Anti-angiogenic therapy blocks VEGF, the signal tumors use to grow their own blood vessels. Bevacizumab is given by drip with chemotherapy or immunotherapy, and tablets such as sunitinib, axitinib, cabozantinib and lenvatinib are taken at home. It treats bowel, liver, kidney, ovarian, cervical, lung and thyroid cancers. Our oncologists check blood pressure, bleeding risk and surgery timing before the first dose and follow you once you are back home.
About This Department
Medical oncology
A tumor cannot grow past a few millimeters without its own blood vessels. Anti-angiogenic drugs block the signal that builds them.
Anti-angiogenic therapy treats cancer by blocking VEGF, the growth factor that tumors release to make new blood vessels grow toward them. Two kinds of drug do this. Antibodies such as bevacizumab, given as a drip every two or three weeks, catch VEGF in the blood before it reaches its receptor, and tablets such as sunitinib, axitinib, cabozantinib and lenvatinib block the receptor from inside the cell. Adding bevacizumab to chemotherapy for bowel cancer that had spread raised median survival from 15.6 to 20.3 months in the trial that led to its approval (Hurwitz and colleagues, New England Journal of Medicine, 2004), and paired with the immunotherapy drug atezolizumab it became a first treatment for liver cancer that cannot be removed (Finn and colleagues, 2020). Kidney, cervical, ovarian, lung, thyroid and brain tumors are treated this way too. This page explains how the drugs work, which cancers they treat and with what results, who should not receive them, the side effects and how they are managed, how treatment is scheduled around surgery, and how patients from abroad arrange it at Biruni Hospital in Istanbul.
20.3
Months median survival with bevacizumab added to chemotherapy for bowel cancer that had spread, against 15.6 months
67
Percent alive at one year on atezolizumab plus bevacizumab for liver cancer, against 55 percent on sorafenib
11
Months before kidney cancer grew on sunitinib tablets, against 5 months on interferon
Free
Review of your pathology report and scans by the medical oncology team
Angiogenesis means the growth of new blood vessels. A tumor that has outgrown the oxygen reaching it by diffusion sends out a chemical call, mainly a protein called VEGF, vascular endothelial growth factor. Nearby vessels answer by sprouting branches toward it. Those new vessels are leaky, twisted and badly organized, yet they feed the tumor and give its cells a route into the bloodstream.
Where each drug acts
Target
Drug type
Examples
VEGF itself, in the blood
Antibody by drip
Bevacizumab and its biosimilars
The VEGF receptor, from outside
Antibody by drip
Ramucirumab
VEGF and related factors, as a decoy
Fusion protein by drip
Aflibercept
The VEGF receptor and other growth receptors, from inside the cell
Injections of anti-VEGF drugs into the eye treat wet macular degeneration and diabetic eye disease, at a tiny fraction of the cancer dose. This page covers cancer treatment only.
The drugs
Antibodies given by drip
Drug
How often
Main cancers
Bevacizumab
Every two or three weeks
Bowel, liver with atezolizumab, lung, ovary, cervix, kidney, recurrent glioblastoma
Ramucirumab
Every two or three weeks
Stomach with paclitaxel, lung with docetaxel, bowel, liver when the AFP level is high
Aflibercept
Every two weeks
Bowel, with FOLFIRI chemotherapy after earlier treatment
Bevacizumab is now made by several manufacturers as a biosimilar, a copy tested to work the same way, and biosimilars have brought the price down in most countries. The first drip runs over 90 minutes. If it goes smoothly the next one takes 60, then 30.
Tablets taken at home
Drug
Schedule
Main cancers
Sunitinib
Daily for four weeks, then two weeks off, or two on and one off
Thyroid, liver, kidney and womb with pembrolizumab
Regorafenib and fruquintinib
Three weeks on, one off
Bowel after other treatments, and regorafenib in liver and stromal tumors
Tablets need no hospital chair. They do need a patient who checks blood pressure at home and reports new symptoms early.
Why tumors do not simply starve
Blocking VEGF rarely kills a tumor outright.
The early hope was that cutting off new vessels would starve cancers to death, and in mice it sometimes did. In patients, bevacizumab alone shrinks few tumors. Its benefit comes mostly alongside chemotherapy or immunotherapy, and the explanation took years to work out. By pruning the chaotic, leaky vessels a tumor builds, the drug leaves a smaller network that carries blood more evenly, so chemotherapy reaches more of the tumor and pressure inside it falls. Blocking VEGF also lifts a brake that VEGF places on the immune system, since the growth factor keeps immune cells out of the tumor and dampens their activity once inside, and this is the reason the pairing with immunotherapy works in liver and kidney cancer. Tumors adapt in the end. They switch to other growth factors, borrow existing vessels or grow along them, and resistance develops over months.
The tablets are different. They block several receptors at once, including some on the cancer cells themselves, and on their own they shrink kidney and thyroid cancers in a large share of patients.
Bowel cancer
The trial that led to approval
The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo (Hurwitz and colleagues, 2004).
