0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Symptomatic Venous Thromboembolism in Cancer Patients Treated With Chemotherapy:  An Underestimated Phenomenon FREE

Hans-Martin M. B. Otten, MD, PHD; Joost Mathijssen, MD; Hugo ten Cate, MD, PHD; Marcel Soesan, MD; Marijke Inghels, MD; Dick J. Richel, MD, PHD; Martin H. Prins, MD, PHD
[+] Author Affiliations

From the Departments of Medical Oncology (Drs Otten and Richel) and Vascular Medicine (Dr Mathijssen), Academic Medical Center, Amsterdam, the Netherlands; the Department of Internal Medicine, Slotervaart Hospital, Amsterdam (Drs Otten, Soesan, and Inghels); and the Departments of Hematology (Dr ten Cate) and Clinical Epidemiology (Dr Prins), Academic Hospital Maastricht, Maastricht, the Netherlands. The authors have no relevant financial interest in this article.


Arch Intern Med. 2004;164(2):190-194. doi:10.1001/archinte.164.2.190.
Text Size: A A A
Published online

Background  The exact incidence of venous thromboembolism (VTE) in cancer patients is unknown, partly because of confounding factors. Prophylactic treatment is warranted in surgical patients with cancer because of a high incidence of VTE. We performed a retrospective study to evaluate if the same applies for cancer patients treated with chemotherapy.

Methods  The medical records of 206 consecutive patients with malignancy, treated with chemotherapy, were identified. The kind of malignancy and chemotherapeutic treatment were recorded, as was the date of treatment. The records were reviewed for other risk factors for VTE, and were searched for proved deep venous thrombosis or pulmonary embolism.

Results  Of those 206 patients, 15 (7.3%) had proved VTE during or within 3 months after chemotherapeutic treatment. The annual incidence was 10.9%. The incidence of VTE was specifically high in the 39 patients treated with a combination of fluorouracil and leucovorin calcium because of colorectal cancer (6 [15%] of the patients were affected). The occurrence of VTE in the latter group of patients was not influenced by factors such as surgery, central venous catheters, or tumor load.

Conclusions  The annual incidence of VTE in patients treated with chemotherapy was high, specifically in patients with colorectal cancer treated with fluorouracil-leucovorin. If these observations are confirmed, trials to evaluate the use of prophylactic anticoagulant treatment should be conducted.

The relation between cancer and venous thromboembolism (VTE) has been known since at least 1865, and it is generally accepted that the incidence of VTE in cancer patients is high.1 Nevertheless, the true incidence of VTE in cancer patients is unknown. One of the reasons for this lack of clarity is the presence of confounding factors. Most cancer patients need surgery for their malignancy, will be exposed to chemotherapy and/or intravenous catheters, and may become immobilized during their disease. The relation between VTE and (different kinds of) chemotherapy has been most extensively investigated in patients with breast cancer.211 In patients with breast cancer stage I or II, the incidence of VTE seemed to increase from 0.2% to 2.0% in those receiving chemotherapy. In most of those studies, patients were also treated with tamoxifen citrate, which itself is thrombogenic.12 In patients with high-grade glioma treated with chemotherapy, the incidence of VTE was 12% in a prospective study13 and 16% in a retrospective study.14 Finally, Grem et al15 reported an incidence of 17% in 36 patients with unresectable or metastatic colon carcinoma treated with a combination of fluorouracil and leucovorin calcium and granulocyte-macrophage colony-stimulating factor. These data suggest a significantly increased risk for VTE in patients with different kinds of malignancies who are receiving chemotherapy.

In general, prevention for VTE is not given to patients with cancer being treated with chemotherapy. However, in analogy with surgical patients, such a prophylaxis might be warranted if the incidence of VTE was demonstrated to be high enough.1619

Therefore, we performed a retrospective study to evaluate the incidence of VTE among consecutive patients treated with chemotherapy for malignant disease in a teaching hospital in Amsterdam.

STUDY DESIGN AND POPULATION

We performed a retrospective, single-institution, cohort study. In the Slotervaart Hospital, all patients are registered according to the Systematic Information center for Health Care system, the Dutch medical registration system. This registration system enabled us to identify all patients, aged at least 18 years, treated with chemotherapy because of malignant disease between January 1, 1995, and January 1, 2000. A search of the registration systems of the internal medicine department and the oncology nurses revealed no additional cases. After identification, the computerized and the medical records of each patient were retrieved and evaluated. The data were retrieved according to the local rules of the medical ethical board.

