BIO (Biotechnology Industry Organization) CEO & Investor Conference Recap

%u25BA Safety, Patent Disputes to Dominate Government’s Biologic Policies

     FDA to Review Safety of Biologic Oncology Drugs on May 10th; PDUFA Deadline Brings 

	     Biologic “Follow-On” Drugs to The Fore

he safety of biologic drugs and the manufacture of ‘generic’ biologics−called follow-on biologics−will be subjects of great political debate for the rest of the year, according to public and private industry experts.

	The issues have taken on added emphasis as the deadline to pass the Food and Drug Administration’s (FDA’s) Prescription Drug User Fee Act, or PDUFA, approaches. The Act, which comes before Congress every five years, determines how  fees collected by the FDA from drug makers will be spent. The Act expires on September 30th.

	“If time runs out [on PDUFA] by the end of the fiscal year, FDA reviewers must be let go,” Nick Littlefield, a partner with the Washington-based law firm Foley Hoag. Mr. Littlefield was part of a Feb. 12th panel discussion during the “BIO CEO & Investor Conference 2007” in New York called “The New Congress: Implications for the LifeSciences Industry.” The panel included James Greenwood, President and CEO of the Biotechnology Industry Organization (BIO); Alex Azar; former Deputy Secretary,

	Department of Health and Human Services; Steve Usdin, Washington Editor, BioCentury Publications Inc.; and Thomas A. Scully, J.D., Senior Counsel, General Partner, Alston & Bird LLP, Welsh, Carson, Anderson & Stowe.

	Two bills in particular, one by New York Democratic Senators Hillary Clinton and Charles Schumer, the other by Senators Edward Kennedy (D-MA) and Mike Enzi (R-WY), address biologics and may delay the passage of PDUFA this year. 

(See our accompanying story in “Politics & Policy” for more.)

	The Clinton-Schumer bill, called “The Access to Life-Saving Medicine Act” would grant FDA the authority to approve follow-on biologics and “create a new statutory pathway for approval of ‘generic’ versions of biotech drugs.” This will speed lower-cost follow-on biologics to market and relive financial burdens on patients, the Medicare system, and private insurers alike, say supporters.

	But the “Access” Act is being vigorously contested by BIO, which represents more than 1,000 biotech companies and their partners.

	“Attaching follow-on biologics legislation to PDUFA would potentially jeopardize reauthorization of the user fee program to the detriment of patients waiting for new therapies, FDA’s internal scientific capabilities, and biomedical innovation,” Mr. Greenwood told the Senate’s Health, Education, Labor and Pensions Committee on March 8th.

	BIO favors the Kennedy-Enzi bill, “The Enhancing Drug Safety and Innovation Act”, which they say takes patient safety  into consideration while “providing incentives [to biologic drug developers] for the innovations that will bring the medical miracles of tomorrow,” according to Sen. Kennedy.

	Participants in the New Congress panel agreed that passing either bill before PDUFA expires will be difficult. Part of the difficulty will be explaining the difference between the manufacture of traditional drugs and biologics—let alone ‘generic’ versions of each&mdash;to lawmakers.

	“The most congressional leaders know about biologics,” Mr. Azar said, “has been over the ‘food fight’ between Amgen’s Aranesp® (darbepoetin alfa) and Johnson & Johnson’s/Ortho Biotech’s Procrit® (epoetin alfa).”

	Both Aranesp and Procrit, erythropoiesis-stimulating agents (ESAs), treat chemotherapy-induced anemia by stimulating the bone marrow to make more red blood cells. J&J sued Amgen late last year for what they allege were unfair sales practices meant to force Procrit offthe market. “The biggest amount of spending the government does has been over the fight between Aranesp and Procrit,” added Mr. Azar.

	On March 9th, the FDA ordered both companies to provide stronger warnings for both Aranesp and Procrit in light of the higher number of life-threatening side effects and deaths among patients receiving either therapy. The FDA is planning to review the safety and efficacy of ESAs at the FDA’s Oncologic Drugs Advisory Committee (ODAC) on May 10, 2007.

%u25BA Hazy Predictions from Preclinical/Early Clinical Trials Hamper Investment in Biologic Cancer

    Are preclinical trials actually valuable predictors?

he inability to predict whether a new biologic cancer therapy will reap financial returns in the early stages of its development is a vexing hurdle between drug developers and would-be investors.

	“We analysts need to decide where to invest,” William Ho, a senior research analyst with Bank of America asked the heads of several biologic drug companies. “[But] it is estimated that only 5% of compounds in development for oncology ever make it to the market compared to an 11% average across all therapeutics areas; early preclinical studies do not appear to reduce the attrition rate as there remains a less than 40% success rate in phase III. Are preclinical trials actually valuable predictors?”

	As a moderator, Mr. Ho posed the question during a workshop titled “Attacking Cancer’s Achilles Heel — Hot Targets in the Pipeline for Oncology Treatment.”

