1 National Cancer Institute and 2 Clinical Center, National Institutes of Health, Bethesda, MD, USA
* Correspondence to:Dr M. W. Saif, University of Alabama at Birmingham, 263 Wallace Tumor Institute, 1530 3rd Avenue South, Birmingham, AL 35294-3300, USA. Tel: +1-205-934-0916; Fax: +1-205-934-1608; Email: wasif.saif{at}ccc.uab.edu
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Abstract |
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Patients and methods: Patients were participants in clinical trials of high-dose chemotherapy with autologous PBSC rescue. They underwent mobilization with either high-dose cyclophosphamide (n=21) or cyclophosphamide/paclitaxel (n=64), followed by filgrastim. Double lumen catheters (12 or 13 Fr) were placed in the femoral vein and removed within 12 h of the last apheresis procedure. Apheresis was performed using a continuous flow cell separator and ACD-A anticoagulant. Thromboembolism was diagnosed by either venous ultrasonography or ventilation-perfusion scan.
Results: Nine of 85 patients (10.6%) undergoing large volume apheresis with use of a femoral catheter developed thromboembolic complications. Pulmonary embolus (PE) was diagnosed in five and femoral vein thrombosis in four patients. Four of the five patients who developed PE were symptomatic; one asymptomatic patient had a pleural-based, wedge-shaped lesion detected on a staging computed tomography scan. The mean number of apheresis procedures was 2.4 (range one to four) and the mean interval between removal of the apheresis catheter and diagnosis of thrombosis was 17.6 days. In contrast, none of 18 patients undergoing apheresis using jugular venous access and none of 54 healthy allogeneic donors undergoing concurrent filgrastim-mobilized PBSC donation (mean 1.7 procedures/donor) using femoral access experienced thromboembolic complications.
Conclusions: Thromboembolism following femoral venous catheter placement for PBSC collection in patients with breast cancer may be more common than previously recognized. Healthy PBSC donors are not at the same risk. Onset of symptoms related to thrombosis tended to occur several weeks after catheter removal. This suggests that the physicians not only need to be vigilant during the period of apheresis, but also need to observe patients for thromboembolic complications after the catheter is removed. The long interval between the removal of apheresis catheter and the development of thromboembolism may have a potential impact on prophylactic strategies developed in future, such as the duration of prophylactic anticoagulation. Avoidance of the femoral site in breast cancer patients, and close prospective monitoring after catheter removal, are indicated.
Key words: apheresis, breast cancer, femoral apheresis catheters, malignancy, peripheral blood stem cell transplantation, thromboembolism
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Introduction |
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Central venous catheters have greatly simplified the performance of apheresis in patients undergoing autologous PBSC collection. It is frequently necessary to process three to four blood volumes daily in order to collect an adequate stem cell dose [6, 7
]. A constant blood inlet flow is required to obtain a stable mononuclear cell layer inside the device, so that mononuclear cell collection can proceed with the greatest efficiency. Moreover, high flow rates are required since apheresis requires withdrawal and return of a large volume of blood [8
]. This constant and high flow rate is often achievable only with use of a large-gauge central venous catheter, particularly in patients who have previously received chemotherapy.
Many different types of catheters and sites of insertion have been used for PBSC collection. Thrombotic occlusion has been reported as a complication of apheresis in as many as 80% of subclavian catheters, whose tips are placed at the junction of the innominate vein and superior vena cava [9], and in 20% of inferior vena cava catheters [10
]. The femoral site has been used less commonly due to concerns over infectious complications, in settings where catheters are in place for extended periods [11
, 12
]. However, placement of femoral catheters for a short duration decreases the risk of infection compared with longer duration placement [13
, 14
], and may be associated with a lower incidence of serious hemorrhagic events related to trauma of critical nearby structures. The femoral vein is increasingly regarded as an optimal short-term catheterization site in patients undergoing PBSC autotransplantation.
