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.

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Challenges Of “Enriched Environment” Significantly Curb Cancer Growth In Mice

Living in an environment rich with physical, mental and social stimulation – a setting that causes mild stress – appears by itself to curb cancer growth in mice, according to a new study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Matthew During, M.D., Ph.D., Professor, Neuroscience, Neurological Surgery & Molecular Virology, Immunology & Medical Genetics, College of Medicine, Ohio State Univ. Medical Center

Living in an environment rich with physical, mental and social stimulation – a setting that causes mild stress – appears by itself to curb cancer growth in mice, according to a new study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

The animal study, published as the lead cover story of the July 9 issue of the journal Cell, also shows how this effect happens and that it might have therapeutic use.

The researchers discovered that an enriched environment activates a nervous-system pathway used by the brain to talk to fat tissue. That pathway, called the hypothalamicsympathoneuraladipocyte (HSA) axis tells fat cells to stop releasing a hormone called leptin into the bloodstream. Leptin normally helps restrain appetite, but this study discovered that it also accelerates cancer growth.

The enriched environment had the same cancer-curbing influence in models of melanoma and colon cancer.

“People tend to think that cancer survivors should avoid stress, but our data suggests that this is not completely true,” says study leader Dr. Matthew J. During, professor of neuroscience, of neurological surgery and of molecular virology, immunology and medical genetics.

“The anti-cancer effect we observed in this study was not due simply to increased activity by the animals, but rather it was induced by social and physical challenges that cause mild stress, as measured by the release of hormones from the adrenal.

“But the most dramatic hormonal change we observed was the drop in leptin from fat after enhanced housing conditions activated the HSA pathway. That pathway is also present in humans, where it is likely to be activated by a more complex and challenging life,” he adds.

The enriched environment created for this study housed 20 mice in large containers equipped with toys, hiding places and running wheels, along with unlimited food and water. Control mice were housed in groups of five in smaller, standard laboratory containers with no toys but with unlimited food and water.

The researchers injected human melanoma cells under the skin in both sets of animals. After three weeks of enriched housing, mice had tumors that were about half the size of those in control mice. After six weeks of enrichment, the tumors dropped to approximately one-fifth the size of those in control animals, and almost 20 percent of enriched-group animals had no visible tumors. In contrast, all of the control animals had visible tumors.

Investigating this effect further, During and his colleagues looked for changes in several metabolic hormones in the blood. Notably, the hormone leptin showed a dramatic drop in the enriched group.

A series of experiments demonstrated that leptin and the nervous system pathway really did influence tumor growth.

Looking closely at the region of the brain called the hypothalamus, the researchers found that a gene called BDNF, which plays an important role in controlling food intake and energy balance, was much more active in the enriched group.

Transplanting extra copies of this gene into the hypothalamus of mice in standard housing mimicked the effects of the enriched environment and reduced the size of the tumors in these animals by 75 percent. Such an intervention is also possible clinically and could potentially be developed into a human therapeutic. Blocking the gene, on the other hand, cancelled this effect and caused even enriched animals to develop large tumors.

“This is the first time anyone has shown that putting a single gene into the brain could have a dramatic impact on cancer,” During says.

Next, they studied a strain of mice that was unable to make leptin and so lacked the hormone altogether. When they infused these animals with leptin, they developed melanoma tumors that were 40 percent larger than those in similar animals infused with a saline solution.

An enriched environment also produced a similar cancer-controlling effect in two colon-cancer models. In one of these, tumors develop spontaneously in the intestine; in the other, visible tumors develop after cancer cells are injected under the skin.

Using the second model, researchers discovered that the anti-cancer effect occurred when animals were placed in the enriched environment six days after visible tumors were well established.

“This finding suggests that such an enriched environment might have therapeutic importance,” During says.

During notes that increased physical activity – running in a wheel – alone did not produce the anti-cancer effect or activate the HSA axis. Increased activity did reduce levels of the stress hormone corticosterone in control animals, whereas levels of this hormone rose in animals in enriched housing, an outcome likely due to the challenges and social conflicts associated with larger and more complex group housing.

“Overall, our study suggests that an environmental or genetic activation of this nervous system pathway leads to a marked drop in serum leptin levels, and that this inhibits tumor growth.”

Funding from the National Institute for Neurological Disorders and Stroke supported this research.

Other researchers involved in this study were first and co-corresponding author Lei Cao, as well as Xianglan Liu, En-Ju D Lin, Chuansong Wang, Eugene Choi and Veronique Riban with The Ohio State University; and Benjamin Lin with Weill Medical College of Cornell University.

About the Ohio State University Comprehensive Cancer Center

The Ohio State University Comprehensive Cancer Center- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (http://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 20 cancer hospitals in the nation, The James is the 180-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 Phase II clinical trials.

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