a
b
Department of Oncology, St Mary’s Hospital, London W2 1NY, UK Mutagenesis Laboratory, Clare Hall Laboratories, I.C.R.F., Blanche Lane, South Mimms, Herts EN6 3LD, UK c Department of Clinical Oncology, Hammersmith Hospital, Ducane Rd, London W12 OHS, UK d Department of Genitourinary Medicine, St Marys Hospital, London W2 1NY, UK Received 26 February 1997; revised version received 15 June 1997; accepted 20 June 1997
Abstract Purpose: A prospective study of the response and cosmetic effect of two short duration radiotherapy regimens in the treatment of epidemic cutaneous Kaposi’s sarcoma. Materials and methods: Between June 1990 and May 1994, 57 patients were recruited into a prospective study of radiotherapy for cutaneous epidemic Kaposi’s sarcoma. Patients were offered treatment of either 16 Gy in four fractions over 4 days or 8 Gy as a single fraction. In total 596 lesions were treated in a prospective fashion. Response was assessed in 590 and pigmentation in 573 lesions. A reproducible scale for assessing response and normal cutaneous damage was developed and used to grade the results of treatment. Results: There was an overall response rate of 78.8% (465/590) for complete responses and pigmented complete responses. Patients receiving 8 Gy as a single fraction had an overall response rate of 77.6% (305/393) and those treated with 16 Gy in four fractions had a response rate of 80.8% (160/198). There was no statistical difference in terms of response between the two groups. There appeared to be a significant variation in response and normal skin pigmentation according to the site irradiated with facial lesions responding best. Conclusions: Radiotherapy is a quick and effective treatment for cutaneous epidemic Kaposi’s sarcoma. A single fraction of 8 Gy is an appropriate treatment for acceptable response and normal skin pigmentation within a group of patients in whom the median life expectancy is limited. 1997 Elsevier Science Ireland Ltd. Keywords: Cosmetic outcome; Fractionation regimens; Kaposi’s sarcoma
1. Introduction Kaposi’s sarcoma (KS) affects up to 20% of patients with AIDS [1]. Numerous local therapies exist. Simple cosmetics, cryosurgery, excision, laser therapy and radiotherapy all play a role in treatment [3,5–8,12,16]. Radiotherapy, though not as yet compared in a prospective fashion with the other modalities, is quick, convenient and associated with a high response rate [2,3,10,11,13–15]. Prospective studies of differing fractionation regimens suggest that 40 Gy/20 fractions/4 weeks is associated with optimal response and a prolonged response duration [15]. For patients with multiple lesions and other AIDS-related conditions the protracted treatment necessary for an optimal response must be * Corresponding author.
balanced against the quality of life in a condition where the median survival is counted in months [9]. Patients with single lesions and no other AIDS-related illness may certainly benefit but these patients are in the minority. Since cosmesis is a major reason for radiotherapy a good cosmetic result is of paramount importance. Successful treatment must flatten and if possible decolour the KS lesions without an unacceptable degree of radiation induced pigmentation in the surrounding skin. Although highly fractionated radiotherapy regimens would achieve this, many HIV infected patients have other medical problems which makes protracted fractionation regimens impractical and often impossible. A balance has to be achieved between a regimen which is effective and cosmetically acceptable and one which is easy to deliver and unobtrusive to the patients life style. For these pragmatic reasons we have adopted
0167-8140/98/$19.00 1998 Elsevier Science Ireland Ltd. All rights reserved PII S0167-8140 (97 )0 0141-2
24
M. Harrison et al. / Radiotherapy and Oncology 46 (1998) 23–28
two fractionation regimens for the treatment of AIDSrelated KS. These are 16 Gy in four fractions over 4–7 days and 8 Gy as a single fraction. Patients are treated using a superficial orthovoltage machine with energies of 75 and 100 kV. Poorly fractionated radiotherapy regimens may lead to pigmentation in the irradiated skin adjacent to the KS lesion. We have developed a means of grading the surrounding normal skin pigmentation using a four-point grading system. The criteria for response for Kaposi’s sarcoma to irradiation differ from other skin tumours; although KS lesions can totally disappear with treatment, they frequently flatten and lose their oedema leaving a pigmented flat macule. These pigmented macules show no evidence of residual Kaposi’s sarcoma on biopsy [3] and are included as a response providing they are totally flat with no other evidence of disease. The purpose of this study was to compare prospectively two radiation regimens, 8 Gy in one fraction and 16 Gy in four fractions, in the context of a randomized trial with each patient having lesions randomized to both regimens. During this study many patients, either because of preconceived ideas or from a personal judgement after entering the study, declined randomization. These lesions formed part of a simultaneous larger non-randomized study. The site of the lesions may also play a major role in both the response to radiotherapy and the normal skin pigmentation sequelae. To examine this possibility the response rates and pigmentation results for different body sites have been assessed.