	It’s not a perfect system, but it’s what we got, according to researchers. “We don’t have better testing systems other than mice,” Dr. Julian Adams, president and chief scientific officer of Infinity Pharmaceuticals said.

	Dr. Kevin Koch of Array BioPharma agreed. “The dirty little secret is that mice are pretty robust little creatures. So there’s no good way of predicting human toxicology.” Testing in higher species, he suggested, may have to be considered.

	In the meantime, mice will have to suffice. ”We need some way to discern that the drug is getting absorbed and hitting the target. Simply shrinking tumors leads to mispredictions.” Infinity has partnered with MedImmune, Inc., the sixth-largest investor in biologic drug research and development (R&D) in 2005, according to a 

 from PharmaLive.com, in the development of IPI-504 to treat cancers resistant to other therapies. By targeting and shutting down a protein called Hsp90,

	Clinical site testing bias, the panelists also agreed, color predictions on whether a drug will go on to succeed.

	“The most important [determining] factor is performance data,” Dr. Robert Fine, associate professor of medicine, division of hematology & medical oncology at New York’s Columbia-Presbyterian Medical Center said. Phase II trials usually take place at top cancer-treatment centers, like Memorial Sloan-Kettering, and usually include upper-middle class patients “who will do better no matter what you do,” Dr. Fine said. Broader phase III studies include “lower-middle class patients who don’t do as well.”

	“I believe biomarkers will play an increasingly important role in the future,” Mr. Ho told 

. “As we continue to see a movement towards more targeted therapies, biomarkers will be helpful indicators of whether a desired target is being met or if the intended effect is occurring. Biomarkers could potentially be used to select for patient populations that are more likely to respond to treatment; this ‘enrichment’ could potentially lead towards higher rates of success in the future.”

%u25BA A Place for Biotechs in a Developing World

    "We can find a creative way for them to participate."

he creation of a financial “safety net” for biotech companies may be one way to encourage their investment in developing countries.

	“We don’t expect a young biotech that is pre-IPO to make a large investment, but that doesn’t mean we can’t find a creative way for them to participate,” Julie Klim, vice president of business development for BIO Ventures for Global Health (BVGH) told 

. One of those ways, suggested by Mark Kessel, managing director of Symphony Capital, a panelist at the “Assessing a Global Health Investment Fund” plenary session Ms. Klim moderated, might be the creation of a

	financial safety net — a fund which guarantees a return on investment down the road.

	OSI Pharmaceuticals CEO Colin Goddard was one of the panelists at Ms. Klim’s seminar. OSI manufactures  biopharmaceuticals Tarceva® (erlotinib) and Novantrone® (mitoxantrone) for the treatment of cancer and has two other in development—OSI-930 and OSI-817. OSI Pharmaceuticals is one of the top-20 biotech companies based on dollars spent on research and development.

	BVGH is a non-profit spin-offof the Biotechnology Industry Organization (BIO) and is supported by the Bill and Melinda Gates Foundation, the Rockefeller Foundation, and leaders in the biotechnology field. BVGH estimates up to 85% of the world’s population is underserved by the biopharmaceutical industry, including areas of high economic growth and established established health care programs. Ms. Klim hopes biotech companies will be inspired by the $1.5 billion recently contributed to

	the Advance Market Committeemen (AMC) fund by seven countries and the Gates Foundation for the creation of pneumococcal vaccines in developing countries.

%u25BA Biologic Drugs Are "Changing the Landscape" of Leukemia Treatment

    Leading Leukemia Society Actively Seeking to Invest in Promising Biologic Treatments

	    to Clear "Bottleneck" In Early Discovery Efforts

new crop of emerging biologic therapies is causing excitement among leukemia researchers who are anxious to get them in the pipeline.

	In the therapeutic workshop entitled “Blood-Borne Cancers − The Alphabet Soup of Leukemias,” it was discovered that identification of certain genetic markers unique to each of the four types of leukemia has given researchers the ability to predict who is most likely to respond to a specific treatment regimen.

	The Leukemia and Lymphoma Society developed an aggressive funding program plan to encourage continued research among biologic drug makers, called the Therapy and Acceleration Program (TAP). The Society says they will not only continue to “invest in research at the early states of discovery, but drive development and regulatory approval of new blood cancer therapies  at the critical clinical stage.”

	“There has been a bottleneck at the drug discovery phase,” Dr. Louis DeGennaro, senior vice president of research at the Leukemia and Lymphoma Society said. “We know biotech companies are looking at compounds to address blood cancers, and we want Society resources to develop these compounds, either by directly dealing with pharmaceutical companies or interacting with biologic/pharmaceutical partnerships. The goal is to bring more therapies to more patients.”

