Manufacturer: Genentech, Inc., South San Francisco, CA Indication: The combination of bevacizumab and 5-fluo-rouracil (5-FU) is a first-line or second-line treatment for patients with metastatic colon or rectal cancer.

Drug Class: Bevacizumab is a therapeutic antibody that is believed to work by targeting and inhibiting the function of a natural protein, vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation, a process known as angiogenesis. In preclinical models, anti-VEGF agents such as bevacizumab may work by causing the following changes in the blood vessels that support tumor growth:

  • regression of existing microvessels: helping to arrest tumor growth and reduce tumor size
  • normalization of surviving mature vasculature: making the tumor vasculature more conducive to effective anti-cancer therapy
  • inhibition of vessel growth and neovascularization (stopping the sprouting of new microvasculature from existing vessels)

5-FU is a commonly used antineoplastic drug to treat cancers of the breast, head and neck, anus, stomach, colon, and some skin cancers. It is a member of the fluoropyrimidine class of anticancer drugs and is part of a group of chemotherapy drugs known as antimetabolites. Antimetabolites are similar to normal body molecules, but they differ slightly in structure. These differences mean that antimetabolites stop cells from working properly instead of helping them. Antimetabolites often prevent cells from making and repairing DNA, which cancer cells need to do in order to grow and multiply. Antimetabolites also inhibit the activities of normal cells.

Uniqueness of the Combination: Bevacizumab is the only biologic therapy with a demonstrated survival benefit. In combination with 5-FU chemotherapy, it may offer a new option to colorectal cancer patients who have received a previous treatment regimen.

The FDA’s approval was based on a study showing that patients who received bevacizumab plus the 5-FU-based chemotherapy regimen (FOLFOX4 (oxaliplatin/5-FU/leu-covorin) had a 25% reduced risk of death (based on a hazard ratio of 0.75). The primary endpoint was equivalent to a 33% improvement in overall survival, compared with patients who received FOLFOX4 alone.

The median survival time for patients receiving bevacizumab plus FOLFOX4 was 13 months. For those patients receiving FOLFOX4 alone, the median survival time was 10.8 months.

Boxed Warning:

Gastrointestinal Perforations. Bevacizumab can result in the development of GI perforation, in some instances resulting in death. Sometimes associated with intra-abdominal abscess, GI perforation occurred throughout treatment with bevacizumab, and it was not correlated with the duration of exposure.

The incidence of GI perforation (fistula formation, intra­abdominal abscess) in patients receiving bevacizumab was 2.4%. The typical presentation was reported as abdominal pain associated with constipation and vomiting. GI perforation should be included in the differential diagnosis of patients presenting with abdominal pain who are receiving bevacizumab. Bevacizumab therapy should be permanently discontinued in patients with GI perforation. Kamagra Oral Jelly

Complications of Wound Healing. Bevacizumab can cause wound dehiscence, in some instances resulting in death. Bevacizumab therapy should be permanently discontinued in patients with wound dehiscence who require medical intervention. The appropriate interval between the termination of bevacizumab and subsequent elective surgery required to avoid the risks of impaired wound healing or wound de-hiscence has not been determined.

Hemorrhage. Serious, and in some cases fatal, hemoptysis has occurred in patients with non-small-cell lung cancer who have been treated with chemotherapy and bevacizumab. In a small study, the incidence of serious or fatal hemoptysis was 31% in patients with squamous histological features and 4% in patients with adenocarcinoma who were receiving beva-cizumab, in contrast to no cases in patients treated with chemotherapy alone. Patients with recent hemoptysis should not receive bevacizumab.

Warnings:

Arterial Thromboembolic Events. Patients receiving the bevacizumab/chemotherapy combination had more arterial thromboembolic events (e.g., cerebral infarction, transient ischemic attacks, myocardial infarction, angina) than patients receiving chemotherapy alone. In some instances, these events were fatal.

In a pooled analysis of randomized, controlled clinical trials involving 1,745 patients, the incidence of arterial thromboembolic events was 4.4% with bevacizumab plus chemotherapy and 1.9% with chemotherapy alone. Fatal outcomes for these events occurred in seven of 963 patients (0.7%) receiving bevacizumab plus chemotherapy and in three of 782 patients (0.4%) receiving chemotherapy alone.
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The incidence of cerebrovascular arterial events (1.9% vs. 0.5%) and cardiovascular arterial events (2.1% vs. 1%) was increased in patients receiving bevacizumab compared with those receiving chemotherapy alone. The relative risk of arterial thromboembolic events was greater in patients 65 years and older (8.5% vs. 2.9%) than in patients younger than age 65 (2.1% vs. 1.4°%).

The safety of resuming bevacizumab therapy after resolution of an arterial thromboembolic event has not been studied. Bevacizumab should be discontinued in patients who experience a severe arterial thromboembolic event during treatment.

