levoleucovorin and Thrombosis

It is a common belief that older patients and those with less-than-ideal performance status do not tolerate chemotherapy as well as other patients. In fact, many otherwise-healthy older patients with metastatic colorectal cancer are not treated with chemotherapy. There is strong evidence that the addition of bevacizumab to the combination of irinotecan, 5-fluorouracil, and leucovorin or to 5-fluorouracil and leucovorin has substantial clinical benefits in patients 65 years of age or older and in those with Eastern Cooperative Oncology Group performance status 1 or 2. The treatment is generally well tolerated, without apparent negative effects on quality of life. However, the toxicity profile differs slightly, and the risk of arterial thrombotic events with bevacizumab-containing regimens, while relatively low, is higher in older patients than in younger patients. Clinicians should weigh the potential survival benefits against the risk of adverse events when choosing therapy for older patients with metastatic colorectal cancer and for those with poorer performance status.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Quality of Life; Thrombosis

The anti-angiogenic agent bevacizumab (Avastin) has been rationally designed to target vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis. Based on its limited roles in adults, VEGF inhibition using bevacizumab would be expected to have limited side effects. Furthermore, because its mechanism of action is different to that of standard chemotherapeutic agents, bevacizumab would not be expected to cause typical cytotoxic agent-related toxicity or to exacerbate the toxicity of concomitant chemotherapy. We have reviewed clinical trials published to date, primarily in metastatic colorectal cancer, and describe the safety profile of bevacizumab. The review focuses on hypertension, proteinuria, arterial thrombosis, effects on wound healing, bleeding and gastrointestinal (GI) perforation, which are the principal bevacizumab-related events seen in clinical trials. These events are for the most part mild to moderate in severity and clinically manageable (hypertension, proteinuria, minor bleeding) or occur uncommonly (wound healing complications, GI perforations and arterial thrombosis). The side-effect profile of bevacizumab makes it a suitable adjunct to standard chemotherapy in settings where efficacy has been demonstrated, and it is now approved for use in the USA, the European Union and other markets worldwide.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Hemorrhage; Humans; Hypertension; Incidence; Intestinal Perforation; Leucovorin; Proteinuria; Thrombosis; Vascular Endothelial Growth Factor A; Wound Healing

Radiofrequency ablation (RFA) of malignant liver lesions is considered a procedure with low morbidity. However, RFA performed close to hilar structures carries the risk of heat-induced biliary tract damage and subsequent septic episodes.. We performed an analysis of complications in 42 patients with 211 liver lesions treated with a combined approach of liver resection and RFA.. One patient died due to postoperative liver failure. There was one case of temporary liver dysfunction, one vena cava thrombosis, and six febrile episodes. Four of the six febrile episodes were related to bile duct injuries. They became evident 3-5 weeks after the procedure. All four patients were treated successfully by the placement of stents within the biliary tract. None of the patients developed a hepatic abscess.. Biliary tract damage is a complication that can occur weeks after RFA. Immediate endoscopic intervention can obviate the occurrence of prolonged septic complications.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract; Carcinoma, Hepatocellular; Catheter Ablation; Chemotherapy, Adjuvant; Cholangiopancreatography, Endoscopic Retrograde; Colorectal Neoplasms; Combined Modality Therapy; Fatal Outcome; Female; Fever; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Failure; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Postoperative Complications; Radiotherapy, Adjuvant; Retrospective Studies; Stents; Thrombosis; Treatment Outcome; Vena Cava, Inferior

The occurrence of arterial thrombosis reported in other breast cancer series has largely been confined to the upper extremities, ipsilateral to a previous mastectomy site and clinically manifest as cerebral vascular accidents. This case report describes 2 patients who experienced iliac artery thrombosis temporally related to receiving granulocyte-macrophage colony-stimulating factor (GM-CSF) and dose-intensive chemotherapy for metastatic breast cancer. A review of the literature concerning arterial thrombosis as relevant to breast cancer treatment and GM-CSF is included.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Iliac Artery; Leucovorin; Middle Aged; Recombinant Proteins; Thrombosis

