Ohio State University Reports That Ovarian Cancer Drug Bevacizumab Is Not Cost-Effective

An analysis conducted by Ohio State University cancer researchers found that adding the targeted therapy bevacizumab to the first-line treatment of patients with advanced ovarian cancer is not cost effective.

An analysis conducted by Ohio State University cancer researchers found that adding the targeted therapy bevacizumab [Avastin®] to the first-line treatment of patients with advanced ovarian cancer is not cost-effective.

The findings comparing the relative value of various clinical strategies were published online March 7 in the Journal of Clinical Oncology (JCO).

Dr. David E. Cohn is a gynecologic oncologist & researcher at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital & Richard J. Solove Research Institute. He is also the lead author of the bevacizumab cost-effectiveness study.

The researchers performed a cost-effectiveness analysis looking at a clinical trial conducted by the Gynecologic Oncology Group (GOG) studying the use of bevacizumab along with standard chemotherapy for patients with advanced ovarian cancer, said first author Dr. David E. Cohn, a gynecologic surgical oncologist and researcher at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Bevacizumab is a novel targeted therapy designed to inhibit angiogenesis, the process by which new blood vessels develop and carry vital nutrients to a tumor.

Although a discussion regarding cost-effectiveness of a potentially life-extending intervention invariably suggests the rationing of limited health care resources, the intent of this study was to provide a framework with which to evaluate the pending results of a clinical trial of three different interventions for ovarian cancer, said Cohn.

“We do not suggest that bevacizumab, also known by the brand name Avastin, should be withheld from a patient with ovarian cancer, but rather argue that studies evaluating the effectiveness of new treatments should also be interpreted with consideration of the expense,” says Cohn, who collaborated with Dr. J. Michael Straughn Jr., an associate professor of obstetrics and gynecology at the University of Alabama at Birmingham.

The results of the randomized phase III [GOG 218] clinical trial demonstrated an additional 3.8 months of progression-free survival (PFS) when maintenance bevacizumab was added for about one year following treatment with standard chemotherapy drugs carboplatin and paclitaxel along with bevacizumab.

“We put together a model looking at the variety of treatment arms on this clinical trial, each of which included 600 patients,” said Cohn. “Given the fact that the addition of the drug was associated with 3.8 months of additional survival without cancer, we set out to determine whether or not that benefit of survival was justified by the expense of the drug.”

The model showed that standard chemotherapy for patients in the clinical trial would cost $2.5 million, compared to $78.3 million for patients who were treated with standard chemotherapy and bevacizumab, plus additional maintenance treatments of bevacizumab for almost one year.

Bevacizumab has been used in the treatment of recurrent ovarian cancer, and the U.S. Food and Drug Administration has approved it for the treatment of colorectal, lung, breast, brain (glioblastoma) and renal cell [kidney] cancers.

Typically each treatment with bevacizumab costs $5,000, with most of those costs directly attributable to the cost of the drug, Cohn said.

Effectiveness was defined as months of progression-free survival, and costs were calculated as total costs per strategy. Cost-effectiveness strategies were defined as the cost per year of progression-free survival. Incremental cost-effectiveness ratio was defined as the costs per progression-free year of life saved.

“Ultimately, we found that if you reduced the drug cost to 25 percent of the baseline, it does become cost effective to treat patients with bevacizumab,” said Cohn. “Or, if the survival could be substantially increased above the 3.8 months of progression-free survival, that could lead to cost-effective treatment for patients with advanced ovarian cancer.”

Ovarian cancer is the most lethal gynecologic cancer, with almost 14,000 women expected to die from the disease this year, according to the American Cancer Society.

“It is anticipated that in the future, there will be increased scrutiny regarding the individual and societal costs of an effective medication,” said Cohn. “We hope that future clinical trials will incorporate the prospective collection of cost, toxicity and quality-of-life data to allow for a fully informed interpretation of the results.”

Other Ohio State researchers involved in the study are Kenneth H. Kim, Kimberly E. Resnick and David O’Malley.

Big Cost For Little Gain in Ovarian Cancer – JCO Editorial

Results of the cost-effectiveness model reported above by Cohen et. al. reveal that paclitaxel plus carboplatin plus bevacizumab, followed by bevacizumab maintenance (PCB-B), as tested in the GOG 218 phase III clinical trial, costs $78.3 million ($1,305,000 per patient) with an incremental cost-effectiveness ratio of $401,088 per progression-free year of life saved. It is important to note that traditional cost-effectiveness study models utilize the costs of improvements in overall survival, as compared to the traditional cost-effective standard of $50,000 per year of life saved, or more recently, $100,000 per year of life saved.  Cohen et. al. found that the traditional standard of $100,000 per progression free year of life saved can be achieved in calculating the incremental cost-effectiveness ratio, but only at a bevacizumab drug price point that is 25% below the actual drug cost.