DATA RETRIEVAL

Besides the age and sex of the patients, the kind of malignant disease and the various chemotherapeutic agents administered to each patient were recorded. We retrieved the exact date the chemotherapy was started and stopped. Furthermore, we reviewed the records of all patients for the exact date and kind of surgery (if any) and the introduction of central venous catheters. In addition, we registered the use of coumarin or heparin calcium derivatives. The radiological history of all patients was checked for the performance of ultrasonography of the extremities, a ventilation-perfusion lung scan, and/or pulmonary angiography. In all patients with proved VTE, we actively searched the records and radiological reports for indicators of tumor load at the time of VTE.

STUDY DEFINITIONS

The malignant disease had to be proved by histological and/or cytological reports according to current standards. The stages of the various cancers are according to the definitions used by the American Joint Committee on Cancer/Union Internationale Contre le Cancer.20 The stage of disease was considered a marker for the tumor load. The criterion for deep venous thrombosis by compression ultrasonography was noncompressibility of a proximal vein.21 A perfusion-ventilation scan was diagnostic for a pulmonary embolism if the perfusion scan showed one or more segmental defects and the ventilation scan showed no abnormalities in the same segment(s) (mismatch).2224 In case of a subsegmental mismatch or a matched defect (perfusion and ventilation defect), pulmonary angiography had to demonstrate pulmonary emboli.25

ANALYSIS

The incidence of VTE, for the entire group of patients, was expressed as a proportion and as an annual incidence. For this latter purpose, we considered the patients at risk for VTE during the treatment with chemotherapy and the first 13 weeks after the last treatment in analogy to postsurgical patients.26 We counted the periods at risk for VTE for all patients, and calculated the years at risk for VTE and the subsequent incidence of VTE per year. In addition, the proportion of patients with VTE was calculated for subgroups of patients defined by type of cancer and chemotherapeutic regimen. If fewer than 6 patients had a specific hematological or solid malignancy, we rubricated them as "other hematological" and "other solid," respectively. If fewer than 6 patients were treated with a specific (combination of) chemotherapeutic agent(s), we classified them as "other for hematological malignancy" and "other for solid malignancy," depending on the underlying malignancy.

If applicable, the 95% confidence interval was calculated using statistical software (StatXact, version 3.0; Cytel Software Corp, Cambridge, Mass).

PATIENT POPULATION

In total, 209 patients with cancer who were treated with chemotherapy because of malignant disease were identified. For 206 (98.6%) of these patients, the hospital medical records were available for review. The mean age at the start of chemotherapy was 58 years (range, 20-88 years), and 116 patients (55.5%) were women. The most common malignancies were colorectal carcinoma, non-Hodgkin disease, breast carcinoma, ovarian carcinoma, multiple myeloma, and Kaposi sarcoma (Table 1). In 8 (3.8%) of the 209 patients, central venous catheter (7 Port-A-Cath systems [Deltec, Inc, St Paul, Minn] and 1 percutaneously inserted central venous catheter) access was present, because of medication or feeding (n = 5) or inaccessible peripheral veins (n = 3). In 94 (45.6%) of the 206 patients, surgical treatment had preceded the chemotherapeutic treatment. The mean interval between surgery and chemotherapy was 7.9 weeks (range, 2-34 weeks). The average period of chemotherapeutic treatment was 22.6 weeks (range, 1-145 weeks). One patient received anticoagulant treatment because of a heart valve prosthesis. Two patients were immobile during the chemotherapeutic treatment. None of the patients was treated with epoetin alfa.

Table Graphic Jump LocationTable 1. Incidence of VTE in Relation to Type of Malignancy
INCIDENCE OF VTE

Overall, 15 (7.3%) of the 206 patients had a proved VTE during, or within 3 months after, chemotherapy. The characteristics of these patients are shown in Table 2. One patient had a retinal vein thrombosis. Two patients had an upper limb thrombosis, 4 had a pulmonary embolism (fatal in 2 of them), and 8 had a deep venous thrombosis of the lower limb. Of these latter 8 patients, 2 had bilateral deep venous thrombosis.

