The Surgeon, the Cancer Patient, and Venous Thromboembolism:
At a symposium held in March 2004, during the Annual Meeting of the Society of Surgical Oncology,a panel of experts discussed
prevention and treatment of venous thromboembolism in surgical oncology patients.
This program was supported by an educational grant from Pfizer Inc.
The Incidence and Risks of Thrombosis in Surgical Oncology Patients
Frederick R. Rickles, MD, Professor of Medicine, Pediatrics, Pharmacology, and Physiology, The George Washington University School of Medicine, Wash-
ington, DC, discussed the epidemiology and pathogenesis of venous thromboembolism (VTE) in cancer patients, as well as the potential role of anticoagulants in prolonging survival.
“From the little data that exist on the incidence of VTE in oncologic surgical patients, it’s possible to make some generalizations,” said Dr. Rickles. For example, the incidence of VTE increases with increasing stage of disease, and cancer patients appear to have a higher rate of recurrence of VTE than non-cancer patients. A prospective study by Prandoni and coworkers looked at 11 years of data and found that the recurrence rate for patients with cancer was about 3.2-fold higher than for those without cancer, even when the patients were on chronic oral anticoagulant therapy and were within the appropriate therapeutic range (Blood. 2002;100: 3484-3488).
Dr. Rickles remarked that VTE is probably a bad prognostic marker. A large, retrospective study of the Medicare data base by Levitan and coworkers found that patients who present with a combination of thrombosis and malignant disease had a four-fold increased risk for death within 183 days of initial hospitalization compared to cancer patients without VTE (Medicine. 1999;78: 285-291). Similar data were published by Sorensen et al. based on a large Scandinavian registry (N Engl J Med. 2000;343:1846-1850).
“Hypercoagulability is a primary characteristic of most cancer patients,” said Dr. Rickles. Furthermore, many cancer patients are at risk for VTE due to prolonged bed rest or vascular injury from direct invasion by the tumor or prolonged use of central venous catheters. Additionally, “tumor cells stick to the vascular endothelium and secrete a variety of inflammatory mediators; they directly injure the endothelium and interact with platelets and host macrophages to further aggravate the host inflammatory response,” he said.
“Activated macrophages interact with malignant cells to generate more procoagulant material and activate clotting via several pathways; ultimately thrombin is generated and fibrin is formed around tumors, which provides a medium ideal for additional tumor growth and activation of clotting,”
Dr. Rickles continued.
Low-Molecular-Weight Heparins and Cancer Survival
“Substantial experimental evidence in model tumor systems suggests that anticoagulants can inhibit primary tumor growth and metastasis in a dose-dependent manner,” said Dr. Rickles. This has been observed with warfarin, unfractionated heparin, and the low-molecular-weight heparins. Clinical trial evidence is less certain, but adding anticoagulants has been associated with improvements in response rate, disease-free and median survivals, and overall survival in some tumor types.
Dr. Rickles cited four prospective, randomized trials, beginning with a study by Von Tempelhoff and colleagues, in which 324 surgical oncology patients with either breast or pelvic cancer were randomized to the low-molecular-weight heparin certoparin or unfractionated heparin at prophylactic doses given two hours preoperatively and daily for seven days to try to mimic the standard prophylactic regimen (Int J Oncol. 2000; 16:815-824). Mortality was reduced with certoparin (11% vs. 31%; p = 0.005) after 1.8 years median follow-up.
In the Malignancy and Low-Molecular-Weight Heparin Therapy (MALT) study by Klerk and coworkers, 302 patients without VTE but with noncurable solid tumors were randomized to placebo or therapeutic doses of the low-molecular-weight heparin nadroparin for two weeks, followed by half that dose for four more weeks (J Thromb Haemost. 2003; July [Suppl 1] abstract OC195). There was a statistically significant increase in median survival extrapolated to eight months for the nadroparin group versus 6.6 months for the placebo group. In an a priori specified subgroup analysis, among those patients who survived greater than 6 months, median survival in the certoparin group was 15.4 months vs. 9.4 months in the placebo group (hazard ratio 0.64; 0.45-0.90).
