Original Article
Acute limb ischemia in cancer patients: Aggressive treatment is justified
Vascular 2015, Vol. 23(1) 55–61 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1708538114537048 vas.sagepub.com
Daniel Silverberg, Tal Yalon, Emanuel R Reinitz, Dmitry Yakubovitch, Tal Segev and Moshe Halak
Abstract Background: The outcome of cancer patients with acute limb ischemia (ALI) is not well defined. The purpose of this study is to report our experience treating patients with active malignancy who developed ALI and compare their outcome with non-cancer patients. Methods: A retrospective review of patients treated for ALI between 2009 and 2012 with ALI. We identified those patients who suffered from ALI and compared the outcome of those with active malignancy to those without malignancy. Results: Of 147 patients treated for ALI (122 lower extremity, 25 upper extremity), 24 (16%) were cancer patients. Mean follow-up was 9.8 months for the malignancy group and 13.4 months for the control. Perioperative mortality rates were similar among cancer and non-cancer patients (20% vs. 16%, respectively, NS). Freedom from major amputation at 30 months was similar (95% vs. 89%, NS). Long-term survival rates of cancer patients were significantly lower compared to non-cancer patients (45% vs. 77% respectively, P < 0.05). Conclusions: Treatment of ALI among cancer patients can be achieved with perioperative mortality and limb salvage rates comparable to non-cancer patients. Aggressive treatment is justified when treating cancer patients with ALI.
Keywords Acute limb ischemia, malignancy, cancer, thrombolysis, embolectomy
Introduction Cancer patients are at increased risk for thromboembolic events. The association between malignancies and venous thromboembolic events (VTE) has been well documented.1,2 Approximately 5–15% of patients with various cancers such as lung, breast and pancreas will develop deep vein thrombosis (DVT).3,4 The overall risk of venous thrombosis has been reported to be increased 7-fold in patients with a malignancy vs. persons without malignancy.1 The association between cancer and peripheral arterial ischemic events is much less defined. Despite the magnitude of data existing for venous thrombotic events among cancer patients, only limited data exist regarding cancer patients who develop acute limb ischemia (ALI). These reports consist mainly of case reports and small non-comparative studies. Historically, cancer patients with ALI have been considered to have a poor outcome,5 and some authors have suggested that acute arterial occlusion in the presence of cancer is a preterminal event best treated by palliative measures only.6,7
The long-term limb salvage rate and overall survival of these patients is not well defined. The purpose of this study was to evaluate the outcome of cancer patients diagnosed and treated for ALI and to compare their outcome with non-cancer patients treated for ALI.
Materials and methods We performed a retrospective analysis of all patients admitted to our institution with ALI between January 2009 and December 2012. Department of Vascular Surgery, The Chaim Sheba Medical Center, Affiliated to the Tel Aviv University Sackler School of Medicine, Tel Hashomer, Israel Corresponding author: Daniel Silverberg, Department of Vascular Surgery, The Chaim Sheba Medical Center, Affiliated to the Tel Aviv University Sackler School of Medicine, Tel Hashomer 52621, Israel. Email: [email protected]
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Patient identification: Electronic charts of all patients admitted to our institution during the study period were queried for the diagnosis of ‘‘acute limb ischemia,’’ ‘‘thrombosis,’’ and ‘‘embolism.’’ An additional search was performed for patients with a combination of the aforementioned diagnoses and any term suggesting malignancy (e.g. cancer, malignancy, metastases, and specific tumors). Charts of all patients were individually reviewed. Included in this study were all patients diagnosed with ALI. Only patients who were recently diagnosed with cancer or were actively being treated for their malignancy were included in the cancer group. We excluded those patients with only a history of cancer who were not being actively treated for their malignancy or those who underwent treatment more than six months prior to the admission.
Fogarty embolectomy balloon. In the minority of cases, additional procedures were added as needed, such as a transpopliteal embolectomy, fasciotomies, etc.
Criteria for revascularization
Postoperative clinic visits which included physical examination and ankle brachial indexes (ABIs) were performed at 3, 6, and 12 months, followed by annual visits and ABIs thereafter. Patient demographics and comorbidities, cancer type and stage, treatment of the ischemic limb, and outcome of the entire group of patients were recorded. We then compared the amputation and mortality rates of patients suffering from cancer with those without cancer. Statistical analysis was performed using the Chi-square test. Survival analysis was performed using the Kaplan–Meier method. Comparison between survival curves was calculated with log-rank tests. The institutional review board at our institution approved this study and waived requirements for informed consent for this retrospective analysis.
Criteria for revascularization included patients presenting with sudden decrease in limb perfusion causing a potential threat to limb viability, based on clinical findings and doppler measurements. All patients who underwent intervention suffered from Rutherford severity score 2a and 2b. All cancer patients with ALI were approached and treated in the same fashion as non-cancer patients, provided they were not in a terminal condition and their physical condition permitted surgery or thrombolysis.