%u25BA Venture Capitalists & Bad Timing Impact Biotech IPO Success

    "Make sure you understand the agreements you've made or [they] will come back to bite you."

escribing his company as “one of those rare and gifted biotechs that went public twice”, Acorda Therapeutics CEO Ron Cohen warned colleagues at small and mid-sized biotechs to do their homework before entertaining thoughts of an initial public offering.

	“Amid much fanfare and delight we went on the road and came back with a deal for $150 million in pre-valuation IPO money,” Mr. Cohen told colleagues at the roundtable titled “IPOs and Alternative Exit Strategies — Is the Glass Half Full, or Half Empty?”

	“But to our surprise, several venture capitalists were displeased with the price and opted not to take part in the deal.” The resistance of a small but powerful minority of venture capitalists, Mr. Cohen said, torpedoed the IPO. The company attempted another IPO in February of 2006 that did go through. “This time we came in with a stunning $90 million pre-valuation IPO,” he said, laughing. Acorda makes Zanaflex® (tizanidine hydrochloride) to treat spasticity and has several drugs in development to treat multiple sclerosis and spinal cord injury.

Articles

This month we report on presentations made at the BIO (Biotechnology Industry Organization)CEO & Investor Conference (February 11-14, 2007, New York, NY).

The Rapid Reporter: April 2007

	Association of Community Cancer Centers 33rd Annual National Meeting

%u25BA Hospice Care Delayed by Targeted Cancer Drug Discoveries

    Oral administration changes perceptions of severity, outcome of illness.

	New cancer treatments, which enable patients to take drugs orally instead of by intravenous infusion, are impacting the way terminal cancer is viewed by patients and doctors.

	“A better understanding of the recentlyapproved oral agents for cancer is making us lean more toward oral administration and away from intravenous infusion, but we’re changing more than that,” Dr. Alice P. Chen of the National Cancer Institute’s Investigative Drug branch said. “We’re changing patient care trends. Patients are always looking for signs that their disease isn’t terminal, and  admission to a hospice confirms it is. Putting patients on oral medications when the response rate may be one percent or less delays acceptance of the terminal nature of the disease and of hospice care.”

	Dr. Chen shared her observations during a presentation at the Association of Community Cancer Centers 33rd Annual National Meeting in March.

	Hospice providers, she said, are already reporting a ‘backlash’ of sorts from the newly approved oral chemotherapies. “Fewer side

	effects and the ability to take medications at home may reinforce a longstanding reluctance to accept that death is approaching,” she said. “Patients may defer enrolling in hospice, or clinicians may wait to refer patients while they try a newer oral medication at the patient’s request.” Patients may suffer needlessly without palliative care and both they and their families have much less time to establish a relationship with the hospice as a result.

%u25BA Counterfeit Drugs: Biopharmaceuticals Not Immune to Crime

    Rising costs, availability of oral versions, likely to heighten risk.

	Biologic drugs, including cancer treatments, are not immune to the attempts of counterfeiters who try to pass sophisticated-looking fakes offas the real thing, according to one large community cancer services provider.

	“Historically, oncolytic agents have been infusible or injectable drugs,” Rolando DeCardenas, vice president of pharmaceutical distribution for US Oncology said at the Association of Community Cancer Centers meeting. “But now that many are available in tablet form, they could potentially be easier to counterfeit.”

	Counterfeiters have already infiltrated the biologic cancer therapy market, as illustrated by a spate of adulterated drugs in 2002. Among the list of adulterated pharmaceuticals that year was Procrit (epoetin alfa). Several cases of the Ortho Biotech drug, used to treat chemotherapy-associated anemia, were replaced by vials containing an extremely diluted version which could have caused patients to be underdosed had the fakes not been discovered.

	The high price of some of the newer anticancer biologics makes them a target for counterfeiters who, as in the Procrit example, literally water them down and sell them at full price to unsuspecting cancer care centers. “Oncology drugs represented about $40 billion in sales in 2005 and 2006,” Mr. DeCardenas says. “This area is expected to grow to even larger.”

	Mr. DeCardenas said oncologists at cancer centers should insist drugs be purchased directly from manufacturers. “It is difficult to tell at the oncologist level if a drug has been adulterated,” he said. “More sophisticated counterfeiters use equipment that makes pills and bottles appear remarkably authentic. These drugs are then sold at steep discounts to secondary wholesalers.” Cancer centers may be tempted to buy from secondary wholesalers rather than manufacturers for lower prices, he said, but these price breaks are rarely passed on to patients.

	US Oncology recently implemented an “electronic pedigree” system which tracks the movement of oncology drugs through the supply chain, from plant to patient. Further down the road, Mr. DeCardenas predicts scannable radio frequency identification tags (RFID) will track drug delivery, allowing the recipient to immediately see the drug’s up-to-the-minute travel history.

%u25BA Genetic Counseling Seeks a Niche in Community Cancer Care

    More referrals can translate into more lives saved, geneticists say.

	As more genetic mutations associated with the potential development of certain cancers are discovered, some genetic counselors say society isn’t keeping up with science.