Martee L. Hensley, M.D., Gynecologic Medical Oncology Service, Memorial Sloan-Kettering Cancer Center

In an accompanying JCO editorial, Martee L. Hensley, M.D., a board-certified medical oncologist who treats women with gynecologic cancers at the Memorial Sloan-Kettering Cancer Center in New York city, raises several important considerations with respect to the Ohio State University study.

First, Dr. Hensley notes that the “costs” accounted for by the Ohio State University researchers only refer to the additional monies incurred by adding bevacizumab to the standard of care paclitaxel-carboplatin treatment.  Specifically, the researchers used a standard cost metholodolgy based upon estimates of drug costs using Medicare reimbursement rates.  The model used does not include indirect costs (e.g., patient out-of-pocket expenses, time lost from work associated with 51 weeks of bevacizumab maintenance, etc.). The only costs related to toxicity of treatment included by researchers were those associated with management of intestinal perforations. Dr. Hensley highlights the fact that the cost model does not include management of grade 2 or worse hypertension or other potential problems that may be caused by bevacizumab or the other chemotherapy drugs.  To the extent that additional costs are added to the model, the cost-effectiveness ratio generated by the researchers would worsen.

Second, Dr. Hensley explains that out of necessity, the researchers’ cost-effectiveness model used PFS data due to the unavailability of overall survival or quality adjusted overall survival data in connection with the three most recent bevacizumab phase III clinical trials. This model construct assumes that the 3.8 month improvement in PFS (as reported by the GOG 218 trial investigators)  provides an improvement in the patient’s experience. Dr. Hensley emphasizes that most ovarian cancer recurrences are identified while the patient is still asymptomatic, with the help of CA-125 blood testing and computed tomography imaging (i.e., CT scan).  Stated differently, it may not be correct to assume that remaining radiographically progression-free for an addtional 3.8 months would improve a patient’s quality of life.  If GOG 218 ultimately finds that PCB-B does not improve overall survival, then the drug’s cost-effectiveness will drift farther away from an acceptable level, says Hensley.

Third, Dr. Hensley points out that only when PFS associated with PCB-B use was hypothetically extended to 32.1 months (observed PFS in GOG 218 was 14.1 months) by the researchers did the incremental cost-effectiveness ratio approach $100,000 per progression-free year of life saved.  Hensley believes that the bevacizumab data accrued to date suggests that a 32.1 month PFS is unlikely. Notably, median PFS is only 24 months among lower-risk patients with optimally debulked stage III ovarian cancer treated with intraperitoneal-based platinum drug/taxane drug therapy.

Fourth, Dr. Hensley explains that it may be possible to achieve a better incremental cost-effectiveness ratio based upon preliminary data derived from the Gynaecologic Cancer Intergroup (GCIG) phase III randomized clinical trail of paclitaxel plus carboplatin, with or without bevacizumab and bevacizumab maintenace therapy (ICON7 trial). The bevacizumab dose tested in ICON7 was only half of that used in GOG 218 (7.5 mg/kg versus 15 mg/kg), and the duration of maintenance therapy in ICON7 was only 36 weeks of continued treatment as compared to 51 weeks in GOG 218. Preliminary results reported by the GCIG in ICON7 indicate that bevacizumab creates a PFS advantage in line with that produced in GOG 218, but at half the dose. Based on these facts, Hensley states that potential use of lower-dose and shorter-duration bevacizumab would improve the incremental cost-effectiveness ratio. Moreover, if lower dose/shorter duration bevacizumab use is also found to reduce the frequency of grade 2 or worse hypertension, the overall costs associated with the drug would also be lower, says Hensley.

Dr. Hensley believes that there are additional steps to be taken (and questions to be answered) which could improve an evaluation of the role and costs of bevacizumab:

  • Is there a clinically meaningful overall survival advantage to PCB-B over paclitaxel plus carboplatin? If PCB-B is not effective, then by definition, it is not cost-effective.
  • Is the data from ICON7 sufficient to permit treatment at half the dose for 9 months instead of 12 months? If so, total bevacizumab costs would be lower.
  • Is there a subset of patients who benefit dramatically from PCB-B?
  • If there is a subset of patients who benefit dramatically from PCB-B, it is necessary to study this group of women to determine if potential biomarkers can identify which patients will or will not benefit from the addition of bevacizumab. Identifying biomarkers that can predict response means commitment to correlative studies as part of large clinical trials.

In sum, Dr. Hensley believes that buying bevacizumab at $78.3 million for 3.8 months of progression-free survival on behalf of approximately 600 women is not sustainable in today’s health care delivery system. Moreover, the incurrence of such costs may hinder basic clinical research to find better compounds that improve PFS by a more meaningful magnitude, says Dr. Hensley.  From Hensley’s perspective, it appears that the stage is set for a potential collision between medicine and policy with respect to where and how a finite number of health care dollars will be spent.