Table Graphic Jump LocationTable 2. Characteristics of the Patients With a VTE During or Within 12 Weeks After Chemotherapeutic Treatment

In the entire group of patients, the annual incidence of VTE was 10.9% (95% confidence interval, 6.1%-18.0%).

RISK FACTORS FOR VTE
Surgery

None of the patients with VTE underwent surgery in the 12 weeks preceding chemotherapeutic treatment. In 5 patients, surgery had been performed 13 to 39 weeks (mean, 21.5 weeks) before the initiation of chemotherapeutic treatment.

Central Venous Catheters

One of the patients with a central venous catheter had a symptomatic deep venous thrombosis a year before the implantation of a central venous access device (Port-A-Cath); none of the others experienced signs of VTE.

Timing of VTE With Regard to Chemotherapy

Nine patients had a VTE during their chemotherapeutic treatment. In 2 patients, the VTE became symptomatic within a week after their last treatment. Two patients experienced the first symptoms within a month and 2 within 2 months after their last treatment.

Chemotherapeutic Treatment

The incidence of VTE in relation to chemotherapeutic regimen is given in Table 3. Venous thromboembolism was most frequent in the 41 patients treated with 5 daily bolus injections of fluorouracil-leucovorin every month (6 [15%] of these 41 patients had a VTE; 95% confidence interval, 6%-29%). Of these patients, 18 had a limited colorectal carcinoma (Dukes classification C) and were treated in an adjuvant setting. In 3 (17%) of these 18 patients, a VTE occurred.

Table Graphic Jump LocationTable 3. Incidence of VTE in Relation to Type of Chemotherapeutic Regimen
Tumor Load

Tumor load was limited in 4 patients with a VTE, of whom 3 had a colorectal carcinoma. The disease of the other patients was extensive, with multiple metastases, stage III multiple myeloma, or stage IV non-Hodgkin disease.

Our retrospective analysis indicates that among patients with malignant disease treated with chemotherapy, the risk of symptomatic VTE is high, with an annual incidence of 10.9%. In general, VTE occurred in all subgroups, defined by kind of malignancy, extent of malignancy, and chemotherapeutic regimen. The observed incidence of VTE is in concordance with the incidence reported by others,27,13,14 as mentioned before. This also applies to the remarkably high incidence (6 [15%] of 39 patients) in those with colorectal carcinoma treated with fluorouracil-leucovorin.15

Our study had several limitations. Because of its retrospective nature, the data could be underestimated. We could only detect patients with symptomatic and objectively proved VTE, and could have missed patients with subtle clinical manifestations of VTE or patients who were treated for probable VTE without performing adequate diagnostic tests. On the other hand, the high incidence could be solely because of chance and could represent a high variation of the normal spectrum.

Because of the relatively few patients, it was impossible to demonstrate a statistically significant difference between the subgroups.

We were not able to find a matched control group because of highly standardized treatment policies for cancer patients in our hospital. In earlier treatment studies of cancer patients comparing a chemotherapeutic regimen with placebo, the occurrence of VTE was seldom mentioned in the toxicity score.

It is unlikely that the high incidence of VTE in patients with colorectal carcinoma treated with fluorouracil-leucovorin can be attributed to the colorectal carcinoma alone: in large epidemiological studies,2729 the reported incidence of VTE in patients with colorectal malignancies did not differ from incidences in patients with other adenocarcinomas. Most patients with breast carcinoma were treated with a fluorouracil-containing chemotherapeutic regimen as well, so it is unlikely that fluorouracil alone is responsible for the excess of VTE in the patients treated with fluorouracil-leucovorin.

Several mechanisms have been proposed to be responsible for the hypercoagulable state of cancer patients treated with chemotherapy. Alterations in coagulation factors,3033 anticoagulant proteins,3436 and endothelial cells33,3742 have been shown to occur following the administration of various cytotoxic agents. In an experimental model, the endothelium of fluorouracil-treated rabbits was badly damaged, leading to intima disruption and denudation of underlying structures, with accompanying platelet accumulation and fibrin formation.43 Two groups31,32 demonstrated a significant increase in fibrinopeptide A levels in patients treated with fluorouracil.

Others3436 discovered a reduction of protein C levels of different degrees during treatment with cyclophosphamide, methotrexate, and fluorouracil, but a link to clinically apparent VTE could not be made. Therefore, the exact pathophysiological mechanism for the observed excess of VTE in our group of patients remains to be determined.