2. Materials and methods 2.1. Patients Fifty-seven patients with 596 cutaneous lesions were treated between June 1990 and May 1994. All patients were male and proven HIV positive by ELISA and Southern blot techniques. HIV had been contracted by sexual contact, either homosexual or heterosexual, in all cases. The mean CD4 count at time of radiotherapy was available for 35 patients and was 41.6 cells/mm3 (range 6–160 cells/mm3). The median survival for all patients entering the study was 17 months (range 3–52 months).
of the treatments arms according to their individual preference. The study was approved by the Parkside Health Authority Ethics Committee and informed consent was obtained from all participating patients. At completion 27 patients had agreed to have their lesions randomized to both regimens and a further 30 were not entered into the study but expressed a preference for one of the regimens. Each lesion was reviewed 6 weeks after radiotherapy and response and cosmesis were judged at this stage. The mean follow-up time for the 57 patients was 19 weeks. 2.3. Treatment technique All patients were treated at St Mary’s Hospital, London, UK, using the superficial orthovoltage treatment machine (75 or 100 kV). Each lesion was irradiated with a 3–5 mm margin of surrounding normal skin to a depth of 1 cm. No more than five lesions were treated for each patient at each visit. 2.4. Response The response and cosmetic effect of radiotherapy was assessed 6 weeks after treatment and at 2-monthly intervals thereafter where possible. All responses were recorded from the time that they were first assessed but had to be maintained for 6 weeks before being confirmed. The responses to radiotherapy were classified according to Table 1. Partial response was not considered to be a particularly meaningful term as relapse was inevitable but difficult to judge. The response rate in this study was taken to be the sum of the complete and pigmented complete responses. 2.5. Pigmentation A means of grading pigmentation was developed to Table 1 Four-point grading system for assessing response Complete response Pigmented complete response
2.2. Study protocol Partial response
Patients were asked if they wished to be entered into a prospective clinical study involving randomization between two fractionation regimes for Kaposi’s sarcoma. The lesions in patients who agreed to enter the randomized study were randomized to receive either 8 Gy in a single fraction or 16 Gy in four fractions over 4–7 days. In treating each lesion individually each patient served as his own control. If patients required further treatments they were given the option of staying in the randomized study or choosing either
No change
Complete flattening of the KS lesion with normal skin colour Complete flattening of a previously raised KS lesion to a flat pigmented macule Any lesion that has flattened by at least 50% with no increase in size following radiotherapy but on palpation has some residual elevation, nodularity or thickening A lesion that has not flattened by 50% following radiotherapy and/or in which there has been either an increase in the size or the development of satellite lesions around the irradiated site
25
M. Harrison et al. / Radiotherapy and Oncology 46 (1998) 23–28
assess whether these high dose-per fraction regimens were accompanied by increased pigmentation in the irradiated adjacent skin. The pigmentation result, judged according to the presence of the radiation stigmata in the irradiated ‘halo’ of skin immediately surrounding the lesion, and not on the overall response of the lesion, was graded as in Table 2. 2.6. Statistical analysis x2 tests were used to compare the difference in response and cosmesis rates. Actuarial local control was calculated according to the method of Kaplan and Meier. P-values of less than 0.05 were regarded as significant.
3. Results 3.1. Overall results Fifty-seven patients with a total of 596 lesions received treatment with a mean follow-up time of 19 weeks. Five hundred ninety lesions were graded according to response and 573 lesions for cosmetic effect. The overall response rate, demonstrated in Table 3 (CR and pigmented CR), for both fractionation regimes was 78.8% (465/590). Cosmetic grade was assessed in 573 lesions and of these 91.3% were of grade 0 or 1 (523/573) (Table 4). One hundred ninety-eight lesions received treatment with 16 Gy in four fractions with an overall response rate of 80.8% (160/198). The remainder were treated with 8 Gy with a response rate of 77.8% (305/392). Statistical analysis using x2 tests showed no difference between the two response rates with P . 0.25. Time to response was usually less than 6 weeks and always less than 3 months. Long term follow-up in this group of patients was frequently impossible making accurate data of recurrence difficult to assess. A total of 109 lesions in 24 of the 57 patients recurred with a median duration of response of 27 weeks (range 10–87 weeks). Pigmentation analysis on the 189 lesions treated with the Table 2
(1) Slight skin pigmentation
(2) Marked skin pigmentation
(3) Severe skin pigmentation or telangiectasia
Overall response (%) for both fractionation regimensa
Complete response Pigmented complete response Partial response No response
Overall
16 Gy/four fractions
8 Gy/one fraction
52 (306/590) 27 (159/590)
49 (97/198) 32 (63/198)
53 (209/392) 25 (96/392)
14 (81/590) 7 (44/590)
15 (29/198) 4 (9/198)
13 (52/392) 9 (35/392)
a
Five hundred ninety-six lesions were irradiated and 590 were evaluated for response according to the response assessment scale.
