Avastin+and+Cancer

Avastin (Bevacizumab)
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Introduction

Bevacizumab is a angiogenesis blocker administered under the trade name Avastin. Avastin is a synthesized antibody that binds to and inhibits VEGF-A, a chemical growth factor that promotes blood vessel formation. The drug inhibits the formation new blood vessels on a systemic level. This system wide blockage is primarily used to inhibit the advances of metastatic cancers. Due to the inhibitory nature of the drug, and its confrontational history with the FDA, Avastin is solely prescribed as an experimental treatment. My project seeks to understand why Avastin was enthusiastically received at first, and then why it was rejected, with my opinion on that rejection.

History/Overview
Bevacizumab was developed by Genentech as a monoclonal antibody.

Avastin was approved for use in 2004 by the FDA for a few forms of metastatic cancer. Four years later in 2008, it was approved for use in several other cancer types, including metastatic breast cancer. Avastin is still undergoing numerous clinical trials, which are exploring its effectiveness across different types of cancer. These tests ultimately resulted in the FDA’s unusual 2010 decision to remove the drug's approval. It is currently undergoing clinical trials to test its uses in several forms of non-metastatic cancer and drug combination tests.

Avasitn garners much of its attention from its role in treating metastatic breast cancer. In clinical trials in patients with metastatic breast cancer, patients who received the drug along with chemotherapy had a delay in worsening of their cancer by an average of five months, a clinically significant amount. It is the first drug to affect angiogenesis in breast cancer.

Angiogenesis is one of the hallmarks of cancer and an important early step in the development of breast cancer. In the absence of angiogenesis, tumor growth is capped at 2mm in diameter. The tumor is deprived of oxygen and can't progress. Thus, metastasis and further invasion is impossible. Avastin has only been administered in late stage cancers where metastasis has already occurred, so its effects in early stage cancers is not known.

Side Effects
In these clinical trials, Bevacizumab was well-tolerated by most of the patients that took the antibody. In Phases I and II, there were some serious side effects. Potential bevacizumab-related toxicities were thrombosis, bleeding, proteinuria, and hypertension. However, the rates of these side effects were the same as in the patients that only took chemotherapy. Only the incidence of arterial thromboembolic complications was increased by about a factor of two in the trials, especially in patients older than 65.

Mechanism of action
Avastin, or [|Bevacizumab], is a monoclanal antibody that prevents the formation of new blood vessels to tumors. It blocks the function of VEGF, a protein that plays a role in the formation of new blood vessels.

VEGF VEGFs are vascular endothelial growth factors, protiens that signal the cell to create new blood vessels. VEGFs are important in developing embryos and for recovering from injuries, and in a variety of other cases. However, they are also important for one of the hallmarks of cancer, sustained angiogenesis. A cancer cannot grow enough to metastasize without its own blood supply, making VEGFs a crucial part of the development of late-stage cancers.There are four types of VEGF, known as VEGF A-D. VEGF-A discovered first and is the most abundant in the body. It also is the only VEGF known to be associated with cancer and as such is the target for Bevacizumab.

When a cell is deprived of oxygen, it produces Hypoxic Inductive Factor (HIF). HIF in turn causes the cell to release VEGF. VEGF's bind to tyrosine kinase receptors on the cell surface (VEGFRs), and the signal is propogated in the cell, leading to angiogenesis. As a monoclonal antibody, bevacizumab binds to extracellular VEGF and prevents it from being able to interact with its receptor.

Uses
Avastin is used in the treatment of several types of cancer. It is widely known for its use in metastatic breast cancer, but it is also used to treat [|renal cell carcinoma], [|glioblastoma multiforme], [|ovarian cancer], castrate-resistant (formally called hormone refractory) [|prostate cancer], non-metastatic unresectable [|liver cancer] and metastatic or unresectable locally advanced [|pancreatic cancer].

Clinical Trials
Due to Avastin's successful application in clinical trials for other cancers, it was then put on the fast track for FDA approval.

Avastin was first approved for clinical trials in colorectal cancer.

The first phase of clinical trials began in 1997, which tested its toxicity. The trials found the antibody was not toxic either by itself or in combination with other chemotherapies, promising results for the new treatment. The Phase II trials in 1998 tested Bevacizumab and chemotherapies with colorectal cancer. The trials compared disease progression and survival rates in patients receiving a mix of Bevacizumab and chemotherapy with those receiving chemotherapy and a placebo. The trial showed that there was a significant increase in the time it took the cancer to progress in the patients who took bevacizumab, so trials progressed to Phase III.

Phase III was a combination of Bevacizumab and chemotherapy tested against chemotherapy and placebo. Patients who received Bevacizumab were given 5mg/kg every two weeks. This phase of the trial showed promising results; treatment of rectal cancer improved which reduced the hazard of death by 34% and increased the median survival time from 15.6 months to 20.3 months. Progression-free survival increased from 6.2 months to 10.6 months. These results were consistent across all populations in the study.

Avastin was then approved for trials in lung cancer. Researchers found that patients in the study who received bevacizumab in combination with standard chemotherapy (a treatment regimen of paclitaxel and carboplatin) had a median overall survival of 12.5 months compared to patients treated with the standard chemotherapy alone, who had a median survival of 10.2 months (5). Breast cancer trials were next.

For breast cancer, the FDA made the primary goal of the trials be extending overall survival. The secondary goal was an increase in progression free survival. The trial looked at a combination of Avastin and chemotherapy (Paclitaxel) against chemotherapy alone. 722 women were tested, and the results were different than the trials with other cancers. Although progression free survival increased by 100%, from 5.9 months to 11.8 months, overall survival was not clinically significant. It only increased by 1.5 months, from 25.2 to 26.7 months. This led the FDA to not approve Avastin for breast cancer.

Conclusion
Avastin's journey through clinical trials for breast cancer is well known; even the Wall Street Journal and The New York Times have covered it. The controversy over the drug arises from the fact that it is so expensive. Genentech charges as much as $80,000/year for the drug, and studies have not conclusively shown that it prolongs lifespan. However, a study showed that it prevented the growth of tumors by 11 months, meaning it improved the quality of life for the patient in question. Overall, according to the various studies, lifespan was only increased by an average of 1 to 3 months, which was not considered clinically relevant. Since metastatic breast cancer is currently incurable, the debate over whether the cost of the drug is worth its benefits is important.

Fortunately, Avastin is still available to breast cancer patients "off label," since it hasn't been approved for use by the FDA. However, insurance companies are less likely to pay for a treatment that does not have FDA approval. In my opinion, the improvement of progression free survival is relevant to the efficacy of the drug and too much focus is paid to whether it prolongs overall survival. While the FDA is correct to make overall survival the primary goal of the treatment, delaying tumor symptoms by months may be just as important to a patient, which should be taken into greater account.

Tumors vary greatly between people with the same type of cancer, and the difference between two different cancers is vast. For this reason, more research needs to be done on the interaction between Avastin and breast cancer tumors, so drug companies can learn how to improve Avastin or begin to work on a new drug that works similarly.

Avastin is an early step in "living with cancer", or treating cancer as if it were a chronic condition that can be treated but not cured.Slowing tumor growth and alleviating symptoms.

(I couldn't figure out how to get the pictures from my powerpoint onto this wiki)

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