In conclusion, the annual incidence of VTE in patients treated with chemotherapy in this study is high (10.9%). A remarkably high incidence of VTE was shown in patients with a colorectal malignancy treated with fluorouracil-leucovorin (15%). Before recommending prophylactic anticoagulant treatment to this category of patients, the observation should be confirmed and the efficacy and safety of the anticoagulants in this setting should be tested; the effect on mortality and the impact on the quality of life of these patients should be tested as well.

Corresponding author: Hans-Martin M. B. Otten, MD, PhD, Department of Internal Medicine, Slotervaart Hospital, Room 0059B, Louwesweg 6, 1066 EC Amsterdam, the Netherlands (e-mail: j.m.otten@amc.uva.nl).

Accepted for publication February 26, 2003.

Trousseau  A Phlegmasia alba dolens. Balliere  JClinique Medicale de l'Hotel-Dieu de Paris.;2nd ed. Paris, France JB Baillière & Fils1865;654- 712
Saphner  TTormey  DCGray  R Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol. 1991;9286- 294
PubMed
Weiss  RBTormey  DCHolland  JFWeinberg  VE Venous thrombosis during multimodal treatment of primary breast carcinoma. Cancer Treat Rep. 1981;65677- 679
PubMed
Clahsen  PCvan de Velde  CJJulien  JPFloiras  JLMignolet  FY Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: a European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group study. J Clin Oncol. 1994;121266- 1271
PubMed
Levine  MNGent  MHirsh  J  et al.  The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med. 1988;318404- 407
PubMed Link to Article
von Tempelhoff  GFDietrich  MHommel  GHeilmann  L Blood coagulation during adjuvant epirubicin/cyclophosphamide chemotherapy in patients with primary operable breast cancer. J Clin Oncol. 1996;142560- 2568
PubMed
Rivkin  SEGreen  SMetch  B  et al.  Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor–positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol. 1994;122078- 2085
PubMed
Fisher  BRedmond  CLegault-Poisson  S  et al.  Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol. 1990;81005- 1018
PubMed
Pritchard  KIPaterson  AHPaul  NAZee  BFine  SPater  JNational Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group, Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol. 1996;142731- 2737
PubMed
Levine  MHirsh  JGent  M  et al.  Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet. 1994;343886- 889
PubMed Link to Article
Goodnough  LTSaito  HManni  AJones  PKPearson  OH Increased incidence of thromboembolism in stage IV breast cancer patients treated with a five-drug chemotherapy regimen: a study of 159 patients. Cancer. 1984;541264- 1268
PubMed Link to Article
Meier  CRJick  H Tamoxifen and risk of idiopathic venous thromboembolism. Br J Clin Pharmacol. 1998;45608- 612
PubMed Link to Article
Brandes  AAScelzi  ESalmistraro  G  et al.  Incidence of risk of thromboembolism during treatment of high-grade gliomas: a prospective study. Eur J Cancer. 1997;331592- 1596
PubMed Link to Article
Cheruku  RTapazoglou  EEnsley  JKish  JACummings  GDal-Sarraf  M The incidence and significance of thromboembolic complications in patients with high-grade gliomas. Cancer. 1991;682621- 2624
PubMed Link to Article
Grem  JLMcAtee  NMurphy  RF  et al.  Phase I and pharmacokinetic study of recombinant human granulocyte-macrophage colony-stimulating factor given in combination with fluorouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma. J Clin Oncol. 1994;12560- 568
PubMed
Kakkar  VVDjazaeri  BFok  JFletcher  MScully  MFWestwick  J Low-molecular-weight heparin and prevention of postoperative deep vein thrombosis. BMJ. 1982;284375- 379
PubMed Link to Article
Clagett  GPReisch  JS Prevention of venous thromboembolism in general surgical patients: results of meta-analysis. Ann Surg. 1988;208227- 240
PubMed Link to Article
Collins  RScrimgeour  AYusuf  SPeto  R Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med. 1988;3181162- 1173
PubMed Link to Article
Nurmohamed  MTRosendaal  FRBuller  HR  et al.  Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet. 1992;340152- 156
PubMed Link to Article
Not Available, TNM Atlas: Illustrated Guide to the TNM/pTNM Classification of Malignant Tumours/UICC. 4th ed (corrected 2nd ed) Berlin, Germany Springer-Verlag1999;
