When a patient with advanced cancer faces a bleak prognosis, the “wonder drug” Avastin appears as a tantalizing promise for a longer life. Manufactured by Genentech, Avastin is a monoclonal antibody that combats cancer cells by disabling vascular endothelial growth factor, which, in turn, severs nutrient supplies to cancer cells. Praised for this combative mechanism, Avastin is one of the most popular cancer drugs worldwide [1]. But even during desperate times, is this drug a worthwhile investment? Recently, Avastin has been criticized for its inability to extend patients’ lives, which is especially troublesome considering the costliness of the drug. Avastin failed its first trial against breast cancer and only slowed the growth of colorectal cancer when compared with current chemotherapy. Despite such drawbacks, patients desperate for the slim chance of survival are willing to give Avastin a chance. And so the dilemma presents itself: on the one hand, this cancer drug is a beacon of hope for patients who have no other options; however, these patients may also be pouring money into a treatment that can theoretically prolong life for a few months, if at all. Furthermore, the price of this drug is so high that some patients do not have the luxury of receiving treatment. In the case of Avastin, the controversial approval by the Food and Drug Administration, compounded with its costly charges and debatable advantages, creates a multitude of problems for the patients [1].

Avastin: Mechanism, Treatment, and Side Effects Avastin, also known as bevacizumab, is a monoclonal antibody that is specifically designed to attack one target— vascular endothelial growth factor. By binding to vascular endothelial growth factors, Avastin inhibits the growth factors’ interaction with tyrosine kinase receptors found on the cell surface. This growth factor plays a key role in regulating angiogenesis, the physiological process of blood vessel growth. Research has shown that inhibiting angiogenesis may be an effective method to combat cancer, because it would separate nutrient and oxygen sources from cancer cells. In doing so, Avastin halts the growth of tumors and delays the worsening of cancer [2]. This mechanism would possibly extend the life span of patients. Avastin first arrived on the market in 2004, fifteen years after its initial development. The FDA approved the drug for treatment of metastatic colorectal cancer when it was found to extend patient life by four months. In 2006, the drug was approved for lung cancer treatment, and was recently approved in February 2008 for treatment of breast cancer. Patients using this drug reported an improvement in the quality of life, such as alleviation of pain and exhaustion [1]. Avastin is able to enhance the beneficial effects of chemotherapy, but is not effective when used alone [1]. It also displays certain side effects that are particularly detrimental, such as blood clots, perforation of the colon, heart failure, and kidney damage. In rare instances, Avastin was shown to cause inflammation of the eye [3,4].

Testing for Efficacy One research study demonstrated that there was little difference between patients who took the drug and those who only had chemotherapy and a placebo [1]. Furthermore, many studies proposed the use of Avastin with standard chemotherapy drugs, such as Taxol. In these dual drug prescription cases, the patient inevitably experiences the side effects of chemotherapy, an adverse reaction Avastin originally meant to avoid [1,5]. In its first clinical trial, Avastin failed to meet its goal of delaying the worsening of cancer [1]. Out of 363 female patients who received Avastin for treatment of breast cancer in another trial, five or six patients died from the drug itself [6]. In a phase III trial, 722 patients were treated with either paclitaxel, a chemotherapy drug, or Avastin with paclitaxel. The results from the trial showed that Avastin doubled median progression-free survival, the time during which the disease did not worsen, from 5.9 months to 11.8 months [7]. Dr. Ian Haines of Monash University in Melbourne, Australia, however, claims that progression free-survival was “an unreliable measure of benefit in metastatic cancer” [8]. Additionally, the overall survival time among patients who received Avastin with paclitaxel was similar compared to those who received paclitaxel alone. Results exhibited a statistically insignificant improvement of 1.5 months. In the same study, incidences of hypertension, proteinuria (excess of proteins in urine), and headaches were higher in patients who received Avastin with paclitaxel [7].

Expensive Promises On top of its questionable efficacy, Avastin also wields a high price tag. As one of the most popular drugs in the world, Avastin accumulated $3.5 billion in sales worldwide in 2007. The extension of the drug’s use to breast cancer was predicted to help Genentech’s sales by $1 billion or more per year [6]. Using this drug can cost from $4000 to more than $9000 a month. Therefore, one patient spends roughly $100,000 a year—a high price tag considering only about five percent of patients benefit significantly from the drug [1]. The rising costs of cancer drugs in general have prompted some insurance companies to begin restructuring their tiered copayment policies, which assign a fixed amount for the patient to payto the type of drug. Avastin, now considered a tier 4 drug for its high cost, will require “coinsurance.” Unlike copayments, coinsurance charges a percentage, usually 20 to 33% of the cost [10]. Therefore, a patient can pay up to $20,000 a year in order to sustain treatment. Genentech justified these costs as years of costly research, testing, and approval processes— all amounting to the “‘high side’ of the industry average” [1]. Compared to other cancer drugs that attack a tumor’s blood supply, Avastin is second highest in cost behind Bristol-Meyers’ Erbitux, which costs $9,600 per month. Unlike most other cancer drugs that target one cancer type, Avastin is approved for three types of cancer, which broadens its influence in the drug market [9].

