This information is about bevacizumab, which is commonly known as Avastin®. It is used to treat people with bowel cancer, which has spread. It may also be used to treat breast cancer which has spread, and advanced non-small cell lung cancer. It is also starting to be used in kidney cancer, stomach cancer, ovarian cancer, prostate cancer and high grade brain tumours.
What is Avastin?
Avastin is one of a new group of cancer drugs known as monoclonal antibodies. It is not a chemotherapy drug. It is a targeted ‘magic bullet’ type biological therapy.
In the UK it is currently given along with chemotherapy, often 5FU and oxaliplatin or irinotecan for bowel cancer, or with a Taxane for breast cancer. It can also be given on its own after a course of chemotherapy has been completed, as ‘continuation’ or ‘maintenance’ therapy.
Although Avastin is licensed and can be prescribed in the UK, it has not been approved for use by NICE for the NHS. NICE gives advice on which new drugs or treatments should be available on the NHS. As a result Avastin may not be widely available on the NHS. Normally the only way to receive it on the NHS is if you are in a clinical trial, or if your local health authority has given special permission – known as an ETA (exceptional treatment arrangement) – This involves a lengthy application process and can be a bit of a lottery.
Monoclonal antibodies can destroy some types of cancer cells while causing little harm to normal cells. They do this by recognising certain proteins that are found on the surface of some types of cancer cells (known as receptors) and ‘locking’ themselves onto them.
There are different types of antibodies that work in different ways. Once the monoclonal antibody has attached to the receptor it can:
- trigger the body’s immune system to attack the cancer cells and cause the cells to destroy themselves
- block the receptor from connecting with a different protein that helps the cell to grow, which may stop the cells from growing and dividing, or prevent the cancer cells from developing a new blood supply.
How Avastin works
Avastin can stop some cancers from developing new blood vessels. This reduces the cancer’s supply of oxygen and nutrients, which causes the tumour to shrink, or at least to stop growing. Drugs that interfere with blood vessel growth in this way are called angiogenesis inhibitors or anti-angiogenics. Any cancer needs to make its own blood supply to grow over 2mm in size.
What it looks like
Avastin is a colourless fluid.
How it is given
Avastin is given through a small tube (cannula) inserted into a vein. It may be given in combination with chemotherapy drugs, usually oxaliplatin, irinotecan, fluorouracil (5FU) and leucovorin (folinic acid). It is normally given as an infusion over 30 – 60 minutes, maybe longer for the first infusion.
Some people have their Avastin and chemotherapy given through a fine plastic tube which is inserted under the skin into a vein near the collarbone (Hickman line / portacath), or passed through a vein in their arm (PICC line).
Possible side effects
Each person’s reaction to cancer treatment is different. Some people have very few side effects, while others may experience more. The side effects described in this information will not affect everyone who is given Avastin. The drug is often used in combination with chemotherapy, so patients will also have side effects from the chemotherapy. The side effects mentioned below are those caused by Avastin.
We have outlined the most common side effects, but have not included those that are very rare and therefore extremely unlikely to affect you. If you notice any effects that you think may be due to the drug, but which are not listed below, please discuss them with your doctor or nurse.
Around 95% of patients given Avastin will experience little or no side effects at all. The other 5% will experience one of the effects described below, and it is important to mention this straight away, as they are all treatable, but potentially dangerous if left untreated.
High blood pressure
Your blood pressure will be checked regularly. If you have any headaches, nosebleeds or feelings of dizziness let your doctor know. This occurs in about 3% of patients, quite rare. Your blood pressure will be measured before and after treatment with Avastin.
It is common to have a slight allergic reaction to Avastin, as it was originally developed from a mouse antibody, but some people have a more severe reaction. Signs of a reaction include skin rashes and itching, a feeling of swelling in the tongue or throat, irritation of the nasal passages, wheezing, a cough and shortness of breath You will be monitored closely during your treatment, but it is very important to tell your nurse or doctor if you have any of these symptoms.
Slow wound healing
Wounds may take longer to heal while you are having treatment with Avastin. This is because wound healing involves the formation of thousands of tiny new blood vessels. In general you should NOT undergo any type of surgical procedure for 6 weeks after Avastin treatment.
Let your doctor know if you develop constipation. This can often be relieved with a high-fibre diet or laxatives.
Circulatory problems and blood clots
There have been some reports of an increased risk of blood clots (DVT), stroke and angina (heart pain) in people taking Avastin. The risk is low, around 2%
Changes in the way your heart works
Symptoms of this will include chest pain, difficulty breathing, and swelling of the ankles (water retention). Let your doctor know immediately if you develop any of these symptoms.
Bruising or bleeding
Avastin can reduce the production of platelets (which help the blood to clot). Let your doctor know if you have any unexplained bruising or bleeding.
Damage to the kidneys
Avastin can sometimes temporarily change the way that your kidneys work and they can leak protein. You will have blood tests to check that your kidneys are working well, and a urine sample will be tested prior to each infusion.
