Prologue: A New Approach to Cancer Treatment
On June 1, 2003, at a worldwide oncology conference, researchers presented data that would change the course of cancer treatment. The results of a new medicine, Avastin® (bevacizumab), marked a milestone in a novel way to fight metastatic colorectal cancer—a fight that began two decades earlier in the laboratory of Napoleone Ferrara. Avastin, which was designed to starve blood supply to the tumor—the “legs of the crab”—had met the study’s primary endpoint.After the FDA approved it one year later, this treatment was available for people with advanced colorectal cancer.
Avastin is approved for metastatic colorectal cancer (mCRC) for first- or second-line treatment in combination with intravenous 5-fluorouracil-based chemotherapy. It is also approved to treat mCRC for second-line treatment when used with fluoropyrimidine-based (combined with irinotecan or oxaliplatin) chemotherapy after cancer progresses following a first-line treatment that includes Avastin. Avastin is not approved for use after the primary treatment of colon cancer that has not spread to other parts of the body.
The information presented in this story was verified as of August 2016. No representation can be made concerning Laura’s current condition. This story should not be used as a substitute for professional medical advice.
Laura Webb was in the sort of physical shape most people only dream about. She loved to travel and exercise, and pushed herself to achieve new goals. A few weeks before her birthday, she began training for a long-distance triathlon—a 2.4-mile swim, 122-mile bike ride and a 26-mile run. She was tough, focused and knew she could handle the grueling race.
But as she trained, pulling another lap in the pool or sweating through another hour of running, she felt a persistent pain in her abdomen. It wasn’t the kind of stitch in her side she’d occasionally get while running, one that would disappear, but rather something deeper that wouldn’t go away. Worried, and with the race nearing, she visited her doctor about the abdominal pain. After a few tests and referrals, a colonoscopy revealed cancerous growths. More tests showed even worse news: The disease had spread to her liver. The triathlon would have to wait.
Devastated, Laura prepared herself for a much more difficult course than the triathlon, one that would take all of her strength and resolve. A month later, she was in surgery.
After her surgical wounds had healed, she began intravenous (IV) 5-FU (fluorouracil)-based chemotherapy and Avastin.
The race that ultimately led to this treatment for Laura’s cancer had started more than two decades before, in the lab of Dr. Napoleone Ferrara. The Italian-American molecular biologist still remembers the events that would change the course of his career and put medical science on the path to develop a new way to fight cancer.
In the late 1980s, when Ferrara was conducting research at the University of California, he would drive to slaughterhouses in Berkeley, San Leandro and the Central Valley to extract pituitary glands from cow carcasses. Often called the “master gland,” the pituitary produces hormones that influence critical activities in the body, including growth, metabolism and the physiological reaction to stress and injury. Ferrara was curious to understand more about how this gland worked.
So he pursued this oddball area of interest, spending countless hours doing basic science on the pituitary gland. Ferrara’s first contribution was to isolate follicular cells in the anterior pituitary that had no known function. The cells didn’t appear to produce hormones like other cells in the pituitary, and Ferrara ran experiment after experiment to determine their purpose. He had an inkling that these follicular cells might have something do with angiogenesis—the growth of new blood vessels—so he decided to test his hunch.
The experiment was elegant in its simplicity. Ferrara added follicular cell culture supernatants to a culture of endothelial cells—the ones that form the interior lining of blood vessels—and waited to see what would happen. The assay was supposed to last for five days, but Ferrara decided to check on the experiment halfway through. He put the dish under the microscope and focused the lens.
“When I looked through the microscope, I said ‘wow,’” Ferrara remembers. The culture fluid from the pituitary cells had signaled the vascular cells to start dividing at a rapid rate. “Something that these cells were secreting was making the endothelial cells multiply. It was a very exciting moment and a very striking result.” This meant that there was a chemical messenger that could be a potent stimulator that caused new blood vessels to grow from existing ones.
In the stories told about science, much is made of the famed “ah-ha” moments, but few outsiders to the lab understand the years of work—the thousands of “oh-well” experiments—that lead up to them. This was a time when gene sequencing was expensive and purifying a particular protein could take a decade of work. Despite the success of his experiment, many of Ferrara’s colleagues counseled him to pick a project that would have a faster payoff.
