1 2 3 4 5 4 5 4 6 7 8 10 11 12 14 Because little is known with respect to the late vascular morbidity of the combined procedure of ILP and EBRT, a retrospective study was conducted to evaluate the long-term locoregional vascular side effects of ILP, followed by delayed surgical resection and adjuvant high-dose EBRT. PATIENTS AND METHODS 15 16 In 2005, 39 patients were still alive and in follow-up. Information about their past and current oncological and vascular status was obtained from the follow-up notes in the medical records. Seven patients were unable to participate in the study because of severe or advanced morbidity or comorbidity (n = 2) or because of nonmedical reasons (n = 5). Consequently, 32 patients, 14 men (44%) and 18 women (56%), with a median age of 47 (range, 14–71) years, were included (response rate, 82%). They completed a vascular checklist that asked questions about their medical vascular history, and they were screened for risk factors of vascular disease, such as smoking, hypertension, and diabetes. A blood sample was drawn to determine the cholesterol spectrum, which was used as an indicator of risk for atherosclerosis. All patients underwent a noninvasive arterial and venous vascular work-up that comprised duplex ultrasonography and vascular pressure measurements. The ankle-brachial index (ABI) and pulsatility index (PI), which are indications of vascular blood flow velocity, were measured to indicate the arterial status of the limb. For evaluation of veins, ultrasonography was performed to detect DVT and insufficiency. All investigations were performed by the same examiner (J.L.). 17 18 1 TABLE 1. Characteristics of patients Age (y) Sex Disease Localization Histology Grade AJCC stage Level EBRT Amputation Follow-up (mo) 18 F Primary Upper leg Embryonal rhabdomyosarcoma 3 3 Iliac N N 159 44 F Recurrent Popliteal fossa Myxoid liposarcoma 1 1 Iliac Y N 152 43 M Primary Upper leg Synovial sarcoma 3 3 Iliac Y N 151 18 M Primary Lower leg Myxoid chondrosarcoma 2 3 Popliteal Y Y 149 48 F Primary Upper leg Well differentiated liposarcoma 1 1 Iliac Y N 143 56 F Primary Proximal tibia PNET 3 3 Iliac Y Y 137 50 F Recurrent Foot PUS 3 3 Popliteal N N 135 25 F Primary Popliteal fossa Synovial sarcoma 2 3 Popliteal Y N 132 44 M Primary Upper leg Myxoid liposarcoma 1 1 Iliac Y N 131 24 M Recurrent Lower leg Synovial sarcoma 2 3 Popliteal Y N 129 37 F Primary Elbow MPNST 2 3 Axillary Y N 121 48 M Primary Popliteal fossa Myxoid liposarcoma 2 3 Iliac Y N 111 63 F Recurrent Lower leg PUS 2 3 Popliteal N Y 107 37 M Primary Upper leg Myxoid liposarcoma 1 1 Iliac Y N 105 58 M Primary Upper leg PUS 2 3 Iliac Y N 98 71 F Primary Upper leg Leiomyosarcoma 1 1 Femoral N N 94 45 F Primary Upper leg PUS 3 3 Iliac N N 82 56 F Primary Lower leg PUS 3 3 Popliteal Y N 61 63 M Primary Popliteal fossa Myxoid chondrosarcoma  3 Femoral Y N 50 37 F Primary Knee Leiomyosarcoma 1 1 Femoral Y N 36 28 M Primary Popliteal fossa Synovial sarcoma 2 3 Femoral Y N 36 57 F Primary Upper leg PUS 3 3 Femoral Y N 35 42 F Primary Knee Synovial sarcoma 2 3 Iliac Y Y 32 47 F Primary Arm PUS 3 3 Axillary Y N 30 58 F Primary Lower leg PUS 3 3 Popliteal Y N 26 27 M Primary Arm Epithelioid sarcoma 3 4 Axillary Y N 26 71 M Recurrent Arm Myxoid fibrosarcoma 1 1 Axillary N N 24 56 F Primary Arm Extraosseal osteosarcoma 3 3 Axillary N N 22 14 M Primary Lower leg PUS 3 3 Popliteal Y N 20 65 F Primary Foot Synovial sarcoma 2 3 Popliteal N Y 18 63 M Primary Upper leg Synovial sarcoma 3 3 Iliac Y N 17 71 M Primary Upper leg Rhabdomyosarcoma 3 3 Iliac Y N 17 AJCC, American Joint Committee on Cancer; EBRT, external-beam radiotherapy; PNET, primitive neuroectodermal tumor; PUS, pleomorphic undifferentiated sarcoma; MPNST, malignant peripheral nerve sheath tumor. P RESULTS 2 TABLE 2. Risk factors for atherosclerosis Risk factor n % Dutch population (%) Hypertension 10 31 a,b Diabetes mellitus 4 13 b Smoking   b   Smokers 9 28    Former smokers 10 31  BMI   BMI >25.0 17 53 b   BMI >30.0 4 13 b Hypercholesterolemia (total cholesterol >6.5) 6 19 c Familiar cardiovascular disease 14 44 NA BMI, body mass index; NA, not available. a b http://www.cbs.nl/ c http://www.hartstichting.nl/ Two patients underwent vascular reconstruction after en-bloc tumor resection with the artery. One patient underwent a reconstruction of the femoral artery with an infragenual