The purpose of this phase II study was to explore the efficacy and safety of an alternating regimen consisting of folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (mFOLFOX6) plus bevacizumab, and folinic acid, 5-FU and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer.. Fifty-two patients with metastatic colorectal cancer received an alternating regimen consisting of four cycles of mFOLFOX6 plus bevacizumab followed by four cycles of FOLFIRI plus bevacizumab until disease progression. The primary endpoint was progression-free survival.. The median age was 60 years (range 37-75 years). Median progression-free survival was 14.2 months (95 % confidence interval [CI] 10.6-16.3) and median overall survival was 28.4 months (95 % CI 22.6-39.1). The overall response rate was 60.0 % (95 % CI 45.2-73.6). Regarding toxicity, the commonest grade 3-4 hematological adverse events were neutropenia (34.6 %) and leukopenia (7.7 %), and the commonest grade 3-4 non-hematological adverse events were anorexia (13.5 %), fatigue (9.6 %), nausea (9.6 %), and vomiting (9.6 %). Bevacizumab-related grade 3-4 adverse events included hypertension (1.9 %) and thrombosis (1.9 %).. An alternating regimen consisting of mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab is an effective and well-tolerated first-line chemotherapy combination for patients with metastatic colorectal cancer.

Topics: Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Fatigue; Female; Fluorouracil; Humans; Hypertension; Leucovorin; Leukopenia; Male; Middle Aged; Nausea; Neutropenia; Organoplatinum Compounds; Survival Rate; Thrombosis; Vomiting

A 58-year-old man underwent low anterior resection for type 2 rectal cancer with liver metastasis. An abdominal computed tomography (CT) scan showed multiple hepatic tumors (in S2, S3, S4, and S6) and a filling defect in the left portal vein. Pathological examination revealed a moderately differentiated adenocarcinoma, pSS, pN0, ly0, v3, with a tumor thrombus in the portal vein. After surgery, the patient was treated with combined chemotherapy of bevacizumab/Leucovorin and fluorouracil with oxaliplatin (FOLFOX4). After 11 courses of chemotherapy, tumor marker levels normalized, and the sizes of the liver metastases and thrombus in the left portal vein remarkably decreased. Resection of the left hepatic lobe and a partial resection of S6 were performed. Pathological examination revealed no residual cancer cells and indicated that the histological classification due to the chemotherapy regimen was Grade 3. The patient was alive for 5 years after the initial surgery, without recurrence.

Topics: Adenocarcinoma; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Sigmoid Neoplasms; Thrombosis

Topics: Adenocarcinoma; Aged; Anemia; Antifibrinolytic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Carcinoma, Squamous Cell; Cecal Neoplasms; Disseminated Intravascular Coagulation; Fatal Outcome; Female; Fibrinogen; Fibrinolysis; Fluorouracil; Heart Diseases; Hemorrhage; Humans; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Multiple Organ Failure; Neoplasms, Multiple Primary; Organoplatinum Compounds; Postoperative Complications; Thrombosis; Tranexamic Acid; Vulvar Neoplasms