In the Fragmin Advanced Malig-nancy Outcome Study (FAMOUS), conducted by Kakkar and coworkers, patients were randomized to placebo or dalteparin (J Clin Oncol. 2004;22:1944-1948). “No difference in survival was seen, although in a post-hoc subgroup analysis of patients who survived longer than 17 months and had less burden of disease at the time of randomization, there was a statistically significant improvement in survival among the
dalteparin group,” said Dr. Rickles.
A post-hoc analysis of the multicenter, randomized, open-label CLOT study (Comparison of Low-Molecular-Weight Heparin versus Oral Anti-coagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer), conducted by Lee and colleagues (N Engl J Med. 2003;349:146-153), in which patients with proximal deep vein thrombosis (DVT), pulmonary embolism (PE), or both all received dalteparin followed by either oral anticoagulants or continued dalteparin for six months, revealed a potential benefit of the dalteparin treatment regimen on survival. The post-hoc analysis showed that while there was no difference in overall 12-month mortality between the two treatment groups, among patients with acute VTE and metastatic solid tumors, long-term dalteparin was associated with a 50% reduction in mortality compared to oral anticoagulant therapy in patients with acute VTE but without observable metastasis at initial presentation (J Clin Oncol. 2003; ASCO abstract 846).
Case Study in Urologic Oncology
Ihor Sawczuk, MD, Chairman, Department of Urology, Hackensack University Medical Center, New Jersey, presented the case of an elderly man with gross hematuria. He had a muscle invasive high-grade transitional cell carcinoma of the bladder and underwent radical cystoprostatectomy with bilateral lymph node dissection and ileo-conduit urinary diversion. Prophylaxis was a low-molecular-weight heparin prior to surgery and daily for seven days, along with IPC and early ambulation. He had no subsequent clinical evidence of VTE.
Risk factors for VTE in urologic patients include advanced age, malignancy, prolonged operative time, pelvic surgery, and immobility. The incidence of VTE is 8% with cystectomies and ranges from 6.3% to 17.4% with open prostatectomies. With radical pelvic surgery, the incidence is 30% without prophylaxis, which decreases to 10% with prophylaxis. However, low-dose heparin is associated with possible surgical complications, including lymphoceles and pelvic drainage and bleeding, and there is an increased incidence of wound hematomas, wound infection, and heparin-induced thrombocytopenia.
Dr. Sawczuk described a study he and coworkers conducted that used dalteparin for VTE prophylaxis in surgical patients with urologic malignancies. Patients were pretreated with dalteparin and then given it daily for seven days (Cancer Investigation. 2002; 20:889-892). “We found no DVTs or PEs,” he said. There was one lymphocele and no other significant side effects. “In these patients, dalteparin is safe and tolerable and there is convenient dosing,” he said.
Case Study in Breast Cancer
“The incidence of VTE with breast cancer is not known, but patients receiving chemotherapy for breast cancer do have an increased incidence of thromboembolic complications,” said Barry Feig, MD, Associate Professor, Department of Surgical Oncology and Medical Director, Surgical/Critical Care Unit, University of Texas, M.D. Anderson Cancer Center, Houston.
He presented the case of a 66-year-old woman with a history of obesity and hypertension. After a normal mammogram, she underwent cosmetic bilateral
reduction mammoplasties, during which invasive lobular carcinoma was detected in her left breast (2 cm, Grade 3). She also had lobular carcinoma in situ (LCIS) in the right breast, and 16 of 16 lymph nodes were positive for metastatic disease. She underwent right and left total mastectomy and a left node dissection. Her locally advanced disease put her at higher than average risk for DVT.
Prophylaxis consisted of IPC boots and elastic compression stockings. She returned on day 13 with right calf tenderness. Ultrasound showed a thrombus, and she was started on intravenous heparin, converted to warfarin, and the pain subsided.
Dr. Feig emphasized that many questions remain about which breast cancer patients require thromboembolic prophylaxis. He cited a study showing higher incidences of thromboembolic disease in postmenopausal women and in women undergoing mastectomy versus lumpectomy.