Embolic vs. thrombotic events Preintervention imaging was performed in 90% of the cases (computerized tomography angiography (CTA), duplex scanning or angiogram). In addition, in cases where there was no obvious source of emboli noted, patients underwent transesophageal echo and/or CTA of the thoracic and abdominal aorta in search for an embolic source. Criteria that suggested an embolic event included patients with atrial fibrillation – not treated with anticoagulation; multiple emboli to other organs seen on preoperative CTA; a single, localized thrombus lodged at an arterial bifurcation; and classic findings of embolism in the artery (meniscal-type cutoff). Criteria that suggested a thrombotic event included no history of atrial fibrillation, diffuse thrombosis throughout the artery, no source of emboli on pre- or postoperative imaging, and an ischemic event that occurred during or shortly after chemotherapy treatment.
Surgical revascularization Surgical embolectomies were generally performed through femoral or brachial arteriotomies using a
Thrombolysis Catheter directed thrombolysis with Urokinase was used in all cases. All patients were administered postoperative anticoagulation with unfractionated heparin or low molecular weight heparin (LMWH). Those who could maintain strict levels of therapeutic INR were discharged with Warfarin. Otherwise, they were discharged with LMWH.
Follow up
Results Over the four-year study period, we identified 152 patients diagnosed with ALI. Of these, 147 were treated for ALI (122 lower extremities, 25 upper extremities). Twenty-four of these patients (16%) suffered from active malignancy. Five cancer patients did not undergo surgical or endovascular intervention. These patients suffered from advanced, metastatic disease (lung, pancreas, colon (2), and melanoma). Three of them were already residing in a hospice due to their advanced disease and therefore were not treated due to their terminal status. One presented with septic shock and was not a candidate for any intervention, and one refused any surgical intervention. All five patients were treated with LMWH, and all expired during the same admission. All acute ischemic events among the cancer patients occurred in the lower extremities. None of the cancer patients experienced upper extremity ischemic events.
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Cancer patients Among the patients suffering from cancer, the mean age was 72 years and 15 (63%) of them were males. The histological types of malignancies and their stages are detailed in Table 1. The majority of patients (58%) suffered from advanced stage cancer, i.e. stages 3 or 4, based on the TNM classification or the relevant tumor specific classification. Nine (37%) were actively being treated with anti-cancer medication (chemotherapy or hormonotherapy) at the time of presentation. Seven patients (29%) were being treated with anticoagulation for prior thromboembolic events at the time of admission. Only one patient was diagnosed with cancer following the ischemic event. The remainder carried a diagnosis of cancer prior to the ischemic event. The demographics and comorbidities of the cancer patient group and the lower extremity ALI group are detailed in Table 2. There was a higher rate of smoking, peripheral vascular disease, prior pulmonary embolism, and DVT among the cancer patients; however, there was no significant difference in the prevalence of atrial fibrillation between the two groups. Based on clinical and imaging findings, the number of embolic events was 15 (62%) and the number of thrombotic events was 9 (38%).
Treatment modality
Perioperative mortality Five patients in the cancer group died within 30 days of treatment, compared to 16 in the non-cancer lower extremity group, resulting in a perioperative mortality rate of 16% vs. 20%, respectively. These differences did not reach statistical significance.
Amputation rate Mean follow-up was 12 months (range 1–49 months). During the follow-up, only one patient in the cancer group required an amputation vs. seven in the noncancer group. Based on Kaplan–Meier curve estimations, freedom from amputation at 30 months was 95% among the cancer patients and 89% among the
Table 2. Demographics and comorbidities of lower extremity ALI patients. Cancer (%)
Non-cancer (%)
P-value
24 15 72 10 5 1 5 12 12 7 1 2 2
98 52 74 45 24 18 27 46 19 11 0 1 3
NS NS NS NS NS 0.02 0.02 0.02 0.03 NS
4, 3, 3 4, 2 3, 1
N Male Age (mean, years) Atrial fibrillation CAD History of CVA Diabetes Hypertension Smoking PVD Prior VTE Prior PE Hypercoagulability
1 ,
CAD: coronary artery disease; CVA: cerebrovascular accident; PVD: peripheral vascular disease; ALI: acute limb ischemia; VTE: thromboembolic events; PE: pulmonary embolism.
There was tendency toward revascularization by surgical embolectomies among non-cancer patients and catheterdirected thrombolytics among the cancer patients; however, these differences did not reach statistical significance (Table 3). No bypass surgery was performed.
Table 1. Malignancies and their stages found in cancer patients.