Very rare side effects
his can usually be easily controlled with medicine (loperamide), but let your doctor know if it is severe or if it continues. It is important to drink plenty of fluids if you have diarrhoea.
Tiredness and a general feeling of weakness
You may feel tired. It is important to allow yourself plenty of time to rest.
Feeling sick (nausea) and being sick (vomiting)
This is extremely unusual with Avastin. If this happens it may begin a few hours after the treatment is given and last for up to a few days. Your doctor can prescribe very effective anti-sickness (anti-emetic) drugs to prevent or greatly reduce nausea.
Let your doctor know if you have persistent headaches while you are having Avastin treatment as it can signify high blood pressure.
Loss of appetite
You may find that you do not feel like eating. A dietitian or specialist nurse at the hospital can give advice.
Perforation of the bowel
This is very unusual, but if you experience severe abdominal pain and/or vomiting seek medical advice straight away.
Pain in the area of the tumour
Some people may have pain in the area of the tumour as the blood supply is cut off.
Some other medicines can be harmful to take when you are having Avastin. Let your doctor know about any medications you are taking, including non-prescribed drugs such as complementary therapies and herbal drugs.
In some people with lung cancer there is a risk of bleeding into the lung tissue (haemoptysis). If people have already coughed up blood they should not have treatment with Avastin.
It is not advisable to become pregnant or father a child while taking Avastin as not enough is known about its effect on the developing foetus. It is important to use effective contraception during your treatment and for a year afterwards. You can discuss this with your doctor or specialist nurse.
ADDITIONAL INFORMATION FOR HEALTHCARE PROFESSIONALS
ADVERSE REACTIONS SIGNIFICANT
Percentages reported as monotherapy and as part of combination chemotherapy regimens. Some studies only reported hematologic toxicities grades =4 and nonhematologic toxicities grades =3.
- Cardiovascular: Hypertension (23% to 67%; grades 3/4: 8% to 18%), thromboembolic event (grades 3/4: 15%), hypotension (7% to 15%)
- Central nervous system: Pain (61% to 62%), headache (26%; grades 3/4: 2% to 4%), dizziness (19% to 26%), fatigue (grades 3/4: 5% to 19%), sensory neuropathy (grades 3/4: 1% to 17%; in combination with paclitaxel: 24%)
- Dermatologic: Alopecia (6% to 32%), dry skin (7% to 20%), exfoliative dermatitis (3% to 19%), skin discoloration (2% to 16%)
- Endocrine & metabolic: Hypokalemia (12% to 16%)
- Gastrointestinal: Abdominal pain (50% to 61%; grades 3/4: 8%), vomiting (47% to 52%; grades 3/4: 6% to 11%), anorexia (35% to 43%), constipation (29% to 40%), diarrhea (grades 3/4: 2% to 34%), stomatitis (30% to 32%), gastrointestinal hemorrhage (19% to 24%), dyspepsia (17% to 24%), taste disorder (14% to 21%), flatulence (11% to 19%), weight loss (15% to 16%), nausea (grades 3/4: 4% to 12%)
- Hematologic: Leukopenia (grades 3/4: 37%), neutropenia (grade 4: 6% to 27%)
- Neuromuscular & skeletal: Weakness (73% to 74%), myalgia (8% to 15%)
- Ocular: Tearing increased (6% to 18%)
- Renal: Proteinuria (36%; grades 3/4: 3%)
- Respiratory: Upper respiratory infection (40% to 47%), epistaxis (32% to 35%), dyspnea (25% to 26%)
- Miscellaneous: Infection (serious: 9% to 14%; pneumonia, catheter, or wound infections)
1% to 10%:
- Cardiovascular: DVT (6% to 9%; grades 3/4: 9%), venous thrombus/embolus (grades 3/4: 5%), arterial thrombosis (3% to 4%), syncope (grades 3/4: 3%), intra-abdominal venous thrombosis (grades 3/4: 3%), cardio-/cerebrovascular arterial thrombotic event (2% to 4%), CHF (2%)
- Central nervous system: Confusion (1% to 6%), abnormal gait (1% to 5%)
- Dermatologic: Nail disorder (2% to 8%), rash desquamation (grades 3/4: 3%), wound dehiscence (1%)
- Endocrine & metabolic: Dehydration (grades 3/4: 3% to 10%), hyponatremia (grades 3/4: 4%)
- Gastrointestinal: Xerostomia (4% to 7%), colitis (1% to 6%), ileus (grades 3/4: 4% to 5%), gingival bleeding (2%), fistula (1%), gastrointestinal perforation (=4%), intra-abdominal abscess (1%)
- Genitourinary: Polyuria/urgency (3% to 6%), vaginal hemorrhage (4%)
- Hematologic: Neutropenic fever/infection (5%; grades 3 and/or 4: 4% to 5%), thrombocytopenia (5%), hemorrhage (grades 3/4: 4% to 5%)
- Hepatic: Bilirubinemia (1% to 6%)
- Neuromuscular & skeletal: Bone pain (grades 3/4: 4%)
- Respiratory: Voice alteration (6% to 9%), pneumonitis/pulmonary infiltrates (grades 3/4: 5%), hemoptysis (nonsquamous histology 2%)
- Miscellaneous: Infusion reactions (<3%)
<1% (Limited to important or life-threatening):
Anastomotic ulceration, angina, cerebral infarction; fistula (biliary, bladder, bronchopleural, duodenal, enterocutaneous, esophageal, gastrointestinal, rectal, tracheoesophageal [TE] and vaginal); hemorrhagic stroke, hypertensive crises, hypertensive encephalopathy, intestinal necrosis, intestinal obstruction, mesenteric venous occlusion, microangiopathic hemolytic anemia (when used in combination with sunitinib), MI, nasal septum perforation, nephrotic syndrome, pancytopenia, polyserositis, pulmonary embolism, pulmonary hemorrhage, pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (RPLS), subarachnoid hemorrhage, transient ischemic attack, ureteral stricture, wound healing complications
Concerns related to adverse effects:
- Bleeding: [U.S. Boxed Warning]: Avoid use in patients with recent hemoptysis (>2.5 mL blood); significant pulmonary bleeding has been reported in patients receiving bevacizumab (primarily in patients with nonsmall cell lung cancer with squamous cell histology [not an FDA-approved indication]). Other serious bleeding events may occur, but with a lower frequency; discontinuation of treatment is recommended in all patients with serious hemorrhage.