	“A lot of insurers don’t cover genetic counseling by a genetic counselor, so many institutions are responsible for our salary,” said Robert Resta, MS, a certified genetic counselor and supervisor of The Heredity Cancer Clinic of Seattle’s Swedish Medical Center. “This limits the number of genetic counselors available.” There are currently 2,500 certified genetic counselors in the United States, according to Mr. Resta, who specialize in the detection of cancer predisposition and other diseases. Medicare will cover the cost of testing in certain cases, but most state Medicaid programs, which cover people under 65 and the disabled, will not. Each test is about $3,200.

	“Doctors have a general tendency to under-refer patients to us,” Mr. Resta says. “This is particularly true, and almost tragic, for those with breast cancer. A small but significant number of women who are predisposed to breast cancer will also be at higher risk for ovarian cancer, which can be prevented with [prophylactic] oophorectomy.”

	Beyond mutations of the BRCA1 and BRAC2 genes, which help doctors identify patients who may be at greater risk of developing breast, ovarian or prostate cancer, geneticists can now identify genetic mutations which may indicate a higher hereditary  risk of developing stomach, kidney, eye, endocrine, and pancreatic cancers.

	Not all patients with select genetic mutations will develop cancer, nor do all patients who develop cancer have a corresponding genetic mutation. However, Mr. Resta says, there has already been at least one case where the family of a young woman who died of ovarian cancer received a substantial out-of-court settlement when it was found she had a BRCA mutation and prophylactic care may have saved or extended her life.

Access to Care Concerns Community Cancer Centers

Surgical and pharmacological treatments not the only issues in access to care.

	Biotechnology and other scientific advances have extended the lifeexpectancy of many cancer patients over the last decade, but may be making them more inaccessible at the same time.

	“There is a lot of excitement about the new treatments coming out as the research the pharmaceutical industry has done in the last decade starts to pay off,” said Christian G. Downs, executive director of the Association of Community Cancer Centers (ACCC). “But is our healthcare system ready for some of these expensive therapies?”

	The question was part of the main theme of access to quality cancer care, which underscored the ACCC annual meeting in Baltimore in late March.

	“Even people with great insurance who can get any treatment do so at a personal and societal cost,” Mr. Downs said. “Providers struggle with the cost/benefit ratio, too. We need to understand advances in cancer treatment are incremental. A new therapy may come on the market and provide two or three more months of survival at a cost of over $10,000. But in the room we’re [oncologists] are working in, this is a significant step forward.”

	Who will ultimately bear the brunt of the cost of novel cancer treatments of the present and future is another access-related concern of the ACCC. “This is a fight that is coming to a head,” Mr. Downs said. “The provider community’s obligation is first and foremost to their patient. That said, they must hold insurers’ accountable to make sure their patients have access to quality treatments. But we must also hold the pharmaceutical industry’s feet to the fire to continue putting out good quality treatments that will continue to move patient care forward.”

	Other access-to-care concerns explored by ACCC meeting attendees centered on improving geographic and physical accessibility to cancer care—from how to best serve cancer patients living in rural settings to designing more “patient-friendly” cancer care centers. Where cancer patients were typically sent to one place for radiation treatment and another for chemotherapy, especially at larger medical centers, “we’re starting to see a trend toward combining everything they need under one roof,” Mr. Downs said. “Improving access to quality cancer care can be as simple as that.”

Current Concepts in the Multidisciplinary Management of Colorectal Cancer

Sidney Kimmel Comprehensive Cancer Center at John Hopkins

%u25BA High-Risk Colon Cancer Patients May be Identified at Earlier Stage of Disease

    Presence or absence of microsatellite instability can help predict success of chemotherapy in

	    postsurgery, stage II colon cancer patients.

	Oncologists may have isolated a genetic marker on color cancer tumors which identifies patients who would benefit from post-surgery chemotherapy and those who would not, a discovery which could potentially reduce recurrence rates among high-risk patients and spare others from additional chemotherapy who would not benefit from it.

	Approximately 25% of all stage II colon cancer patients will have a recurrence, even if the cancer is removed while still confined to the colon. The current follow-up standard of treatment for these patients is close postsurgery monitoring for any signs of returning disease.

	“Our insights into treatment can now be based on what is known about the tumor,” Dr. Ross Donehower, director of medical oncology at John Hopkins University said. “This is a huge step forward; this is the first time this has been looked at in any respective way.” Dr. Donehower presented the finding to colleagues at a recent colorectal cancer meeting at Baltimore’s John Hopkins University.

	The discovery is currently the subject of high-priority phase III clinical trial sponsored by the National Cancer Institute and the Eastern Cooperative Oncology Group (ECOG). Researchers have discovered a link between microsatellite instability (MSI) on the long arm of chromosome 18 in certain stage II colon cancer tumors and progression of disease. “The presence of MSI means a better prognosis and the patient may not have recurrence,” Dr. Donehower said. “But patients with MS stable tumors have a worse prognosis and would probably benefit from chemotherapy after surgery.”