Stomach Lung Bladder Ovary BCC Breast CLL Glioblastoma GIST Pancreas Melanoma Rectum Total
Pre and postoperative ABIs were 0.1 and 0.78, respectively, among the cancer patients and 0.1 and 0.89, respectively, among the non-cancer patients (NS).
Number of cases
Stages
4 3 3 1 2 3 1 1 1 2 2 1 24
4, 4, 1, 3 1, 1, 1 4 4 3, 4, 3
a a
4 4
a Data not available. BCC: basal cell carcinoma, CLL: chronic lymphocytic leukemia, GIST: gastrointestinal stromol tumor.
(62) (41) (21) (4) (21) (50) (50) (29) (4) (8) (8)
(53) (46) (24) (18) (27) (47) (19) (11) (0) (1) (3)
Table 3. Therapeutic procedures among lower extremity ALI patients. Treatment
Cancer (%)
Non-cancer (%)
P-value
Embolectomy Thrombolysis Total
15 (63) 9 (37) 24
71 (72) 27 (27) 98
NS NS
ALI: acute limb ischemia.
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non-cancer patients. (Figure 1) These differences did not reach statistical significance. No patient with upper extremity ischemia required an amputation. Long-term survival rates of cancer patients were significantly lower compared to non-cancer patients. During the period of follow up, 9 cancer patients and 16 non-cancer patients expired. Causes of death among the cancer patients were the following: 4 died from sepsis, 3 from general deterioration related to malignancy, and 2 from unknown causes. Based on Kaplan–Meier curve estimations, overall survival rates among the cancer and non-cancer patients were 45% vs. 77%, respectively. These differences were statistically significant (P < 0.05) (Figure 2).
Discussion The pathogenesis of thrombosis in a cancer patient is complex and multifactorial, and several etiologies have been implicated in this process: cancer patients suffer from several humoral abnormalities that contribute to thrombosis formation. A key initiating factor is the release of procoagulants such as tissue factor and cancer procoagulant which activate factor X and the clotting cascade. Patients with malignancy develop increased levels of circulating inflammatory cytokines which lead to endothelial dysfunction and prime the
vascular endothelium into a prothrombotic state. In addition, they suffer from increased levels of clotting factors (fibrinogen, factors V, VII, IX, and XII), thrombocytosis, impaired fibrinolytic activity, decreased levels of protein C and S, and increased levels of antiphospholipid antibodies (APLA).8 Additional factors have a role in the development of thrombosis. Several chemotherapeutic agents and hormonal medications used to treat cancer patients are a well-recognized risk factor for venous thrombosis.9 Direct tumor compression of arterial walls and distal embolization all may have a role in this process. The data that exist on the association between cancer and arterial thrombotic events is scarce and the conclusions that can be derived from these studies are conflicting. One of the reasons for this is because the methodology and patients included in the different studies greatly differ. In general, the incidence of arterial thrombotic events is low compared to venous events, and therefore the number of patients included in these reports is small. Most published reports describe the experience treating cancer patients with ALI without comparison to non-cancer patients. Some series report on cancer patients with active malignancies, while others report on patients with a history of cancer. The majority of reports combine results of upper limb ischemia with lower limb ischemia, which limits the ability to reach a conclusion regarding each extremity separately. In addition, the
Figure 1. Amputation-free survival.
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therapeutic modalities and degrees of aggressiveness in the treatment vary. Several reports combine patients who were treated surgically with patients who were not candidates for invasive therapy of any type, while others report on their experience using surgical interventions only. Finally, as all these reports are retrospective studies, they suffer from selection bias. As such, it is reasonable to assume that patients who were not suitable for invasive treatment were generally in poor condition with an anticipated poor prognosis, while patients who were in better overall condition were assumed to have a favorable outcome and therefore were treated aggressively, either surgically or with thrombolytics. Tsang reported 16 cancer patients who developed ALI.6 All patients underwent surgical embolectomies. He reported favorable results with an in-house mortality of 12% and 63% limb salvage at four years. While this study is unique as it provides information regarding active cancer patients, no comparison is performed to non-cancer patients. Contrary to that, other studies have reported a poor outcome of ALI when an underlying malignancy is present.5,7 Morris compared the results of revascularization in 14 patients with ALI and a history of cancer to 102 patients without cancer. He found an extremely high 30 day mortality rate among the cancer patients vs. non-cancer patient (50% vs. 30%, respectively, P ¼ 0.03) and recommended against revascularization of cancer patients
who develop ALI. In this series, the cancer patients did not necessarily suffer from cancer at the time of presentation. Javid et al. published a series of 20 patients with acute arterial thrombosis and cancer and reported a generally poor outcome of these patients.5 In this series, only eight patients were treated surgically (thromboembolectomies or bypasses) while the remaining 12 patients were treated conservatively. Almost all attempts to surgically revascularize the patients failed, resulting in two patients who required major amputations and survival rates of 50% at 3 months and 17% at 1 year. In our series, no patient underwent bypass surgery. The limited reported data on the results of bypass surgery in this patient population suggest poor outcome.5 Our approach was that we would attempt to revascularize the limb by performing a minimally invasive procedure (catheter directed thrombolysis) or low risk surgery (thrombectomy) as these procedures do not require general anesthesia or a prolonged surgical procedure; however, we avoided performing surgical bypasses due to the anticipated grim results. In our series, overall perioperative mortality rates and long-term freedom from amputation did not differ between the cancer patients and those without cancer. This is despite the fact that the majority suffered from an advanced stage of malignancy on presentation. Although we did exclude five terminally ill cancer patients from surgical or endovascular interventions,
Figure 2. Survival following revascularization.