Today bevacizumab is added to FOLFOX or FOLFIRI chemotherapy for bowel cancer that has spread, most of all when the tumor lacks a RAS mutation on the right side of the colon, or carries one anywhere. It is continued with the second chemotherapy after the first stops working. Later lines use ramucirumab or aflibercept with FOLFIRI, and then the tablets regorafenib or fruquintinib, or trifluridine and tipiracil with bevacizumab. Bevacizumab has no place after surgery for bowel cancer that has not spread, since trials found no benefit there.
1
Before liver surgery
When chemotherapy with bevacizumab shrinks liver metastases enough to remove them, the last dose of bevacizumab is given at least six weeks before the operation, and treatment restarts no sooner than four weeks after it, once the wound has healed.
Liver cancer
Atezolizumab plus bevacizumab against sorafenib
Measure
Atezolizumab plus bevacizumab
Sorafenib
Alive at 12 months
67.2 percent
54.6 percent
Median time before growth
6.8 months
4.3 months
Serious side effects, grade 3 or 4
56.5 percent
55.1 percent
In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib (Finn and colleagues, 2020).
1
An endoscopy first
Liver cancer comes with cirrhosis in most patients, and cirrhosis brings swollen veins in the esophagus that can bleed. Bevacizumab raises that risk. Before the first dose, a gastroscopy checks for these veins, and any large ones are banded. The trial required it within six months of starting.
Patients who cannot receive the combination, because of bleeding risk, an autoimmune disease or a transplant, take lenvatinib or sorafenib tablets instead. After progression, the options include cabozantinib, regorafenib and, when the blood marker AFP is 400 or higher, ramucirumab. The liver itself has to be working reasonably well, in the range doctors call Child-Pugh A, for any of these drugs to help.
2
Combining with local treatment
Chemoembolization, radioembolization and radiation to the liver can be used before, alongside or after the drugs, and the liver tumor board plans the sequence.
Kidney cancer
Clear cell kidney cancer is the most vessel-hungry tumor in the body. A faulty gene, VHL, makes its cells behave as if they lacked oxygen, and they pour out VEGF constantly. Tablets that block the VEGF receptor were the first drugs to change the outlook of this cancer.
The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), and the objective response rate was 31 percent against 6 percent (Motzer and colleagues, 2007).
First treatment for kidney cancer that has spread
Combination
Drugs
Given as
Immunotherapy with a VEGF tablet
Pembrolizumab with axitinib, nivolumab with cabozantinib, pembrolizumab with lenvatinib
Drip every three to six weeks, tablet daily
Two immunotherapy drugs
Nivolumab with ipilimumab
Drip, no tablet
A VEGF tablet alone
Sunitinib, pazopanib, cabozantinib, tivozanib
For patients who cannot receive immunotherapy
The combinations of an immunotherapy drug with a VEGF tablet shrink tumors in more than half of patients and are now the usual first choice.
Other cancers
Anti-angiogenic drugs in other cancers
Cancer
Drug
Setting
Ovarian cancer
Bevacizumab
With chemotherapy and then as maintenance, alone or with olaparib
Cervical cancer
Bevacizumab
With chemotherapy, and with pembrolizumab, when the cancer has come back or spread
Lung cancer, non-squamous
Bevacizumab, ramucirumab, nintedanib
With chemotherapy, never in squamous cancer because of bleeding
Stomach cancer
Ramucirumab
With paclitaxel as the second treatment
Thyroid cancer
Lenvatinib, sorafenib, cabozantinib
When radioactive iodine no longer works
Womb cancer
Lenvatinib
With pembrolizumab after chemotherapy
Glioblastoma that has come back
Bevacizumab
Eases swelling and symptoms and lowers steroid needs
Soft tissue sarcoma
Pazopanib
After chemotherapy, in types other than liposarcoma
1
Cervical cancer
In the GOG 240 trial of 452 women with cervical cancer that had come back or spread, adding bevacizumab to chemotherapy raised median survival from 13.3 to 17.0 months and the response rate from 36 to 48 percent (Tewari and colleagues, 2014). The price was more high blood pressure, 25 percent against 2, and bowel fistulas in 3 percent, which were concentrated in women whose pelvis had been irradiated.
Who should not receive it
1
Checks before the first dose
Blood pressure, a urine test for protein, blood counts, clotting, kidney and liver tests, a thyroid test before tablets, and a review of recent surgery, bleeding, heart attack and stroke. In liver cancer, the gastroscopy described above.
Who is not a candidate?
Patients who have had major surgery within the past four weeks or whose wound is still open, those with active bleeding or coughing up blood, and those who had a stroke or heart attack within the last six months. Blood pressure that stays high despite medicines has to be controlled first. A tumor that invades or wraps around a large blood vessel, a bowel that is blocked or has an abscess, and pregnancy also rule treatment out. Anticoagulants such as heparin can continue in most cases with careful monitoring.
Age alone does not exclude anyone. Patients in their eighties receive bevacizumab and the tablets when their heart, kidneys and blood pressure allow, and the oncologist weighs the benefit against the added risk of clots in older patients.