About the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (cancer.osu.edu) is one of only 40 Comprehensive Cancer Centers in the United States designated by the National Cancer Institute. Ranked by U.S. News & World Report among the top cancer hospitals in the nation, The Arthur G. James Hospital is the 205-bed adult patient-care component of the cancer program at The Ohio State University. The OSUCCC – James is one of only seven funded programs in the country approved by the NCI to conduct both phase I and II clinical trials.

Sources:

PBS Documentary, “The Whisper: The Silent Crisis of Ovarian Cancer.”

To raise ovarian cancer awareness, Long Island’s Public Broadcasting Service (PBS) affiliate WLIW-Channel 21 will present the exclusive New York metro area premiere of a half-hour television documentary entitled, “The Whisper: the silent crisis of ovarian cancer.” The program will debut at 7 P.M. (EDT) on Friday, September 24 in the New York metro area, and will be rolled out to other PBS affiliates across the country over the next 12 months.

More than 13,000 women this year will be struck down by ovarian cancer, which is the most lethal gynecologic cancer. Ovarian cancer statistics are staggering; nearly three out of every four women with this disease will die because of it. Chances of survival can improve if it is detected early and confined to the ovaries. Unfortunately, only about 25 percent of women are diagnosed with early stage disease because there is no reliable early stage screening test available. Victims of ovarian cancer include President Obama’s mother Ann Soetoro, Coretta Scott King and comedienne Gilda Radner.

To raise awareness of this devastating disease, Long Island’s Public Broadcasting Service (PBS) affiliate WLIW-Channel 21 will present the exclusive New York metro area premiere of a half-hour television documentary entitled, The Whisper: The Silent Crisis of Ovarian Cancer.  A preview trailer of the documentary is provided below.

The Whisper:  the silent crisis of ovarian cancer — PBS Documentary

The program will debut at 7 P.M. (EDT) on Friday, September 24, with encore presentations scheduled for 10:30 P.M. on Monday, September 27, and 11:30 P.M. on Friday, October 1. The program will be rolled out to other PBS affiliates across the country over the next 12 months.

The documentary was made possible by a generous grant from the Sonia L. Totino Foundation and the Rocco Totino family. Mr. Totino, a New York resident, lost his wife Sonia to ovarian cancer several years ago, and wished to honor her with an initiative that seeks to raise awareness among women of the warning signs of ovarian cancer, and by doing so, reduce the number of women lost to this devastating disease.

Sharon Blynn is the founder of Bald is Beautiful & the host of “The Whisper: the silent crisis of ovarian cancer” (a PBS documentary)

The host featured in the documentary is Sharon Blynn, who is an ovarian cancer survivor and the founder of the Bald Is Beautiful campaign. Through this campaign, Sharon wants to send a message to women that they can “flip the script” on the many traumatic aspects of the cancer experience, and embrace every part of their journey with self-love, empowerment, and a deep knowing that their beauty and femininity radiate from within and are not diminished in any way by the effects of having cancer.  As an “actorvist,” Sharon communicates the Bald Is Beautiful message through acting, writing, modeling and spokesperson appearances, and she continues to do patient outreach through one-on-one correspondence via her website, hospital visitations, being a chemo buddy and other such activities.

Other Bald Is Beautiful highlights include an international print campaign for the Kenneth Cole “We All Walk in Different Shoes” campaign, an international print and TV campaign for Bristol-Myers Squibb, appearances in “Sex and the City” and a principal role in Seal’s music video “Love’s Divine.” She has been featured in magazine and newspaper articles in Glamour, Vogue, Marie Claire (US & Italia), Organic Style, BUST, the Miami Herald and other publications. Sharon has also performed onstage as part of the “Off the Muff” collective, and she was commissioned to write and perform her one-woman theatrical piece “How Are We Feeling Today?” which saw its world premiere in Los Angeles and was presented in New York City. A QuickTime video compilation of Sharon’s past projects can be viewed here.

Blynn was awarded the prestigious 2010 Lilly Tartikoff/Entertainment Industry Foundation Hope Award at the 2010 National Coalition for Cancer SurvivorshipRays of Hope Gala” held in Washington, D.C. Sharon has also been selected to be part of Lifetime Television Network’s Every Woman Counts “Remarkable Women” campaign, and will appear in a 30-second spot that will run the week of Sept 17–23, 2010.

The nationally-renowned ovarian cancer experts featured in the documentary include:

Barbara A. Goff, M.D., Professor, Gynecologic Oncology, University of Washington School of Medicine. Dr. Goff is the principal investigator responsible for critical ovarian cancer research which revealed that ovarian cancer is generally accompanied by four primary warning signs or symptoms — bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, and urinary symptoms (urgency or frequency).  Goff’s research became the foundation for the Ovarian Cancer Symptoms Consensus Statement, which was sponsored and co-authored by the American Cancer Society, Gynecologic Cancer Foundation, and Society of Gynecologic Oncologists in July 2007.