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the vast majority of cancer patients who developed ALI in this series did undergo interventions despite the status of their malignancy. The long-term survival rates among the non-cancer patients was 77% at 30 months, a rate that correlates well with previous reports.10 Survival rates among the cancer patients is, not surprisingly, lower (45% at 30 months); however, the mortalities were not a result of the revascularization and the majority did not occur during the perioperative period. Interestingly, no events of upper extremity ischemia occurred among the cancer patients and no amputations were required in this group. Arm ischemia is seldom limb threatening and treatment decisions are less urgent.11,12 We anticipated that including such patients would limit our ability to reach accurate conclusions regarding the outcome of the more common lower extremity ischemia. Therefore, we reported on these cases but, however, did not include them in the statistical analysis. The types of malignancies detected in the cancer patients are worthy of mentioning. Both solid and hematologic malignancies are associated with a high risk of DVT.1,2 In Blom et al.’s report on the association between malignancies and VTE, patients with hematological malignancies had the highest risk of venous thrombosis followed by lung cancer and gastrointestinal cancers.1 Such a distinctive association has not been clearly defined regarding arterial thrombotic events and malignancies. A wide variety of malignancies including leukemias, myeloproliferative disorders, and solid tumors have all been described.8 Patients with myeloproliferative disorders such as Polycythemia Vera and Essential Thrombocytosis have classically been described to be associated with acute peripheral and coronary ischemic events.13,14 In our study, only one of the 24 patients suffered from a hematological malignancy, and the remainder from solid tumors. Regarding our postoperative anticoagulation regimen: LMWH is the preferred anticoagulant for longterm treatment in patients with cancer and VTE. This preference is based upon its superior performance in reducing the rate of recurrent VTE that was observed in large prospective randomized studies.15 Despite this, no clear recommendations exist regarding the desired anticoagulation regimen among cancer patients who experience ALI. Therefore, we individualized their postoperative anticoagulation treatment based upon their compliance and ability to monitor INR levels. The majority of our patients (58%) suffered from advanced stage of malignancy on presentation (stages 3 and 4 based on the TNM classification). Comparison of these findings to other studies is difficult as most reported series reported only the histological type of the tumor without specifying the stage. Javid et al.
reported that 12 of 20 patients with ALI suffered from metastatic disease, and 10 of those who died had metastatic disease.
Conclusion In contrast to previous reports that suggest decreased limb salvage rates among cancer patients with acute limb ischemia, this comparative study suggests that limb salvage rates following revascularization for ALI is favorable and can be achieved with comparable perioperative mortality rates and comparable limb salvage rates to non-cancer patients. Despite the decreased long-term survival rates of cancer patients, these findings suggest that cancer patients should be considered for revascularization and they should be treated aggressively with the intention of salvaging the limb. This is true even in the presence of advanced metastatic disease. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Blom JW, Doggen CJ, Osanto S, et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715–722. 2. Falanga A and Zacharski L. Deep vein thrombosis in cancer: the scale of the problem and approaches to management. Ann Oncol 2005; 16: 696–701. 3. El Sakka K, Gambhir RP, Halawa M, et al. Association of malignant disease with critical leg ischaemia. Br J Surg 2005; 92: 1498–501. 4. Monreal M, Lafoz E, Casals A, et al. Occult cancer in patients with deep venous thrombosis. A systematic approach. Cancer 1991; 67: 541–545. 5. Javid M, Magee TR and Galland RB. Arterial thrombosis associated with malignant disease. Eur J Vasc Endovasc Surg 2008; 35: 84–87. 6. Tsang JS, Naughton PA, O’Donnell J, et al. Acute limb ischemia in cancer patients: should we surgically intervene? Ann Vasc Surg 2011; 25: 954–960. 7. Morris-Stiff G and Lewis MH. Surgical treatment of acute limb ischaemia in the presence of malignancy. Int J Surg 2010; 8: 233–235. 8. Sanon S, Lenihan DJ and Mouhayar E. Peripheral arterial ischemic events in cancer patients. Vasc Med 2011; 16: 119–130. 9. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809–815.
