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Subclavian and axillary vein thrombosis following radiotherapy for carcinoma of the breast
Clinical Radiology (1987) 38,
95-96
Subclavian and Axillary Vein Thrombosis Following Radiotherapy for Carcinoma of the Breast C. B. WILSON, H. E. L A M B E R T and R. D. SCOTT*
Department of Radiotherapy and Oncology, Hammersrnith Hospital, London, and *King Edward Hospital, Windsor
Two cases are presented of subclavian and axillary vein thrombosis in patients with carcinoma of the breast treated by radiotherapy and at least 2 years of therapy with tamoxifen. We suggest that radiation fibrosis may have been the major aetiological factor but that the treatment with tamoxifen might also have contributed to the venous thromboses.
Two cases of axillary and subclavian artery thrombosis secondary to radiation damage have previously been described (Mayor et al., 1973). Although upper limb venous thrombosis is well documented following the combination of mastectomy and radiotherapy (Veal and Hussey, 1943; Coon and Willis, 1967), we are not aware of any reports attributing venous thrombosis to radiotherapy without previous major surgery. Upper limb venous thrombosis secondary to neoplasia is well recognised. It has been reported following direct operative injury in radical mastectomy; it can also result from tumour or nodal compression, or as a manifestation of a migrating thrombophlebitis. Aetiological factors not directly associated with malignancy include strenuous exercise (Paget-Schroetter syndrome), congestive heart failure, central venous cannulisation and clotting diatheses. We report two cases of carcinoma of the breast initially treated by radiotherapy who developed subclavian and axillary vein thrombosis. Neither patient had a history of thr0mbophlebitis, and neither patient smoked. The only other possible relevant factor was that both women were being treated with tamoxifen.
CASE REPORTS Case 1. E . C . , a w o m a n aged 67, presented in June 1981 with a T3 NO MO poorly differentiated ulcerating carcinoma in the upper medial quadrant of her right breast. She was started on tamoxifen 40 mg daily and was treated with 60Co external beam therapy, receiving 50 Gy in 20 fractions over 4 weeks to the right breast using opposed tangential fields. The supraclavicular fossa received 50 Gy peak dose in 20 fractions via an anterior field, and a posterior field was applied to bring the mid axillary dose up to 45 Gy in 20 fractions. A further 10 Gy in five fractions using 12 M e V electrons was given to the tumour scar. Two years after treatment some induration was noted in the region of the right supraclavicular fossa, resulting in limitation of shoulder m o v e m e n t and slight swelling of right upper arm. In January 1985 the arm became more swollen and by April 1985 she had noticed pain on exercising it. Examination revealed marked telangectasia with induration of the supra- and infraclavicular fossae. Her right arm was grossly swollen and was dusky blue in colour. Superficial venules were present over the upper arm (Fig. l). There was no clinical evidence of local recurrence or metastatic spread of her carcinoma. Full blood count (including platelet count) biochemical profile and a chest radiograph were all normal. A right sided venogram confirmed that the subclavian
vein was completely obstructed by thrombus; thrombus was also present in the basilic vein and several collaterals had formed. She was treated initially with intravenous heparin and subsequently maintained on warfarin. Her arm slowly improved and by six weeks had returned to an appearance similar to that seen in January. Her tamoxifen therapy was stopped. Case 2. M.B., a w o m a n aged 65, presented in 1978 with a T1 NO poorly differentiated duct carcinoma of the right breast which was treated by local excision only. in October 1982, she developed a 2 cm recurrence deep to the medial end of the scar. There was 11o palpable lymphadenopathy. The recurrence was excised and proved to be a poorly differentiated duct carcinoma without skin involvement. She was treated with a similar course of radiotherapy to that described in Case 1. She also started on tamoxifen 40 mg daily. Two years later fibrosis of her right anterior axilla and restricted m o v e m e n t s of her right shoulder were noted. Her chest radiograph showed healed fractures of several ribs on the right, changes consistent with previous radiotherapy. In April 1985 she presented with a 3 day history of acute painful swelling of the right arm. This was swollen and dusky blue in colour. She had prominent veins over the dorsum of her right hand. There was no clinical evidence of t u m o u r recurrence or spread. Blood indices and biochemical profile were all within normal limits. A venogram of the right arm failed to demonstrate the axillary or subclavian vein. Small collaterals were visible and it was a s s u m e d that the large vessels were completely occluded by t h r o m b u s (Fig. 2). She was treated with intravenous hcparin and then warfarin. The pain and swelling improved over the following week, although a hard, palpable axillary vein was still present. Tamoxifen was discontinued.