Beth Y. Karlan, M.D., Board of Governors Endowed Chair, Director, Women’s Cancer Research Institute and Division of Gynecologic Oncology, Cedars-Sinai Medical Center; Professor, Obstetrics and Gynecology, David Geffen School of Medicine ,University of California, Los Angeles (UCLA). Dr. Karlan is a world-renowned expert in the field of gynecologic oncology, specifically ovarian cancer surgery, early detection, targeted therapies and inherited cancer susceptibility. She is a past-president of the Society of Gynecologic Oncologists, the Editor-in-Chief of Gynecologic Oncology, and has held many international leadership positions.  She is committed to both scientific advancement and enhancing public awareness about gynecologic cancers.

John Lovecchio, M.D., Chief of Gynecologic Oncology, North Shore-Long Island Jewish Health System; Leader of the North Shore-LIJ Cancer Institute; Professor of Obstetrics and Gynecology, the New York University School of Medicine.  Dr. Lovecchio’s major areas of research are in uterine and ovarian cancers, and he holds administrative and leadership positions in regional and national professional organizations and has published extensively in peer-reviewed journals. Lovecchio is widely regarded as a leading physician-surgeon and has received numerous awards in recognition of his academic and professional achievements.  In the documentary, Dr. Lovecchio offers his insight on ways to combat this deadly form of cancer. He is also credited as the technical advisor for the documentary.

Maurie Markman, M.D., Vice President of Patient Oncology Services & National Director of Medical Oncology, Cancer Treatment Centers of America.  For more than 20 years, Dr. Markman has been engaged in clinical research in the area of gynecologic malignancies, with a particular focus on new drug development and exploring novel management strategies in female pelvic cancers.  Dr. Markman’s many accomplishments include serving as Editor-In-Chief for the Current Oncology Reports journal and Oncology (Karger Publishers) journal, and serves as Chairman of the Medical Oncology Committee of the national Gynecologic Oncology Group.  In addition, Dr. Markman has served on numerous editorial boards, including the Journal of Clinical Oncology and Gynecologic Oncology.  Dr. Markman has been the primary author, or co-author, on more than 1,000 published peer-reviewed manuscripts, reviews, book chapters, editorials or abstracts, and he has edited or co-edited 14 books on various topics in the management of malignant disease, including Atlas of Oncology and the most recent edition of Principles and Practice of Gynecologic Oncology.

“Taking part in this program was a labor of love and concern for my patients,” said Dr. Lovecchio, who is based at North Shore University Hospital in Manhasset. “I wanted to make sure that women are getting the right information, and are aware of the signs and symptoms of ovarian cancer. They must be alert to their own bodies and recognize that abdominal bloating, abdominal pain, pelvic pain, urinary symptoms, difficulty in eating, and feeling full quickly may not be the norm.”

“I wanted to make sure that women are getting the right information, and are aware of the signs and symptoms of ovarian cancer. They must be alert to their own bodies and recognize that abdominal bloating, abdominal pain, pelvic pain, urinary symptoms, difficulty in eating, and feeling full quickly may not be the norm.”

— John Lovecchio, M.D., Chief of Gynecologic Oncology, North Shore-Long Island Jewish Health System

“Women should seek the advice of experts trained in this field and not think that they are being alarmists. Other medical experts and patients interviewed in this documentary are all seeking the same outcome — to make every woman aware of her own body and to encourage every woman to seek help if she feels that something is not quite right,” said Dr. Lovecchio, who was interviewed for the documentary along with Drs. Goff, Karlan, and Markman.

Source:  PBS Documentary on Ovarian Cancer, News Release, North Shore-Long Island Jewish Health System, September 9, 2010.

GOG Says Continuation of Pivotal OPAXIO Maintenance Therapy Trial (GOG-212) Remains High Priority

Gynecologic Oncology Group (GOG) Notifies CTI That Continuation of GOG-212 Pivotal Trial of OPAXIO Maintenance Therapy in Front Line Ovarian Cancer Remains High Priority.  GOG-218 Bevacizumab Results Do Not Influence Importance of GOG-212

Cell Therapeutics, Inc. (“CTI”) announced today that the company received a statement on March 1, 2010 from the Gynecologic Oncology Group (GOG) leadership that the phase III GOG-212 clinical trial of CTI’s OPAXIO™ (formerly known as Xyotax or CT-2103) used as maintenance therapy for ovarian cancer remains a high priority and enrollment will continue. The GOG made the statement to clarify that the recent results of the GOG-218 clinical trial bevacizumab in maintenance therapy for ovarian cancer has not influenced the importance of completing the GOG-212 clinical trial. The Gynecologic Oncology Group (GOG) is one of the National Cancer Institute’s (NCI) funded cooperative cancer research groups. The GOG is a multidisciplinary cooperative clinical trial research group focused on the study of gynecologic malignancies. The GOG is conducting phase III trials in ovarian cancer and other gynecologic cancers and has established standard treatments for these diseases in the U.S.