Lensing  AWPrandoni  PBrandjes  D  et al.  Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med. 1989;320342- 345
PubMed Link to Article
Hull  RDHirsh  JCarter  CJ  et al.  Diagnostic value of ventilation-perfusion lung scanning in patients with suspected pulmonary embolism. Chest. 1985;88819- 828
PubMed Link to Article
PIOPED Investigators, Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA. 1990;2632753- 2759
PubMed Link to Article
Hull  RDRaskob  GEPineo  GFBrant  RF The low-probability lung scan: a need for change in nomenclature. Arch Intern Med. 1995;1551845- 1851
PubMed Link to Article
Dalen  JEBrooks  HLJohnson  LWMeister  SGSzucs  MM  JrDexter  L Pulmonary angiography in acute pulmonary embolism: indications, techniques, and results in 367 patients. Am Heart J. 1971;81175- 185
PubMed Link to Article
Kearon  CSalzman  EWHirsh  J Epidemiology, pathogenesis and natural history of venous thrombosis. Colman  RWHemostasis and Thrombosis Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa Lippincott Williams & Wilkins2001;1153- 1160
Nordstrom  MLindblad  BAnderson  HBergqvist  DKjellstrom  T Deep venous thrombosis and occult malignancy: an epidemiological study. BMJ. 1994;308891- 894
PubMed Link to Article
Sorensen  HTMellemkjaer  LSteffensen  FHOlsen  JHNielsen  GL The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med. 1998;3381169- 1173
PubMed Link to Article
Baron  JAGridley  GWeiderpass  ENyren  OLinet  M Venous thromboembolism and cancer. Lancet. 1998;3511077- 1080
PubMed Link to Article
Canobbio  LFassio  TArdizzoni  A  et al.  Hypercoagulable state induced by cytostatic drugs in stage II breast cancer patients. Cancer. 1986;581032- 1036
PubMed Link to Article
Kuzel  TEsparaz  BGreen  DKies  M Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer. 1990;65885- 889
PubMed Link to Article
Edwards  RLKlaus  MMatthews  EMcCullen  CBona  RDRickles  FR Heparin abolishes the chemotherapy-induced increase in plasma fibrinopeptide A levels. Am J Med. 1990;8925- 28
PubMed Link to Article
Zurborn  KHGram  JGlander  K  et al.  Influence of cytostatic treatment on the coagulation system and fibrinolysis in patients with non–Hodgkin's lymphomas and acute leukemias. Eur J Haematol. 1991;4755- 59
PubMed Link to Article
Rogers 2nd  JSMurgo  AJFontana  JARaich  PC Chemotherapy for breast cancer decreases plasma protein C and protein S. J Clin Oncol. 1988;6276- 281
PubMed
Feffer  SECarmosino  LSFox  RL Acquired protein C deficiency in patients with breast cancer receiving cyclophosphamide, methotrexate, and 5-fluorouracil. Cancer. 1989;631303- 1307
PubMed Link to Article
Rella  CCoviello  MGiotta  F  et al.  A prothrombotic state in breast cancer patients treated with adjuvant chemotherapy. Breast Cancer Res Treat. 1996;40151- 159
PubMed Link to Article
Lazo  JS Endothelial injury caused by antineoplastic agents. Biochem Pharmacol. 1986;351919- 1923
PubMed Link to Article
Nicolson  GLCustead  SE Effects of chemotherapeutic drugs on platelet and metastatic tumor cell–endothelial cell interactions as a model for assessing vascular endothelial integrity. Cancer Res. 1985;45331- 336
PubMed
Orr  FWAdamson  IYYoung  L Promotion of pulmonary metastasis in mice by bleomycin-induced endothelial injury. Cancer Res. 1986;46891- 897
PubMed
Jackson  AMRose  BDGraff  LG  et al.  Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med. 1984;10141- 44
PubMed Link to Article
Harrell  RMSibley  RVogelzang  NJ Renal vascular lesions after chemotherapy with vinblastine, bleomycin, and cisplatin. Am J Med. 1982;73429- 433
PubMed Link to Article
Bertomeu  MCGallo  SLauri  DLevine  MNOrr  FWBuchanan  MR Chemotherapy enhances endothelial cell reactivity to platelets. Clin Exp Metastasis. 1990;8511- 518
PubMed Link to Article
Kinhult  SAlbertsson  MEskilsson  JCwikiel  M Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation. Scanning. 2001;231- 8
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Incidence of VTE in Relation to Type of Malignancy
Table Graphic Jump LocationTable 2. Characteristics of the Patients With a VTE During or Within 12 Weeks After Chemotherapeutic Treatment
Table Graphic Jump LocationTable 3. Incidence of VTE in Relation to Type of Chemotherapeutic Regimen