Preventing Venous Thromboembolism in the Cancer Patient
“Cancer patients undergoing surgery have a particularly high risk of developing VTE,” said Agnes Lee, MD, Assistant Professor, Division of Hematology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. In addition to the reasons described by Dr. Rickles, the type of underlying surgery affects the risk for VTE.
Dr. Lee discussed primary and secondary prophylaxis. Beginning with primary prophylaxis, she noted that early ambulation, elastic stockings, and intermittent pneumatic compression (IPC) boots may reduce the risk of DVT, but no solid evidence shows that they reduce the incidence of PE.
“There is evidence that the pharmacologic agents are highly effective in reducing both DVT and PE,” she said. According to a meta-analysis by Mismetti and coworkers, once-daily low-molecular-weight heparin and two or three times daily low-dose unfractionated heparin are equivalent in their ability to prevent asymptomatic VTE and PE. There is also no difference in the incidence of death, major hemorrhage, wound hematoma, and need for transfusion (Br J Surg. 2001;88:913-930).
Dr. Lee discussed types of surgery,beginning with colorectal. She cited two studies of patients undergoing colorectal surgery (one included both cancer and noncancer patients, while the other involved only cancer patients). In both studies, there was no difference in rates of DVT or PE between groups receiving perioperative enoxaparin and those receiving low-dose unfractionated heparin.
Dr. Lee noted that in both studies the event rate, even with prophylaxis, was about 15%. It has been suggested that this could be further reduced by
extending prophylaxis beyond the time of hospitalization. In the ENOXACAN II study by Bergqvist and colleagues, patients undergoing elective surgery for curative colorectal cancer received enoxaparin for the first 6 to 10 days in the hospital, and then were randomized to receive enoxaparin or placebo for three weeks (N Engl J Med. 2002;346: 975-980). The low-molecular-weight heparin reduced the rate of VTE by 60%, bringing the event rate down to about 5%.
In a more recent study by Ras-mussen and coworkers, patients undergoing elective abdominal surgery for cancer received dalteparin for seven days and then were randomized to dalteparin or no treatment for 21 days (not yet published; reviewed in Cancer Trial Rev. 2002; 28:141-144). There was a significant reduction in the proximal DVT event rate in patients who received prolonged treatment with dalteparin.
Gynecologic and urologic cancer
Dr. Lee next addressed VTE prophylaxis in patients undergoing surgery for gynecologic cancer, noting that the postoperative risk of DVT and PE is 12% to 35%. Very little data are available on this group, but it has been shown that low-dose unfractionated heparin given twice a day is ineffective; however, if it’s given three times a day, risk is reduced by about 50%. Small studies have shown that once-daily low-molecular-weight heparin also reduces risk by about the same degree.
Patients undergoing urologic surgery have also not been well studied. Small studies have suggested that prophylaxis with low-dose unfractionated heparin or low-molecular-weight heparin are effective and safe; however, because of the risk for pelvic hematoma and lymphocele formation, surgeons tend to be reluctant to use pharmacological prophylaxis. The American College of Chest Physicians (ACCP) guidelines recommend early ambulation for low risk procedures and the combination of mechanical methods and low-dose unfractionated heparin or low-molecular-weight heparin for high risk ones.
Neurosurgery and orthopedic surgery
The risk of VTE in patients undergoing neurosurgery, most of whom have malignancies, is about 30% to 40%. However, because these patients also have a high risk for intracranial or intraspinal hemorrhage, mechanical prophylaxis has always been the preferred method of prophylaxis.
“The use of anticoagulant prophylaxis remains controversial despite three well-conducted, randomized trials that showed that low-molecular-weight
heparin is effective and safe in patients undergoing neurosurgery,” said Dr. Lee. Iorio and Agnelli performed a meta-analysis of trials that compared low-molecular-weight heparin to use of elastic stockings and demonstrated that the anticoagulant reduced VTE by about 40% to 50% (Arch Intern Med. 2000;160: 2327-2332).