GOG leadership noted the following:

GOG-218 and GOG-212 differ in the type of patients under study. It is important to note that some of the patients who completed the initial 6 cycles of chemotherapy in GOG-218 had clinical evidence of persistent tumor and were randomized to either placebo (no treatment) or bevacizumab [Avastin®]. Thus a subset of GOG-218 patients received no therapy, despite the presence of persistent tumor. This is not the typical setting of using maintenance or consolidation therapy and it is not the setting for patients enrolled in GOG-212. In GOG-212, only patients who have achieved a complete clinical response are considered candidates for enrollment in the trial.

Reliance upon the data from GOG-218 to establish the “standard of care” must take into consideration the actual treatment effect (i.e., duration of benefit), the cost of the treatment, and the associated toxicity… [in GOG-212] the toxicity of the intervention may have less associated mortality and the incremental cost-effectiveness ratio may be more acceptable to patients and the health care economists. Thus the GOG has no intention to discontinue enrollment in GOG 212 as they feel that the study is addressing a different scientific question and the primary outcome study goal is survival, not progression free survival, an outcome of greater importance to both physicians and patients.

The Data Monitoring Committee is scheduled to conduct an interim analysis of overall survival when 130 events are recorded among patients in the no maintenance treatment arm. The statistical analysis plan utilizes pre-specified boundaries for early stopping for success. Based on current enrollment and study duration, the interim analysis could be conducted as early as 2011. If successful, CTI could utilize those results to form the basis of its New Drug Application for OPAXIO.

About Cell Therapeutics, Inc.

Headquartered in Seattle, CTI is a biopharmaceutical company committed to developing an integrated portfolio of oncology products aimed at making cancer more treatable. For additional information, please visit http://www.celltherapeutics.com/.

Sources:

Genentech Announces Positive Results of Avastin Phase III Study in Women with Advanced Ovarian Cancer

Genentech announces positive results of Avastin Phase III study (GOG 218) in women with advanced ovarian cancer. The study showed that women who continued maintenance use of Avastin alone, after receiving Avastin in combination with chemotherapy, lived longer without the disease worsening compared to those who received chemotherapy alone. This is the first Phase III study of an anti-angiogenic therapy in advanced ovarian cancer to meet its primary endpoint.

Tumor angiogenesis is the proliferation of a network of blood vessels that penetrates into cancerous growths, supplying nutrients and oxygen and removing waste products. Tumor angiogenesis actually starts with cancerous tumor cells releasing molecules that send signals to surrounding normal host tissue. This signaling activates certain genes in the host tissue that, in turn, make proteins to encourage growth of new blood vessels. Photo credit: NCI

Genentech, Inc., a wholly owned member of the Roche Group , today announced that a Phase III study showed the combination of Avastin® (bevacizumab) and chemotherapy followed by maintenance use of Avastin alone increased the time women with previously untreated advanced ovarian cancer lived without the disease worsening (progression-free survival or PFS), compared to chemotherapy alone. A preliminary assessment of safety noted adverse events previously observed in pivotal trials of Avastin. Data from the study will be submitted for presentation at the American Society of Clinical Oncology (ASCO) annual meeting, June 4 – 8, 2010.

In the three-arm study, known as Gynecologic Oncology Group (GOG) 0218, women with newly diagnosed advanced ovarian cancer who already had surgery to remove as much of the tumor as possible were randomized to receive one of the following:

  • Arm 1: Placebo in combination with carboplatin and paclitaxel chemotherapy followed by placebo alone, for a total of up to 15 months of therapy
  • Arm 2: Avastin in combination with carboplatin and paclitaxel chemotherapy followed by placebo alone, for a total of up to 15 months of therapy
  • Arm 3: Avastin in combination with carboplatin and paclitaxel chemotherapy followed by the maintenance use of Avastin alone, for a total of up to 15 months of therapy.

The study showed that women who continued maintenance use of Avastin alone, after receiving Avastin in combination with chemotherapy (Arm 3), lived longer without the disease worsening compared to those who received chemotherapy alone. Women who received Avastin in combination with chemotherapy, but did not continue maintenance use of Avastin alone (Arm 2), did not live longer without the disease worsening compared to chemotherapy alone.

“Additional medicines are urgently needed for women with newly diagnosed advanced ovarian cancer, as most women’s cancer will worsen after their initial treatment,” said Hal Barron, M.D., F.A.C.C., Executive Vice President, Global Development and Chief Medical Officer. “We are encouraged by the positive findings of this study, which highlight the importance of continuing maintenance Avastin after combining Avastin with chemotherapy in this setting. We will discuss these results with the U.S. Food and Drug Administration.”