References

Trousseau  A Phlegmasia alba dolens. Balliere  JClinique Medicale de l'Hotel-Dieu de Paris.;2nd ed. Paris, France JB Baillière & Fils1865;654- 712
Saphner  TTormey  DCGray  R Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol. 1991;9286- 294
PubMed
Weiss  RBTormey  DCHolland  JFWeinberg  VE Venous thrombosis during multimodal treatment of primary breast carcinoma. Cancer Treat Rep. 1981;65677- 679
PubMed
Clahsen  PCvan de Velde  CJJulien  JPFloiras  JLMignolet  FY Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: a European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group study. J Clin Oncol. 1994;121266- 1271
PubMed
Levine  MNGent  MHirsh  J  et al.  The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med. 1988;318404- 407
PubMed Link to Article
von Tempelhoff  GFDietrich  MHommel  GHeilmann  L Blood coagulation during adjuvant epirubicin/cyclophosphamide chemotherapy in patients with primary operable breast cancer. J Clin Oncol. 1996;142560- 2568
PubMed
Rivkin  SEGreen  SMetch  B  et al.  Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor–positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol. 1994;122078- 2085
PubMed
Fisher  BRedmond  CLegault-Poisson  S  et al.  Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol. 1990;81005- 1018
PubMed
Pritchard  KIPaterson  AHPaul  NAZee  BFine  SPater  JNational Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group, Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol. 1996;142731- 2737
PubMed
Levine  MHirsh  JGent  M  et al.  Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet. 1994;343886- 889
PubMed Link to Article
Goodnough  LTSaito  HManni  AJones  PKPearson  OH Increased incidence of thromboembolism in stage IV breast cancer patients treated with a five-drug chemotherapy regimen: a study of 159 patients. Cancer. 1984;541264- 1268
PubMed Link to Article
Meier  CRJick  H Tamoxifen and risk of idiopathic venous thromboembolism. Br J Clin Pharmacol. 1998;45608- 612
PubMed Link to Article
Brandes  AAScelzi  ESalmistraro  G  et al.  Incidence of risk of thromboembolism during treatment of high-grade gliomas: a prospective study. Eur J Cancer. 1997;331592- 1596
PubMed Link to Article
Cheruku  RTapazoglou  EEnsley  JKish  JACummings  GDal-Sarraf  M The incidence and significance of thromboembolic complications in patients with high-grade gliomas. Cancer. 1991;682621- 2624
PubMed Link to Article
Grem  JLMcAtee  NMurphy  RF  et al.  Phase I and pharmacokinetic study of recombinant human granulocyte-macrophage colony-stimulating factor given in combination with fluorouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma. J Clin Oncol. 1994;12560- 568
PubMed
Kakkar  VVDjazaeri  BFok  JFletcher  MScully  MFWestwick  J Low-molecular-weight heparin and prevention of postoperative deep vein thrombosis. BMJ. 1982;284375- 379
PubMed Link to Article
Clagett  GPReisch  JS Prevention of venous thromboembolism in general surgical patients: results of meta-analysis. Ann Surg. 1988;208227- 240
PubMed Link to Article
Collins  RScrimgeour  AYusuf  SPeto  R Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med. 1988;3181162- 1173
PubMed Link to Article
Nurmohamed  MTRosendaal  FRBuller  HR  et al.  Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet. 1992;340152- 156
PubMed Link to Article
Not Available, TNM Atlas: Illustrated Guide to the TNM/pTNM Classification of Malignant Tumours/UICC. 4th ed (corrected 2nd ed) Berlin, Germany Springer-Verlag1999;
Lensing  AWPrandoni  PBrandjes  D  et al.  Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med. 1989;320342- 345
PubMed Link to Article
Hull  RDHirsh  JCarter  CJ  et al.  Diagnostic value of ventilation-perfusion lung scanning in patients with suspected pulmonary embolism. Chest. 1985;88819- 828
PubMed Link to Article