Because insufficient data exist regarding cancer patients undergoing orthopedic surgery, most information is extrapolated from elective joint
replacement studies. Risk of postoperative DVT and PE in these patients is substantially elevated and low-molecular-weight heparin has been shown to be superior to low-dose unfractionated heparin for efficacy and safety.
If a surgical oncology patient does not receive primary VTE prophylaxis or it fails to work, treatment for VTE may become necessary. To evaluate the safety and efficacy of dalteparin versus oral anticoagulation for the acute treatment of VTE and long-term prevention of recurrence, Dr. Lee and her colleagues conducted the CLOT in Cancer Patients study (described by Dr. Rickles). The study, which compared long-term therapy with a unique dalteparin dosing regimen to standard warfarin anticoagulation, found that “dalteparin dramatically reduced the risk of recurrent venous thrombosis in oncology patients compared to warfarin,” said Dr. Lee (see Figure 1).
“For secondary VTE prophylaxis, monotherapy with a low-molecular-weight heparin, such as dalteparin, is more effective than warfarin and it’s more convenient,” she said.
Case Study in Thoracic Surgery
“VTE is a substantial problem in thoracic patients, including those with malignancies of the lung, esophagus, pleura, and mediastinum,” said Steven Mentzer, MD, Director of the Thoracic Surgery Intensive Care Unit, Department of Surgery, Brigham and Women’s Hospital, Boston.
He reviewed the case of a 56-year-old woman presenting with phlegmasia alba dolens. She had few risk factors for either lung cancer or VTE. A right lower lobe mass was detected on a chest x-ray. A lower extremity ultrasound confirmed a diagnosis of femoral clot. There was no evidence of extra-
thoracic malignancy and she was begun on heparin.
Cervical mediastinoscopy demonstrated extensive paratracheal nodal disease with metastatic adenocarcinoma in her contra- lateral lymph nodes (Stage 3B). She received perioperative heparin and later switched to postoperative warfarin. During subsequent chemoradiation therapy, she developed recurrent femoral clot. The warfarin was discontinued and she was begun on maintenance enoxaparin. After the completion of her chemo-radiation, and negative restaging, she underwent a limited thoracoscopic resection of the lower lobe mass. Almost five years later she developed a mediastinal recurrence and died.
Dr. Mentzer explained that patients with lung cancer present a challenge to balance the risk of VTE and the risk of bleeding from the primary or metastatic sites of disease (e.g., brain or adrenal glands).
Case Studies in Colorectal Surgery
Walter Longo, MD, Professor and Chief, Gastrointestinal Surgery, Yale School of Medicine, New Haven, Connecticut, listed the following risk factors for VTE in colorectal cancer surgery patients: patient positioning, sepsis, preoperative radiation therapy, neoadjuvant therapy, history of previous thromboembolic event, hereditary hypercoagulable states, older age, morbid obesity, and use of oral contraceptives.
He reviewed the case of a 77-year-old healthy white female with a history of thrombosed hemorrhoids and intermittent rectal bleeding. Thirty-four years
previously, she had a lower extremity DVT, treated with anticoagulation. A colonoscopy revealed a 5 cm mass in her ascending colon and she had elevated CEA. She underwent laparoscopic right hemicolectomy. Pathology revealed Stage 3 disease and she received 5-FU and leucovorin.
Because of her risk factors for VTE, she was given low-molecular-weight heparin as prophylaxis. “The question is whether these patients need longer term prophylaxis,” said Dr. Longo. He cited two studies showing that certain patients have a high risk for VTE and may benefit. He also noted that there appears to be no increased risk for VTE with laparoscopy versus open colectomy.
A second case was a 54-year-old white male. Colonoscopy revealed a classic concentric lesion 8 cm from the anal verge. Biopsy proved adenocarcinoma; the patient had a high CEA level. The large lesion did not have distant metastasis, but there was severe lymph node involvement. The patient was given preoperative neoadjuvant therapy and underwent a four- to six-hour proctectomy with a coloanal anastomosis.
Because the patient was over 40, required a long surgical procedure, had an advanced malignancy, and received radiation therapy Dr. Longo recommended mechanical and pharmaceutical prophylaxis, with IPC plus heparin.
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