Robert Allen Burger, MD, FACOG, FACS, Fox Chase Cancer Center, Philadelphia, Pennsylvania

“This is good news for women with ovarian, primary peritoneal or fallopian tube cancers,” said GOG 0218 study chair Robert Burger, M.D., Fox-Chase Cancer Center in Philadelphia. “This study showed that after initial surgery, the combination of Avastin and chemotherapy followed by extended treatment with Avastin improves progression-free survival in women with newly diagnosed advanced tumors.”

The trial is sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement between the NCI and Genentech, and is being conducted by a network of researchers led by the GOG.

Avastin is being studied worldwide in more than 450 clinical trials for multiple types of cancer, including approximately 25 ongoing clinical trials in the United States for women with various stages of ovarian cancer.

About Ovarian Cancer

According to the American Cancer Society, ovarian cancer is the fifth leading cause of cancer death among American women. In 2009 an estimated 21,500 women were diagnosed with ovarian cancer and approximately 14,500 died from the disease in the U.S. The disease causes more deaths than any other gynecologic cancer, and the American Cancer Society estimates that nearly 70 percent of women with advanced disease will die from it within five years.

Ovarian cancer is associated with high levels of vascular endothelial growth factor (VEGF), a protein associated with tumor growth and spread. Studies have shown a correlation between a high level of VEGF and a poorer prognosis in women with ovarian cancer. Currently, treatment options for women with this disease are limited to surgery and chemotherapy.

About the GOG 0218 Study

GOG 0218 is an international, multicenter, randomized, double-blind, placebo-controlled Phase III study in 1,873 women with previously untreated advanced epithelial ovarian, primary peritoneal or fallopian tube carcinoma. The study evaluates Avastin (5 cycles) in combination with carboplatin and paclitaxel chemotherapy (6 cycles) compared to carboplatin and paclitaxel chemotherapy alone (6 cycles). The trial is also designed to assess the maintenance use of Avastin alone following the initial combined regimen of Avastin and chemotherapy (for a total of up to 15 months of therapy), compared to carboplatin and paclitaxel chemotherapy alone (6 cycles).

The primary endpoint of the study is PFS as assessed by trial investigators. Secondary and exploratory endpoints of the study include overall survival, PFS by independent review, objective response rate, safety, quality of life measures and analysis of patient tumor and blood samples.

Detailed safety assessments are ongoing. A preliminary assessment of safety performed by the GOG identified Avastin-related serious adverse events noted in previous pivotal studies, including fatal neutropenic infection and gastrointestinal perforation. The full study results, including safety information, will be presented at a future medical meeting.

About Avastin

Avastin is a solution for intravenous infusion and is a biologic antibody designed to specifically bind to a protein called VEGF. VEGF plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels, a process known as angiogenesis. Avastin interferes with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. Avastin does not bind to receptors on normal or cancer cells. The tumor blood supply is thought to be critical to a tumor’s ability to grow and spread in the body (metastasize). For more information about angiogenesis, visit http://www.gene.com.

Boxed WARNINGS and Additional Important Safety Information

People treated with Avastin may experience side effects. In clinical trials, some people treated with Avastin experienced serious and sometimes fatal side effects, including:

Gastrointestinal (GI) perforation: Treatment with Avastin can result in the development of a potentially serious side effect called GI perforation, which is the development of a hole in the stomach, small intestine or large intestine. In clinical trials, this side effect occurred in more people who received Avastin than in the comparison group (0.3 percent to 2.4 percent). In some cases, GI perforation resulted in fatality.

Surgery and wound healing problems: Treatment with Avastin can lead to slow or incomplete wound healing (for example, when a surgical incision has trouble healing or staying closed). In some cases, this event resulted in fatality. Surgery and wound healing problems occurred more often in people who received Avastin than in the comparison group. Avastin therapy should not be started for at least 28 days after surgery and until the surgical wound is fully healed. The length of time between stopping Avastin and having voluntary surgery without the risk of having surgery and wound healing problems following surgery has not been determined.

Severe bleeding: Treatment with Avastin can result in serious bleeding, including coughing up blood, bleeding in the stomach, vomiting of blood, bleeding in the brain, nosebleeds and vaginal bleeding. These events occurred up to five times more often in people who received Avastin. Across cancer types, 1.2 percent to 4.6 percent of people who received Avastin experienced severe to fatal bleeding. People who have recently coughed up blood (greater than or equal to a half teaspoon of red blood) or have serious bleeding should not receive Avastin.