PIOPED Investigators, Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA. 1990;2632753- 2759
PubMed Link to Article
Hull  RDRaskob  GEPineo  GFBrant  RF The low-probability lung scan: a need for change in nomenclature. Arch Intern Med. 1995;1551845- 1851
PubMed Link to Article
Dalen  JEBrooks  HLJohnson  LWMeister  SGSzucs  MM  JrDexter  L Pulmonary angiography in acute pulmonary embolism: indications, techniques, and results in 367 patients. Am Heart J. 1971;81175- 185
PubMed Link to Article
Kearon  CSalzman  EWHirsh  J Epidemiology, pathogenesis and natural history of venous thrombosis. Colman  RWHemostasis and Thrombosis Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa Lippincott Williams & Wilkins2001;1153- 1160
Nordstrom  MLindblad  BAnderson  HBergqvist  DKjellstrom  T Deep venous thrombosis and occult malignancy: an epidemiological study. BMJ. 1994;308891- 894
PubMed Link to Article
Sorensen  HTMellemkjaer  LSteffensen  FHOlsen  JHNielsen  GL The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med. 1998;3381169- 1173
PubMed Link to Article
Baron  JAGridley  GWeiderpass  ENyren  OLinet  M Venous thromboembolism and cancer. Lancet. 1998;3511077- 1080
PubMed Link to Article
Canobbio  LFassio  TArdizzoni  A  et al.  Hypercoagulable state induced by cytostatic drugs in stage II breast cancer patients. Cancer. 1986;581032- 1036
PubMed Link to Article
Kuzel  TEsparaz  BGreen  DKies  M Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer. 1990;65885- 889
PubMed Link to Article
Edwards  RLKlaus  MMatthews  EMcCullen  CBona  RDRickles  FR Heparin abolishes the chemotherapy-induced increase in plasma fibrinopeptide A levels. Am J Med. 1990;8925- 28
PubMed Link to Article
Zurborn  KHGram  JGlander  K  et al.  Influence of cytostatic treatment on the coagulation system and fibrinolysis in patients with non–Hodgkin's lymphomas and acute leukemias. Eur J Haematol. 1991;4755- 59
PubMed Link to Article
Rogers 2nd  JSMurgo  AJFontana  JARaich  PC Chemotherapy for breast cancer decreases plasma protein C and protein S. J Clin Oncol. 1988;6276- 281
PubMed
Feffer  SECarmosino  LSFox  RL Acquired protein C deficiency in patients with breast cancer receiving cyclophosphamide, methotrexate, and 5-fluorouracil. Cancer. 1989;631303- 1307
PubMed Link to Article
Rella  CCoviello  MGiotta  F  et al.  A prothrombotic state in breast cancer patients treated with adjuvant chemotherapy. Breast Cancer Res Treat. 1996;40151- 159
PubMed Link to Article
Lazo  JS Endothelial injury caused by antineoplastic agents. Biochem Pharmacol. 1986;351919- 1923
PubMed Link to Article
Nicolson  GLCustead  SE Effects of chemotherapeutic drugs on platelet and metastatic tumor cell–endothelial cell interactions as a model for assessing vascular endothelial integrity. Cancer Res. 1985;45331- 336
PubMed
Orr  FWAdamson  IYYoung  L Promotion of pulmonary metastasis in mice by bleomycin-induced endothelial injury. Cancer Res. 1986;46891- 897
PubMed
Jackson  AMRose  BDGraff  LG  et al.  Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med. 1984;10141- 44
PubMed Link to Article
Harrell  RMSibley  RVogelzang  NJ Renal vascular lesions after chemotherapy with vinblastine, bleomycin, and cisplatin. Am J Med. 1982;73429- 433
PubMed Link to Article
Bertomeu  MCGallo  SLauri  DLevine  MNOrr  FWBuchanan  MR Chemotherapy enhances endothelial cell reactivity to platelets. Clin Exp Metastasis. 1990;8511- 518
PubMed Link to Article
Kinhult  SAlbertsson  MEskilsson  JCwikiel  M Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation. Scanning. 2001;231- 8
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 111

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

The Rational Clinical Examination
Make the Diagnosis: Cancer, Family History

The Rational Clinical Examination
Original Article: Does This Patient Have a Family History of Cancer?