523063 research-article2014
VMJ0010.1177/1358863X14523063Vascular MedicineMouhayar et al.
Original Article
Outcome of acute limb ischemia in cancer patients
Vascular Medicine 2014, Vol. 19(2) 112–117 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1358863X14523063 vmj.sagepub.com
Elie Mouhayar, Jean Tayar, Mark Fasulo, Reem Aoun, Mona Massey, Simon Abi-Aad, Cezar Iliescu, Kamran Ahrar and Tam Huynh Abstract
The optimal management strategy for acute limb ischemia (ALI) in patients with a concomitant malignancy is not well established. A very high mortality rate (83–100%) at 1 year has been reported in those who are treated surgically. Accordingly, a conservative management approach has been suggested as the main therapeutic modality. Our aim was to evaluate the survival outcomes of cancer patients treated for ALI at our cancer center. Cancer patients treated for ALI at the MD Anderson Cancer Center from 2001 to 2011 were included in this study. Overall survival and amputation-free survival rates were calculated. A total of 74 cancer patients with concomitant ALI were included in the study. Surgery was the most common therapy (36 patients; 49%). Percutaneous catheter-based interventions were used in 21 patients (28%). Eighteen patients (24%) received anticoagulation therapy only, and six patients (8%) received no therapy. The 30-day, 6-month, and 1-year overall survival rates were 80% (95% confidence interval [CI], 69% to 87%), 59% (95% CI, 47% to 69%), and 48% (95% CI, 36% to 59%), respectively. Eight patients (11%) underwent amputation. The 1-year amputation-free survival rate was 47% (95% CI, 35% to 58%). In conclusion, we did not find an invasive approach for the treatment of ALI in cancer patients to be associated with the very high mortality rates previously reported. In our opinion, the indications for surgery or catheter-based intervention in these patients should not differ from patients without cancer. Keywords acute limb ischemia, cancer, ischemia, mortality, peripheral vascular disease
Introduction Acute limb ischemia (ALI) is a vascular emergency and is associated with significant morbidity and mortality. Clinical trials in the general population have established the benefit of catheter-directed thrombolysis and surgery in treating patients who present with this condition.1 Selection of the initial treatment modality varies and depends on several factors including etiology, duration of symptoms, and the severity of ischemia on initial presentation. In general, catheter-directed thrombolysis has been shown to improve limb salvage and to decrease early mortality in selected patients.1 Urgent surgery is appropriate if embolic etiology is suspected or if the limb is immediately threatened, or when thrombolytic therapy is contraindicated. There is no evidence of a difference in the amputation and mortality rates at 1 year between patients initially treated with surgery and those initially treated with thrombolysis.1 Mild ischemic events can sometimes be managed by watchful observation or by anticoagulation therapy alone. Amputation is indicated if irreversible ischemia is established on presentation. Despite the remarkable progress in treating this condition over the past 50 years, data from recent large clinical studies still show a 30-day mortality
rate of up to 15% and amputation rates between 15% and 30%.2 The 1-year survival rate is approximately 80%.2 Much worse outcomes have been reported in patients with certain comorbidities, including cancer. In the Thrombolysis or Peripheral Arterial Surgery (TOPAS) trial, cancer was present in 12% of patients with ALI (12% in the thrombolysis arm, 11% in the surgical arm) and patients with cancer had a higher rate of morbidity and mortality.3,4 Outcomes in cancer patients whose limb ischemia was treated with surgery were extremely poor in two other separate studies that found the associated mortality to be as high
The University of Texas MD Anderson Cancer Center, Houston, TX, USA Corresponding author: Elie Mouhayar The University of Texas MD Anderson Cancer Center 1515 Holcombe Blvd Houston, TX 77030 USA Email: [email protected]
Downloaded from vmj.sagepub.com at NEW YORK UNIV MEDICAL CENTER on April 12, 2015
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Mouhayar et al. as 100% at 2 months.5,6 Based on these findings, conservative management and palliative therapy have been advocated as the most appropriate treatment modality for cancer patients with limb ischemia,7 whereas surgical intervention has been strongly discouraged.5–7 Such an approach, however, is not supported by other researchers: In their recent retrospective analysis of outcomes in 16 cancer patients with ALI, Tsang and colleagues8 reported a 44% survival rate at 1 year following surgical revascularization. Similar findings were reported by Ouriel et al.3 in their subgroup analysis from the TOPAS trial, with an observed 50% amputation-free survival rate at 1 year. To the best of our knowledge, outcomes of other therapeutic interventions (medical therapy, catheter-based intervention, or observation) have not been reported in cancer patients with concomitant ALI. Our objective was to describe and evaluate the survival outcomes of cancer patients presenting with and treated for ALI at our cancer center.