DISCUSSION Venous thrombosis can be caused by stasis, injury and coagulation abnormalities. Both our patients presented with fibrosis secondary to radiation. It is probable that this could have caused distortion of the venous anatomy producing stasis. Veins, as opposed to arteries, have a low intrinsic wall pressure and intraluminal pressure and are therefore more vulnerable to extrinsic compression. Extensive fibrosis occurring in the axilla or infraclavicular area may be sufficient to cause a compression analogous to that found in the 'thoracic outlet syndrome'. The radiation dose in the gap between the tangential and supraclavicular fields is not always h o m o genous. Local high dose effects, manifested clinically as fibrosis, may occur. The rarity of reports of upper limb venous thrombosis following radiotherapy alone suggests that such thromboses are uncommon. Many patients develop clinically detectable fibrosis following such treatment. It may be that the radiation fibrosis is, of itself, insufficient to produce thrombosis. Other mechanisms may be involved. Experimental studies have shown that radiation can produce sclerosis of the vasa vasorum, proliferation of medial and subendothelial elements leading to narrowing of the lumen (Rubin and Casarett, 1968). The effects of radiation on endothelial function are not well known and there is controversy as to whether direct endothelial
96
CLINICAL RADIOLOGY
Fig..2- Right upper limb venogram. There is no fillingof the axillaryor subclavian vein; small collaterals are visible.
a n d axillary v e i n t h r o m b o s i s but t a m o x i f e n might well have played a role. P r o m p t r e c o g n i t i o n a n d t r e a t m e n t of this c o m p l i c a t i o n is r e w a r d e d by rapid clinical response.
REFERENCES
Fig. 1 The radiotherapy induced changes in the right breast are shown. There is oedema of the right arm with visible superficial venules.
d a m a g e is a necessary c o m p o n e n t of v e n o u s t h r o m b o genesis ( T h o m a s et al., 1985). N e i t h e r of o u r p a t i e n t s had t h r o m b o p h l e b i t i s m i g r a n s n o r a n y other m a n i f e s t a t i o n of a h y p e r c o a g u l a b l e state. N e i t h e r p a t i e n t had active b r e a s t c a n c e r at the time the t h r o m b o s e s occurred. Both p a t i e n t s had h o w e v e r b e e n o n t a m o x i f e n , a drug which has b e e n suspected of producing t h r o m b o e m b o l i c c o m p l i c a t i o n s ( N e v a s a a r i et al., 1978; H e n d r i c k a n d S u b r a m a n i a n , 1980; J a c q u o t et al., 1981 ; L i p t o n et al., 1984; D a h a n et al., 1985), b u t most of these c o m p l i c a t i o n s occurred in older w o m e n with w i d e s p r e a d m e t a s t a t i c disease. T a m o x i f e n m a y cause a fall in a n t i - t h r o m b i n III activity ( E n c k and Rios, 1984). U n f o r t u n a t e l y a n t i - t h r o m b i n 11I activity was n o t m e a s u r e d in o u r patients. It is likely that r a d i o t h e r a p y i n d u c e d fibrosis was the m a j o r aetiological factor in these two cases of subclavian
Coon, WW & Willis, PW (1967). Thrombosis of axillary and subclavian veins. American Heart Journal, 25,355. Dahan, R, Espie, M, Mignot, L, Houlbert, D & Chanu, B (1985). Tamoxifen and arterial thrombosis. Lancet, i, 638. Enck, RE & Rios, CN (1984). Tamoxifen treatment of metastatic breast cancer and antithrombin III level. Cancer, 53, 2607-2609. Hendrick, A & Subramanian, VP (1980). Tamoxifen and thromboembolism. Journal of the American Medical Association, 243, 514515. Jacquot, C, Graterol, R, Bariety, J, Capron, L & Fiessinger, JN (1981). DES versus tamoxifen in advanced breast cancer. New England Journal of Medicine, 304, 1042. Lipton, A, Harvey, HA & Hamilton, RN (1984). Venous thrombosis as a side effect of tamoxifen treatment. Cancer Treatment Reports, 68, 887-889. Mayor, GE, Kasenally, AT, Harper, DR & Woodruff, PH (1973). Thrombosis of the subclavian-axillary artery following radiotherapy for carcinoma of the breast. British Journal of Surgery, 60, 983. Nevasaari, K, Heikkinen, M & Taskinen, P (1978). Tamoxifen and thrombosis. Lancet, ii, 946-947. Rubin, P & Casarett, GW (1968). ClinicalRadiation Pathology, Vol I, pp. 512-514. W. B. Saunders, Philadelphia. Thomas, DP, Merton, RE, Wood, RD & Hockley, DJ (1985). British Journal of HaemotoIogy, 59, 449. Veal, JR & Hussey, HH (1943). Thrombosis of the subclavian and axillary veins. American Heart Journal, 25, 355.