	Patients enrolled in the E5202 trial are assigned into two groups. Those considered at low risk for recurrent colon cancer receive the traditional “close monitoring” treatment. Those at high risk of recurrence are randomized into one of two groups: one will receive standard combo chemotherapy of fluorouracil-5FU and oxaliplatin (folfox), the other will receive folfox plus bevacizumab. The trial is still accepting patients.

%u25BA Tumor Expression, Genetic Markers, May Help Tailor Approaches to Colon Cancer

    New discoveries may help match the right treatments to the right patients.

	While there are more treatment options for colon cancer available now than a decade ago, doctors say their next challenge is to match the right treatment to the right patient.

	“We’ve come to a point where we have a number of treatment options but have fallen short on our ability to predict who will respond to which treatment,” Dr. Daniel Laheru, assistant professor of oncology at John Hopkins University said. “Our ability to figure out who will respond to which drug is really critical.”

	Doing so would improve survival rates among colon cancer patients in several ways. “Right now, we try one drug or drug combination and keep them on it until the drug stops working or the side effects are too severe,” Dr. Laheru said.

	There are several chemotherapy regimens used to treat colon cancer, most are a combination of fluorouracil (5-FU) and leucovorin. Others agents include bevacizumab, capecitabine, cetuximab and panitumumab. These drugs has roughly doubled the average survival rate of advanced stage colon cancer—from 12 months between combos are working in individual patients.

	Oncologists hope better understanding the molecular genetics of colon cancer will help create treatments that zero in on tumor cells and interfere with their growth. For example, identification of an overexpression of the enzyme thymidylate synthase (TS), an enzyme key to cell proliferation, can help doctors select which chemotherapy may be most effective for individual patients. “High levels of TS are associated with resistance to 5-FU,” Dr. Laheru said. “If we know someone’s tumor expresses TS, we may consider doing something different.”

	Other future strategies may include the combination of 5-FU and radiation therapy for patients with low-risk of recurrent colon cancer, or replacing 5-FU with another drug plus radiation for those with a higher risk of recurrence, based on certain genetic markers. Detecting the duplicative presence of a genotype considered to be associated with a higher risk of colon cancer complications is another strategy on the horizon.

	“As encouraging as this is, none of these markers are suggested for consideration for treating colon cancer now,” Dr. Laheru said. “Hopefully this will change in the next year or so.”

This month we report on presentations made at the Association of Community Cancer Centers 33rd Annual National Meeting (March 28-31, 2007, Rockville, MD) and at a colorectal cancer meeting held at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University (March 28-31, 2007, Baltimore, MD). 

The Rapid Reporter: May 2007 

	Like the Vikings of old, scientists are hoping a new “longboat” drug delivery system will compromise the walls of resistant cancer cells and fight them with high-dose chemotherapy released only when they are inside.

	The new delivery system, detailed in the July issue of the 

 (JACS), uses soluble, single-walled nanotubes (SWNT) about 50,000 times thinner than a human hair. These longboats, as they are described by researchers, are then tethered with platinum-based chemotherapy drugs similar to those already considered highly effective in fighting testicular and colorectal-based cancers: carboplatin, cisplatin and oxaliplatin. According to the JACS article, although attempts to devise platinum drugs that surpass the anticancer properties of drugs like cisplatin have produced many compounds that display biological activity, only a handful have shown any real promise in clinical trials. “This loss of activity in the body can be associated with poor circulation and delivery to the tumor as well as deactivation mechanisms that irreversibly alter the chemistry of these molecules, particularly those of platinum, rendering them ineffective,” the article reports.

	“The key to success in the end is for the platinum not be released before it is delivered to the cell,” Dr. Stephen J. Lippard, a key researcher from the Massachusetts Institute of Technology’s Department of Chemistry in Cambridge, says. Dr. Lippard is currently working on tweaking the chemical makeup of the chemotherapeutic agents so they will adhere to the “oars” of the SWNT longboat and detonate only when they are inside of the cancer cell. The researchers believe when an SWNT-platinum conjugate meets a cancer cell it is pulled inside the cell by endocytosis upon which, in Trojan horse—like fashion, it releases its deadly cargo.

	“The nanotubes work because they have unique properties that give them the unique ability to penetrate the cell membrane and deliver their cargo,” Dr. Hongjie Dai of Stanford University’s Department of Chemistry says. “They work with cancer cells as well as T-cells.” The long, skinny shape and surface chemistry of the nanotube seems to be key to its success, Dr. Dai says, “because it binds over the cell for a long length, which is required for uptake.”

