Long-term activation of the pro-coagulant response after neoadjuvant chemoradiation and major cancer surgery.
BACKGROUND
The association between cancer, major surgery and venous thromboembolism (VTE) is well established. Multimodal therapy is increasingly being used as standard treatment for localised gastrointestinal cancer. The aim of this study was to examine the markers of pro-coagulation response and VTE risk in an exemplar multimodal model of pre-operative combination chemotherapy and radiation therapy, followed by complex cancer surgery.


METHODS
Consecutive patients (n=36) with localised oesophageal cancer were studied at baseline after the first and second cycles of chemoradiation, and on post-operative days 1-28, and at 3, 6 and 9 months. Factors regulating the pro- and anti-coagulant response, as well as pro-inflammatory markers including NFkappaB activation in peripheral blood mononuclear cells, were examined. All patients received enoxaparin 40 mg s.c. postoperatively up to discharge, and underwent pulmonary CT-pulmonary angiography and venography on day 10 postoperatively.


RESULTS
Four (11%) non-fatal thromboembolic events were documented, all after hospital discharge. Neoadjuvant therapy before surgery activated factor VIII (FVIII) and pro-inflammatory NFkappaB, and increased D-dimers, pro-thrombin fragment 1+2 (F1+2) and the thrombin-anti-thrombin complex (TAT). Surgery significantly (P<0.05) increased pro-thrombin time (PT), activated partial thromboplastin time, fibrinogen, D-dimers, TAT, F1+2 and FVIII up to 6 months.


CONCLUSIONS
These data highlight the linked pro-coagulant and immunoinflammatory pathways in the multimodal management of oesophageal cancer, and suggest that the duration of current standard thromboprophylaxis regimens warrants further study.
Byrne
M
M
Department of Surgery, St James's Hospital, Trinity College, Dublin 8, Ireland.
Reynolds
J V
JV
O'Donnell
J S
JS
Keogan
M
M
White
B
B
Byrne
M
M
Murphy
S
S
Maher
S G
SG
Pidgeon
G P
GP
D000230:Adenocarcinoma / Q000097:blood* / Q000188:drug therapy / Q000276:immunology / Q000532:radiotherapy / Q000601:surgery; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D015415:Biomarkers; D002294:Carcinoma, Squamous Cell / Q000097:blood* / Q000188:drug therapy / Q000276:immunology / Q000532:radiotherapy / Q000601:surgery; D003131:Combined Modality Therapy; D016207:Cytokines / Q000097:blood; D017984:Enoxaparin / Q000627:therapeutic use; D004938:Esophageal Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000276:immunology / Q000532:radiotherapy / Q000601:surgery; D016629:Esophagectomy; D005169:Factor VIII / Q000378:metabolism; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005500:Follow-Up Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000378:metabolism; D011183:Postoperative Complications / Q000097:blood / Q000139:chemically induced / Q000209:etiology*; D011655:Pulmonary Embolism / Q000000981:diagnostic imaging / Q000209:etiology; D019851:Thrombophilia / Q000097:blood / Q000139:chemically induced / Q000209:etiology*; D014057:Tomography, X-Ray Computed; D054556:Venous Thromboembolism / Q000209:etiology*
D000925:Anticoagulants; D015415:Biomarkers; D016207:Cytokines; D017984:Enoxaparin; D005338:Fibrin Fibrinogen Degradation Products; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D005169:Factor VIII