95-96
Subclavian and Axillary Vein Thrombosis Following Radiotherapy for Carcinoma of the Breast C. B. WILSON, H. E. L A M B E R T and R. D. SCOTT*
Department of Radiotherapy and Oncology, Hammersrnith Hospital, London, and *King Edward Hospital, Windsor
Two cases are presented of subclavian and axillary vein thrombosis in patients with carcinoma of the breast treated by radiotherapy and at least 2 years of therapy with tamoxifen. We suggest that radiation fibrosis may have been the major aetiological factor but that the treatment with tamoxifen might also have contributed to the venous thromboses.
Two cases of axillary and subclavian artery thrombosis secondary to radiation damage have previously been described (Mayor et al., 1973). Although upper limb venous thrombosis is well documented following the combination of mastectomy and radiotherapy (Veal and Hussey, 1943; Coon and Willis, 1967), we are not aware of any reports attributing venous thrombosis to radiotherapy without previous major surgery. Upper limb venous thrombosis secondary to neoplasia is well recognised. It has been reported following direct operative injury in radical mastectomy; it can also result from tumour or nodal compression, or as a manifestation of a migrating thrombophlebitis. Aetiological factors not directly associated with malignancy include strenuous exercise (Paget-Schroetter syndrome), congestive heart failure, central venous cannulisation and clotting diatheses. We report two cases of carcinoma of the breast initially treated by radiotherapy who developed subclavian and axillary vein thrombosis. Neither patient had a history of thr0mbophlebitis, and neither patient smoked. The only other possible relevant factor was that both women were being treated with tamoxifen.
CASE REPORTS Case 1. E . C . , a w o m a n aged 67, presented in June 1981 with a T3 NO MO poorly differentiated ulcerating carcinoma in the upper medial quadrant of her right breast. She was started on tamoxifen 40 mg daily and was treated with 60Co external beam therapy, receiving 50 Gy in 20 fractions over 4 weeks to the right breast using opposed tangential fields. The supraclavicular fossa received 50 Gy peak dose in 20 fractions via an anterior field, and a posterior field was applied to bring the mid axillary dose up to 45 Gy in 20 fractions. A further 10 Gy in five fractions using 12 M e V electrons was given to the tumour scar. Two years after treatment some induration was noted in the region of the right supraclavicular fossa, resulting in limitation of shoulder m o v e m e n t and slight swelling of right upper arm. In January 1985 the arm became more swollen and by April 1985 she had noticed pain on exercising it. Examination revealed marked telangectasia with induration of the supra- and infraclavicular fossae. Her right arm was grossly swollen and was dusky blue in colour. Superficial venules were present over the upper arm (Fig. l). There was no clinical evidence of local recurrence or metastatic spread of her carcinoma. Full blood count (including platelet count) biochemical profile and a chest radiograph were all normal. A right sided venogram confirmed that the subclavian
vein was completely obstructed by thrombus; thrombus was also present in the basilic vein and several collaterals had formed. She was treated initially with intravenous heparin and subsequently maintained on warfarin. Her arm slowly improved and by six weeks had returned to an appearance similar to that seen in January. Her tamoxifen therapy was stopped. Case 2. M.B., a w o m a n aged 65, presented in 1978 with a T1 NO poorly differentiated duct carcinoma of the right breast which was treated by local excision only. in October 1982, she developed a 2 cm recurrence deep to the medial end of the scar. There was 11o palpable lymphadenopathy. The recurrence was excised and proved to be a poorly differentiated duct carcinoma without skin involvement. She was treated with a similar course of radiotherapy to that described in Case 1. She also started on tamoxifen 40 mg daily. Two years later fibrosis of her right anterior axilla and restricted m o v e m e n t s of her right shoulder were noted. Her chest radiograph showed healed fractures of several ribs on the right, changes consistent with previous radiotherapy. In April 1985 she presented with a 3 day history of acute painful swelling of the right arm. This was swollen and dusky blue in colour. She had prominent veins over the dorsum of her right hand. There was no clinical evidence of t u m o u r recurrence or spread. Blood indices and biochemical profile were all within normal limits. A venogram of the right arm failed to demonstrate the axillary or subclavian vein. Small collaterals were visible and it was a s s u m e d that the large vessels were completely occluded by t h r o m b u s (Fig. 2). She was treated with intravenous hcparin and then warfarin. The pain and swelling improved over the following week, although a hard, palpable axillary vein was still present. Tamoxifen was discontinued.