	Dr. Dai and Dr. Lippard hope this discovery will, unlike the traditional delivery of chemotherapy, spare healthy tissue unaffected by cancer and pave the way for an oral formulation of platinum chemotherapeutic drugs, which are currently delivered intravenously. The SWNT delivery system has already been tested in animal models using doxorubicin and paclitaxel. Both researchers anticipate using SWNT with platinum drugs later this year.

Like the Vikings of old, scientists are hoping a new "longboat" drug delivery system will compromise the walls of resistant cancer cells and fight them with high-dose chemotherapy released only when they are inside.

"Longboat" Delivery May Invade Tumor Cells and Deliver Chemotherapy

	While retinoblastoma is diagnosed in only 350 children annually in the United States (and at similar rates worldwide), the standard cure is often physically and emotionally traumatic: the removal of one or both eyes and the optic nerve. But an experimental intra-arterial delivery system, which injects high-dose chemotherapy directly into the ocular tumor may not only save the eye, but the vision as well.

	At least 10 children have participated in clinical trials at Memorial Sloan-Kettering and New York-Presbyterian Hospitals, both in New York. Dr. David H. Abramson, Chief of the Ophthalmic Oncology Service at MSK, says he and his colleague Dr. Pierre Gobin of NewYork Presbyterian are now performing the procedure on a weekly basis.

	Standard treatment for retinoblastoma, which often occurs in children under the age of two, is six-to-nine months of chemotherapy to shrink the ocular tumor until it is small enough to be extracted. Doctors often opt to remove the entire eye (enucleation) to insure all of the cancer has been removed, resulting in a cure rate of up to 95%.

	But the new procedure, which the doctors are calling ‘chemosurgery’ may spare the eye. A catheter described by Dr. Abramson as about “half the thickness of a string of angel hair pasta” is inserted into the groin, threaded up the vessels in the chest, up into the carotid artery and finally the patient’s ophthalmic artery. Once there, an extremely high concentration of a chemotherapeutic agent, in this case, melphalan (Alkeran), is delivered directly to the retina. “There’s only one blood vessel that supplies all of the blood to the eye,” Dr. Abramson says, “so, unlike some other tumors, it is a blood supply we can control.”

	Dr. Abramson acknowledges he was ‘grateful’ to discover that, not only did just a teaspoon of melphalan do the trick, but it stuck only to the cancer cells in the retina with no toxicity to surrounding areas of healthy tissue and, in some cases, saved or even restored vision in the affected eye.

	“If these trials are successful, intra-arterial chemotherapy may replace enucleation for the majority of retinoblastoma cases,” Dr. Abramson says. “That would be a revolutionary improvement in the treatment of this disease.”

An experimental intra-arterial delivery system injects high-dose chemotherapy directly into the ocular tumor and may not only save the eye, but the vision as well.

Children's Eyes May Be Spared by New Intra-arterial 'Chemosurgery'

THE AMERICAN HEAD AND NECK SOCIETY’S ANNUAL MEETING

New Role for Immune Activation of Antibody Therapy May Fine-Tune Approach to

Presence of FcyR genotype may point to best therapeutic approach in some patients

	Identifying head and neck cancer patients who possess the FcyR genotype may help predict whether they will respond to monoclonal antibodies, which work by killing cancer cells bearing epidermal growth factor receptors (EGFR) on their surface.

	“There may be a relationship between patients who possess this certain FcR genotype and their ability to mediate immune activation with certain monoclonal antibody therapies, but this is still to be validated,” said Robert L. Ferris, MD, Associate Professor, Co-Leader of the Cancer Immunology Program and Chief of Head and Neck Surgery at the University of Pittsburgh Cancer Institute. [Dr. Ferris and his colleague, Dr. Andres Lopez-Albaitero, presented their findings at the American Head and Neck Society’s {AHNS} recent Annual Meeting in San Diego.]

	This finding may be potentially substantial because monoclonal antibodies like Erbitux (cetuximab) by Bristol-Myers Squibb/ ImClone, which was originally approved to treat advanced colorectal cancer, are now used to treat some forms of mouth, tongue and voice box cancer. A study published in the 

 in February 2006, for example, found cetuximab plus radiation therapy nearly doubled the median survival in patients with certain head and neck cancers, particularly oropharyngeal cancers. Another EGFR-specific antibody, panitumumab (Vectibix) is also FDA approved. Identifying patients with the FcyR genotype may further fine-tune whether these monoclonal antibodies will work for them. Until this is proven, however, chemoradiotherapy with cisplatin remains the accepted standard of care for these types of cancers. Toxicity with this platinum-based treatment remains high, however, leading researchers to look for other alternatives.

	“We know that antibody-dependent cell-mediated cytotoxicity (ADCC) can happen even with low levels of EGFR, and the may be due to the presence of the FG gamma receptor,” said Dr. Ferris, who has served as a consultant and investigator for both BMS/Im- Clone and Amgen, respectively. “If the FcyR genotype influences the antitumor response to [a monoclonal antibody such as] cetuximab in squamous cell carcinoma cells of the head and neck 

, ADCC activity should be correlated with the FcR genotype and other immune biomarkers.”

