levoleucovorin and Proteinuria

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

In the present study, either modified IFL regimen (modified irinotecan, fluorouracil and leucovorin, mIFL) alone or in combination with bevacizumab was used to treat patients with metastatic colorectal cancer (CRC). Treatment efficacy was assessed using coupled tomography imaging diagnosis. The toxicity accompany with treatment was evaluated, as well as T cell receptor (TCR) repertoire before and several cycles after therapy was dynamically monitored by analyzing the complementarity-determining region 3 (CDR3) length distribution within CD4(+) and CD8(+) T cell subsets. The degrees of normalization of the T cell repertoire in CRC patients treated with the two methods were compared. The results showed that mIFL combined with bevacizumab was more effective in treating patients with metastatic CRC, and was accompanied by an increase in side effects such as proteinuria and hematuria. An even more restricted CDR3 profile in patients with metastatic CRC compared with healthy control has been detected. A prominent usage of TCR beta chain variable (BV) gene BV12 and BV16 families within the CD4(+) T cell subset and BV19 and BV21 families within the CD8(+) T cell subset have been found before treatment. Moreover, CD8(+) T cells showed more restricted patterns than CD4(+) T cells, especially in patients before treatment. For patients with stable disease (SD) or partial remission (PR) after treatment, a less restricted CDR3 profile in post-treatment compared with pre-treatment has been found, but the opposite result was observed for patients with progressive disease (PD). The less restricted CDR3 pattern suggested a trend toward normalization of the TCR repertoire. The normalization of TCR repertoire significantly increased in patients treated with mIFL in combination with bevacizumab, but slightly in patients treated with mIFL alone. The results demonstrate a positive correlation between post-therapy TCR repertoire normalization and remission of metastatic CRC.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Complementarity Determining Regions; Female; Fluorouracil; Genes, T-Cell Receptor beta; Hematuria; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Proteinuria; Receptors, Antigen, T-Cell; T-Lymphocyte Subsets; Tomography, X-Ray Computed; Treatment Outcome

The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC).. mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups.. We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01).. Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Incidence; Leucovorin; Proteinuria; Ramucirumab; Rectal Neoplasms

We report 2: Cases of advanced colorectal cancer that developed nephrotic syndrome after ramucirumab(RAM)administration. Case 1: A 54-year-old woman with rectal cancer, liver and lung metastases, and peritoneal dissemination underwent sigmoid colon double-barrel colostomy for perforation management. The patient received 15 postoperative CAPOX plus bevacizumab(Bev)courses. FOLFIRI plus RAM was introduced as the second-line treatment. After 2 courses, the patient showed marked proteinuria and hypoalbuminemia and was diagnosed with nephrotic syndrome. The patient's condition improved promptly with administrating diuretics and antihypertensive drugs. Case 2: A 72-year-old man underwent sigmoid colon cancer resection with duodenal infiltration. Despite the treatment, a tumor was identified at the radial margin(RM1), with a positive cytological test(CY1)result. Therefore, postoperative mFOLFOX6 plus Bev was administered for 17 courses. FOLFIRI plus RAM was introduced as the second-line treatment due to residual tumor growth. After 2 courses, the patient showed accentuated proteinuria and was diagnosed with nephrotic syndrome and heart failure. The patient's condition improved after administrating diuretics, antihypertensive drugs, and V2-receptor antagonists. In both cases, marked proteinuria was observed after shifting to second-line treatment with two RAM administrations. Therefore, monitoring nephrotic syndrome development during the early RAM introduction stage is essential.

Topics: Aged; Antihypertensive Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nephrotic Syndrome; Proteinuria; Ramucirumab; Sigmoid Neoplasms

Bevacizumab (Avastin(®)) was approved in Japan in April 2007 for patients with advanced or metastatic colorectal cancer. To address the limited clinical experience in Japanese patients, a post-approval surveillance study was undertaken in bevacizumab-treated patients in Japan.. Bevacizumab (5 or 10 mg/kg every 2 weeks) was administered with chemotherapy; patients were observed for 26 weeks from initiation of treatment. The primary objective was to investigate the incidence of adverse drug reactions, particularly those of interest for bevacizumab. Univariate and multivariate analyses were performed to identify potential risk factors for adverse drug reactions.. In total, 2712 patients were registered and 2696 patients were included in the safety analysis. Hypertension (13.1%), hemorrhage (10.5%) and proteinuria (4.5%) were the most common adverse drug reaction. The incidences of serious adverse drug reactions were low: gastrointestinal perforation occurred in 0.9% of patients, hemorrhage in 1.3%, arterial thromboembolic events in 0.3%, venous thromboembolic events in 1.3% and wound-healing complications in 0.4%. The incidence of bevacizumab-specific adverse drug reactions was not influenced by the bevacizumab dose. Multivariate analyses identified risk factors for the following adverse drug reactions: hypertension (prior/concurrent hypertension); tumor-associated bleeding (performance status, prior/concomitant anticoagulant or nonsteroidal anti-inflammatory drug use); proteinuria (sex, performance status, prior/concurrent diabetes and proteinuria); gastrointestinal perforation (primary tumor in situ, concurrent nonsteroidal anti-inflammatory drug use); venous thromboembolic event (treatment stage, port insertion).. The safety profile of bevacizumab-containing regimens in this Japanese population was comparable with studies performed in Western countries. Bevacizumab is generally well tolerated in Japanese patients with advanced or metastatic colorectal cancer.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Heart Failure; Hemorrhage; Humans; Hypertension; Japan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Product Surveillance, Postmarketing; Proteinuria; Risk Factors

To assess the efficacy and safety of bevacizumab (BEV) plus chemotherapeutic agents in the treatment of metastatic colorectal cancer (mCRC).. Seventy-seven mCRC patients received BEV plus 5-Fu type, oxaliplatin or irinotecan-based chemotherapy. The clinical efficacy and bevacizumab-related adverse reactions were observed. The efficacy assessment was conducted after at least 2 cycles of BEV therapy. The adverse reactions were recorded in each therapy cycle. Among the 77 cases, 64 patients had finished the efficacy assessment. The adverse reactions in all patients were assessed.. The overall response rate (ORR) of BEV plus chemotherapy regimen was 18.75% (12/64), and the disease control rate (DCR) was 75.0% (48/64). In 27 patients who received the regimen as first-line treatment, the ORR reached 37.0% (10/27), while the DCR was 85.2%. Four patients with potentially resectable lesions became resectable after the regimen and received R0 resection of the liver metastases successfully. Twenty-five patients who received the regimen as second line therapy had poor result with ORR 8.0% and DCR 76.0%. Hypertension was observed in 12 cases, with 8 cases of grade 1, 3 cases of grade 2, 1 case of grade 3. Various bleedings occurred in 24/77 cases (31.2%), all were of grade 1-2, including 17 cases of epistaxis, grade 1 hemorrhoid bleeding in one case, hematuria in 3 case (2 of grade 1, 1 of grade 2), GI bleeding in 2 cases, hemoptysis in 1 case (grade 2), and proteinuria in 4 cases (grade 1). Intestinal perforation occurred in 1 case (0.3%). In two patients who had incomplete intestinal obstruction history appeared exacerbated intestinal obstruction symptoms after the application of BEV plus CPT11 regimen.. BEV plus chemotherapy regimen as first-line treatment can improve the ORR and DCR of mCRC patients. When it was used as second- or later-line therapy, it may display satisfied DCR, although with a poor efficacy. The bevacizumab-related toxicity is mild and can be well tolerated.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Hemorrhage; Humans; Hypertension; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Proteinuria; Rectal Neoplasms; Remission Induction; Young Adult

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