DISCUSSION Venous thrombosis can be caused by stasis, injury and coagulation abnormalities. Both our patients presented with fibrosis secondary to radiation. It is probable that this could have caused distortion of the venous anatomy producing stasis. Veins, as opposed to arteries, have a low intrinsic wall pressure and intraluminal pressure and are therefore more vulnerable to extrinsic compression. Extensive fibrosis occurring in the axilla or infraclavicular area may be sufficient to cause a compression analogous to that found in the 'thoracic outlet syndrome'. The radiation dose in the gap between the tangential and supraclavicular fields is not always h o m o genous. Local high dose effects, manifested clinically as fibrosis, may occur. The rarity of reports of upper limb venous thrombosis following radiotherapy alone suggests that such thromboses are uncommon. Many patients develop clinically detectable fibrosis following such treatment. It may be that the radiation fibrosis is, of itself, insufficient to produce thrombosis. Other mechanisms may be involved. Experimental studies have shown that radiation can produce sclerosis of the vasa vasorum, proliferation of medial and subendothelial elements leading to narrowing of the lumen (Rubin and Casarett, 1968). The effects of radiation on endothelial function are not well known and there is controversy as to whether direct endothelial
96
CLINICAL RADIOLOGY
Fig..2- Right upper limb venogram. There is no fillingof the axillaryor subclavian vein; small collaterals are visible.
a n d axillary v e i n t h r o m b o s i s but t a m o x i f e n might well have played a role. P r o m p t r e c o g n i t i o n a n d t r e a t m e n t of this c o m p l i c a t i o n is r e w a r d e d by rapid clinical response.
REFERENCES
Fig. 1 The radiotherapy induced changes in the right breast are shown. There is oedema of the right arm with visible superficial venules.
d a m a g e is a necessary c o m p o n e n t of v e n o u s t h r o m b o genesis ( T h o m a s et al., 1985). N e i t h e r of o u r p a t i e n t s had t h r o m b o p h l e b i t i s m i g r a n s n o r a n y other m a n i f e s t a t i o n of a h y p e r c o a g u l a b l e state. N e i t h e r p a t i e n t had active b r e a s t c a n c e r at the time the t h r o m b o s e s occurred. Both p a t i e n t s had h o w e v e r b e e n o n t a m o x i f e n , a drug which has b e e n suspected of producing t h r o m b o e m b o l i c c o m p l i c a t i o n s ( N e v a s a a r i et al., 1978; H e n d r i c k a n d S u b r a m a n i a n , 1980; J a c q u o t et al., 1981 ; L i p t o n et al., 1984; D a h a n et al., 1985), b u t most of these c o m p l i c a t i o n s occurred in older w o m e n with w i d e s p r e a d m e t a s t a t i c disease. T a m o x i f e n m a y cause a fall in a n t i - t h r o m b i n III activity ( E n c k and Rios, 1984). U n f o r t u n a t e l y a n t i - t h r o m b i n 11I activity was n o t m e a s u r e d in o u r patients. It is likely that r a d i o t h e r a p y i n d u c e d fibrosis was the m a j o r aetiological factor in these two cases of subclavian
Coon, WW & Willis, PW (1967). Thrombosis of axillary and subclavian veins. American Heart Journal, 25,355. Dahan, R, Espie, M, Mignot, L, Houlbert, D & Chanu, B (1985). Tamoxifen and arterial thrombosis. Lancet, i, 638. Enck, RE & Rios, CN (1984). Tamoxifen treatment of metastatic breast cancer and antithrombin III level. Cancer, 53, 2607-2609. Hendrick, A & Subramanian, VP (1980). Tamoxifen and thromboembolism. Journal of the American Medical Association, 243, 514515. Jacquot, C, Graterol, R, Bariety, J, Capron, L & Fiessinger, JN (1981). DES versus tamoxifen in advanced breast cancer. New England Journal of Medicine, 304, 1042. Lipton, A, Harvey, HA & Hamilton, RN (1984). Venous thrombosis as a side effect of tamoxifen treatment. Cancer Treatment Reports, 68, 887-889. Mayor, GE, Kasenally, AT, Harper, DR & Woodruff, PH (1973). Thrombosis of the subclavian-axillary artery following radiotherapy for carcinoma of the breast. British Journal of Surgery, 60, 983. Nevasaari, K, Heikkinen, M & Taskinen, P (1978). Tamoxifen and thrombosis. Lancet, ii, 946-947. Rubin, P & Casarett, GW (1968). ClinicalRadiation Pathology, Vol I, pp. 512-514. W. B. Saunders, Philadelphia. Thomas, DP, Merton, RE, Wood, RD & Hockley, DJ (1985). British Journal of HaemotoIogy, 59, 449. Veal, JR & Hussey, HH (1943). Thrombosis of the subclavian and axillary veins. American Heart Journal, 25, 355.