Side effects
The side effects come from the drug's action on normal vessels. They differ from those of chemotherapy. Hair loss and nausea are uncommon with the antibodies, and blood counts are rarely affected.
Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo, 11.0 percent against 2.3 percent, but was easily managed (Hurwitz and colleagues, 2004).
High blood pressure, the commonest effect, controlled with ordinary blood pressure tablets in nearly every patient.
Protein in the urine, checked with a dipstick before each dose.
Nosebleeds and gum bleeding, mostly minor.
With the tablets, sore and peeling skin on the palms and soles, diarrhea, tiredness, mouth sores, a hoarse voice and an underactive thyroid.
Rare but serious effects
Effect
How rare
Warning sign
Hole in the bowel
One to two percent with bevacizumab
Sudden severe belly pain, fever
Clot in an artery
A few percent
Chest pain, weakness on one side, sudden change in speech
Major bleeding
Under one to a few percent, higher in squamous lung cancer
Coughing or vomiting blood, black stools
Poor wound healing
Rare when surgery is timed well
A wound that opens or does not close
Swelling in the brain, called PRES
Very rare
Headache, confusion, seizures, vision change
Every patient leaves the first visit with a card listing these warning signs and a telephone number that answers day and night.
Schedule and surgery
1
Infusion day
Blood pressure and a urine dipstick, a blood test if chemotherapy is given the same day, then the drip, 30 to 90 minutes for bevacizumab. Patients go home the same afternoon.
Treatment continues as long as it controls the cancer and the side effects are acceptable. In ovarian cancer, maintenance bevacizumab stops after 15 months in total. In bowel and liver cancer it runs until progression.
2
Tablets at home
Tablets start at a set dose and are adjusted in the first weeks to the patient's blood pressure, skin and bowel. A home blood pressure monitor is part of treatment, with readings twice a day at first.
Surgery needs planning. Bevacizumab lingers in the body for weeks, so elective operations are scheduled at least six weeks after the last dose. Tablets are stopped between one and three weeks before, depending on the drug. Dental extractions follow the same logic.
How long does treatment last?
There is no fixed length for disease that has spread. Some patients take a VEGF tablet for kidney cancer for several years. Others switch after a few months when the scans show growth or the side effects become too much. Scans every two to three months guide the decision.
Treatment for patients from abroad
What to send before the first visit
Document
Why
Format
Pathology report and, if available, tumor blocks
Confirms the diagnosis and allows further tests
PDF, blocks by courier
Recent scans
Staging and baseline for response
Image files with the written reports
Treatment so far and current medicines
Plans the next line and spots interactions
A list or clinic letters
Antibodies given every two or three weeks suit two patterns. Some patients stay in Istanbul for the whole course of chemotherapy with bevacizumab, in an apartment near the hospital. Others come for the consultation and the first one or two cycles, then continue with an oncologist at home who follows the plan we send, returning here for scans every two to three months. Tablets fit the second pattern best, with a supply dispensed before departure and blood pressure and blood test results sent to us from home.
A typical first visit
Day
What happens
Duration
Day 1
Consultation, blood and urine tests, blood pressure
Half a day
Days 2 to 4
Scans or gastroscopy if needed, tumor board review
One to three days
Day 5
First dose, observation, written plan for home
Most of a day
1
Length of stay and fitness to fly
One to two weeks for the first visit. Patients are fit to fly the day after an uncomplicated infusion, and after starting tablets once the first week passes with stable blood pressure.
One coordinator from the international patients office handles arrangements from the first message through discharge and answers the same WhatsApp number once you are back home. The office works in English, Arabic, French, Russian, Serbian, Romanian and Spanish and books interpreters for other languages, and it arranges the visa invitation letter, airport transfers, daily transport and accommodation near the hospital. Halal, vegetarian and diabetic meals, a prayer room on site, and a female physician on request wherever the rota allows.
Living with treatment
Work, travel and exercise continue for nearly everyone.
The home routine is simple. Measure blood pressure each morning and evening and write it down. Moisturize hands and feet twice a day on the tablets, wear soft shoes and treat thickened skin before it cracks. Tell every doctor and dentist about the treatment before any procedure, since a tooth extraction or a minor operation needs the same pause as major surgery. Pregnancy has to be avoided during treatment and for six months after bevacizumab.
Cost
The price depends on the drug, whether a biosimilar is used, the patient's weight for the antibodies and the chemotherapy given with them. Tablets are priced by the month. Compare quotes for the same drug and the same number of cycles.
What a quote for anti-angiogenic therapy covers
Item
Included
Priced separately
The drug
Each dose of the antibody, or a month of tablets
The partner chemotherapy or immunotherapy, when quoted apart
Treatment day
Consultation, blood pressure, urine test, day unit chair
Admission for a complication
Tests
Routine blood tests
Scans, gastroscopy, heart tests
References
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.
Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905.
Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115-124.
Tewari KS, Sill MW, Long HJ, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370(8):734-743.
Editor's note
Written by the Biruni Hospital medical editorial team. Reviewed by Prof. Dr. Özcan YILDIZ, Medical Oncology.