Patients with adenocarcinoma are known to be at increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE). Since the prevalence of catheter-associated thromboembolism with short-term femoral vein catheters is not known, we performed a retrospective study of catheter-related thrombotic events in patients with breast cancer undergoing femoral vein catheterization to facilitate autologous PBSC collection.
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Patients and methods |
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Study 1
A pilot study of paclitaxel/cyclophosphamide and high dose melphalan/etoposide with autologous PBSC rescue for the treatment of metastatic and high risk breast cancer (n=92). PBSCs were collected during filgrastim-assisted recovery (10 µg/kg/day for 1014 days) after at least three cycles of cyclophosphamide (2.7 g/m2) plus paclitaxel (160 mg/m2). Patients subsequently received high-dose melphalan and etoposide followed by PBSC infusion.
Study 2
Antimetabolite induction, high-dose alkylating agent consolidation and gene-modified PBSC infusion, followed by sequential paclitaxel and doxorubicin for stage IV breast cancer (n=27). The intent of this trial was to determine whether MDR1-modified PBSC could be expanded in vivo after non-ablative chemotherapy. Patients received methotrexate, leucovorin and 5-fluorouracil for two to four cycles, followed by three cycles of high-dose cyclophosphamide (4 g/m2). PBSC were collected during filgrastim-assisted recovery (10 µg/kg/day for 1014 days) after the first cyclophosphamide cycle. High-dose thiotepa with PBSC rescue and daily filgrastim was then followed by four cycles of infusional paclitaxel and four cycles of doxorubicin [15].
Catheters
Femoral venous access was achieved by using a rigid polyurethane heparin-coated double-lumen catheter (12 or 13 Fr; Arrow International, Reading, PA, USA) initially designed for hemodialysis. For jugular venous access, a double-lumen Hickman catheter (12 Fr; Bard Access Systems, Salt Lake City, UT, USA) or a triple-lumen Pheres-Flow catheter (12 Fr, Horizon Medical Products, Manchester, GA, USA) was used. All catheters were placed under local anesthesia by a member of the vascular access device placement team, immediately prior to the start of leukapheresis. Informed consent for catheter placement was obtained in all cases. Catheters were inserted percutaneously into the femoral vein (right : left ratio, 4 : 1) using a modified Seldinger guide wire. They were sutured in place and the site was covered with sterile dressing. Following each apheresis session, the catheter ports were flushed with 5 ml of saline and 1.5 ml of heparin solution (Heparin Lock Flush, 100 U/ml; Abbott Laboratories, North Chicago, IL, USA) and then capped. The site of insertion was cleaned with alcohol and Betadine and covered with a sterile dressing. Catheters were removed within 12 h of the last apheresis procedure, when quantitation of the cellular content of the apheresis product was completed.
All patients were admitted as in-patients if more than one apheresis procedure was required. Prophylactic anticoagulation was not administered. Daily inspection of the insertion site for redness, tenderness, rash or leakage was performed by nursing staff. Occlusion of the catheter was suspected when inadequate blood flow rates or inability to withdraw blood were observed.
Apheresis
Collections were initiated when the white cell count first exceeded 4 x 109/l or when a measurable population of CD34 + cells (>20 cells/µl) was found in the circulating blood during daily flow cytometric monitoring. Apheresis was performed using a CS-3000 Plus continuous-flow cell separator (Baxter Healthcare, Deerfield, IL, USA) with acid citrate dextrose formula A (ACD-A) anticoagulant at a 1 : 12 to 1 : 13 ratio with whole blood. Inlet blood flow rates ranged from 50 to 85 ml/min. The minimum targeted stem cell dose was 2 x 106 CD34+ cells/kg. Attempts were undertaken to limit any single collection to <5 h.
Study design
Thromboembolic events were detected by retrospective review of medical records, protocol toxicity records and imaging studies of patients with breast cancer enrolled in two high-dose chemotherapy trials. The relevant records of all patients who had undergone central venous catheter placement to facilitate PBSC collection were examined The medical records and follow-up information on all healthy allogeneic donors undergoing PBSC donation with use of a femoral catheter (12 or 13 Fr; Arrow International) during the same period were also reviewed.