- Gastrointestinal perforation: [U.S. Boxed Warning]: Gastrointestinal perforation, fistula (including gastrointestinal, enterocutaneous, esophageal, duodenal, and rectal fistulas), and intra-abdominal abscess have been reported in patients (not related to treatment duration); monitor patients for signs/symptoms (eg, abdominal pain with constipation and/or vomiting). Permanently discontinue in patients who develop these complications.
- Hypertension: May cause and/or worsen hypertension significantly; use caution in patients with pre-existing hypertension and monitor BP closely in all patients. Permanent discontinuation is recommended in patients who experience a hypertensive crisis or encephalopathy. Temporarily discontinue in patients who develop uncontrolled hypertension.
- Infusion reactions: Infusion reactions (eg, hypertension, hypertensive crisis, wheezing, hypersensitivity, chest pain, headache, diaphoresis) may occur with the first infusion (uncommon). Interrupt therapy in patients experiencing severe infusion reactions; there are no data to address reinstitution of therapy in patients who experience severe infusion reactions.
- Nephrotic syndrome/proteinuria: Proteinuria and/or nephrotic syndrome has been associated with use; discontinue in patients with nephrotic syndrome.
- Nongastrointestinal fistula formation: Nongastrointestinal fistula formation (including tracheoesophageal, bronchopleural, biliary, vaginal, and bladder fistulas) has been observed, most commonly within the first 6 months of treatment. Permanently discontinue in patients who develop internal organ fistulas.
- Reversible posterior leukoencephalopathy syndrome (RPLS): Cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Symptoms (which include headache, seizure, confusion, lethargy, blindness and/or other vision, or neurologic disturbances) may occur from 16 hours to 1 year after treatment initiation. RPLS may be associated with hypertension; discontinue therapy and begin management of hypertension, if present.
- Wound dehiscence: [U.S. Boxed Warning]: Wound dehiscence/wound healing complications have been reported in patients (not related to treatment duration); monitor patients for signs/symptoms of improper wound healing. Permanently discontinue in patients who develop these complications. The appropriate intervals between administration of bevacizumab and surgical procedures to avoid impairment in wound healing has not been established. Therapy should not be initiated within 28 days of major surgery and only following complete healing of the incision. Bevacizumab should be discontinued prior to elective surgery and the estimated half-life (20 days) should be considered.
- Cardiovascular disease: The risk for heart failure, including left ventricular dysfunction, is higher in patients receiving bevacizumab plus chemotherapy when compared to chemotherapy alone. Use with caution in patients with cardiovascular disease; patients with significant recent cardiovascular disease were excluded from clinical trials. The safety of therapy resumption or continuation in patients with cardiac dysfunction has not been studied. An increased risk for arterial thromboembolic events (eg, stroke, MI, TIA, angina) is associated with use in combination with chemotherapy. History of arterial thromboembolism or =65 years of age may present an even greater risk; permanently discontinue if serious arterial thromboembolic events occur.
- CNS metastases: Avoid use in patients with CNS metastases; patients with CNS metastases were excluded from clinical trials due to concerns for bleeding.
MECHANISM OF ACTION
Bevacizumab is a recombinant, humanized monoclonal antibody which binds to, and neutralizes, vascular endothelial growth factor (VEGF), preventing its association with endothelial receptors, Flt-1 and KDR. VEGF binding initiates angiogenesis (endothelial proliferation and the formation of new blood vessels). The inhibition of microvascular growth is believed to retard the growth of all tissues (including metastatic tissue).
PHARMACODYNAMICS / KINETICS
- Distribution: Vd: 46 mL/kg
- Half-life elimination: ~20 days (range: 11-50 days)
- Excretion: Clearance: 2.75-5 mL/kg/day