Sinusoidal obstruction syndrome (SOS) following oxaliplatin based chemotherapy can have a significant impact on post-operative outcome following resection of colorectal liver metastases. To date no relevant experimental models of oxaliplatin induced SOS have been described. The aim of this project was to establish a rodent model which could be utilised to investigate mechanisms underlying SOS to aid the development of therapeutic strategies.. C57Bl/6 mice, maintained on a purified diet, were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for five weeks and culled one week following final treatment. Sections of the liver and spleen were fixed in formalin and paraffin embedded for histological analysis. The role of oxidative stress on experimental-induced SOS was determined by dietary supplementation with butylated hydroxyanisole and N-acetylcysteine.. FOLFOX treatment was associated with the development of sinusoidal dilatation and hepatocyte atrophy on H&E stained sections of the liver in keeping with SOS. Immunohistochemistry for p21 demonstrated the presence of replicative senescence within the sinusoidal endothelium. FOLFOX induced endothelial damage leads to a pro-thrombotic state within the liver associated with upregulation of PAI-1 (p<0.001), vWF (p<0.01) and Factor X (p<0.001), which may contribute to the propagation of liver injury. Dietary supplementation with the antioxidant BHA prevented the development of significant SOS.. We have developed the first reproducible model of chemotherapy induced SOS that reflects the pathogenesis of this disease in patients. It appears that the use of antioxidants alongside oxaliplatin based chemotherapy may be of value in preventing the development of SOS in patients with colorectal liver metastases.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Cell Cycle; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cytokines; Disease Models, Animal; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Inflammation Mediators; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Organoplatinum Compounds; Oxaliplatin; Oxidative Stress; Serpin E2; Thrombosis

After approval of bevacizumab in Japan, post-marketing surveillance studies reported on safety. However, few reports have shown the efficacy of bevacizumab as used in daily practice. We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients in daily practice.. All unresectable metastatic colorectal cancer patients who began receiving bevacizumab in participating facilities from June 2007 to October 2008 were retrospectively analyzed for safety and efficacy. Adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Response Evaluation in Solid Tumors criteria, version 1.0, was used for the tumor response rate.. A total of 212 patients from 17 institutions were assessed. Grade 3 or higher adverse events related to bevacizumab included gastrointestinal perforation in 3, thrombosis in 7, hypertension in 30 and gastrointestinal bleeding in 2. Response rates were 62.5, 30.1 and 11.8% overall among patients receiving bevacizumab as first-, second- and third-line or greater therapy. Median progression-free survival was 14.4 [95% confidence interval (CI): 10.8-18.1], 7.8 (95% CI: 6.5-9.1) and 6.0 (95% CI: 4.6-7.3) months, and median overall survival was 32.5 (95% CI: 24.6-40.3), 16.4 (95% CI: 14.4-18.5) and 11.8 (95% CI: 8.6-15.0) months, respectively.. The general cohort of patients in HGCSG0801 showed a similar efficacy and safety profile of bevacizumab as seen in clinical trials. Although the sample size was small and there were several study limitations, these results suggest that colorectal cancer patients in Japan might safely receive and benefit from bevacizumab in combination with chemotherapy in daily practice, as is seen in patients in other countries.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cohort Studies; Colorectal Neoplasms; Confidence Intervals; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Epistaxis; Female; Fluorouracil; Gastrointestinal Hemorrhage; Humans; Hypertension; Irinotecan; Japan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxonic Acid; Proteinuria; Retrospective Studies; Tegafur; Thrombosis; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Endothelial Growth Factors; Fluorouracil; Hemorrhage; Humans; Intercellular Signaling Peptides and Proteins; Leucovorin; Lymphokines; Neoplasm Metastasis; Thrombosis; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Warfarin

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cardiovascular Diseases; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Syndrome; Thrombosis

Interleukin-3 (IL-3) is an experimental agent used to ameliorate neutropenia in patients receiving chemotherapy. Arterial thrombotic episodes after use of IL-3 have not been reported previously.. The case of a patient with Stage III adenocarcinoma of the breast who developed hypotension and acute cerebellar artery and superior mesenteric artery thrombosis after receiving chemotherapy and treatment with IL-3 is reported.. To the authors' knowledge, this is the first patient with arterial thrombosis reported after treatment with IL-3.. Interleukin-3 may be associated with increased propensity for thrombosis.

Topics: Acute Disease; Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cerebellum; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Interleukin-3; Intracranial Embolism and Thrombosis; Leucovorin; Mesenteric Artery, Superior; Middle Aged; Myeloproliferative Disorders; Thrombosis