In clinical trials for different cancer types, there were additional serious and sometimes fatal side effects that occurred in more people who received Avastin than in those in the comparison group. The formation of an abnormal passage from parts of the body to another part (non-GI fistula formation) was seen in 0.3 percent or less of people. Severe to life-threatening stroke or heart problems were seen in 2.4 percent of people. Too much protein in the urine, which led to kidney problems, was seen in less than 1 percent of people. Additional serious side effects that occurred in more people who received Avastin than those in the comparison group included severe to life-threatening high blood pressure, which was seen in 5 percent to 18 percent of people, and nervous system and vision disturbances (reversible posterior leukoencephalopathy syndrome), which was seen in less than 0.1 percent of people. Infusion reactions with the first dose of Avastin were uncommon and occurred in less than 3 percent of people and severe reactions occurred in 0.2 percent of people.

Common side effects that occurred in more than 10 percent of people who received Avastin for different cancer types, and at least twice the rate of the comparison group, were nosebleeds, headache, high blood pressure, inflammation of the nose, too much protein in the urine, taste change, dry skin, rectal bleeding, tear production disorder, back pain and inflammation of the skin (exfoliative dermatitis). Across all trials, treatment with Avastin was permanently stopped in 8.4 percent to 21 percent of people because of side effects.

Avastin may impair fertility. Patients who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risk of loss of the pregnancy or the potential risk of Avastin to the fetus during and following Avastin therapy, and the need to continue an effective birth control method for at least six months following the last dose of Avastin.

For full Prescribing Information and Boxed WARNINGS on Avastin please visit http://www.avastin.com.

About Genentech

Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a wholly owned member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

About The Gynecologic Oncology Group (GOG)

The Gynecologic Oncology Group is a non-profit organization of more than 300 member institutions with the purpose of promoting excellence in the quality and integrity of clinical and basic scientific research in the field of Gynecologic malignancies. The Group is committed to maintaining the highest standards in the clinical trial development, execution, analysis and distribution of results. Continuous evaluation of our processes is utilized in order to constantly improve the quality of patient care.

GOG receives support from the National Cancer Institute (NCI) of the National Institutes for Health (NIH).

Sources:

Modified Chemo Regime Increases Survival In Advanced Ovarian Cancer Patients But Adds Toxicity

Women with advanced ovarian cancer lived longer and without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers reported last week. In a large phase III clinical trial, women who received carboplatin every 3 weeks and a reduced dose of paclitaxel (Taxol®) once a week for 3 weeks instead of carboplatin and a higher single dose of paclitaxel every 3 weeks had a 29 percent improvement in progression-free survival and a 25 percent improvement in overall survival after 3 years of follow-up.

Women with advanced ovarian cancer lived longer and without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers reported last week. In a large phase III clinical trial, women who received carboplatin every 3 weeks and a reduced dose of paclitaxel (Taxol®) once a week for 3 weeks instead of carboplatin and a higher single dose of paclitaxel every 3 weeks had a 29 percent improvement in progression-free survival and a 25 percent improvement in overall survival after 3 years of follow-up. The results were published online September 18 in The Lancet.

Although the toxicities of this dose-dense regimen were greater than they were in women who received the standard combination, survival benefits of this magnitude “have been rare in women with advanced ovarian cancer,” wrote Dr. Noriyuki Katsumata and colleagues from the Japanese Gynecologic Oncology Group (JGOG).

trimble

Edward L. Trimble, MD, MPH; Head - Gynecologic Cancer Therapeutics and Quality of Cancer Care Therapeutics, Clinical Investigation Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis.

The results, explained Dr. Ted Trimble, from NCI’s Division of Cancer Treatment and Diagnosis, are consistent with what has been seen in breast cancer using a dose-dense chemotherapy regimen. The idea, he continued, is “to balance efficacy and toxicity by using a weekly schedule rather than every 3 weeks.”

Although the findings are important, “they won’t change practice overnight,” Dr. Trimble said. There are still several significant unknowns, including whether a lower dose of paclitaxel might be as effective but less toxic; the optimal timing of surgery; and where intraperitoneal chemotherapy fits into the treatment mix. The JGOG trial results, however, will influence the design of a number of phase III clinical trials, all of which include dose-dense chemotherapy, he added.

More than 630 women at 85 hospitals across Japan enrolled in the trial. Patients were randomly assigned to either of the two treatment groups. After 3 years of follow-up, women who received the dose-dense treatment had a median progression-free survival of 28 months, compared with 17 months for those who received the standard treatment.

bookman

Michael A. Bookman, M.D., Chief, Hematology/Oncology Section, Arizona Cancer Center

Not enough time has passed to determine with statistical confidence whether the overall survival advantage will be maintained. However, in ovarian cancer, improvements in progression-free survival tend to predict overall survival, said Dr. Michael A. Bookman, chief of the Hematology/Oncology Section at the Arizona Cancer Center, in an accompanying editorial in The Lancet.

