Bevacizumab (brand name, Avastin) is a targeted therapy often used to treat advanced or recurrent endometrial cancer. The incidence of endometrial cancer is on the rise and along with it the rate of death. The original death rate was 0.3% per year from 1997-2008. Now the death rate is 1.9% per year and rising. For patients with advanced disease or recurrent, metastatic cancer, treatment options become limited.
Bevacizumab was initially approved by the FDA (Food and Drug Administration) for use with metastatic breast cancer, but this approval was later revoked. In breast cancer patients it did not significantly extend overall survival and was associated with a higher risk of severe side effects, including bleeding, blood clots and bowel perforations. The FDA determined that the risks outweighed the benefits for breast cancer patients.
Bevacizumab has been FDA approved for the treatment of ovarian and cervical cancers and it is used off-label for the treatment of endometrial cancer. In this post I will tell you more about this drug and review some of the current studies. Is it really effective and do the benefits outweigh the risks for endometrial cancer patients? Keep reading.
HISTORY OF BEVACIZUMAB
In 1971, Dr. Judah Folkmann, a surgeon and researcher at Harvard Medical School published an article proposing his “angiogenesis hypothesis”. This hypothesis suggested that tumors need to recruit their own blood supply through angiogenesis (the formation of new blood vessels) to be able to expand and metastasize. He theorized that if this process could be inhibited, tumors could be starved and their growth controlled. This was a radical idea at the time as cancer research was mainly focused on directly killing cancer cells. In 1989, Dr. Napoleone Ferrara and colleagues isolated and purified a protein from the pituitary gland that strongly stimulated the growth of endothelial cells that form blood vessels and they named it vascular endothelial growth factor (VEGF).
In 1993, these same researchers developed a mouse antibody that would bind to and block the function of VEGF. They went on to demonstrate in pre-clinical mouse models that this anti-VEGF antibody could significantly inhibit tumor growth. This was the evidence they needed to show that inhibiting angiogenesis could be a strategy for cancer therapy.
To be used in humans, the mouse antibody needed to be “humanized” to reduce the risk of immune reactions. They genetically engineered the antibody and this humanized anti-VEGF monoclonal antibody became known as bevacizumab (Avastin) around 1997.
HOW DOES BEVACIZUMAB WORK?
Bevacizumab is a human monoclonal antibody. Antibodies are highly specialized proteins designed to recognize and attach to an antigen (cancer cell, bacteria, virus). Once the antibody attaches through a “lock and key” mechanism, it either neutralizes the antigen or flags it for other immune cells to destroy.
A monoclonal antibody is different. Mono means one and clonal means made from a single copy. It is an antibody designed to be very specific and pinpoint one target. In the lab, they make millions of exact copies of this antibody. In the case of bevacizumab, it specifically targets the protein VEGF-A, which cancer cells use for angiogenesis.
VEGF-A is a protein secreted by various cells, including many cancer cells. VEGF receptors (VEGFR) are proteins found on the surface of cells, primarily endothelial cells that line the blood vessels, but cancer cells have VEGF receptors as well. When VEGF-A binds to its receptors on the endothelial cells, it triggers a cascade of signals that promotes new blood vessel formation.
Bevacizumab binds to free floating VEGF-A before it can reach and bind to its receptors. By neutralizing VEGF-A, bevacizumab prevents the activation of the VEGF receptors, thereby inhibiting the growth of new blood vessels that tumors need to grow and survive. Bevacizumab does not bind to the VEGF receptors on the cells themselves.
Cancer cells need a large blood supply to grow and spread and they often produce excessive amounts of VEGF-A. Unlike traditional chemotherapy, which directly attacks cancer cells, bevacizumab disrupts the tumor’s blood supply, which should slow down or inhibit tumor growth.
Bevacizumab is an intravenous drug that is typically administered once every 3 weeks. It is often used in combination with chemotherapy. It is a palliative therapy at best with only modest improvements in survival as you will see.
RESEARCH STUDIES AND RESULTS
1. Phase II Trial of Bevacizumab in Recurrent or Persistent Endometrial Cancer 2011
There were 52 patients with persistent or recurrent endometrial cancer in this study. All had at least 1-2 prior chemotherapy regimens and measurable disease. 29 had prior radiation.
- Only 7 had a clinical response (13.5%), with 1 complete response and 6 partial responses.
- The median response duration was 6 months with 21 patients surviving progression free for 6 months. However, the overall median progression free survival was only 4.17 months.
- The median overall survival was 10.55 months.
- 3 women were removed from the study due to severe toxicity. Reported major adverse reactions were hemorrhage in the gastrointestinal tract, blood clots and embolisms, proteinuria and hypertension.
- Interestingly, of the 6 partial responses, 3 had high-grade serous carcinoma and 1 had clear cell carcinoma.
- They stained the tumors for VEGF-A and found it was low in 15 patients and high in 29 patients. There was an association (not statistically significant) between high tumor VEGF-A staining and a reduced risk of death.
- Ironically, high circulating blood levels of VEGF-A correlated with a worse outcome and increased risk of death.
2. Carboplatin-Paclitaxel Compared to Carboplatin-Paclitaxel-Bevacizumab in Advanced or Recurrent Endometrial Cancer 2019
I can only highlight the abstract here as I am unable to open the complete study. There were 108 patients in this phase II trial.
- The overall response rate, progression free survival and overall survival were not statistically significantly different between patients treated with carboplatin/paclitaxel chemotherapy alone vs. chemotherapy + bevacizumab.