Hypertension. The incidence of severe hypertension was increased in patients receiving bevacizumab compared with controls. Throughout clinical studies, the incidence of NCI CTC grade 3 or 4 hypertension ranged from 8% to 18%.

Classes of medications used for the management of patients with grade 3 hypertension receiving bevacizumab included angiotensin-converting enzyme (ACE)-inhibitors, beta blockers, diuretics, and calcium-channel blockers. Development or worsening of hypertension can necessitate hospitalization or discontinuation of bevacizumab in up to 1.7% of patients. Hypertension can persist after discontinuation of bevacizumab. Complications can include hypertensive encephalopathy and subarachnoid hemorrhage.

In the postmarketing experience, acute increases in blood pressure associated with initial or subsequent infusions of bevacizumab were reported. Some cases were serious and associated with clinical sequelae.

Bevacizumab should be permanently discontinued in patients with hypertensive crisis and temporarily suspended in patients with severe hypertension that is not controlled with medical management.

Proteinuria. In studies 1 and 3, the incidence of NCI CTC grade 3 and 4 proteinuria, characterized as more than 3.5 g per 24 hours, ranged up to 1.8% in patients treated with beva-cizumab.

Nephrotic syndrome occurred in five of 1,032 (0.5%) patients receiving bevacizumab in clinical studies. One patient died, and one required dialysis. In three patients, proteinuria decreased in severity several months after discontinuation of bevacizumab. Normalization of urinary protein levels, as assessed by 24-hour urine collections, was not observed in any of the patients after discontinuation of bevacizumab therapy.

The highest incidence of proteinuria was observed in a dose-ranging, placebo-controlled, randomized study of bevacizumab in patients with metastatic renal cell carcinoma, an indication for which bevacizumab is not approved. Twenty-four-hour urine collections were obtained in approximately half of the patients enrolled. Among this group of patients, four of 19 patients (21%) receiving bevacizumab 10 mg/kg every two weeks, two of 14 patients (14%) receiving bevacizumab 3 mg/kg every two weeks, and none of the 15 placebo patients experienced NCI CTC grade 3 proteinuria (above 3.5 g of protein per 24 hours).

Bevacizumab should be discontinued in patients with nephrotic syndrome. The safety of continued bevacizumab treatment in patients with moderate-to-severe proteinuria has not been evaluated. In most clinical studies, bevacizumab was interrupted if 2 g or more of proteinuria per 24 hours was present, and it was resumed when proteinuria was less than 2 g per 24 hours. Patients with moderate-to-severe proteinuria, as determined by 24-hour collections, should be regularly monitored until improvement or resolution is observed.
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Congestive Heart Failure. Congestive heart failure (CHF), defined as NCI CTC grade 2-4 left ventricular dysfunction, was reported in 22 of 1,032 (2%) patients receiving bevacizumab in clinical studies. The risk of CHF appears to be higher in patients receiving bevacizumab who have received previous or concurrent anthracyclines.

In a controlled study in patients with breast cancer (an un-labeled indication), the incidence of CHF was higher in the bevacizumab/chemotherapy arm than in the chemotherapy-alone arm. CHF occurred in 13 of 299 (4%) patients who received prior anthracyclines or irradiation to the left chest wall. CHF occurred in six of 44 (14%) patients with relapsed acute leukemia (an unlabeled indication) who were receiving bevacizumab and concurrent anthracyclines in a single-arm study.
The safety of continuing or resuming bevacizumab therapy

in patients with cardiac dysfunction has not been studied.

Dosage and Administration: Bevacizumab, used in combination with IV 5-FU-based chemotherapy, is administered as an IV infusion of 5 mg/kg or 10 mg/kg every 14 days until disease progression. It should not be administered as an IV push or as a bolus.

The initial bevacizumab dose should be delivered over 90 minutes as an IV infusion following chemotherapy. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be given over 30 minutes.

Patients receive 5-FU/LV (5-fluorouracil 500 mg/m2, leucovorin 500 mg/m2 weekly for six weeks every eight weeks) or 5-FU/LV plus bevacizumab (5 mg/kg every two weeks) or 5-FU/LV plus bevacizumab (10 mg/kg every two weeks).

Commentary: Colorectal cancer is the second leading cause of cancer deaths in the U.S. The American Cancer Society estimates that nearly 150,000 new cases of colorectal cancer were diagnosed in 2003. Metastatic colorectal cancer, which has spread from its site of origin to distant places in the body, often invades vital organs. Most patients with advanced colorectal cancer are treated not with the intent to cure but with the goal of improving the duration of survival or quality of life.
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Bevacizumab is the only biologic therapy with a demonstrated survival benefit in colorectal cancer. In combination with 5-FU, this new indication for metastatic disease offers another option to patients who have received a previous treatment regimen. The addition of bevacizumab to 5-FU/LV as the initial therapy for metastatic colorectal cancer appears to improve survival and progression-free survival more than 5-FU/LV alone.