femoral-popliteal bypass, and the second patient underwent a popliteal artery reconstruction with an autologous vein graft. A DVT in the lower leg was diagnosed in the postoperative period in three patients (7.7%). Nine (23%) of the 39 alive patients underwent a lower limb amputation at different levels after ILP with or without EBRT. No amputations of the upper extremity were performed. In two patients with microscopically involved resection margins, an amputation of the affected limb was indicated because adjuvant radiotherapy was contraindicated. One patient underwent amputation due to tumor recurrence 18 months after ILP and EBRT. Amputation was performed for critical leg ischemia due to atherosclerosis in two patients at 110 and 125 months after ILP and EBRT. Because of severe obstruction of the crural vessels, reconstructive therapy was not suitable. 1 FIG. 1. Flow chart illustrating treatment, outcome, and reasons for amputation. EBRT, external-beam radiotherapy; AMP, amputation; NI, not included in this study.  Arterial Vascular Disease With a median follow-up of 88 (range, 17–159) months, no patient experienced peripheral arterial occlusive disease. With duplex ultrasonography, however, two patients showed a complete arterial occlusion at the level of cannulation (6%). One of them underwent an iliac perfusion and EBRT because of a STS of the lower leg in 1993. After 10 years, she had signs of critical leg ischemia, which required a transfemoral amputation. She is now free of pain and can walk with a well-functioning prothesis. The other patient showed an axillary occlusion 10 years after an axillary perfusion, followed by resection and EBRT at the forearm. She did not have any symptoms of arterial occlusive disease, and her arm functions normally. Duplex ultrasonography showed good collateral flow. Two other patients (6%) showed an arterial stenosis at cannulation level at 22 and 30 months after axillary perfusions, followed by EBRT at the upper arm and axilla in one and systemic chemotherapy in both patients. They had normal arm function without any signs of ischemia. The arteries at resection level were also evaluated. One patient with a fossa poplitea STS had complete occlusion of the superficial femoral artery 6 years after ILP and EBRT, with open arteries below knee level. A femoral-popliteal bypass was considered but was not performed because of the absence of any symptoms. At the time of evaluation, the ABI was .50; the patient did not have any complaints besides compression ulcers on his feet, which responded well to conservative therapy. The patient who needed an autologous vein graft of the popliteal artery has a stenosis at this level without clinical signs of arterial occlusive disease. Twenty-two of the total 32 patients included underwent ABI measurements; 22 had their PI determined at the femoral level and 20 at the popliteal level. Five patients were excluded because of amputation of the limb; another five were excluded because of a STS located in the upper limb. Of the remaining 22 patients, 18 received postoperative EBRT for the above-described indications. P P P 3 4 P P P 5 TABLE 3. Results of ankle-brachial index (ABI) and pulsatility index (PI) measurements in lower extremities of 22 patients Index Treated extremity, median (range) Contralateral extremity, median (range) P ABI 1.02 (.50–1.20) 1.090 (.91–1.36) .001 PI femoral 6.30 (2.1–23.9) 7.35 (4.8–21.9) .011 PI popliteal 8.35 (.0–21.4) 10.95 (8.0–32.6) <.0005 TABLE 4.  P values of differences between subgroups in decrease of ankle-brachial index (ABI) and pulsatility index (PI) for 22 patient s Characteristic Sex Follow-up after EBRT Age F M Yes No >5 y <5 y <50 y >50 y No. of patients 11 11 18 4 14 8 13 9 ABI .619 .241 .024 .963 – – – – PI femoral decrease .619 .907 .024 .963 – – – – PI popliteal decrease .269 .937 .221 .414 – – – – EBRT, external-beam radiotherapy. TABLE 5. Differences in decreases in measurements according to length of follow-up Decrease in perfused leg Follow-up, n (%) P >5 y (n = 14) <5 y (n = 8) ABI 13 (93%) 4 (50%) .024 PI femoral 13 (93%) 4 (50%) .024 PI popliteal a 7 (88%) .221 ABI, ankle-brachial index; PI, pulsatility index. a Venous Vascular Disease Many patients had some symptoms of venous insufficiency, such as lower limb pain, feelings of heaviness and discomfort, night palsies, paresthesia, and