four fraction regimen and 384 lesions treated with a single fraction showed that for the four fraction regimen an acceptable pigmentation result (grade 0 or 1) was seen in 87.2% (165/189) of lesions treated and for the single fraction regimen in 93.2% (358/384) of lesions treated. Statistical assessment shows that there is a significant difference between the two pigmentation sequelae with P , 0.025 and P . 0.001. This implies a significant advantage for the single fraction regimen. 3.2. Non-randomized lesions Forty-nine patients were treated and 424 lesions received irradiation in non-randomized treatments. Single fraction treatments were given to 318 lesions and four fraction treatments were given to 106 lesions. Response was evaluable in 419 lesions and cosmesis in 407. There was an overall response rate of 79.5% (333/419). Patients receiving 8 Gy had a response rate of 79.2% (248/313) and those receiving 16 Gy had a response rate of 80.2% (85/106). There is no significant difference between these two response rates (P . 0.5). Cosmesis of an acceptable quality (0 or 1) was found in 94.5% (290/306) of lesions treated with a single fraction and 85.1% (86/101) of lesions treated with four fractions. Statistical analysis shows a significant difference between the two groups (P . 0.001) with an advantage to the single fraction regimen. 3.3. Randomized lesions
Four-point grading system for assessing normal skin pigmentation following irradiation (0) No evidence of pigmentation
Table 3
Normal skin as judged by an experienced observer This reaction may be accepted as a skin blemish or normal but would be recognized as a radiation induced stigmata by an experienced observer This reaction would be considered abnormal by radiotherapists and would attract the attention of untrained observers An abnormally severe skin reaction leading to cosmetic disfigurement
One hundred seventy-two lesions in 27 patients received irradiation as part of the prospective randomized study. All Table 4 Overall normal skin pigmentation result (%) in 573 evaluable lesions for both fractionation regimens Grade
Overall
16 Gy/four fractions
8 Gy/one fraction
0 1 2 3
54 (312/573) 37 (211/573) 9 (49/566) 0
57 30 12 1
53 (205/384) 40 (153/384) 7 (26/384)
(107/189) (58/189) (23/189) (1/189)
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M. Harrison et al. / Radiotherapy and Oncology 46 (1998) 23–28
Table 5
Table 7
Response assessment (%) in 172 lesions treated in randomized fashion (response was assessable in all lesions)
Response (%) according to site
Complete response Pigmented complete response Partial response No change
Overall
8 Gy
16 Gy
50 (86/172) 27 (46/172)
47 (38/80) 24 (19/80)
52 (48/92) 29 (27/92)
13 (23/172) 10 (17/172)
15 (12/80) 14 (11/80)
12 (11/92) 7 (6/92)
lesions were assessable for response and 166 lesions were assessable for cosmesis. Ninety-two lesions were treated with 16 Gy in four fractions and 80 lesions were treated with 8 Gy as a single fraction. A response rate of 71.3% (57/80) was seen for the 8 Gy treatment and 81.5% (75/92) for the 16 Gy treatment. There is no statistical difference between the two regimens in terms of response (0.25 . P . 0.1). Cosmesis grades 0 or 1 was found in 87.1% (67/77) of patients treated with a single fraction and 89.9% (80/89) of patients treated with four fractions. No statistical difference can be seen between the two treatment regimens (P . 0.5) (Tables 5 and 6). 3.4. Site variation There appeared to be considerable variation in both response and normal skin pigmentation according to the area of the body treated. Higher rates of response may be seen for lesions affecting the face, hands, neck and feet with a response of 86–96% compared to the chest, abdomen and back with complete responses of 57–66% (Table 7). Normal skin pigmentation also varied according to site with a higher number of grade 0 for facial lesions (88%) than any other subsites such as the arm, back and chest where only 35– 39% of skin reactions were graded 0 (Table 8).
4. Discussion Kaposi’s sarcoma is the most common of the AIDSrelated malignancies affecting between 15–20% of patients with AIDS. For many patients KS will prove a local problem and a cosmetic nuisance. A smaller subgroup with more extensive cutaneous or visceral disease will require systemic therapy. Effective treatment strategies for both
Site
Complete response
Pigmented complete response
Partial response
No change
Arm Back Chest Face Feet Hands Legs Neck Abdomen
56 41 61 81 65 100 49 65 50
19 27 7 15 23 0 27 26 8
10 18 21 2 12 0 16 9 15
15 14 11 2 0 0 8 0 27
(54/96) (20/49) (35/57) (54/66) (11/17) (5/5) (53/109) (15/23) (13/26)
Overall
8 Gy
16 Gy
0 1 2 3
54 (89/166) 35 (58/166) 11 (18/166) 0
48 (37/77) 39 (30/77) 13 (10/77) 0
59 31 9 1
(52/89) (28/89) (8/89) (1/89)
(18/109) (2/23) (4/26)
(14/96) (7/49) (6/57) (1/66)
(9/109) (7/26)
Table 8 Normal skin pigmentation (%) according to site 0
Grade
(29/109) (6/23) (2/26)
(10/96) (9/49) (12/57) (1/66) (2/17)
local and advanced disease are necessary for maintaining a good quality of life [1,7,12,16]. Local disease may be controlled with radiotherapy using orthovoltage, megavoltage or electrons. Response rates are high and the duration of response is related to the dose administered [15]. Local treatment alternatives to radiotherapy have overall response rates of between 60 and 80%. Cryosurgery or photodynamic therapy seem better suited to smaller lesions with poorer response and cosmesis rates in larger, more nodular lesions [6,8]. Intralesional chemotherapy, particularly with vinblastine, is associated with response rates of 88% but with marked local toxicity [5]. Newer developments include topically applied vitamin D analogues. There have been several prospective and retrospective studies of radiotherapy in the treatment of both classical and AIDS-related KS. Radiotherapy for local disease is effective, non-toxic and acceptable to the patient. The optimal treatment regime is 40 Gy in 20 fractions over 4 weeks which is associated with an 83% complete response rate and a response duration of 43 weeks [15]. However, patients with AIDS-related KS have a median life expectancy of between 11 and 12 months and have many other AIDSrelated medical problems. For these patients local treatment with extended overall time and fractionation may be inappropriate given the amount of time the patients will spend receiving treatment and their estimated overall survival time. A further complication is that often multiple lesions require treatment. These considerations have resulted in a
Table 6 Normal skin pigmentation assessment (%) in 172 lesions treated in randomized fashion (166 lesions were assessable)
(18/96) (13/49) (4/57) (10/66) (4/17)
Arm Back Chest Face Feet Hands Legs Neck Abdomen
45 42 40 85 76 100 51 65 59
1 (40/89) (20/48) (21/53) (56/66) (13/17) (5/5) (55/109) (13/20) (13/22)
46 42 51 15 24 0 32 20 36
2 (41/89) (20/48) (27/53) (10/66) (4/17) (35/109) (4/20) (8/22)
9 16 7 0 0 0 17 15 5
3 (8/89) (8/48) (4/53)