Robots and Lasers Change the Face of Head and Neck Cancer Surgery

	Precision robotic arms and targeted carbon laser are changing the face of traditional head and neck surgery while preserving the faces of patients, especially those with advanced and hard-to-reach cancers. Surgeons who support these new approaches hope they will one day render the current “saw-to-jaw” approach to many head and neck cancers obsolete.

	“Traditional oral cancer surgery often requires making an incision, removing the lymph nodes and moving the jaw bone just to get to the cancer,” said Dr. Michael L. Hinni of the Mayo Clinic in Scottsdale, Arizona. “Transoral laser microsurgery (TLM) allows us to come in right through the mouth, completely remove the tumor, and achieve clear margins.” Dr. Hinni presented his findings and the results of some of his surgeries at an American Head and Neck Cancer meeting this past Spring.

	With TLM, a high-powered microscope is threaded down to the larynx, a common site for hard-to-reach and advanced oral cancers. Once the tumor and surrounding cancerous tissue is identified, a CO2 laser carves it out. The advantages, Dr. Hinni says, are many.

	“The CO2 laser does not put a lot of heat into surrounding tissues,” he says, “and not taking a patient’s face apart avoids a lot of swelling.” Additionally, Dr. Hinni says, TLM can reduce the need to perform a tracheotomy from the current 100% for cancers located at the base of the tongue to less than 25%, further speeding the patient’s return to normalcy after surgery.

	Dr. Hinni and his colleagues conducted a multicenter trial where patients with Stage III or Stage IV squamous cell carcinoma of the glottic or supraglottic larynx were treated with TLM and followed up for two years. “The results,” he said, “were quite acceptable.” Dr. Hinni is guarded about stating more exact results because, while no “standard of care” for the treatment of advanced stage laryngeal cancer exists, radiation and chemotherapy remain the accepted standard to approach tumors that have become too large or too inaccessible to safely remove or remove without creating a need for extensive reconstructive facial surgery. However, he hopes that TLM will change this one day soon.

	“Laryngeal cancer is a complex disease that poses challenges to patients, their families, and the health care professionals,” he says. “Current surgical approaches can profoundly affect how a patient eats, breathes, or talks. The best treatment should be individualized, and one of these treatment options may be TML.”

	Robotic surgery, where surgeons use robotically controlled “hands” to remove tumors with near-perfect precision, is also giving head and neck cancer patients other options besides chemotherapy to shrink tumors. Like laser surgery, fine robotic instruments can now allow doctors easier access to what once may have been near-inaccessible tumors, particularly those located in the parapharygeal space, infratemporal fossa, anterior skull base and other hard-to-reach areas of the head and neck. For cancers located in these areas, according to Bert W. O’Malley, Jr., of the otorhinolaryngology department at the University of Pennsylvania Health System, Philadelphia, surgical options have been extremely limited. Like Dr. Hinni of the Mayo Clinic, Dr. O’Malley concurs that oral cancer surgery with jaw involvement “has a tremendous impact on speech and swallowing, and can cause extensive cosmetic defects, so chemotherapy and radiation has been the only option for some patients.” Since the introduction of robotic instruments at the University of Pennsylvania in 2005, Dr. O’Malley says he and his colleagues “have performed over 130 transoral head and neck procedures involving robotics.” In these procedures, robotic instruments enter through the oral cavity without having to cut away at the jawbone, neck, or other surrounding organs in the region just to get at the tumor. Thus far, according to Dr. O’Malley, 25 head and neck surgeons in the U.S. based at The Mayo Clinic, The University of Alabama, and Mount Sinai Hospital in New York, among others, have been trained to use robotic instruments in surgery. The procedure is currently awaiting FDA approval.

	“I think robotics bring surgery back as an option for many head and neck tumors that were once only treatable by chemotherapy,” Dr. O’Malley says, who also presented his findings at the AHNS meeting this spring. “Now we can use the appropriate level of surgery and radiation and prevent many of the traditional side effects.”

	Both TLM and robotic surgery for head and neck cancers may potentially impact yet another traditional complication of surgery—operating time and post-op recovery. Transoral laser microsurgery, Dr. Hinni says, has the potential of reducing a head and neck cancer patient’s hospital stay to just over 3 days, as opposed to the current standard of one week. Dr. O’Malley says robotic instruments in the operating room have the potential of reducing operation time from 8 to 15 hours down to about 2. Both doctors say the cost of these advanced procedures is offset by the cost savings realized in postoperative care, including the need for patients to undergo expensive and often extensive reconstructive surgery.

Advances in Head and Neck Cancer Treatment Compel Clinical Trials and

Old ways of measuring drug efficacy for traditional drugs may need to

	    catch up with more complex medicines

	As more advanced drugs for head and neck cancers emerge, traditional clinical trial designs and measures used to gauge the success of these new agents need to advance, or at least change, along with them.