But Ferrara was persistent, even stubborn, in pursuing his experiments. Throughout the late 1980s, he authored a series of papers advancing the understanding of follicular cells and their relationship to vascular growth. If his interest had only been in the basic science, the work might have been rewarding enough. But Ferrara had trained in Italy as a physician and wanted to push his discovery toward an outcome that could help treat patients. Angiogenesis, he knew, was critical in both healthy development and in many diseases’ processes—including the growth of tumors.
Dr. Philippe Bishop, former vice president, product development, oncology
“As Napoleone was working on his own time, on these scientific questions in the non-directive way, I don’t think anybody could imagine that those projects were going to translate into something that would have such a great impact.”
The Legs of the Crab
Ferrara joined Genentech in 1988, where he was first tasked with studying a hormone thought to ease the discomfort of childbirth. His interest in the triggers of angiogenesis, however, never wavered. He spent countless hours in the evenings and on weekends on his passion project—trying to decipher what factor in those follicular cells made the blood vessel cells grow.
Dr. Napoleone Ferrara
“When we had this initial data in tumor growth, in tumorigenesis, that was absolutely stunning because we didn’t expect it. It was very difficult to predict all of that.”
Ferrara was aware that learning how to trigger or inhibit angiogenesis might be important to understanding tumor growth. Indeed, the observations that tumors are often surrounded by a robust network of blood vessels may be connected to cancer’s very name, which is derived from the name of a giant crab in Greek mythology, “karkinos.” The network of blood vessels branching away from a tumor, as one story goes, reminded Hippocrates of a crab with its legs dug into the sand.1 This begged the question: Could you kill the crab by cutting off its legs?
In the early 1970s, Dr. Judah Folkman from Harvard Medical School was the main proponent of the theory that inhibiting the creation of new blood vessels around a tumor could become a critical method of fighting the disease.2 While tumors smaller than a couple of millimeters aren’t vascularized, they must recruit their own blood supply to grow bigger. If the malignancy could be deprived of oxygen and nutrients, its growth and metastatic progression might be slowed. The hypothesis that growing tumors release a “blood vessel growth stimulating factor” required for tumor angiogenesis was first proposed in the 1930s and 1940s, but at that time the biochemical and molecular tools needed to test and advance this hypothesis were lacking. In the 1980s, several potential angiogenic factors were discovered, but inhibiting these molecules did not appear to have a major impact on tumor growth. Perhaps some important angiogenic molecules had yet to be discovered.3 Ferrara pursued this idea and sought to isolate the angiogenic molecule secreted by follicular cells.
Even though it was his side project, Ferrara made tremendous progress studying angiogenesis during his first six months at Genentech. With the advanced technology and expertise available at the company, he was able to identify and purify the factor that was sparking the growth in vascular cells that he had observed years earlier. Identifying the protein directly related to blood vessel growth, called the “vascular endothelial growth factor,” (VEGF), was a true breakthrough, published in the prestigious journal Science in 1989.4 After that success, Ferrara turned his full-time attention to the possible uses for the discovery.
Ferrara reasoned that if tumors needed their own vascular structure to grow, perhaps that process relied on the VEGF molecule. Ferrara and his colleagues worked to develop a VEGF antibody that would bind to the VEGF molecule and interfere with the growth of new blood vessels around a tumor. In 1993, Ferrara and his colleagues published a study showing that they had created an antibody that had reduced the growth of tumors in mice.5 This was the first clear evidence that tumor growth could be influenced by targeting the blood supply, and affirmed Ferrara’s belief that his research might have applications for future cancer treatments. Indeed, over the next few years, Genentech moved forward, turning this new antibody into a medication that they would test in the laboratory and in human trials.
First, the Bad News
Early human trials for this novel cancer medication, bevacizumab (later trademarked as Avastin®), began in 1997. The molecule was unlike any that had come before it: Instead of attacking cancer cells directly, Avastin targets the blood supply that is used by both normal tissues and tumors to grow and spread. As the new millennium dawned, researchers began enrolling large numbers of patients in two critical Phase III trials for Avastin.
The early studies respectively enrolled people with metastatic breast cancer and advanced colorectal cancer that had progressed following first-line chemotherapy.
The results of the study, which evaluated the use of Avastin and chemotherapy in 426 women with metastatic breast cancer who had previously received treatment, came in first. The data were disappointing as the study did not meet its primary endpoint.6
Many scientists at the company thought that these results meant the end of their efforts to target angiogenesis, but others persisted.
Then, in May 2003, the results of the Phase III colorectal cancer trial for Avastin were revealed. When the data were unblinded, the study’s authors immediately knew that the results were big news.
The researchers announced their breakthrough at the American Society of Clinical Oncology (ASCO), the most prominent oncology conference in the world, attended by thousands of doctors and researchers. The study was a late addition to the meeting, but news spread fast that something important was afoot. The stakes were high, and there was speculation across the cancer research community about whether Avastin, an entirely new way of fighting cancer at that time, would be effective. When the time came for Dr. Herbert Hurwitz from Duke University Medical Center to make the presentation, the room was standing room only.
Hurwitz, the lead academic author of the paper and a clinical oncologist, had a personal stake in the results. Several of his patients had consented to be part of the study. “The decision to participate,” he said, “is a huge expression of trust in everybody who is part of the clinical research process.” And while his patients were motivated by the possibility that the new drug might help them, many also told Hurwitz that they hoped that by participating, they could also help improve the lives of thousands of people who would be in their position in the future.
At the podium, Hurwitz worked methodically through the slides, describing the design of the study and how it was conducted. Everyone in the room waited for the critical slide, the one that would reveal the efficacy, in what’s called a Kaplan-Meier survival curve. This curve provides the measure that every cancer patient is ultimately concerned with: increases in survival time. The moment Hurwitz clicked to the critical slide, the room of oncologists and researchers erupted in applause.
Indeed, the Kaplan-Meier graph showed the patients who were given Avastin with chemotherapy, as opposed to chemotherapy alone, had lived a median of 4.7 months longer [Hazard ratio (HR)=0.65 (95% confidence interval [CI], 0.54–0.81); P'0.001].7 Hurwitz explained that on the slide, the line representing the control group and the one representing patients who received Avastin separated early and distinctly, showed that those who received Avastin had a hazard ratio of 0.65, meaning that Avastin was shown to lower their risk of dying from the disease by a third. The median time that patients lived on the medication increased from 15.6 months in the chemotherapy only arm to 20.3 months in the Avastin plus IV 5-FU-based chemotherapy arm. The trial also met the secondary endpoints of progression-free survival, duration of response and response rate. This was the first time a medicine extended survival for people with advanced colorectal cancer, compared with chemotherapy alone.
Every patient reacts differently to Avastin therapy, so it’s important to know what the side effects are. Although some people may have a life-threatening side effect, most do not. A doctor will stop treatment if any serious side effects occur. Patients should contact their health care team if they have symptoms related to these side effects.
Serious, sometimes fatal side effects are not common, but can occur. Symptoms, like pain in the abdomen, nausea, vomiting, constipation or fever could be caused by a GI perforation, a hole that develops in the stomach or intestine. A cut made during surgery can be slow to heal or may not fully heal. Avastin should not be used for at least 28 days before or after surgery and until surgical wounds are fully healed. Serious bleeding, such as vomiting or coughing up blood, bleeding in the stomach, brain or spinal cord, nosebleeds and vaginal bleeding has also been reported. If patients have recently coughed up blood or had serious bleeding, they should tell their doctor.
The oncologists were excited. For any Phase III trial of a cancer medicine to show any effect is important news, particularly if the drug could potentially extend the lives of their patients. Few could have guessed that Avastin would eventually impact many individual patients over the coming decades, like Laura Webb.
As the applause died down, many in attendance also knew that they had witnessed a bit of history in the long, collective, scientific struggle against cancer. The study results represented the first solid proof that targeting the blood supply of tumors could have a significant impact when treating people.
“There had been a lot of successes in the lab but no successes in the patients up to that point,” said Hurwitz. “It was a landmark for a whole new therapeutic class.”
Ferrara remembers learning about the results of the study before it was presented at ASCO. He was in Siena, Italy, lecturing at a seminar when he got a message to call Art Levinson, Genentech’s then CEO. “I knew the call was likely related to the Avastin trial,” Ferrara remembers. “I was afraid it was bad news.” Instead, Levinson had called to congratulate Ferrara, saying that the study results were positive.“I was totally stunned to hear that the news was good,” says Ferrara. For him, the positive results were a validation of nearly two decades of work.
It was morning in California, but already late evening in Siena, so Ferrara opened a bottle of fine Italian Chianti. “It was a delicious wine,” he said, “and a very sweet memory.”
A new front had been opened on the war against cancer. In 2004, Avastin in combination with IV 5-FU-based chemotherapy was approved for the treatment of metastatic colorectal cancer.
A Difficult Decision
For the next decade, this medicine would become one of the most intensely studied approaches to cancer treatment.
In 2008, Genentech received accelerated approval for the use of Avastin in combination with paclitaxel chemotherapy, for the treatment of patients who have not received chemotherapy for their metastatic HER2-negative breast cancer. The approval was based on the results of a study that suggested that Avastin, combined with paclitaxel chemotherapy, had some activity on the cancer compared with the chemotherapy alone. This effect is clinically known as progression-free survival, which measures how long a patient lives without the disease getting worse.8
While there was a progression-free survival effect observed in the study, it did not show the women who received Avastin and chemotherapy were living longer, compared to chemotherapy alone. Nevertheless, the FDA decided, based on the effect on the tumors seen with Avastin, that the medicine warranted inclusion in the agency’s accelerated approval program, which allows seriously ill patients access to a medication while more conclusive studies are underway.
Two years later, in 2010, the FDA began proceedings to examine its approval of Avastin for breast cancer treatment, and proposed to withdraw the approval of Avastin for treatment of metastatic breast cancer, since further studies of Avastin did not replicate the magnitude of progression-free survival seen in the original study or show that patients who received Avastin in combination with chemotherapy lived longer than those who received chemotherapy alone. FDA Commissioner Dr. Margaret Hamburg noted in her final decision: “The [subsequent] studies did not confirm that the increase in [progression-free survival] was as substantial as the original study had suggested.”
Part of the discussion was centered on how best to look at the data. Also at issue was whether the use of progression-free survival was a measure of clinically meaningful benefit in first-line trials for solid tumors.
Genentech requested a public hearing with a decision to be made by the Commissioner.
Dr. Hal Barron, then executive vice president of Genentech, testified in favor of the medicine at the hearing. “We acknowledge the complexity of the decision the Commissioner must make in that the magnitude of benefit is inherently subjective,” he told the agency.
Together with women who received Avastin, Dr. Barron passionately argued for the FDA to consider keeping Avastin’s approval in this setting. These FDA hearings made national news with coverage that often featured emotional patients attesting to their personal experiences taking the medicine.
In November 2011, the FDA informed Genentech of its final decision to revoke the approval of Avastin for the treatment of metastatic breast cancer. “The FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments,” said Dr. Hamburg in a statement. “This was a difficult decision.”
Sandra Horning, chief medical officer
“We want a culture that speaks up and challenges, and that’s what we did. We want a culture that follows the science and is data driven, and we believe that we did that as well.”
The FDA determined that without extending survival, the slowing of the disease did not outweigh the risks of using the medicine. Genentech sent letters to both the doctors who were prescribing Avastin for breast cancer and to the patients themselves, informing them of the decision. “Genentech is disappointed with this outcome and we understand this may be a difficult time for you and your loved ones,” the letter to patients read. “Genentech’s scientists, doctors and employees remain committed to advancing the scientific understanding of cancer and discovering new medicines.”
In the years since the hearing, the FDA has continued to evolve its position on the use of progression-free survival and measures (called endpoints) as a way to evaluate new medicines. The industry, working with the FDA, had sponsored many trials to use this measure as a principal outcome to quickly evaluate new medicines for breast cancer and other types of cancer.
The FDA has been recognized as a global leader in collaborating with the industry, medical community and patient advocates to pioneer the use of a number of different endpoints to evaluate the safety and efficacy of new medicines.
A Promising Future in Fighting Cancer
Avastin’s robust clinical development program continued despite this setback in breast cancer, and the medicine would be proven to be effective in treating patients with a wide variety of cancers. By 2016, the medicine would deliver additional positive results in Phase III studies, and more than 10 articles were published in the New England Journal of Medicine, along with numerous data presentations at prominent medical meetings around the world.
This volume of research would lead to approvals in additional different types of cancer, including:
- Advanced nonsquamous non–small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease.
- Metastatic kidney cancer (mRCC) when used with interferon alfa.
- Advanced cervical cancer (CC) in combination with paclitaxel and cisplatin or paclitaxel and topotecan is approved to treat persistent, recurrent or metastatic cancer of the cervix.
- Recurrent ovarian cancer (rOC). Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan, is approved to treat platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) in women who received no more than two prior chemotherapy treatments. Avastin, either in combination with carboplatin and paclitaxel or with carboplatin and gemcitabine, followed by Avastin alone, is approved for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psOC).
Other possible serious side effects can occur with Avastin. Abnormal passage in the body – known as a fistula – is an irregular connection from one part of the body to another and can sometimes be fatal. Severe high blood pressure has also been reported. This includes blood pressure that severely spikes or shows signs of affecting the brain. Blood pressure should be monitored every 2 to 3 weeks while on Avastin and after stopping treatment. Kidney problems caused by too much protein in the urine can sometimes be fatal. Infusion reactions were uncommon with the first dose (less than 3% of patients). 0.2% of patients had severe reactions. Infusion reactions include high blood pressure or severe high blood pressure that may lead to stroke, trouble breathing, decreased oxygen in red blood cells, a serious allergic reaction, chest pain, headache, tremors and excessive sweating. A doctor or nurse will monitor patients for signs of infusion reactions. Severe stroke or heart problems, including blood clots, mini-stroke, heart attack and chest pain have been reported and can sometimes be fatal. Nervous system and vision problems, such as headache, seizure, high blood pressure, sluggishness, confusion and blindness, can be associated with treatment of Avastin.
After 25 years at Genentech, and nearly 30 years following “The Hunch,” Ferrara moved back to the academic research world in 2013 at the University of California, San Diego. Today, he says he sees many parallels between anti-angiogenesis and the current interest in immunotherapy approaches to cancer treatment, because of the excitement in the medical community, and the possibility in a broad range of settings.
For Ian Clark, Genentech CEO, the story of the development of Avastin has come to exemplify two principles that still guide the company today. “First is the extent that we can make genuine scientific progress,” he says. “Second is where we think there is a genuine unmet need.”
Hurwitz believes that Avastin will be seen as an important proof of principle. “Very often the lessons learned in one field become helpful as the knowledge base in other fields is built,” he says. Avastin’s headline-making studies and many FDA approvals are only the most well-known aspects of the massive amount of research and advances that have built on the early successes of the medicine. Treatment advances like Avastin not only have an effect on the lives of individual patients, they take their place in the history of our long war against cancer and influence the discoveries to come.
Edward Lang, senior director for external communications
“The story of Avastin is definitely one that has evolved over time. It’s had some of the highest highs and what some may believe the lowest lows and I think when you pull that all together and start looking forward as to what the future of the medicine will be, I think there is a lot of excitement.”
Laura’s Race Continues
Throughout her treatment for cancer, Laura Webb made the commitment to herself that her life would not be defined by her illness. Despite her diagnosis, her other passion, travel, continued. But once again, the doctors found a small spot on her lungs. Laura’s cancer had returned. After treatment for the cancer on her lungs, Laura’s battle wasn’t over. She underwent surgery to have yet another tumor removed.
Now, Laura is a vocal advocate for colorectal cancer awareness in her community and has continued traveling, visiting South America.
Laura’s story—just like Avastin’s—isn’t typical. Both are stories of passion, perseverance and an indefatigable spirit that will leave a lasting impact.
Genentech would like to thank Laura for sharing her story, the doctors, scientists, employees and especially the people who participated in clinical trials and their loved ones, for their important contributions to the development of Avastin.
What it Treats
Avastin is approved for:
- Metastatic colorectal cancer (mCRC) for first- or second-line treatment in combination with intravenous 5-fluorouracil–based chemotherapy. It is also approved to treat mCRC for second-line treatment when used with fluoropyrimidine-based (combined with irinotecan or oxaliplatin) chemotherapy after cancer progresses following a first-line treatment that includes Avastin.
- Avastin is not approved for use after the primary treatment of colon cancer that has not spread to other parts of the body.
- Advanced nonsquamous non–small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease.
- Metastatic kidney cancer (mRCC) when used with interferon alfa.
- Glioblastoma (GBM) in adult patients whose cancer has progressed after prior treatment (recurrent or rGBM)
- Advanced cervical cancer (CC) in combination with paclitaxel and cisplatin or paclitaxel and topotecan is approved to treat persistent, recurrent, or metastatic cancer of the cervix.
- Recurrent ovarian cancer (rOC) Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan, is approved to treat platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) in women who received no more than two prior chemotherapy treatments. Avastin, either in combination with carboplatin and paclitaxel or with carboplatin and gemcitabine, followed by Avastin alone, is approved for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psOC).
Possible serious side effects
Everyone reacts differently to Avastin therapy. So it’s important to know what the side effects are. Although some people may have a life-threatening side effect, most do not. Your doctor will stop treatment if any serious side effects occur. Be sure to contact your health care team if there are any signs of these side effects.
Most serious side effects (not common, but sometimes fatal):
- GI perforation. A hole that develops in your stomach or intestine. Symptoms include pain in your abdomen, nausea, vomiting, constipation, or fever
- Wounds that don’t heal. A cut made during surgery can be slow to heal or may not fully heal. Avastin should not be used for at least 28 days before or after surgery and until surgical wounds are fully healed
- Serious bleeding. This includes vomiting or coughing up blood; bleeding in the stomach, brain, or spinal cord; nosebleeds; and vaginal bleeding. If you recently coughed up blood or had serious bleeding, be sure to tell your doctor
Other possible serious side effects
- Abnormal passage in the body. This type of passage—known as a fistula—is an irregular connection from one part of the body to another and can sometimes be fatal
- Severe high blood pressure. Blood pressure that severely spikes or shows signs of affecting the brain. Blood pressure should be monitored every 2 to 3 weeks while on Avastin and after stopping treatment
- Kidney problems. These may be caused by too much protein in the urine and can sometimes be fatal
- Infusion reactions. These were uncommon with the first dose (less than 3% of patients). 0.2% of patients had severe reactions. Infusion reactions include high blood pressure or severe high blood pressure that may lead to stroke, trouble breathing, decreased oxygen in red blood cells, a serious allergic reaction, chest pain, headache, tremors, and excessive sweating. Your doctor or nurse will monitor you for signs of infusion reactions
- Severe stroke or heart problems. These may include blood clots, mini-stroke, heart attack, and chest pain. These can sometimes be fatal
- Nervous system and vision problems. Signs include headache, seizure, high blood pressure, sluggishness, confusion, and blindness
Side effects seen most often
In clinical studies across different types of cancer, some patients experienced the following side effects:
- High blood pressure
- Too much protein in the urine
- Rectal bleeding
- Back pain
- Taste change
- Dry skin
- Inflammation of the skin
- Inflammation of the nose
- Watery eyes
Avastin is not for everyone
Talk to your doctor if you are:
- Undergoing surgery. Avastin should not be used for 28 days before or after surgery and until surgical wounds are fully healed
- Pregnant or think you are pregnant. Data have shown that Avastin may harm your unborn baby. Use birth control while on Avastin. If you stop Avastin, you should keep using birth control for 6 months before trying to become pregnant
- Planning to become pregnant. Taking Avastin could cause a woman’s ovaries to stop working and may impair her ability to have children.
- Breastfeeding. Breastfeeding while on Avastin may harm your baby and is therefore not recommended
In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%).
If you have any questions about your condition or treatment, talk to your doctor.
You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.
Please see full Product Information, including Serious Side Effects, and additional Important Safety Information at www.avastin.com.
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2 Ribatti, D. (2008). Judah Folkman, a pioneer in the study of angiogenesis. Angiogenesis, 11(1), 3–10. http://doi.org/10.1007/s10456-008-9092-6
3 Ferrara, N. VEGF and the quest for tumour angiogenesis factors. Nature Rev. Cancer. 2, 795-803, 2002.
4 Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).
5 Kim, K. J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362, 841–844 (1993).
6 Miller K, Linnea IC, Holmes, FA, Cobleigh MA, et al. Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer. J Clin Oncol 23:792-799. (March 2005)
7 Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.
8 Miller K, Wang M, Gralow J, et al. Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer. N Engl J Med. 2007;357:2666-76.