(19/109) (3/20) (1/22)
0 0 2 (1/53) 0 0 0 0 0 0
M. Harrison et al. / Radiotherapy and Oncology 46 (1998) 23–28
more pragmatic approach to the radiotherapy of AIDSrelated KS within our practice. Patients are offered two fractionation regimens, i.e. 16 Gy/four fractions/4 days or 8 Gy in a single fraction. These two fractionation regimens have been derived historically from the several regimens utilized at St. Mary’s Hospital since the start of the AIDS epidemic. Outcome is measured according to a modification of the World Health Organization criteria for cutaneous tumour response with the addition of another group, that of pigmented complete response. This is an important grouping based upon the observations of Cooper at al. [3]. The pigmentation is due to residual haemosiderin within the skin following tumour shrinkage and is comparable to a complete response in terms of response duration. There is an overall response rate (complete response and pigmented complete response) of 78.8% (465/590) which compares favourably with other studies of radiotherapy for AIDSrelated KS. Statistical comparison (x2) of both fractionation regimes shows no difference in response between the single (77.6%) and four fraction (80.8%) treatments. Response rates in the randomized and non-randomized groups are also equivalent which would be expected given the similarity of the patients throughout the cohort. Duration of response proved difficult to measure in all patients. This was due to a combination of intercurrent events such as severe infection, initiation of chemotherapy and patient non-attendance. For those patients in whom response duration was measured the median duration of response was 27 weeks. This is comparable with other published studies of radiotherapy for this disease. Since improving cosmesis is a major reason for the local treatment of AIDS-related KS, a scoring system for the normal surrounding skin radiation response was developed. Resolution of the lesion but with residual skin pigmentation due to radiation damage is of little benefit. Means of assessing this endpoint are important both in the treatment of AIDS-related KS with radiotherapy and also for other non-AIDS-related skin malignancies. The four-point scale developed is an easily followed protocol, particularly for those experienced in the assessment of normal tissue damage following radiotherapy. For those not experienced, the various grades of damage can be easily taught allowing follow-up in both the HIV and Oncology clinic. Variation in response according to anatomical site has been reported for basal cell carcinomas treated with radiotherapy though with a converse result to the one seen in our study [4]. The mediocre performance of radiotherapy, both in terms of response and cosmesis, for lesions affecting sites other than the face and particularly the abdomen has led us to consider that more highly fractionated regimens may be required for KS lesions on these sites. A possible explanation is that lesions affecting the abdomen, the lower limbs and upper limbs are not immediately obvious and do not present the cosmetic nuisance of lesions affecting the face. Treatment is consequently delayed until the lesion is much more mature than would be the case for a facial lesion and
27
the response to treatment is less satisfactory. This does not explain the difference in cosmetic results between the different sites following radiotherapy. These results may be attributable to variations in skin thickness. A single fraction of 8 Gy produces a response with adequate cosmesis comparable with that obtained with a fractionated regimen. Since in AIDS-related KS all treatment is palliative this would appear to be the correct method for treating patients in a HIV oncology clinic. Variations in response and cosmesis are seen but may be minimized by the early treatment of lesions and, possibly, by increasing the total dose and fractions for certain mature lesions. Recent advances in antiretroviral therapy have considerably increased the life expectancy of patients with HIV and AIDS. Information on the development of KS within this new group of treated patients is limited but our early impression is of a decreased amount of KS consistent with improvements in immune function. Future radiotherapy for KS may well be for single isolated lesions in patients with a much longer life expectancy. More extended fractionation regimens will then come to the fore but will require prospective testing.
References [1] Beral, V. The epidemiology of cancer in AIDS patients. AIDS 5 (Suppl. 2): 99–103, 1991. [2] Chang, L.F., Reddy, S. and Shidnia, H. Comparison of radiation therapy of classic and epidemic Kaposi’s sarcoma. Am. J. Clin. Oncol. 15: 200–206, 1992. [3] Cooper, J.S., Steinfeld, A.D. and Lerch, I. Intentions and outcomes in the radiotherapeutic management of epidemic Kaposi’s sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 20: 419–422, 1991. [4] Dublin, N. and Kopf, A.W. Multivariate risk score for recurrence of cutaneous basal cell carcinomas. Arch. Dermatol. 119: 373–377, 1983. [5] Flaitz, C.M., Nichols, C.M. and Hicks, M.J. The role of intralesional vinblastine administration in treatment of intraoral Kaposi’s sarcoma in AIDS. Eur. J. Cancer B. Oral. Oncol. 31B: 280–285, 1995. [6] Hebeda, K.M., Huizing, M.T., Brouwer, P.A. et al. Photodynamic therapy in AIDS related cutaneous Kaposi’s sarcoma. J. AIDS Hum. Retrovirol. 10: 61–70, 1995. [7] Krown, S.E., Myskowski, P.L. and Paredes, J. Medical management of AIDS patients: Kaposi’s sarcoma. Med. Clin. North Am. 76: 235– 252, 1992. [8] Langtry, J.A., Bottomley, D.M., Phillips, R.H. and Staughton, R.C. The infra red coagulator in the treatment of AIDS related Kaposi’s sarcoma and a comparison with radiotherapy. Clin. Exp. Dermatol. 19: 23–25, 1994. [9] Miles, S.A., Wang, H., Elashoff, R. and Mitsuyashu, R.T. Improved survival for patients with AIDS related Kaposi’s sarcoma. J. Clin. Oncol. 12: 1910–1916, 1994. [10] Piccinno, R., Caccialanza, M. and Cusini, M. Role of radiotherapy in the treatment of epidemic Kaposi’s sarcoma. Experience with 65 cases. J. Am. Acad. Dermatol. 32: 1000–1003, 1995. [11] Piedbois, P., Frikha, H., Martin, L., Levy, E., Haddad, E. and Le Bourgeois, J.P. Radiotherapy in the management of epidemic Kaposi’s sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 30: 1207–1211, 1994. [12] Schwartz, R.A. Kaposi’s sarcoma: advances and perspectives. J. Am. Acad. Dermatol. 34: 804–814, 1996. [13] Stein, M.E., Lakier, R., Kuten, A., Spencer, D., Ruff, P. and Bez-
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woda, W.R. Radiation therapy in endemic (African) Kaposi’s sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 27: 1181–1184, 1993. [14] Stein, M.E., Lakier, R., Spencer, D., Dale, J., Kuten, A., Macphail, P. and Bezwoda, W.R. Radiation therapy for non AIDS associated (classic and endemic African) and epidemic Kaposi’s sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 28: 613–619, 1994.
[15] Stelzer, K.J. and Griffin, T.W. A randomized prospective trial of radiation therapy for AIDS associated Kaposi’s sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 27: 1057–1061, 1993. [16] Volm, M.D. and Von Roehn, J.H. Treatment strategies for epidemic Kaposi’s sarcoma. Curr. Opin. Oncol. 7: 429–436, 1995.
Response and cosmetic outcome of two fractionation regimens for AIDS-related Kaposi’s sarcoma Mark Harrison a , b ,*, Kevin J. Harrington c, David R. Tomlinson d, J. Simon W. Stewart a a
b
Department of Oncology, St Mary’s Hospital, London W2 1NY, UK Mutagenesis Laboratory, Clare Hall Laboratories, I.C.R.F., Blanche Lane, South Mimms, Herts EN6 3LD, UK c Department of Clinical Oncology, Hammersmith Hospital, Ducane Rd, London W12 OHS, UK d Department of Genitourinary Medicine, St Marys Hospital, London W2 1NY, UK Received 26 February 1997; revised version received 15 June 1997; accepted 20 June 1997
Abstract Purpose: A prospective study of the response and cosmetic effect of two short duration radiotherapy regimens in the treatment of epidemic cutaneous Kaposi’s sarcoma. Materials and methods: Between June 1990 and May 1994, 57 patients were recruited into a prospective study of radiotherapy for cutaneous epidemic Kaposi’s sarcoma. Patients were offered treatment of either 16 Gy in four fractions over 4 days or 8 Gy as a single fraction. In total 596 lesions were treated in a prospective fashion. Response was assessed in 590 and pigmentation in 573 lesions. A reproducible scale for assessing response and normal cutaneous damage was developed and used to grade the results of treatment. Results: There was an overall response rate of 78.8% (465/590) for complete responses and pigmented complete responses. Patients receiving 8 Gy as a single fraction had an overall response rate of 77.6% (305/393) and those treated with 16 Gy in four fractions had a response rate of 80.8% (160/198). There was no statistical difference in terms of response between the two groups. There appeared to be a significant variation in response and normal skin pigmentation according to the site irradiated with facial lesions responding best. Conclusions: Radiotherapy is a quick and effective treatment for cutaneous epidemic Kaposi’s sarcoma. A single fraction of 8 Gy is an appropriate treatment for acceptable response and normal skin pigmentation within a group of patients in whom the median life expectancy is limited. 1997 Elsevier Science Ireland Ltd. Keywords: Cosmetic outcome; Fractionation regimens; Kaposi’s sarcoma
1. Introduction Kaposi’s sarcoma (KS) affects up to 20% of patients with AIDS [1]. Numerous local therapies exist. Simple cosmetics, cryosurgery, excision, laser therapy and radiotherapy all play a role in treatment [3,5–8,12,16]. Radiotherapy, though not as yet compared in a prospective fashion with the other modalities, is quick, convenient and associated with a high response rate [2,3,10,11,13–15]. Prospective studies of differing fractionation regimens suggest that 40 Gy/20 fractions/4 weeks is associated with optimal response and a prolonged response duration [15]. For patients with multiple lesions and other AIDS-related conditions the protracted treatment necessary for an optimal response must be * Corresponding author.
balanced against the quality of life in a condition where the median survival is counted in months [9]. Patients with single lesions and no other AIDS-related illness may certainly benefit but these patients are in the minority. Since cosmesis is a major reason for radiotherapy a good cosmetic result is of paramount importance. Successful treatment must flatten and if possible decolour the KS lesions without an unacceptable degree of radiation induced pigmentation in the surrounding skin. Although highly fractionated radiotherapy regimens would achieve this, many HIV infected patients have other medical problems which makes protracted fractionation regimens impractical and often impossible. A balance has to be achieved between a regimen which is effective and cosmetically acceptable and one which is easy to deliver and unobtrusive to the patients life style. For these pragmatic reasons we have adopted
0167-8140/98/$19.00 1998 Elsevier Science Ireland Ltd. All rights reserved PII S0167-8140 (97 )0 0141-2
24
M. Harrison et al. / Radiotherapy and Oncology 46 (1998) 23–28
two fractionation regimens for the treatment of AIDSrelated KS. These are 16 Gy in four fractions over 4–7 days and 8 Gy as a single fraction. Patients are treated using a superficial orthovoltage machine with energies of 75 and 100 kV. Poorly fractionated radiotherapy regimens may lead to pigmentation in the irradiated skin adjacent to the KS lesion. We have developed a means of grading the surrounding normal skin pigmentation using a four-point grading system. The criteria for response for Kaposi’s sarcoma to irradiation differ from other skin tumours; although KS lesions can totally disappear with treatment, they frequently flatten and lose their oedema leaving a pigmented flat macule. These pigmented macules show no evidence of residual Kaposi’s sarcoma on biopsy [3] and are included as a response providing they are totally flat with no other evidence of disease. The purpose of this study was to compare prospectively two radiation regimens, 8 Gy in one fraction and 16 Gy in four fractions, in the context of a randomized trial with each patient having lesions randomized to both regimens. During this study many patients, either because of preconceived ideas or from a personal judgement after entering the study, declined randomization. These lesions formed part of a simultaneous larger non-randomized study. The site of the lesions may also play a major role in both the response to radiotherapy and the normal skin pigmentation sequelae. To examine this possibility the response rates and pigmentation results for different body sites have been assessed.