edema. One patient (3%) wore compression stockings because of superficial vena saphena magna insufficiency, and one patient (3%) had unilateral superficial varicosis in the treated leg. Another three patients (9%) showed uni- or bilateral deep insufficient venous vasculature by duplex ultrasonography, which in all cases was located at the level of resection. One DVT (3%) and one partial venous obstruction (3%) were found, both at the resection level. Venous vascular obstruction was not seen at the level of cannulation. DISCUSSION 4 5 7 19 20 11 19 20 2 10 9 21 21 23 12 24 13 22 16 25 4 26 27 Fortunately, these patients did not have invalidating symptoms of arterial occlusive disease. In most cases, vascular pressure measurements and duplex ultrasonographic evaluation showed statistically lower values compared with the contralateral extremity, but these were still within the normal range. This could explain the absence of symptoms. 28 It is important to realize that blood vessels lose their elasticity with the years and are subject to the normal process of atherosclerosis. Furthermore, unilateral peripheral arterial occlusive disease is common. However, the fact that lower rates of ABI and PI were found in the treated leg in almost all patients and that no marked difference was found between younger and older patients makes the assumption of treatment-induced differences plausible. 29 Major late vascular complications after the combined procedure, like critical leg ischemia necessitating amputation, were found in two patients in this study. One patient had no risk factors for peripheral arterial occlusive disease besides smoking. He had had intermittent claudication 8 years after ILP and EBRT, and a normal ABI of 1.09. His condition did not improve after 2 years of conservative therapy and reconstruction was impossible, so he underwent an amputation 125 months after the initial limb salvage treatment strategy. The second patient, who had diabetes mellitus and familial cardiovascular disease, experienced no complications the first few years after ILP and EBRT. After 6 years, she experienced a pathological proximal tibia fracture due to radiation-induced osteonecrosis in the previous surgically treated area and needed to wear a brace. She lived for 3 years with a disabling function impairment of the knee and then developed signs of critical leg ischemia. An upper leg amputation was performed 110 months after the initial treatment. She now walks with a well-functioning prothesis. . Recently, one patient was successfully treated with thrombectomy for an acute popliteal artery occlusion. This patient, who underwent an ILP at femoral level followed by EBRT for a STS in the fossa poplitea 5 years before, had no complaints of peripheral arterial occlusive disease during his vascular work-up for this study 10 months earlier. ABI (1.03) and femoral PI (6.3) were normal; popliteal PI was low (5.3). With duplex ultrasonography, some atherosclerosis in the femoropopliteal section was seen. This patient has diabetes and hypertension, is obese (body mass index >30), and was a former smoker, so he was especially at risk for developing atherosclerosis. This study shows that despite the importance of preventing major late vascular complications after the combined procedure of ILP and EBRT, a routine noninvasive vascular work-up does not seem to add value to normal follow-up. It is more important to realize that patients after the limb salvage treatment strategy of ILP, followed by delayed tumor resection and EBRT, are at risk for late vascular complications. This risk is substantially raised when personal risk factors such as smoking, diabetes, hypertension, obesity, and hypercholesterolemia are present. Because symptoms of vascular complications can be masked by the normal effects of the treatment itself, the possibility of vascular morbidity should be considered if the patient has any complaint. Furthermore, all patients must be convinced of the importance of reducing their additional personal risk factors for atherosclerosis. In conclusion, objective measurements show a time-related decrease (>5 years’ follow-up) of ABI and femoral PI in the treated leg, usually without subjective complaints. ILP followed by delayed resection and EBRT for a locally advanced STS can lead to major late vascular morbidity that requires amputation.