Diagnosis of DVT and PE
The diagnoses of DVT and PE were confirmed with venous ultrasound and ventilation-perfusion scan, respectively. The occurrence of thrombosis in the catheterized femoral vein, in the absence of thrombosis in the contralateral vein, was considered a positive finding. Patients who had bilateral femoral thrombosis were noted but not included in the calculations of catheter-associated thrombosis. Not only symptomatic patients but also patients with radiological imaging consistent with pulmonary thromboembolism (PTE) were also included. A computed tomography (CT) scan finding suggesting PTE such as a wedge-shaped defect was followed by a V/Q scan to further confirm the diagnosis and differentiate from a pulmonary metastatsis.
Statistical methods
The significance of differences between populations was determined using Fisher's exact test.
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Results |
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Mean time between removal of the apheresis catheter and diagnosis of a thromboembolic event was 17.6 days (range 235). Similarly, mean time elapsed between the last dose of chemotherapy and diagnosis of thromboembolism was 14 days. Average leukocyte counts on the first day of apheresis and on the day the thromboembolic event was diagnosed were 26 300 and 2351/µl, respectively. Average platelet counts on the first day of apheresis and on the day of diagnosis of the thromboembolic event were 27 000 and 170 000/µl, respectively. During the same period as these events, January 1996 to January 2000, none of 54 healthy allogeneic donors (38 males and 16 females, mean age 38.3 years, mean number of apheresis procedures 1.7) developed symptomatic thromboembolic events following filgrastim-mobilized PBSC donation using femoral venous access (Table 1).
Comparison of the two breast cancer treatment groups revealed that the proportion of patients developing thromboembolic events, four of 21 (19%) in the group undergoing stem cell mobilization with cyclophosphamide alone, was not significantly different from that of the group undergoing mobilization with cyclophosphamide plus paclitaxel, five of 64 (8%) (P=0.08). However, the occurrence of thrombosis in patients who underwent PBSC collection using femoral access (nine of 85) was significantly greater than in cases where jugular access alone was used (zero of 18 patients) (P <0.05). Lastly, thrombosis occurred significantly more often in patients with breast cancer donating for autologous use (nine of 85) than in healthy subjects donating for allogeneic use (zero of 54) (P=0.02).
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Discussion |
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Placement of femoral catheters was initially discouraged, due to an increased incidence of bacteremia when such applicances were left in place for a long time, as in hemodialysis [11]. However, the short-term nature of the catheter requirement for PBSC collection, the increasing discomfort and hemorrhagic risk of large bore catheters placed in the subclavian location, the lack of pneumothorax risk and lack of need for radiographic confirmation of correct placement, all combined to make femoral access an increasingly attractive option for temporary apheresis access. The absence of catheter-related bacteremia in our study patients, and the fact that a transplantable number of progenitor cells could be collected in one or two sessions in >90% of patients, confirm these expectations.
A surprisingly high incidence of symptomatic venous thrombosis was detected in our study, despite the short-term nature of the catheter use. More than 10% of all patients (nine of 85) developed thrombosis, 9% (eight of 85) experienced symptomatic events and nearly 6% (five of 85) developed PE. Although thrombotic occlusion has been reported as a complication of apheresis in a high proportion of long-term catheters, reaching 80% with subclavian [9] and 20% with inferior vena cava [10
] catheters, the incidence of PE was markedly higher in our study than in prior studies of long-term indwelling catheters (subclavian or internal jugular, 0.2% [18
]). Even more surprisingly, our data suggest that thrombotic complications can develop long after the removal of the apheresis catheter, in contrast to prior studies in which thrombosis was detected while the catheter was still in the blood vessel [17
19
]. Furthermore, it is likely that our study design, a retrospective chart review, underestimated the true incidence of thrombosis, in that only symptomatic cases were detected, and prospective surveillance studies were not performed.
In contrast to our findings, two prior studies of short-term femoral catheterization for autologous PBSC collection revealed a lower incidence of thrombotic events, although study methods differed (Table 3). Shariatmadar and Noto [16] retrospectively reviewed the records of 63 cancer patients who underwent 101 PBSC collections via femoral access. No thrombotic complications were encountered. The longest duration of catheter placement was 6 days. Adorno et al. [17
] prospectively studied 147 cancer patients undergoing 488 PBSC collections using dual-lumen femoral access. Mobilization was with granulocyte colony-stimulating factor alone or in combination with chemotherapy. All patients received systemic anticoagulation with low molecular weight heparin and ultrasound examination was routinely performed after removal of the catheter. Seven of 147 patients (4.8%) developed thrombosis as evidenced by ultrasound carried out immediately after catheter removal. Although this experience is similar to the rate of symptomatic femoral thrombosis found in the current study, no episodes of PE were seen. It is possible that differing diagnoses (hematologic malignancy versus adenocarcinoma) or treatment regimens, varying methods of patient follow-up, differing techniques of catheter placement or removal, or different types of catheters could explain these divergent findings. Our study data argue against a strong effect of catheter type, however, in that the same femoral catheter that was associated with a 10% incidence of thrombosis in breast cancer patients did not result in symptomatic thrombosis when placed in the jugular location in breast cancer patients, or when placed in the femoral location in healthy allogeneic donors. This suggests a unique and increased risk for catheter-related thrombosis in patients with advanced breast cancer undergoing short-term femoral vein catheterization. It is possible that the sustained immobility and obligate bed-rest necessitated by sequential daily 45 h apheresis procedures using femoral access are responsible for this increased risk. Patients with jugular access were not obligated to observe strict bed-rest between procedures, or to be strictly immobile during lengthy apheresis procedures. Healthy donors were younger, had their catheters in place for significantly shorter periods of time, did not have systemic disease or sustained immobility and were not receiving chemotherapy.
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The role of growth factors in promoting thrombus formation is unclear. Enhanced neutrophil-endothelial cell interactions and aggregation of sticky neutrophils at catheter tips, where they can cause damage to vascular endothelium, have been hypothesized [26]. The role of platelets in catheter thrombosis is also unclear. Previous investigators have found a longer thrombus-free survival in patients whose catheter was placed when their platelet count was <80 K as compared with the presence of a higher platelet count in the patients who developed thrombosis [32
]. Thrombocytopenia at the time of catheter placement may delay thrombus formation, which becomes evident only days to weeks later when the platelet count returns to normal [32
]. The development of clinical thrombosis days to weeks after catheter placement in the majority of our subjects, at a time when chemotherapy-induced thrombocytopenia had resolved, supports this mechanism as evidenced by an average platelet count of 27 K on day 1 of apheresis and 170 K on the day of diagnosis of a thromboembolic event.
Systemic anticoagulation and use of antiplatelet agents have both been recommended as prophylactic measures to reduce the incidence of thrombosis in central venous catheter placement for PBSC collection. Haire et al. [32] reported a significant reduction in inferior vena cava catheter occlusion rates with aspirin 325 mg daily. In contrast, Adorno et al. [17
] found a 4.8% (seven of 147) incidence of femoral thrombosis with use of prophylactic low molecular weight heparin.
Our study shows that short-term femoral venous catheters for PBSC collection in patients with advanced breast cancer are not as safe as previously thought. Prospective non-invasive monitoring at the time of catheter removal and close clinical follow-up for several weeks after catheter removal are indicated. We also suggest that the physicians need to be vigilant during the period of apheresis for thromboembolic complications as well as observe these patients for such complications after the catheter is removed. The long interval between the removal of apheresis catheter and the development of thromboembolism may have a potential impact on prophylactic strategies developed in future, such as the duration of prophylactic anticoagulation. Our data also suggest that in this population, jugular rather than femoral catheterization may be preferable. In addition, healthy allogeneic donors do not appear to be at the same risk for catheter-related thrombosis as patients with breast cancer.
Received for publication September 26, 2003. Revision received April 30, 2004. Accepted for publication May 3, 2004.
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