2. Materials and methods 2.1. Patients Fifty-seven patients with 596 cutaneous lesions were treated between June 1990 and May 1994. All patients were male and proven HIV positive by ELISA and Southern blot techniques. HIV had been contracted by sexual contact, either homosexual or heterosexual, in all cases. The mean CD4 count at time of radiotherapy was available for 35 patients and was 41.6 cells/mm3 (range 6–160 cells/mm3). The median survival for all patients entering the study was 17 months (range 3–52 months).
of the treatments arms according to their individual preference. The study was approved by the Parkside Health Authority Ethics Committee and informed consent was obtained from all participating patients. At completion 27 patients had agreed to have their lesions randomized to both regimens and a further 30 were not entered into the study but expressed a preference for one of the regimens. Each lesion was reviewed 6 weeks after radiotherapy and response and cosmesis were judged at this stage. The mean follow-up time for the 57 patients was 19 weeks. 2.3. Treatment technique All patients were treated at St Mary’s Hospital, London, UK, using the superficial orthovoltage treatment machine (75 or 100 kV). Each lesion was irradiated with a 3–5 mm margin of surrounding normal skin to a depth of 1 cm. No more than five lesions were treated for each patient at each visit. 2.4. Response The response and cosmetic effect of radiotherapy was assessed 6 weeks after treatment and at 2-monthly intervals thereafter where possible. All responses were recorded from the time that they were first assessed but had to be maintained for 6 weeks before being confirmed. The responses to radiotherapy were classified according to Table 1. Partial response was not considered to be a particularly meaningful term as relapse was inevitable but difficult to judge. The response rate in this study was taken to be the sum of the complete and pigmented complete responses. 2.5. Pigmentation A means of grading pigmentation was developed to Table 1 Four-point grading system for assessing response Complete response Pigmented complete response
2.2. Study protocol Partial response
Patients were asked if they wished to be entered into a prospective clinical study involving randomization between two fractionation regimes for Kaposi’s sarcoma. The lesions in patients who agreed to enter the randomized study were randomized to receive either 8 Gy in a single fraction or 16 Gy in four fractions over 4–7 days. In treating each lesion individually each patient served as his own control. If patients required further treatments they were given the option of staying in the randomized study or choosing either
No change
Complete flattening of the KS lesion with normal skin colour Complete flattening of a previously raised KS lesion to a flat pigmented macule Any lesion that has flattened by at least 50% with no increase in size following radiotherapy but on palpation has some residual elevation, nodularity or thickening A lesion that has not flattened by 50% following radiotherapy and/or in which there has been either an increase in the size or the development of satellite lesions around the irradiated site
25
M. Harrison et al. / Radiotherapy and Oncology 46 (1998) 23–28
assess whether these high dose-per fraction regimens were accompanied by increased pigmentation in the irradiated adjacent skin. The pigmentation result, judged according to the presence of the radiation stigmata in the irradiated ‘halo’ of skin immediately surrounding the lesion, and not on the overall response of the lesion, was graded as in Table 2. 2.6. Statistical analysis x2 tests were used to compare the difference in response and cosmesis rates. Actuarial local control was calculated according to the method of Kaplan and Meier. P-values of less than 0.05 were regarded as significant.
3. Results 3.1. Overall results Fifty-seven patients with a total of 596 lesions received treatment with a mean follow-up time of 19 weeks. Five hundred ninety lesions were graded according to response and 573 lesions for cosmetic effect. The overall response rate, demonstrated in Table 3 (CR and pigmented CR), for both fractionation regimes was 78.8% (465/590). Cosmetic grade was assessed in 573 lesions and of these 91.3% were of grade 0 or 1 (523/573) (Table 4). One hundred ninety-eight lesions received treatment with 16 Gy in four fractions with an overall response rate of 80.8% (160/198). The remainder were treated with 8 Gy with a response rate of 77.8% (305/392). Statistical analysis using x2 tests showed no difference between the two response rates with P . 0.25. Time to response was usually less than 6 weeks and always less than 3 months. Long term follow-up in this group of patients was frequently impossible making accurate data of recurrence difficult to assess. A total of 109 lesions in 24 of the 57 patients recurred with a median duration of response of 27 weeks (range 10–87 weeks). Pigmentation analysis on the 189 lesions treated with the Table 2
(1) Slight skin pigmentation
(2) Marked skin pigmentation
(3) Severe skin pigmentation or telangiectasia
Overall response (%) for both fractionation regimensa
Complete response Pigmented complete response Partial response No response
Overall
16 Gy/four fractions
8 Gy/one fraction
52 (306/590) 27 (159/590)
49 (97/198) 32 (63/198)
53 (209/392) 25 (96/392)
14 (81/590) 7 (44/590)
15 (29/198) 4 (9/198)
13 (52/392) 9 (35/392)
a
Five hundred ninety-six lesions were irradiated and 590 were evaluated for response according to the response assessment scale.