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10. Pemberton M, Varty K, Nydahl S, et al. The surgical management of acute limb ischemia due to native vessel occlusion. Eur J Vasc Endovasc Surg 1999; 17: 72–76. 11. Stonebridge PA, Clason AE, Duncan AJ, et al. Acute ischaemia of the upper limb compared with acute lower limb ischaemia; a 5-year review. Br J Surg 1989; 76: 515–516. 12. Eyers P and Earnshaw JJ. Acute non-traumatic arm ischaemia. Br J Surg 1998; 85: 1340–1346. 13. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 2005; 23: 2224–2232.
14. Rossi C, Randi ML, Zerbinati P, et al. Acute coronary disease in essential thrombocythemia and polycythemia vera. J Intern Med 1998; 244: 49–53. 15. Akl EA, Labedi N, Barba M, et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2011 Jun 15; (6): CD006650.
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Acute limb ischemia in cancer patients: Aggressive treatment is justified
Vascular 2015, Vol. 23(1) 55–61 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1708538114537048 vas.sagepub.com
Daniel Silverberg, Tal Yalon, Emanuel R Reinitz, Dmitry Yakubovitch, Tal Segev and Moshe Halak
Abstract Background: The outcome of cancer patients with acute limb ischemia (ALI) is not well defined. The purpose of this study is to report our experience treating patients with active malignancy who developed ALI and compare their outcome with non-cancer patients. Methods: A retrospective review of patients treated for ALI between 2009 and 2012 with ALI. We identified those patients who suffered from ALI and compared the outcome of those with active malignancy to those without malignancy. Results: Of 147 patients treated for ALI (122 lower extremity, 25 upper extremity), 24 (16%) were cancer patients. Mean follow-up was 9.8 months for the malignancy group and 13.4 months for the control. Perioperative mortality rates were similar among cancer and non-cancer patients (20% vs. 16%, respectively, NS). Freedom from major amputation at 30 months was similar (95% vs. 89%, NS). Long-term survival rates of cancer patients were significantly lower compared to non-cancer patients (45% vs. 77% respectively, P < 0.05). Conclusions: Treatment of ALI among cancer patients can be achieved with perioperative mortality and limb salvage rates comparable to non-cancer patients. Aggressive treatment is justified when treating cancer patients with ALI.
Keywords Acute limb ischemia, malignancy, cancer, thrombolysis, embolectomy
Introduction Cancer patients are at increased risk for thromboembolic events. The association between malignancies and venous thromboembolic events (VTE) has been well documented.1,2 Approximately 5–15% of patients with various cancers such as lung, breast and pancreas will develop deep vein thrombosis (DVT).3,4 The overall risk of venous thrombosis has been reported to be increased 7-fold in patients with a malignancy vs. persons without malignancy.1 The association between cancer and peripheral arterial ischemic events is much less defined. Despite the magnitude of data existing for venous thrombotic events among cancer patients, only limited data exist regarding cancer patients who develop acute limb ischemia (ALI). These reports consist mainly of case reports and small non-comparative studies. Historically, cancer patients with ALI have been considered to have a poor outcome,5 and some authors have suggested that acute arterial occlusion in the presence of cancer is a preterminal event best treated by palliative measures only.6,7
The long-term limb salvage rate and overall survival of these patients is not well defined. The purpose of this study was to evaluate the outcome of cancer patients diagnosed and treated for ALI and to compare their outcome with non-cancer patients treated for ALI.
Materials and methods We performed a retrospective analysis of all patients admitted to our institution with ALI between January 2009 and December 2012. Department of Vascular Surgery, The Chaim Sheba Medical Center, Affiliated to the Tel Aviv University Sackler School of Medicine, Tel Hashomer, Israel Corresponding author: Daniel Silverberg, Department of Vascular Surgery, The Chaim Sheba Medical Center, Affiliated to the Tel Aviv University Sackler School of Medicine, Tel Hashomer 52621, Israel. Email: [email protected]
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Patient identification: Electronic charts of all patients admitted to our institution during the study period were queried for the diagnosis of ‘‘acute limb ischemia,’’ ‘‘thrombosis,’’ and ‘‘embolism.’’ An additional search was performed for patients with a combination of the aforementioned diagnoses and any term suggesting malignancy (e.g. cancer, malignancy, metastases, and specific tumors). Charts of all patients were individually reviewed. Included in this study were all patients diagnosed with ALI. Only patients who were recently diagnosed with cancer or were actively being treated for their malignancy were included in the cancer group. We excluded those patients with only a history of cancer who were not being actively treated for their malignancy or those who underwent treatment more than six months prior to the admission.
Fogarty embolectomy balloon. In the minority of cases, additional procedures were added as needed, such as a transpopliteal embolectomy, fasciotomies, etc.
Criteria for revascularization
Postoperative clinic visits which included physical examination and ankle brachial indexes (ABIs) were performed at 3, 6, and 12 months, followed by annual visits and ABIs thereafter. Patient demographics and comorbidities, cancer type and stage, treatment of the ischemic limb, and outcome of the entire group of patients were recorded. We then compared the amputation and mortality rates of patients suffering from cancer with those without cancer. Statistical analysis was performed using the Chi-square test. Survival analysis was performed using the Kaplan–Meier method. Comparison between survival curves was calculated with log-rank tests. The institutional review board at our institution approved this study and waived requirements for informed consent for this retrospective analysis.
Criteria for revascularization included patients presenting with sudden decrease in limb perfusion causing a potential threat to limb viability, based on clinical findings and doppler measurements. All patients who underwent intervention suffered from Rutherford severity score 2a and 2b. All cancer patients with ALI were approached and treated in the same fashion as non-cancer patients, provided they were not in a terminal condition and their physical condition permitted surgery or thrombolysis.
Embolic vs. thrombotic events Preintervention imaging was performed in 90% of the cases (computerized tomography angiography (CTA), duplex scanning or angiogram). In addition, in cases where there was no obvious source of emboli noted, patients underwent transesophageal echo and/or CTA of the thoracic and abdominal aorta in search for an embolic source. Criteria that suggested an embolic event included patients with atrial fibrillation – not treated with anticoagulation; multiple emboli to other organs seen on preoperative CTA; a single, localized thrombus lodged at an arterial bifurcation; and classic findings of embolism in the artery (meniscal-type cutoff). Criteria that suggested a thrombotic event included no history of atrial fibrillation, diffuse thrombosis throughout the artery, no source of emboli on pre- or postoperative imaging, and an ischemic event that occurred during or shortly after chemotherapy treatment.
Surgical revascularization Surgical embolectomies were generally performed through femoral or brachial arteriotomies using a
Thrombolysis Catheter directed thrombolysis with Urokinase was used in all cases. All patients were administered postoperative anticoagulation with unfractionated heparin or low molecular weight heparin (LMWH). Those who could maintain strict levels of therapeutic INR were discharged with Warfarin. Otherwise, they were discharged with LMWH.
Follow up
Results Over the four-year study period, we identified 152 patients diagnosed with ALI. Of these, 147 were treated for ALI (122 lower extremities, 25 upper extremities). Twenty-four of these patients (16%) suffered from active malignancy. Five cancer patients did not undergo surgical or endovascular intervention. These patients suffered from advanced, metastatic disease (lung, pancreas, colon (2), and melanoma). Three of them were already residing in a hospice due to their advanced disease and therefore were not treated due to their terminal status. One presented with septic shock and was not a candidate for any intervention, and one refused any surgical intervention. All five patients were treated with LMWH, and all expired during the same admission. All acute ischemic events among the cancer patients occurred in the lower extremities. None of the cancer patients experienced upper extremity ischemic events.
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Cancer patients Among the patients suffering from cancer, the mean age was 72 years and 15 (63%) of them were males. The histological types of malignancies and their stages are detailed in Table 1. The majority of patients (58%) suffered from advanced stage cancer, i.e. stages 3 or 4, based on the TNM classification or the relevant tumor specific classification. Nine (37%) were actively being treated with anti-cancer medication (chemotherapy or hormonotherapy) at the time of presentation. Seven patients (29%) were being treated with anticoagulation for prior thromboembolic events at the time of admission. Only one patient was diagnosed with cancer following the ischemic event. The remainder carried a diagnosis of cancer prior to the ischemic event. The demographics and comorbidities of the cancer patient group and the lower extremity ALI group are detailed in Table 2. There was a higher rate of smoking, peripheral vascular disease, prior pulmonary embolism, and DVT among the cancer patients; however, there was no significant difference in the prevalence of atrial fibrillation between the two groups. Based on clinical and imaging findings, the number of embolic events was 15 (62%) and the number of thrombotic events was 9 (38%).
Treatment modality
Perioperative mortality Five patients in the cancer group died within 30 days of treatment, compared to 16 in the non-cancer lower extremity group, resulting in a perioperative mortality rate of 16% vs. 20%, respectively. These differences did not reach statistical significance.
Amputation rate Mean follow-up was 12 months (range 1–49 months). During the follow-up, only one patient in the cancer group required an amputation vs. seven in the noncancer group. Based on Kaplan–Meier curve estimations, freedom from amputation at 30 months was 95% among the cancer patients and 89% among the
Table 2. Demographics and comorbidities of lower extremity ALI patients. Cancer (%)
Non-cancer (%)
P-value
24 15 72 10 5 1 5 12 12 7 1 2 2
98 52 74 45 24 18 27 46 19 11 0 1 3
NS NS NS NS NS 0.02 0.02 0.02 0.03 NS
4, 3, 3 4, 2 3, 1
N Male Age (mean, years) Atrial fibrillation CAD History of CVA Diabetes Hypertension Smoking PVD Prior VTE Prior PE Hypercoagulability
1 ,
CAD: coronary artery disease; CVA: cerebrovascular accident; PVD: peripheral vascular disease; ALI: acute limb ischemia; VTE: thromboembolic events; PE: pulmonary embolism.
There was tendency toward revascularization by surgical embolectomies among non-cancer patients and catheterdirected thrombolytics among the cancer patients; however, these differences did not reach statistical significance (Table 3). No bypass surgery was performed.
Table 1. Malignancies and their stages found in cancer patients.
Stomach Lung Bladder Ovary BCC Breast CLL Glioblastoma GIST Pancreas Melanoma Rectum Total
Pre and postoperative ABIs were 0.1 and 0.78, respectively, among the cancer patients and 0.1 and 0.89, respectively, among the non-cancer patients (NS).
Number of cases
Stages
4 3 3 1 2 3 1 1 1 2 2 1 24
4, 4, 1, 3 1, 1, 1 4 4 3, 4, 3
a a
4 4
a Data not available. BCC: basal cell carcinoma, CLL: chronic lymphocytic leukemia, GIST: gastrointestinal stromol tumor.
(62) (41) (21) (4) (21) (50) (50) (29) (4) (8) (8)
(53) (46) (24) (18) (27) (47) (19) (11) (0) (1) (3)
Table 3. Therapeutic procedures among lower extremity ALI patients. Treatment
Cancer (%)
Non-cancer (%)
P-value
Embolectomy Thrombolysis Total
15 (63) 9 (37) 24
71 (72) 27 (27) 98
NS NS
ALI: acute limb ischemia.
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non-cancer patients. (Figure 1) These differences did not reach statistical significance. No patient with upper extremity ischemia required an amputation. Long-term survival rates of cancer patients were significantly lower compared to non-cancer patients. During the period of follow up, 9 cancer patients and 16 non-cancer patients expired. Causes of death among the cancer patients were the following: 4 died from sepsis, 3 from general deterioration related to malignancy, and 2 from unknown causes. Based on Kaplan–Meier curve estimations, overall survival rates among the cancer and non-cancer patients were 45% vs. 77%, respectively. These differences were statistically significant (P < 0.05) (Figure 2).
Discussion The pathogenesis of thrombosis in a cancer patient is complex and multifactorial, and several etiologies have been implicated in this process: cancer patients suffer from several humoral abnormalities that contribute to thrombosis formation. A key initiating factor is the release of procoagulants such as tissue factor and cancer procoagulant which activate factor X and the clotting cascade. Patients with malignancy develop increased levels of circulating inflammatory cytokines which lead to endothelial dysfunction and prime the
vascular endothelium into a prothrombotic state. In addition, they suffer from increased levels of clotting factors (fibrinogen, factors V, VII, IX, and XII), thrombocytosis, impaired fibrinolytic activity, decreased levels of protein C and S, and increased levels of antiphospholipid antibodies (APLA).8 Additional factors have a role in the development of thrombosis. Several chemotherapeutic agents and hormonal medications used to treat cancer patients are a well-recognized risk factor for venous thrombosis.9 Direct tumor compression of arterial walls and distal embolization all may have a role in this process. The data that exist on the association between cancer and arterial thrombotic events is scarce and the conclusions that can be derived from these studies are conflicting. One of the reasons for this is because the methodology and patients included in the different studies greatly differ. In general, the incidence of arterial thrombotic events is low compared to venous events, and therefore the number of patients included in these reports is small. Most published reports describe the experience treating cancer patients with ALI without comparison to non-cancer patients. Some series report on cancer patients with active malignancies, while others report on patients with a history of cancer. The majority of reports combine results of upper limb ischemia with lower limb ischemia, which limits the ability to reach a conclusion regarding each extremity separately. In addition, the
Figure 1. Amputation-free survival.
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therapeutic modalities and degrees of aggressiveness in the treatment vary. Several reports combine patients who were treated surgically with patients who were not candidates for invasive therapy of any type, while others report on their experience using surgical interventions only. Finally, as all these reports are retrospective studies, they suffer from selection bias. As such, it is reasonable to assume that patients who were not suitable for invasive treatment were generally in poor condition with an anticipated poor prognosis, while patients who were in better overall condition were assumed to have a favorable outcome and therefore were treated aggressively, either surgically or with thrombolytics. Tsang reported 16 cancer patients who developed ALI.6 All patients underwent surgical embolectomies. He reported favorable results with an in-house mortality of 12% and 63% limb salvage at four years. While this study is unique as it provides information regarding active cancer patients, no comparison is performed to non-cancer patients. Contrary to that, other studies have reported a poor outcome of ALI when an underlying malignancy is present.5,7 Morris compared the results of revascularization in 14 patients with ALI and a history of cancer to 102 patients without cancer. He found an extremely high 30 day mortality rate among the cancer patients vs. non-cancer patient (50% vs. 30%, respectively, P ¼ 0.03) and recommended against revascularization of cancer patients
who develop ALI. In this series, the cancer patients did not necessarily suffer from cancer at the time of presentation. Javid et al. published a series of 20 patients with acute arterial thrombosis and cancer and reported a generally poor outcome of these patients.5 In this series, only eight patients were treated surgically (thromboembolectomies or bypasses) while the remaining 12 patients were treated conservatively. Almost all attempts to surgically revascularize the patients failed, resulting in two patients who required major amputations and survival rates of 50% at 3 months and 17% at 1 year. In our series, no patient underwent bypass surgery. The limited reported data on the results of bypass surgery in this patient population suggest poor outcome.5 Our approach was that we would attempt to revascularize the limb by performing a minimally invasive procedure (catheter directed thrombolysis) or low risk surgery (thrombectomy) as these procedures do not require general anesthesia or a prolonged surgical procedure; however, we avoided performing surgical bypasses due to the anticipated grim results. In our series, overall perioperative mortality rates and long-term freedom from amputation did not differ between the cancer patients and those without cancer. This is despite the fact that the majority suffered from an advanced stage of malignancy on presentation. Although we did exclude five terminally ill cancer patients from surgical or endovascular interventions,
Figure 2. Survival following revascularization.
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Vascular 23(1)
the vast majority of cancer patients who developed ALI in this series did undergo interventions despite the status of their malignancy. The long-term survival rates among the non-cancer patients was 77% at 30 months, a rate that correlates well with previous reports.10 Survival rates among the cancer patients is, not surprisingly, lower (45% at 30 months); however, the mortalities were not a result of the revascularization and the majority did not occur during the perioperative period. Interestingly, no events of upper extremity ischemia occurred among the cancer patients and no amputations were required in this group. Arm ischemia is seldom limb threatening and treatment decisions are less urgent.11,12 We anticipated that including such patients would limit our ability to reach accurate conclusions regarding the outcome of the more common lower extremity ischemia. Therefore, we reported on these cases but, however, did not include them in the statistical analysis. The types of malignancies detected in the cancer patients are worthy of mentioning. Both solid and hematologic malignancies are associated with a high risk of DVT.1,2 In Blom et al.’s report on the association between malignancies and VTE, patients with hematological malignancies had the highest risk of venous thrombosis followed by lung cancer and gastrointestinal cancers.1 Such a distinctive association has not been clearly defined regarding arterial thrombotic events and malignancies. A wide variety of malignancies including leukemias, myeloproliferative disorders, and solid tumors have all been described.8 Patients with myeloproliferative disorders such as Polycythemia Vera and Essential Thrombocytosis have classically been described to be associated with acute peripheral and coronary ischemic events.13,14 In our study, only one of the 24 patients suffered from a hematological malignancy, and the remainder from solid tumors. Regarding our postoperative anticoagulation regimen: LMWH is the preferred anticoagulant for longterm treatment in patients with cancer and VTE. This preference is based upon its superior performance in reducing the rate of recurrent VTE that was observed in large prospective randomized studies.15 Despite this, no clear recommendations exist regarding the desired anticoagulation regimen among cancer patients who experience ALI. Therefore, we individualized their postoperative anticoagulation treatment based upon their compliance and ability to monitor INR levels. The majority of our patients (58%) suffered from advanced stage of malignancy on presentation (stages 3 and 4 based on the TNM classification). Comparison of these findings to other studies is difficult as most reported series reported only the histological type of the tumor without specifying the stage. Javid et al.
reported that 12 of 20 patients with ALI suffered from metastatic disease, and 10 of those who died had metastatic disease.
Conclusion In contrast to previous reports that suggest decreased limb salvage rates among cancer patients with acute limb ischemia, this comparative study suggests that limb salvage rates following revascularization for ALI is favorable and can be achieved with comparable perioperative mortality rates and comparable limb salvage rates to non-cancer patients. Despite the decreased long-term survival rates of cancer patients, these findings suggest that cancer patients should be considered for revascularization and they should be treated aggressively with the intention of salvaging the limb. This is true even in the presence of advanced metastatic disease. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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