FDA’s Role Leads to Bigger Question In 2008, the U.S. Food and Drug Administration approved Avastin for advanced breast cancer against the advise of its panel experts [1]. Some factors the FDA considers for efficacy of cancer drugs are survival, quality of life, tumor response, and time until treatment failure, with survival and quality of life as the primary parameters. Even though the requirement of survival is inconsistent among different classes of drugs, survival is the main concern of metastatic cancer patients [11]. The vote against approval of the drug by the FDA’s advisors was a slim 5-4 margin in December 2007. Based on data from clinical trials, the panel of experts, comprised of oncologists and patient representatives, was not convinced of Avastin’s ability to improve the patient’s quality of life or prolong their lifespan. Trials also demonstrated the toxic effects of the drug [6]. The FDA ultimately overruled their advisors’ decision, because Avastin reduced tumor volume and increased progression free-survival [6]. From their standpoint, the drug’s ability to hamper disease progression overshadowed its toxicity. These two opposing opinions raise issues that plague guidelines for approving cancer drugs: what should determine the efficacy of a cancer drug— its ability to prolong life, or its ability to delay the worsening of cancer? In a clash between a federal agency and its advisory committee, whose opinions should dominate? [1]. While some experts like Dr. Haine believe progression free-survival is an unreliable indicator, supporters of the drug believe that the goal of the drug is to “maximize disease control and quality of life, thereby, sparing patients for as long as possible from symptoms of progressive breast cancer … and the psychological burden and uncertainty that come with progression” [8]. The case of Avastin epitomizes the ambiguities surrounding the cancer drug approval process. Although increased survival is the main criterion for approval of a drug, the FDA based its decision on a drug’s ability to control disease. This form of measurement for efficacy is still debatable among experts. For the past four years, Avastin demonstrated its staying power in the cancer drug market. Currently, Avastin is studied as a potential treatment for eye diseases and even brain cancer, one of the most formidable cancers [12,13]. However, if an expensive drug delays disease progression but does not extend life, it may not be as cost-effective as manufacturers, regulators, or patients have hoped.

Jane Yang is currently a student at Cornell University.

References :
[1] Kolata G, Pollack A. Costly cancer drug offers hope, but also a dilemma. The
New York Times 2008 Jul 6 < http://www.nytimes.com/2008/07/06/health/06avastin.
html?ref=policy>.
[2] Muhsin M, Graham J, Kirkpatrick P. Bevacizumab. Nature 2004 Dec; 3:995-996.
Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid
malignancies. Clinical Therapeutics 2006 Nov;28[11]:1779-1802.
[3] Fintak DR, Shah GK, Blinder KJ, Regillo CD, Pollack J, Heier JS, Hollands
H, Sharma S. Incidence of endophthalmitis related to intravitreal injection of
bevacizumab and ranibizumab. Retina 2008 Sept 26.
[4] Mitchel L. New anticancer drugs can trigger hypertension; Cardiovascular
Medicine; Report. Internal Medicine News 2008 Jul 1;41[13]:36.
[5] De Gramont A, Van Cutsem E. Investigating the potential of bevacizumab in other
indications: metastatic renal cell, non-small cell lung, pancreatic and breast cancer.
Oncology 2005 Nov 21;69:46.
[6] Pollack A. Advisory panel rejects new use for cancer drug. The New York Times
2007 Dec 6 751C1A9619C8B63&fta=y>.
[7] Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella
D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic
breast cancer. N Engl J Med 2007 Dec 27;357[26]:2666-76.
[8] Haines I. Paclitaxel plus bevacizumab for metastatic breast cancer. N Engl J Med
2008 Apr 10; 358[15]:1637-1638.
[9] Berenson A. A cancer drug shows promise, at a price that many can’t pay. The
New York Times 2006 Feb 15 html?scp=3&sq=avastin&st=cse>.
[10] Lee TH, Emanuel EJ. Tier 4 drugs and the fraying of the social compact. N Engl J
Med 2008 Jul 24;359[4]:333-5.
[11] Johnson JR, Temple R. Food and drug administration requirements for approval
of new anticancer drugs. Cancer Treat Rep 1985 Oct; 69: 1155-1159.
[12] Lu F, Adelman RA. Are intravitreal bevacizumab and ranibizumab effective in a
rat model of choroidal neovascularization? Graefes Arch Clin Exp Ophthalmol 2008
Sep 10; 247(2):171-7.
[13] Desjardins A, Reardon DA, Herndon JE 2nd, Marcello J, Quinn JA, Rich JN,
Sathornsumetee S, Gururangan S, Sampson J, Bailey L, Bigner DD, Friedman AH,
Friedman HS, Vredenburgh JJ. Bevacizumab plus irinotecan in recurrent WHO grade
3 malignant gliomas. Clin Cancer Res 2008 Nov 1; 14(21):7068-73.
[14] http://www.fda.gov/oc/tfrm/image17.gif