Methods Patient selection This is a retrospective chart review of cancer patients treated for ALI at The University of Texas MD Anderson Cancer Center from 2001 to 2011. The study protocol was reviewed and approved by the institutional review board and a waiver of informed consent was obtained. Patients were identified by their discharge diagnostic codes, and were included if they met the criteria of concomitant malignancy and ALI with symptoms occurring within 15 days prior to current admission. We excluded patients with benign tumors or without active malignancy, and also patients with iatrogenic limb ischemia related to a tumor chemoembolization procedure. Patients’ clinical characteristics, including age, sex, type and stage of malignancy, type of chemotherapy, cardiovascular risk factors and medications at the time of the ischemic event, were extracted from the medical record and tabulated. Advanced malignancy was defined as metastatic disease in patients with solid tumors and as disease relapse or need for stem cell transplantation in patients with hematologic malignancies. The Rutherford staging criteria9 were used to classify the severity of limb ischemia based on the reported initial clinical evaluation by the treating physician. Catheter-based interventions included catheter-directed thrombolysis, arterial angioplasty and/or arterial stenting. Surgical procedures included thrombectomy, embolectomy and/or bypass surgery. The medical therapy category included patients receiving anticoagulation therapy only (heparin or low molecular weight heparin with or without antiplatelets). Pathology reports summarizing histological findings of the retrieved specimen during surgery were reviewed and divided into four separate categories: (1) predominately atherosclerosis, (2) pure thrombus, (3) predominately malignant cells/tumor, and (4) tumor invasion of vessel wall.
Data analysis Overall survival (OS) was defined as the time from the date of hospitalization with the ischemic event to the date of
Table 1. Patients’ clinical characteristics (n=74). Characteristic Age, years Median (range) Sex Female Male Type of cancer Genitourinary tract Gastrointestinal tract Lung Soft tissue and/or sarcoma Hematologic malignancy Other Stage of cancer Advanced Limited Chemotherapy within 6 weeks Cisplatin-based chemotherapy History of atherosclerosis History of atrial fibrillation History of congestive heart failure Cardiovascular risk factors Diabetes mellitus Current smoker Dyslipidemia Hypertension Medications at time of event Aspirin Clopidogrel Unfractionated heparin Low molecular weight heparin Statin Ace inhibitor
Number (%) 61 (25–80) 40 (54) 34 (46) 17 (23) 15 (20) 14 (19) 10 (14) 8 (11) 10 (14) 48 (65) 26 (35) 23 (31) 18 (24) 26 (35) 8 (11) 2 (3) 9 (12) 31 (42) 26 (35) 38 (51) 27 (36) 11 (15) 11 (15) 11 (15) 22 (30) 22 (30)
death or last follow-up. Amputation-free survival was defined as the time from the date of hospitalization for the ischemic event to the date of amputation or death or last follow-up. The Kaplan-Meier method was used to estimate overall survival outcomes. Cox proportional hazards models were fitted to determine the association of patient and clinical characteristics with survival outcomes. Factors that were significantly associated with survival outcomes in the univariate log-rank test were considered in the multivariate Cox models. The final multivariate model only contained factors that had statistical significance. Results were expressed in hazard ratios (HR) and 95% confidence intervals (CIs). A p-value less than 0.05 was considered statistically significant; all tests were two-sided. Statistical analyses were carried out using SAS 9.1 (SAS Institute Inc., Cary, NC, USA) and S-Plus 7.0 (Insightful Corporation, Seattle, WA, USA).
Results Between January 2001 and December 2011, we identified 74 cancer patients with concomitant ALI that met our inclusion criteria. Patients’ clinical characteristics are summarized in Table 1. The median age was 61 years (range 25–80
Downloaded from vmj.sagepub.com at NEW YORK UNIV MEDICAL CENTER on April 12, 2015
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Vascular Medicine 19(2)
Table 2. Treatment modality by severity of limb ischemia. Rutherford class n (%)
Catheter-based intervention
Surgery
Anticoagulation only
No therapy
Amputation
Class I 13 (18%) Class IIa 30 (40%)
1
0
10
2
0
1
17 (6 failed, referred to surgery)
4
2
3
3
3
2
4
10
1
0
1
1
6 (8%)
8 (11%)
Class IIb 29 (39%)
3 (1 failed, referred to surgery)
Class III 2 (3%) Total 74 (100%)
0
14 1. Embolectomy / thrombectomy (7) 2. Bypass (4) 3. Combination (3) 22 1. Embolectomy / thrombectomy (16) 2. Bypass (3) 3. Combination (3) 0
21 (28%)
36 (49%)
18 (24%)
years) and 46% were men. The most common malignancies were of the genitourinary system, followed by the gastrointestinal system. The femoropopliteal or tibial segments were the most commonly affected arteries (48 patients, 65%), followed by the aorto-iliac segments (15 patients, 20%). Brachial or subclavian artery acute thrombosis was found in four patients (three and one, respectively). The majority of patients were categorized as having Rutherford class IIa or IIb (79%) ALI, and only two patients (3%) presented with class III ischemia. Table 2 summarizes the treatment modalities by severity of limb ischemia on initial presentation. The majority of patients with class I ischemia were treated with anticoagulation only with no limb loss and only one died within 30 days. Of the patients with class IIa ischemia, three patients underwent limb amputation (two after failed thrombolysis and one after failed surgery) and three died within 30 days from the ischemic event. Most patients with class IIb ischemia (22 out of 29 patients) underwent surgical revascularization with four failures requiring limb amputation. A total of 10 patients in this group died within 30 days, including two patients who received no therapy, three patients who received anticoagulation therapy only, one patient who received thrombolysis and four surgical patients. Severe co-morbidities that were prohibitive to any invasive or medical intervention were encountered with six patients (8%): one recovering from brain surgery for a metastatic lesion, three with severe thrombocytopenia (
VMJ0010.1177/1358863X14523063Vascular MedicineMouhayar et al.
Original Article
Outcome of acute limb ischemia in cancer patients
Vascular Medicine 2014, Vol. 19(2) 112–117 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1358863X14523063 vmj.sagepub.com
Elie Mouhayar, Jean Tayar, Mark Fasulo, Reem Aoun, Mona Massey, Simon Abi-Aad, Cezar Iliescu, Kamran Ahrar and Tam Huynh Abstract
The optimal management strategy for acute limb ischemia (ALI) in patients with a concomitant malignancy is not well established. A very high mortality rate (83–100%) at 1 year has been reported in those who are treated surgically. Accordingly, a conservative management approach has been suggested as the main therapeutic modality. Our aim was to evaluate the survival outcomes of cancer patients treated for ALI at our cancer center. Cancer patients treated for ALI at the MD Anderson Cancer Center from 2001 to 2011 were included in this study. Overall survival and amputation-free survival rates were calculated. A total of 74 cancer patients with concomitant ALI were included in the study. Surgery was the most common therapy (36 patients; 49%). Percutaneous catheter-based interventions were used in 21 patients (28%). Eighteen patients (24%) received anticoagulation therapy only, and six patients (8%) received no therapy. The 30-day, 6-month, and 1-year overall survival rates were 80% (95% confidence interval [CI], 69% to 87%), 59% (95% CI, 47% to 69%), and 48% (95% CI, 36% to 59%), respectively. Eight patients (11%) underwent amputation. The 1-year amputation-free survival rate was 47% (95% CI, 35% to 58%). In conclusion, we did not find an invasive approach for the treatment of ALI in cancer patients to be associated with the very high mortality rates previously reported. In our opinion, the indications for surgery or catheter-based intervention in these patients should not differ from patients without cancer. Keywords acute limb ischemia, cancer, ischemia, mortality, peripheral vascular disease
Introduction Acute limb ischemia (ALI) is a vascular emergency and is associated with significant morbidity and mortality. Clinical trials in the general population have established the benefit of catheter-directed thrombolysis and surgery in treating patients who present with this condition.1 Selection of the initial treatment modality varies and depends on several factors including etiology, duration of symptoms, and the severity of ischemia on initial presentation. In general, catheter-directed thrombolysis has been shown to improve limb salvage and to decrease early mortality in selected patients.1 Urgent surgery is appropriate if embolic etiology is suspected or if the limb is immediately threatened, or when thrombolytic therapy is contraindicated. There is no evidence of a difference in the amputation and mortality rates at 1 year between patients initially treated with surgery and those initially treated with thrombolysis.1 Mild ischemic events can sometimes be managed by watchful observation or by anticoagulation therapy alone. Amputation is indicated if irreversible ischemia is established on presentation. Despite the remarkable progress in treating this condition over the past 50 years, data from recent large clinical studies still show a 30-day mortality
rate of up to 15% and amputation rates between 15% and 30%.2 The 1-year survival rate is approximately 80%.2 Much worse outcomes have been reported in patients with certain comorbidities, including cancer. In the Thrombolysis or Peripheral Arterial Surgery (TOPAS) trial, cancer was present in 12% of patients with ALI (12% in the thrombolysis arm, 11% in the surgical arm) and patients with cancer had a higher rate of morbidity and mortality.3,4 Outcomes in cancer patients whose limb ischemia was treated with surgery were extremely poor in two other separate studies that found the associated mortality to be as high
The University of Texas MD Anderson Cancer Center, Houston, TX, USA Corresponding author: Elie Mouhayar The University of Texas MD Anderson Cancer Center 1515 Holcombe Blvd Houston, TX 77030 USA Email: [email protected]
Downloaded from vmj.sagepub.com at NEW YORK UNIV MEDICAL CENTER on April 12, 2015
113
Mouhayar et al. as 100% at 2 months.5,6 Based on these findings, conservative management and palliative therapy have been advocated as the most appropriate treatment modality for cancer patients with limb ischemia,7 whereas surgical intervention has been strongly discouraged.5–7 Such an approach, however, is not supported by other researchers: In their recent retrospective analysis of outcomes in 16 cancer patients with ALI, Tsang and colleagues8 reported a 44% survival rate at 1 year following surgical revascularization. Similar findings were reported by Ouriel et al.3 in their subgroup analysis from the TOPAS trial, with an observed 50% amputation-free survival rate at 1 year. To the best of our knowledge, outcomes of other therapeutic interventions (medical therapy, catheter-based intervention, or observation) have not been reported in cancer patients with concomitant ALI. Our objective was to describe and evaluate the survival outcomes of cancer patients presenting with and treated for ALI at our cancer center.
Methods Patient selection This is a retrospective chart review of cancer patients treated for ALI at The University of Texas MD Anderson Cancer Center from 2001 to 2011. The study protocol was reviewed and approved by the institutional review board and a waiver of informed consent was obtained. Patients were identified by their discharge diagnostic codes, and were included if they met the criteria of concomitant malignancy and ALI with symptoms occurring within 15 days prior to current admission. We excluded patients with benign tumors or without active malignancy, and also patients with iatrogenic limb ischemia related to a tumor chemoembolization procedure. Patients’ clinical characteristics, including age, sex, type and stage of malignancy, type of chemotherapy, cardiovascular risk factors and medications at the time of the ischemic event, were extracted from the medical record and tabulated. Advanced malignancy was defined as metastatic disease in patients with solid tumors and as disease relapse or need for stem cell transplantation in patients with hematologic malignancies. The Rutherford staging criteria9 were used to classify the severity of limb ischemia based on the reported initial clinical evaluation by the treating physician. Catheter-based interventions included catheter-directed thrombolysis, arterial angioplasty and/or arterial stenting. Surgical procedures included thrombectomy, embolectomy and/or bypass surgery. The medical therapy category included patients receiving anticoagulation therapy only (heparin or low molecular weight heparin with or without antiplatelets). Pathology reports summarizing histological findings of the retrieved specimen during surgery were reviewed and divided into four separate categories: (1) predominately atherosclerosis, (2) pure thrombus, (3) predominately malignant cells/tumor, and (4) tumor invasion of vessel wall.
Data analysis Overall survival (OS) was defined as the time from the date of hospitalization with the ischemic event to the date of
Table 1. Patients’ clinical characteristics (n=74). Characteristic Age, years Median (range) Sex Female Male Type of cancer Genitourinary tract Gastrointestinal tract Lung Soft tissue and/or sarcoma Hematologic malignancy Other Stage of cancer Advanced Limited Chemotherapy within 6 weeks Cisplatin-based chemotherapy History of atherosclerosis History of atrial fibrillation History of congestive heart failure Cardiovascular risk factors Diabetes mellitus Current smoker Dyslipidemia Hypertension Medications at time of event Aspirin Clopidogrel Unfractionated heparin Low molecular weight heparin Statin Ace inhibitor
Number (%) 61 (25–80) 40 (54) 34 (46) 17 (23) 15 (20) 14 (19) 10 (14) 8 (11) 10 (14) 48 (65) 26 (35) 23 (31) 18 (24) 26 (35) 8 (11) 2 (3) 9 (12) 31 (42) 26 (35) 38 (51) 27 (36) 11 (15) 11 (15) 11 (15) 22 (30) 22 (30)
death or last follow-up. Amputation-free survival was defined as the time from the date of hospitalization for the ischemic event to the date of amputation or death or last follow-up. The Kaplan-Meier method was used to estimate overall survival outcomes. Cox proportional hazards models were fitted to determine the association of patient and clinical characteristics with survival outcomes. Factors that were significantly associated with survival outcomes in the univariate log-rank test were considered in the multivariate Cox models. The final multivariate model only contained factors that had statistical significance. Results were expressed in hazard ratios (HR) and 95% confidence intervals (CIs). A p-value less than 0.05 was considered statistically significant; all tests were two-sided. Statistical analyses were carried out using SAS 9.1 (SAS Institute Inc., Cary, NC, USA) and S-Plus 7.0 (Insightful Corporation, Seattle, WA, USA).
Results Between January 2001 and December 2011, we identified 74 cancer patients with concomitant ALI that met our inclusion criteria. Patients’ clinical characteristics are summarized in Table 1. The median age was 61 years (range 25–80
Downloaded from vmj.sagepub.com at NEW YORK UNIV MEDICAL CENTER on April 12, 2015
114
Vascular Medicine 19(2)
Table 2. Treatment modality by severity of limb ischemia. Rutherford class n (%)
Catheter-based intervention
Surgery
Anticoagulation only
No therapy
Amputation
Class I 13 (18%) Class IIa 30 (40%)
1
0
10
2
0
1
17 (6 failed, referred to surgery)
4
2
3
3
3
2
4
10
1
0
1
1
6 (8%)
8 (11%)
Class IIb 29 (39%)
3 (1 failed, referred to surgery)
Class III 2 (3%) Total 74 (100%)
0
14 1. Embolectomy / thrombectomy (7) 2. Bypass (4) 3. Combination (3) 22 1. Embolectomy / thrombectomy (16) 2. Bypass (3) 3. Combination (3) 0
21 (28%)
36 (49%)
18 (24%)
years) and 46% were men. The most common malignancies were of the genitourinary system, followed by the gastrointestinal system. The femoropopliteal or tibial segments were the most commonly affected arteries (48 patients, 65%), followed by the aorto-iliac segments (15 patients, 20%). Brachial or subclavian artery acute thrombosis was found in four patients (three and one, respectively). The majority of patients were categorized as having Rutherford class IIa or IIb (79%) ALI, and only two patients (3%) presented with class III ischemia. Table 2 summarizes the treatment modalities by severity of limb ischemia on initial presentation. The majority of patients with class I ischemia were treated with anticoagulation only with no limb loss and only one died within 30 days. Of the patients with class IIa ischemia, three patients underwent limb amputation (two after failed thrombolysis and one after failed surgery) and three died within 30 days from the ischemic event. Most patients with class IIb ischemia (22 out of 29 patients) underwent surgical revascularization with four failures requiring limb amputation. A total of 10 patients in this group died within 30 days, including two patients who received no therapy, three patients who received anticoagulation therapy only, one patient who received thrombolysis and four surgical patients. Severe co-morbidities that were prohibitive to any invasive or medical intervention were encountered with six patients (8%): one recovering from brain surgery for a metastatic lesion, three with severe thrombocytopenia (