four fraction regimen and 384 lesions treated with a single fraction showed that for the four fraction regimen an acceptable pigmentation result (grade 0 or 1) was seen in 87.2% (165/189) of lesions treated and for the single fraction regimen in 93.2% (358/384) of lesions treated. Statistical assessment shows that there is a significant difference between the two pigmentation sequelae with P , 0.025 and P . 0.001. This implies a significant advantage for the single fraction regimen. 3.2. Non-randomized lesions Forty-nine patients were treated and 424 lesions received irradiation in non-randomized treatments. Single fraction treatments were given to 318 lesions and four fraction treatments were given to 106 lesions. Response was evaluable in 419 lesions and cosmesis in 407. There was an overall response rate of 79.5% (333/419). Patients receiving 8 Gy had a response rate of 79.2% (248/313) and those receiving 16 Gy had a response rate of 80.2% (85/106). There is no significant difference between these two response rates (P . 0.5). Cosmesis of an acceptable quality (0 or 1) was found in 94.5% (290/306) of lesions treated with a single fraction and 85.1% (86/101) of lesions treated with four fractions. Statistical analysis shows a significant difference between the two groups (P . 0.001) with an advantage to the single fraction regimen. 3.3. Randomized lesions
Four-point grading system for assessing normal skin pigmentation following irradiation (0) No evidence of pigmentation
Table 3
Normal skin as judged by an experienced observer This reaction may be accepted as a skin blemish or normal but would be recognized as a radiation induced stigmata by an experienced observer This reaction would be considered abnormal by radiotherapists and would attract the attention of untrained observers An abnormally severe skin reaction leading to cosmetic disfigurement
One hundred seventy-two lesions in 27 patients received irradiation as part of the prospective randomized study. All Table 4 Overall normal skin pigmentation result (%) in 573 evaluable lesions for both fractionation regimens Grade
Overall
16 Gy/four fractions
8 Gy/one fraction
0 1 2 3
54 (312/573) 37 (211/573) 9 (49/566) 0
57 30 12 1
53 (205/384) 40 (153/384) 7 (26/384)
(107/189) (58/189) (23/189) (1/189)
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M. Harrison et al. / Radiotherapy and Oncology 46 (1998) 23–28
Table 5
Table 7
Response assessment (%) in 172 lesions treated in randomized fashion (response was assessable in all lesions)
Response (%) according to site
Complete response Pigmented complete response Partial response No change
Overall
8 Gy
16 Gy
50 (86/172) 27 (46/172)
47 (38/80) 24 (19/80)
52 (48/92) 29 (27/92)
13 (23/172) 10 (17/172)
15 (12/80) 14 (11/80)
12 (11/92) 7 (6/92)
lesions were assessable for response and 166 lesions were assessable for cosmesis. Ninety-two lesions were treated with 16 Gy in four fractions and 80 lesions were treated with 8 Gy as a single fraction. A response rate of 71.3% (57/80) was seen for the 8 Gy treatment and 81.5% (75/92) for the 16 Gy treatment. There is no statistical difference between the two regimens in terms of response (0.25 . P . 0.1). Cosmesis grades 0 or 1 was found in 87.1% (67/77) of patients treated with a single fraction and 89.9% (80/89) of patients treated with four fractions. No statistical difference can be seen between the two treatment regimens (P . 0.5) (Tables 5 and 6). 3.4. Site variation There appeared to be considerable variation in both response and normal skin pigmentation according to the area of the body treated. Higher rates of response may be seen for lesions affecting the face, hands, neck and feet with a response of 86–96% compared to the chest, abdomen and back with complete responses of 57–66% (Table 7). Normal skin pigmentation also varied according to site with a higher number of grade 0 for facial lesions (88%) than any other subsites such as the arm, back and chest where only 35– 39% of skin reactions were graded 0 (Table 8).
4. Discussion Kaposi’s sarcoma is the most common of the AIDSrelated malignancies affecting between 15–20% of patients with AIDS. For many patients KS will prove a local problem and a cosmetic nuisance. A smaller subgroup with more extensive cutaneous or visceral disease will require systemic therapy. Effective treatment strategies for both
Site
Complete response
Pigmented complete response
Partial response
No change
Arm Back Chest Face Feet Hands Legs Neck Abdomen
56 41 61 81 65 100 49 65 50
19 27 7 15 23 0 27 26 8
10 18 21 2 12 0 16 9 15
15 14 11 2 0 0 8 0 27
(54/96) (20/49) (35/57) (54/66) (11/17) (5/5) (53/109) (15/23) (13/26)
Overall
8 Gy
16 Gy
0 1 2 3
54 (89/166) 35 (58/166) 11 (18/166) 0
48 (37/77) 39 (30/77) 13 (10/77) 0
59 31 9 1
(52/89) (28/89) (8/89) (1/89)
(18/109) (2/23) (4/26)
(14/96) (7/49) (6/57) (1/66)
(9/109) (7/26)
Table 8 Normal skin pigmentation (%) according to site 0
Grade
(29/109) (6/23) (2/26)
(10/96) (9/49) (12/57) (1/66) (2/17)
local and advanced disease are necessary for maintaining a good quality of life [1,7,12,16]. Local disease may be controlled with radiotherapy using orthovoltage, megavoltage or electrons. Response rates are high and the duration of response is related to the dose administered [15]. Local treatment alternatives to radiotherapy have overall response rates of between 60 and 80%. Cryosurgery or photodynamic therapy seem better suited to smaller lesions with poorer response and cosmesis rates in larger, more nodular lesions [6,8]. Intralesional chemotherapy, particularly with vinblastine, is associated with response rates of 88% but with marked local toxicity [5]. Newer developments include topically applied vitamin D analogues. There have been several prospective and retrospective studies of radiotherapy in the treatment of both classical and AIDS-related KS. Radiotherapy for local disease is effective, non-toxic and acceptable to the patient. The optimal treatment regime is 40 Gy in 20 fractions over 4 weeks which is associated with an 83% complete response rate and a response duration of 43 weeks [15]. However, patients with AIDS-related KS have a median life expectancy of between 11 and 12 months and have many other AIDSrelated medical problems. For these patients local treatment with extended overall time and fractionation may be inappropriate given the amount of time the patients will spend receiving treatment and their estimated overall survival time. A further complication is that often multiple lesions require treatment. These considerations have resulted in a
Table 6 Normal skin pigmentation assessment (%) in 172 lesions treated in randomized fashion (166 lesions were assessable)
(18/96) (13/49) (4/57) (10/66) (4/17)
Arm Back Chest Face Feet Hands Legs Neck Abdomen
45 42 40 85 76 100 51 65 59
1 (40/89) (20/48) (21/53) (56/66) (13/17) (5/5) (55/109) (13/20) (13/22)
46 42 51 15 24 0 32 20 36
2 (41/89) (20/48) (27/53) (10/66) (4/17) (35/109) (4/20) (8/22)
9 16 7 0 0 0 17 15 5
3 (8/89) (8/48) (4/53)
(19/109) (3/20) (1/22)
0 0 2 (1/53) 0 0 0 0 0 0
M. Harrison et al. / Radiotherapy and Oncology 46 (1998) 23–28
more pragmatic approach to the radiotherapy of AIDSrelated KS within our practice. Patients are offered two fractionation regimens, i.e. 16 Gy/four fractions/4 days or 8 Gy in a single fraction. These two fractionation regimens have been derived historically from the several regimens utilized at St. Mary’s Hospital since the start of the AIDS epidemic. Outcome is measured according to a modification of the World Health Organization criteria for cutaneous tumour response with the addition of another group, that of pigmented complete response. This is an important grouping based upon the observations of Cooper at al. [3]. The pigmentation is due to residual haemosiderin within the skin following tumour shrinkage and is comparable to a complete response in terms of response duration. There is an overall response rate (complete response and pigmented complete response) of 78.8% (465/590) which compares favourably with other studies of radiotherapy for AIDSrelated KS. Statistical comparison (x2) of both fractionation regimes shows no difference in response between the single (77.6%) and four fraction (80.8%) treatments. Response rates in the randomized and non-randomized groups are also equivalent which would be expected given the similarity of the patients throughout the cohort. Duration of response proved difficult to measure in all patients. This was due to a combination of intercurrent events such as severe infection, initiation of chemotherapy and patient non-attendance. For those patients in whom response duration was measured the median duration of response was 27 weeks. This is comparable with other published studies of radiotherapy for this disease. Since improving cosmesis is a major reason for the local treatment of AIDS-related KS, a scoring system for the normal surrounding skin radiation response was developed. Resolution of the lesion but with residual skin pigmentation due to radiation damage is of little benefit. Means of assessing this endpoint are important both in the treatment of AIDS-related KS with radiotherapy and also for other non-AIDS-related skin malignancies. The four-point scale developed is an easily followed protocol, particularly for those experienced in the assessment of normal tissue damage following radiotherapy. For those not experienced, the various grades of damage can be easily taught allowing follow-up in both the HIV and Oncology clinic. Variation in response according to anatomical site has been reported for basal cell carcinomas treated with radiotherapy though with a converse result to the one seen in our study [4]. The mediocre performance of radiotherapy, both in terms of response and cosmesis, for lesions affecting sites other than the face and particularly the abdomen has led us to consider that more highly fractionated regimens may be required for KS lesions on these sites. A possible explanation is that lesions affecting the abdomen, the lower limbs and upper limbs are not immediately obvious and do not present the cosmetic nuisance of lesions affecting the face. Treatment is consequently delayed until the lesion is much more mature than would be the case for a facial lesion and
27
the response to treatment is less satisfactory. This does not explain the difference in cosmetic results between the different sites following radiotherapy. These results may be attributable to variations in skin thickness. A single fraction of 8 Gy produces a response with adequate cosmesis comparable with that obtained with a fractionated regimen. Since in AIDS-related KS all treatment is palliative this would appear to be the correct method for treating patients in a HIV oncology clinic. Variations in response and cosmesis are seen but may be minimized by the early treatment of lesions and, possibly, by increasing the total dose and fractions for certain mature lesions. Recent advances in antiretroviral therapy have considerably increased the life expectancy of patients with HIV and AIDS. Information on the development of KS within this new group of treated patients is limited but our early impression is of a decreased amount of KS consistent with improvements in immune function. Future radiotherapy for KS may well be for single isolated lesions in patients with a much longer life expectancy. More extended fractionation regimens will then come to the fore but will require prospective testing.
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woda, W.R. Radiation therapy in endemic (African) Kaposi’s sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 27: 1181–1184, 1993. [14] Stein, M.E., Lakier, R., Spencer, D., Dale, J., Kuten, A., Macphail, P. and Bezwoda, W.R. Radiation therapy for non AIDS associated (classic and endemic African) and epidemic Kaposi’s sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 28: 613–619, 1994.
[15] Stelzer, K.J. and Griffin, T.W. A randomized prospective trial of radiation therapy for AIDS associated Kaposi’s sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 27: 1057–1061, 1993. [16] Volm, M.D. and Von Roehn, J.H. Treatment strategies for epidemic Kaposi’s sarcoma. Curr. Opin. Oncol. 7: 429–436, 1995.