- The bevacizumab group did have an increase in 6 month disease control rate, but also experienced more frequent > or = grade 2 cardiovascular events, including hypertension and thromboembolic events.
- Read More
3. Bevacizumab in Advanced Endometrial Cancer 2022
In this study they used bevacizumab as a single therapy for 101 patients with advanced endometrial cancer. 46 of the patients were stage 4. All types of endometrial cancers were represented.
- There were 0 complete or partial responses and only 19 achieved stable disease for a clinical benefit rate of 19%. Interestingly, 9 of these patients had serous cell carcinoma.
- The median progression free survival was 2.6-4.9 months.
- The 3 year overall survival rate was 3.4 years.
- The more prior lines of treatment a patient had received the longer the median overall survival.
- The main complication was hypertension, which developed in 45 patients. 35 were grade 1-2 and 10 were grade 3. One woman had a stroke.
- Overall, 13 patients developed grade 3 toxicities (10 hypertension and 3 bowel obstructions due to cancer progression).
- Their conclusion was that in heavily pre-treated patients, bevacizumab had modest clinical efficacy and remained an option in the palliative setting.
4. TP53 Sequencing and p53 Immunohistochenistry Predict Outcomes When Bevacizumab is Added to Frontline Chemotherapy in Endometrial Cancer 2022
This is a retrospective, very technical paper, which I will briefly outline here.
In this study, they analyzed 213 patients that had received either bevacizumab + chemotherapy or temsirolimus + chemotherapy. They were specifically trying to determine if there was an increased benefit for patients that had TP53 mutations and subsequent p53 over expression present on tumor analysis. Patients with p53 over expression often have a poor outcome and standard treatments are not very effective.
- 28% of patients had over expression of p53 and these were women with high-grade endometrioid adenocarcinomas and serous cell carcinomas. This means that p53 staining was present in at least 80% of the tumor cell nuclei.
- For patients in this high risk tumor genotype group, bevacizumab + chemotherapy increased median overall survival in the bevacizumab group (30 months) vs. the temsirolimus + chemotherapy group (14.4 months).
- They outlined a potential clinical strategy based on their findings.
- If p53 is over expressed in the tumor cells, adding bevacizumab to chemotherapy up front may significantly improve progression free survival and overall survival.
- If p53 is not over expressed or even null ( no staining), then adding in bevacizumab may not help and the risks for adverse events outweigh the benefits.
- If patients are in the p53 wild-type genotype, there is no clear benefit to adding bevacizumab to chemotherapy up front.
SIDE EFFECTS OF BEVACIZUMAB
Bevacizumab is not a benign drug and it comes with risks for major side effects. Make sure to discuss these with your oncologist prior to considering the use of bevacizumab.
- The most common side effect is high blood pressure (hypertension). This often needs to be managed with medication and increases the risk for heart attacks and strokes in cancer patients who are already at higher risk for forming blood clots. If a woman has a history of hypertension and/or blood clots, bevacizumab may not be recommended. It is very important to have your blood pressure monitored frequently if you are on this drug. I would ask your doctor to monitor d-Dimer and fibrinogen blood tests as well, as these can be early indicators of blood clots forming.
- Other common side effects include bleeding, such as nosebleeds, bleeding gums and vaginal bleeding. Fatigue, headaches, muscle and joint pain, changes in taste, loss of appetite, dry skin and a stuffy or runny nose are also common.
- Serious side effects include gastrointestinal perforation or fistula. Although rare, these problems can be life threatening. Symptoms include severe abdominal pain, nausea, vomiting, constipation and fever.
- Bevacizumab can also impair wound healing. It should not be used before or after surgery for a period of time or until after any wounds are completely healed.
- Serious bleeding can occur leading to coughing up blood, bleeding in the brain or stomach and heavy vaginal bleeding. Not only that, but bevacizumab can cause blood clots, which can lead to mini-strokes, heart attacks or chest pain.
- Bevacizumab can damage the kidneys, often leading to proteinuria, which is too much protein in the urine. This also increases the risk of blood clots and in some cases can be fatal.
- Infusion related reactions can occur including high blood pressure, trouble breathing, allergic reactions, chest pain, headache, tremors and excessive sweating.
- Although rare, nervous system and vision problems can occur.
KEY TAKEAWAYS
- Women with TP53 mutations and p53 over expression on their tumor analysis may benefit from chemotherapy + bevacizumab up front.
- Women with serous cell carcinoma seem to have higher benefit with the use of bevacizumab.
- High VEGF-A tumor staining is associated with a lower risk of death and possibly more benefit with the use of bevacizumab
- High circulating levels of VEGF-A in the blood are associated with a poor outcome and increased risk of death.
- Ask your doctor to check your VEGF-A blood level prior to considering this treatment.
- Women with pre-existing hypertension or higher risk of forming blood clots are not good candidates for bevacizumab. It would be helpful to know your d-Dimer and fibrinogen blood levels before treatment to see if you are at risk for blood clots.
- Make sure they monitor your blood pressure and check for elevated protein in your urine on a frequent basis if you are using this drug.
- Contact your doctor immediately if you have any symptoms of bleeding or blood clots. I wrote a whole blog post on the subject of blood clots here.
SUPPLEMENTS TO INHIBIT ANGIOGENESIS
To avoid all these serious side effects, there are natural ways to inhibit angiogenesis. Here is a list of effective supplements for this purpose.
Curcumin
Green tea extract (ECGC)
Artemisia
Mistletoe
Baicalin
Quercetin
Shark cartilage
Resveratrol
Ginseng
Gingko biloba
Grape seed extract
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