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Thalassemic osteoarthropathy treated by radiotherapy
Radiotherapy and Oncology, 24 (1992) 120-128 © 1992 Elsevier Science Publishers B.V. All rights reserved. 0167-8140/92/$05.00
120 R A D I O N 00997
Letters to the Editors THALASSEMIC OSTEOARTHROPATHY T R E A T E D BY R A D I O T H E R A P Y To the Editors, Patients with thalassemia are prone to develop - besides the transfusional arthritis, gout and septic arthritis often encountered in the various hemoglobinopathies - a nonerosive seronegative osteoarthropathy of varying severity characterized by soft tissue swelling and pain. It is usually, but not always, localized in the ankle joints. As specific therapy does not exist, we report a case treated successfully by a single dose of radiotherapy. D. M. is a 64-year-old Greek man with a long history of intermediate a-thalassemia who has been periodically transfused. Recently he was complaining of intractable pain of both ankles. This pain was worse after exercise. Physical examination relevant to the present illness revealed a slight edema of both ankles. A radiograph of the ankle revealed osteoporosis, coarse trabeculation, thinning of the cortex and some osteosclerosis. In addition, M R I revealed microfractures. The bone marrow on M R I was also hypointensive due to reconversion of the fatty marrow to red marrow (Fig. 1). A scanning of the marrow revealed considerable increased diffuse radioactivity (Fig. 2a). Tests for various arthritides were negative. His peripheral blood was as follow: R B C = 3 . 6 × 1 0 6 / p l , H b = 8 . 2 g / d l , H C t = 2 8 . 5 ~ o , P L T = 402 x 109/#1, W B C = 6.2 × 109 ,ttl, P = 61 ~o, M = 3 ~o, H = 4~o,
(Fig. 2b), we decided 2 weeks later to irradiate the left ankle. The patient now, 4 months after completion of radiotherapy, is asymptomatic. This type of arthritis has been reported by Gratwick et al. [3] in patients with thalassemia, major and intermediate, but also in patients with the trait [2]. Patients present swelling of the joints, and pain or stiffness of varying degree. Sometimes the symptoms are so severe that the subjects become disabled and confined to wheelchairs.
j
j
c=32%. We decided to have him treated by irradiation. Six Gy were given by two lateral fields covering the lower tibia and ankle region on the right. Since there was a gradual decrease of the pain and a repeat scan revealed considerable decrease of the radioactivity of the treated leg
ia
b Fig. 1. SagittalMRI(SE2000/25) ofthetibiotalarjoint. Multiple microfractures in the subchondral area of the tibia are clearly seen. The bone marrow appears hypointensive due to reconversion of the fatty marrow to red marrow.
Fig. 2. Bone marrow scan of the tibiae (a) before and (b) after irradiation. An homogenous tracer (99mTc) uptake along both tibiae is seen in the initial scan (a). A pronounced decreased uptake appears along the right tibia, particularly in its distal third (irradiated field), 14 days after radiotherapy.
121 It is believed that this type of osteoarthropathy is due to the underlying bone disease. Indeed, these patients present osteomalacia, thin bone cortices, coarse trabeculation and microfractures adjacent to the weight-bearing joints [ 1 ]. Although for the development of these changes parathormone regulation and vitamin D function may play a role, the most important contributing factor is the bone marrow proliferation and expansion which is due to the ineffective hemopoiesis and increased red cell senencence observed in thalassemia. Increase of the pain after exercise suggests that stress on these weight-bearing joints is also a contributing factor. There is no specific therapy for this condition. Indomethacin is not indicated as it is believed that this substance may delay the healing of microfractures. The reason for employing radiotherapy is 2-fold. First, it is thought that radiotherapy, by inhibiting the bone marrow expansion and proliferation, may result in the improvement of coarse trabeculation,
widened marrow spaces and cortical thinning of the underlying bone, changes which as it has already been mentioned are the causative factors of this arthritis. The changes of bone marrow scan after radiotherapy (Fig. 2b) prove that the dose of radiotherapy was effective in suppressing the marrow. Second, radiotherapy has been used traditionally for the treatment of various arthritides as a non-specific agent. Sincerely, C. Papavasiliou, G. Plataniotis, G. Limouris, A. Kalovidouris, A. Gouliamos and L. Vlahos (Received 22 October 1991, revision received
16 December 1991, accepted 19 February 1992) Department of Radiology, 76, Vas. Sophias Ave. Areteion Hospital GRI15 28 Athens, Greece
References
l Choremis, C., Liakakos, D., Thessi, C. and Moskovakis, G. Pathogenesis of osseous lesions in thalassemia. J. Pediatr. 66: 962-963, 1965. 2 Dowart, B. B. and Schumaker, H.R. Arthritis in 6 thalassemia trait. Clinical radiological features. Ann. Rheum. Dis. 40: 185-189, 1981.
3 Gratwick, G.M., Bullough, P. G., Bohne, W. H., Markenson, A. L. and Paterson, C.M. Thalassemic osteoarthropathy. Ann. Intern. Med. 88: 494-501, 1978.
R A D I O N 01011
C A R B O G E N A N D N I C O T I N A M I D E : E X P E C T A T I O N S TOO H I G H ? (response to J. Martin Brown) 240
~
To the Editors,
This issue of Radiotherapy Oncology contains a Commentary by J. Martin Brown on the use of carbogen and nicotinamide as radiosensitizers of human tumours, in which Brown expresses his reservations about the expected clinical benefit of combining these two treatments [1]. I will state at the onset that I am somewhat in agreement with him, although not necessarily for the same reasons. His cautiousness regarding the success of nicotinamide is 2-fold. Firstly, he argues that the doses ofnicotinamide that can be administered clinically may be too low for radiosensitization. Figure 1 shows peak plasma levels of nicotinamide measured either in humans after oral ingestion of escalating doses up to 6 g or in mice following single intraperitoneal injection of different doses. For both sets of data these peak levels were achieved within 30 min after drug administration. The peak plasma level in humans after a drug dose of 6 g ranged from 120 to 190/~g/ml, which is the plasma level seen in mice after administration of between 100 and 200 mg/kg. Such doses will enhance radiation damage in murine turnours, with enhancement ratios of between 1.1 and 1.3 observed in both a C3H/Tifmammary carcinoma (Horsman, unpublished data) and an EMT6 sarcoma [5]. In both of these murine tumours larger enhancements can be obtained with higher nicotinamide doses. Clinically, greater enhancements should also be possible since the values of 1.1-1.3 are based on the plasma levels measured after ingestion of only 6 g in humans, and as Brown points out, doses of almost twice that
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300 NICOTINAMIDE
600
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Fig. 1. Peak nicotinamide concentrations measured by high-performance liquid chromatography analysis of human or mouse plasma samples. Human volunteers received escalating oral doses of 1(O), 3 (A), or 6 g ( I ) nicotinamide in capsule form, and CDF 1 mice were given a single intraperitoneal injection of between 100 and 800 mg/kg nicotinamide dissolved in saline (©). Lines were fitted by linear-regression analysis (Horsman, unpublished observations).
120 R A D I O N 00997
Letters to the Editors THALASSEMIC OSTEOARTHROPATHY T R E A T E D BY R A D I O T H E R A P Y To the Editors, Patients with thalassemia are prone to develop - besides the transfusional arthritis, gout and septic arthritis often encountered in the various hemoglobinopathies - a nonerosive seronegative osteoarthropathy of varying severity characterized by soft tissue swelling and pain. It is usually, but not always, localized in the ankle joints. As specific therapy does not exist, we report a case treated successfully by a single dose of radiotherapy. D. M. is a 64-year-old Greek man with a long history of intermediate a-thalassemia who has been periodically transfused. Recently he was complaining of intractable pain of both ankles. This pain was worse after exercise. Physical examination relevant to the present illness revealed a slight edema of both ankles. A radiograph of the ankle revealed osteoporosis, coarse trabeculation, thinning of the cortex and some osteosclerosis. In addition, M R I revealed microfractures. The bone marrow on M R I was also hypointensive due to reconversion of the fatty marrow to red marrow (Fig. 1). A scanning of the marrow revealed considerable increased diffuse radioactivity (Fig. 2a). Tests for various arthritides were negative. His peripheral blood was as follow: R B C = 3 . 6 × 1 0 6 / p l , H b = 8 . 2 g / d l , H C t = 2 8 . 5 ~ o , P L T = 402 x 109/#1, W B C = 6.2 × 109 ,ttl, P = 61 ~o, M = 3 ~o, H = 4~o,
(Fig. 2b), we decided 2 weeks later to irradiate the left ankle. The patient now, 4 months after completion of radiotherapy, is asymptomatic. This type of arthritis has been reported by Gratwick et al. [3] in patients with thalassemia, major and intermediate, but also in patients with the trait [2]. Patients present swelling of the joints, and pain or stiffness of varying degree. Sometimes the symptoms are so severe that the subjects become disabled and confined to wheelchairs.
j
j
c=32%. We decided to have him treated by irradiation. Six Gy were given by two lateral fields covering the lower tibia and ankle region on the right. Since there was a gradual decrease of the pain and a repeat scan revealed considerable decrease of the radioactivity of the treated leg
ia
b Fig. 1. SagittalMRI(SE2000/25) ofthetibiotalarjoint. Multiple microfractures in the subchondral area of the tibia are clearly seen. The bone marrow appears hypointensive due to reconversion of the fatty marrow to red marrow.
Fig. 2. Bone marrow scan of the tibiae (a) before and (b) after irradiation. An homogenous tracer (99mTc) uptake along both tibiae is seen in the initial scan (a). A pronounced decreased uptake appears along the right tibia, particularly in its distal third (irradiated field), 14 days after radiotherapy.
121 It is believed that this type of osteoarthropathy is due to the underlying bone disease. Indeed, these patients present osteomalacia, thin bone cortices, coarse trabeculation and microfractures adjacent to the weight-bearing joints [ 1 ]. Although for the development of these changes parathormone regulation and vitamin D function may play a role, the most important contributing factor is the bone marrow proliferation and expansion which is due to the ineffective hemopoiesis and increased red cell senencence observed in thalassemia. Increase of the pain after exercise suggests that stress on these weight-bearing joints is also a contributing factor. There is no specific therapy for this condition. Indomethacin is not indicated as it is believed that this substance may delay the healing of microfractures. The reason for employing radiotherapy is 2-fold. First, it is thought that radiotherapy, by inhibiting the bone marrow expansion and proliferation, may result in the improvement of coarse trabeculation,
widened marrow spaces and cortical thinning of the underlying bone, changes which as it has already been mentioned are the causative factors of this arthritis. The changes of bone marrow scan after radiotherapy (Fig. 2b) prove that the dose of radiotherapy was effective in suppressing the marrow. Second, radiotherapy has been used traditionally for the treatment of various arthritides as a non-specific agent. Sincerely, C. Papavasiliou, G. Plataniotis, G. Limouris, A. Kalovidouris, A. Gouliamos and L. Vlahos (Received 22 October 1991, revision received
16 December 1991, accepted 19 February 1992) Department of Radiology, 76, Vas. Sophias Ave. Areteion Hospital GRI15 28 Athens, Greece
References
l Choremis, C., Liakakos, D., Thessi, C. and Moskovakis, G. Pathogenesis of osseous lesions in thalassemia. J. Pediatr. 66: 962-963, 1965. 2 Dowart, B. B. and Schumaker, H.R. Arthritis in 6 thalassemia trait. Clinical radiological features. Ann. Rheum. Dis. 40: 185-189, 1981.
3 Gratwick, G.M., Bullough, P. G., Bohne, W. H., Markenson, A. L. and Paterson, C.M. Thalassemic osteoarthropathy. Ann. Intern. Med. 88: 494-501, 1978.
R A D I O N 01011
C A R B O G E N A N D N I C O T I N A M I D E : E X P E C T A T I O N S TOO H I G H ? (response to J. Martin Brown) 240
~
To the Editors,
This issue of Radiotherapy Oncology contains a Commentary by J. Martin Brown on the use of carbogen and nicotinamide as radiosensitizers of human tumours, in which Brown expresses his reservations about the expected clinical benefit of combining these two treatments [1]. I will state at the onset that I am somewhat in agreement with him, although not necessarily for the same reasons. His cautiousness regarding the success of nicotinamide is 2-fold. Firstly, he argues that the doses ofnicotinamide that can be administered clinically may be too low for radiosensitization. Figure 1 shows peak plasma levels of nicotinamide measured either in humans after oral ingestion of escalating doses up to 6 g or in mice following single intraperitoneal injection of different doses. For both sets of data these peak levels were achieved within 30 min after drug administration. The peak plasma level in humans after a drug dose of 6 g ranged from 120 to 190/~g/ml, which is the plasma level seen in mice after administration of between 100 and 200 mg/kg. Such doses will enhance radiation damage in murine turnours, with enhancement ratios of between 1.1 and 1.3 observed in both a C3H/Tifmammary carcinoma (Horsman, unpublished data) and an EMT6 sarcoma [5]. In both of these murine tumours larger enhancements can be obtained with higher nicotinamide doses. Clinically, greater enhancements should also be possible since the values of 1.1-1.3 are based on the plasma levels measured after ingestion of only 6 g in humans, and as Brown points out, doses of almost twice that
,
-,
,
s
~
Humons
~ •
i II
.! z
O0 0
1200
30 ~
<
,
i
60 ,
,
,
90 ~
/
",
1
....
Mice
40O
0
0
300 NICOTINAMIDE
600
900
DOSE ( m g l k g )
Fig. 1. Peak nicotinamide concentrations measured by high-performance liquid chromatography analysis of human or mouse plasma samples. Human volunteers received escalating oral doses of 1(O), 3 (A), or 6 g ( I ) nicotinamide in capsule form, and CDF 1 mice were given a single intraperitoneal injection of between 100 and 800 mg/kg nicotinamide dissolved in saline (©). Lines were fitted by linear-regression analysis (Horsman, unpublished observations).