The dose-dense chemotherapy regimen used in the trial was also dose-intense, meaning the total dose of paclitaxel patients received was actually higher than in those who received standard treatment. This was associated with some toxic side effects that caused treatment delays and modifications and also led to patients receiving less caboplatin than intended. In fact, more than half of the women in the dose-dense group discontinued treatment early, and most of them did so because of the toxicity.

Although it’s possible that the dose intensity was responsible for the survival improvements, Dr. Bookman wrote, the more frequent, lower-dose treatment schedule is the most “plausible explanation.” As a result, “similar results might be achieved” with a lower dose, he concluded, “with improved tolerability.”

As for why the dose-dense approach is more effective than the standard approach, the Japanese researchers suggested that it hampers the formation of blood vessels that feed tumors. In animal model studies, dose-dense chemotherapy, like a similar treatment also under active investigation called metronomic chemotherapy, has been shown to have such an antiangiogenic effect. And in the JGOG trial, the researchers noted, tumor shrinkage following treatment did not differ between those receiving dose-dense chemotherapy and standard chemotherapy. This suggests that the dose-dense treatment “might promote tumor dormancy by maintaining tumor size and preventing outgrowth,” they wrote.

alvarez

Ronald Alvarez, M.D., Director, Division of Gynecologic Oncology, University of Alabama at Birmingham

The U.S.-based Gynecologic Oncology Group is planning to launch a phase III clinical trial in advanced ovarian cancer combining the dose-dense approach with the targeted antiangiogenic drug bevacizumab (Avastin), said Dr. Ronald Alvarez, director of the Division of Gynecologic Oncology at the University of Alabama at Birmingham. This should help to confirm the Japanese trial’s results.

In the meantime, “Given the potential toxicity, clinicians should discuss with their patients the risks versus the benefits of this approach in comparison with other treatment strategies,” Dr. Alvarez said, particularly with those patients who have advanced disease and whose tumors could not be mostly eradicated by surgery.

Source: Modified Chemo Regimen Effective in Advanced Ovarian Cancer, by Carmen Phillips, NCI Cancer Bulletin Volume 6 / Number 18, National Cancer Institute, September 22, 2009.

References:

GOG Reports on Evaluation of Pemetrexed in Treatment of Recurrent Platinum-Resistant Ovarian Cancer

A phase II Gynecologic Oncology Group (GOG) clinical study found that pemetrexed (Altima®)-an antifolate antineoplastic agent that disrupts folate-dependent cell replication metabolic processes-is sufficiently active in the treatment of recurrent platinum-resistant ovarian cancer to warrant further investigation.  “Thus [pemetrexed] should be considered for combination with other agents, especially carboplatin, in first-line therapy,” said David Miller, M.D., F.A.C.S. (University of Texas Southwestern Medical Center, Dallas, USA) and colleagues.

millerdavid

David Miller, M.D. F.A.C.S., Professor, Gynecologic Oncology, University of Texas Southwestern Medical Center

A phase II Gynecologic Oncology Group (GOG) clinical study found that pemetrexed (Altima®)-an antifolate antineoplastic agent that disrupts folate-dependent cell replication metabolic processes-is sufficiently active in the treatment of recurrent platinum-resistant ovarian cancer to warrant further investigation.  “Thus [pemetrexed] should be considered for combination with other agents, especially carboplatin, in first-line therapy,” said David Miller, M.D., F.A.C.S. (University of Texas Southwestern Medical Center, Dallas, USA) and colleagues.

The purpose of the GOG study was to estimate the antitumor activity of pemetrexed in patients with persistent or recurrent, platinum-resistant epithelial ovarian or primary peritoneal cancer and to determine the nature and degree of toxicities.  The patients that participated in the study experienced disease progression on platinum-based primary chemotherapy or recurred within 6 months. Pemetrexed at a dose of 900 mg/m2 was administered as an intravenous infusion over 10 minutes every 21 days. Dose delay and adjustments were permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects.  From July 6, 2004, to August 23, 2006, 51 patients enrolled in the study.  A total of 259 cycles (median, four; range one to 19 cycles) of pemetrexed were administered, with 40% of the patients receiving six or more cycles.

According to the investigators, the study produced the following results:

  • No treatment -related deaths were reported;
  • Eighteen patients (38%) had progressive disease. Three patients (6%) were not assessable;
  • One patient (2%) had a complete response (CR) and nine patients (19%) had partial responses (PRs), with a median duration response of 8.4 months. Seventeen patients (35%) had stable disease (SD) for a median of 4.1 months. Clinical benefit rate (CR + PR + SD) was 56%; and

Based upon the foregoing results, the investigators noted that pemetrexed “exhibited activity more favorable than that seen in other agents that have been test in first-line combinations by the GOG.” Pemetrexed, according to the investigators, has sufficient activity in the treatment of recurrent platinum-resistant ovarian cancer at the dose and schedule tested to warrant further investigation.

Sources: