Oncologists Speak on Avastin

Duration of therapy: Comments from leading oncologists

Ronald B. Natale, MD

"Avastin continued until disease progression or unacceptable toxicity is the appropriate treatment strategy since that’s how Study E4599 was conducted and that is the only data we have….To not use Avastin after the completion of 4 or 6 cycles of induction chemotherapy is stepping back from the results of a clinical trial that has established this standard of care."

Ronald B. Natale, MD, is the Senior Research Advisor and National Director of the Lung Cancer Research Program for Aptium Oncology and an attending physician at the Cedars-Sinai Outpatient Cancer Center in Los Angeles, California. Dr Natale earned his medical degree from Wayne State University School of Medicine in Detroit, Michigan where he also did his medical residency. He completed a fellowship in hematology/oncology at the Memorial Sloan-Kettering Cancer Center in New York and a research fellowship at the National Cancer Institute. Prior to his current positions, he was a faculty member at the University of Michigan, where he also served as Associate Director of the Comprehensive Cancer Center, and at the University of Southern California, where he served as Associate Director of Medical Oncology.

Dr Natale is internationally renowned for his clinical research efforts in lung and genitourinary cancers. He has published over 250 articles and abstracts, co-authored several books, and presented results of his research at cancer research meetings all over the world. He has been cited as one of the best cancer doctors by Los Angeles Magazine, Good Housekeeping, and in each edition of Best Doctors in America since its inception.

Dr Ronald Natale BIO

Mark F. Kozloff, MD

"I continue Avastin until disease progression or unacceptable toxicities….That’s the way Study E4599 was done and that’s where the 2-month survival advantage is, so stopping Avastin prematurely may not produce the same efficacy results."

Mark F. Kozloff, MD, is a Clinical Associate of Medicine in the Section of Hematology/Oncology at the University of Chicago in Chicago, Illinois, and Director of Oncology at the Ingalls Cancer Care Center at Ingalls Memorial Hospital in Harvey, Illinois. He also practices internal medicine in Orland Park and Tinley Park, Illinois, and in Munster, Indiana. Dr. Kozloff earned his medical degree from the University of Michigan in Ann Arbor. He served a residency in internal medicine at Michael Reese Hospital in Chicago and completed a fellowship in hematology at the University of Michigan. He is a member of the Eastern Cooperative Oncology Group, National Surgical Adjuvant Breast and Bowel Project, Southwest Oncology Group, American Society of Hematology, and American Society of Clinical Oncology. Dr. Kozloff is board certified in hematology and medical oncology.

Dr Mark Kozloff BIO

Edward S. Kim, MD

"I tell patients that, if they can get past 6 cycles of chemotherapy with Avastin, then they’re already into a favorable group, because there are many patients who never make it past 6 cycles of chemotherapy. So once they get to this point, we just go with [continuing] Avastin therapy."

Edward S. Kim, MD, is an Assistant Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas, where he is also the Director of Educational Programs and Director of Residency Training in Oncology. He received his medical degree from Northwestern University in Chicago, Illinois. Dr Kim completed his residency in internal medicine at Baylor College of Medicine in Houston, and his medical oncology fellowship at the University of Texas MD Anderson Cancer Center. Dr Kim has served as principal investigator on numerous research projects and grant awards and has authored numerous publications on lung and other cancers.

Dr Ed Kim BIO

Oncologist comments were solicited in Genentech-sponsored interviews. Participating physicians received compensation for participating in the interviews. Opinions expressed herein reflect the professional views of the oncologists. Their opinions are provided for informational purposes only and should not substitute for your independent medical judgment or assessment of the risks and benefits of using Avastin to treat particular patients.

Avastin plus PC has been proven to increase overall survival (OS) when given until disease progression or unacceptable toxicity

Avastin was continued until disease progression or unacceptable toxicity in Study E45991,2

In Study E4599, patients who were responding or had stable disease after 6 cycles of Avastin plus PC continued on Avastin alone until disease progression or unacceptable toxicity.3

NCCN recommends continuing bevacizumab following the combination of bevacizumab plus chemotherapy, as investigated in Study E45991-4

NCCN Guidelines

Important treatment considerations—Dose modifications

Discontinue Avastin in patients with GI perforations (GI perforations, fistula formation in the GI tract, intra-abdominal abscess), fistula formation involving an internal organ, wound dehiscence and wound healing complications requiring medical intervention, serious hemorrhage (ie, requiring medical intervention), severe ATE, hypertensive crisis or hypertensive encephalopathy, RPLS (symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae), and nephrotic syndrome. Temporarily suspend Avastin for at least 4 weeks prior to elective surgery, severe hypertension not controlled with medical management, moderate to severe proteinuria pending further evaluation, and severe infusion reactions. The safety of resumption of Avastin therapy in patients that experienced RPLS, ATE, and moderate to severe proteinuria is unknown.

Indication

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Boxed WARNINGS and additional important safety information

  • Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation

  • Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention

  • Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

  • Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

  • The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

  • Grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

Please see full Prescribing Information, including Boxed WARNINGS for additional safety information.

Next: Efficacy in NSCLC

References
  1. Avastin Prescribing Information, Genentech, Inc. July 2009.
  2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.
  3. Data on file. Genentech, Inc.
  4. The NCCN Non-Small Cell Lung Cancer Clinical Practice Guidelines in Oncology (Version 2.2009). ©2008 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed August 20, 2009. To view the most recent and complete version of the guidelines, go online to www.nccn.org.