	“Our challenge will soon be not whether there is an agent that will work, but which one to use,” said Dr. Jennifer Rubin Grandis, professor of otolaryngology & pharmacology and leader of the head & neck cancer program at the University of Pittsburgh.

	After more than a 45-year lull in the development of new drugs for head and neck cancers, a host of new and advanced therapies are now either in use or under investigation, Dr. Grandis pointed out at a head and neck cancer presentation earlier this year. Monoclonal antibodies that disable epidermal growth factor receptors (EGFR), overexpressed by the cells of many head and neck cancer tumors, are already being used (erlotinib, gefitinib, cetuximab), to treat patients. Angiogenesis inhibitors like bevacizumab (Avastin), which successfully cut offtumor blood supply in cancers elsewhere in the body, are now being investigated for cancers of the head and neck. Proteosome inhibitors, vaccine therapies, gene therapies and farnesyl transferase inhibitors (FITs) are also being investigated to treat head and neck cancers with or without additional surgery or radiation.

	But along with these new options, Dr. Grandis says, comes the need for change in the way clinical trials are conducted and outcomes are measured. Dr. Grandis points to the new EGFR targeting agents as an example. “We know EGFR targeting works, but the challenge now is how to use it right; how to test our patients for their sensitivity to these agents before treating them with it or whether we should be enrolling them in new trials. If we knew this ahead of time we can use resources more wisely. I have a strong bias that every patient should be treated, but if there’s no evidence a particular agent will work for them, we should try to put them in another protocol or on another molecular agent.”

	Success outcomes, Dr. Grandis says, may also need to be reconsidered in the age of targeted therapies. Clinical endpoints traditionally measure survival time and time to disease progression to judge whether an agent is working or not in clinical trials. Dr. Grandis suggests it may be time to test tumor responses (or lack of) to agents more frequently during the trial. Additionally, Dr. Grandis says, it may be time to consider improvement in disease-related systems as an endpoint, as many of the new agents do vastly improve a patient’s quality of life and ability to function normally.

	Dr. Grandis concedes the ability to prescreen which patients may respond to the new agents may be limited and testing tumor responses at more regular intervals during trials may be complicated, but thinks it behooves patients and the medical community to be proactive. “If we don’t do it electively,” she says, “the insurance companies are going to find ways to stop spending money on things they don’t think work.”

Clear Connection Between Diagnosis of Advanced Head and Neck Cancer and

	    Insurance Coverage, ACS Study Reports

Study Gives Glimpse Into Current National Debate on Health Care Accesibility

	While anecdotal evidence and mainstream thought suggest a connection between the quality of a person’s medical insurance—or lack thereof&mdash;and their health for some time, a recent study from the American Cancer Society on head and neck cancer has come up with some statistical insights.

	Dr. Amy Y. Chen, MD, MPH, an associate professor of otolaryngology at Emory in Atlanta and director of health service research for the American Cancer Society, conducted a retrospective cohort study using the National Cancer Database spanning the years 1996 to 2003.

	The study looked at the records of over 40,000 patients who had been diagnosed with invasive oropharyngeal cancer and whose insurance status was known: lack of insurance, private insurance, or Medicaid. After adjusting for what the paper calls “other sociodemographic characteristics” (data collected from the Census Bureau by zip code) the study found patients with advanced oropharyngeal cancer at the time of their diagnosis were more likely to be insured or covered by Medicaid compared wih those who had private insurance.

	While Dr. Chen and her colleagues note the results of the Medicaid group “may have been influenced by the post-diagnostic enrollment of uninsured patients, insurance coverage appeared to be a highly modifiable predictor of cancer stage.” These preliminary findings are potentially concerning because screening for head and neck cancer, which can be done during normal health check-ups and dental exams, can prevent many of these types of cancers from advancing to such serious, life-threatening stages.

	Dr. Chen says the findings in the head and neck cancer study are indicative of a larger problem. “This is the whole national debate on health care,” she says. “If a patient is diagnosed with cancer, they should have equal access to care and sufficient resources to deal with it, whether by Medicaid or another policy. As a clinician, I see the effects of not having adequate health care coverage every day, and it’s up to us as a society to take care of these patients.” Dr. Chen is currently working on another paper looking at the presentation of cancers other than head and neck in relation to insurance coverage and says she is seeing similar results “across the board.”

	“Most of the uninsured and underinsured are treated at academic centers, which are then unfairly burdened with the cost of caring for these patients,” Dr. Chen says. “So eventually we’re all going to have to pay for it.”

Identifying head and neck cancer patients who possess the FcyR genotype may help predict whether they will respond to monoclonal antibodies, which work by killing cancer cells bearing epidermal growth factor receptors (EGFR) on their surface.

The RapidReporter: Recent Developments, Findings, and Research in Head and Neck Cancer

The ability to predict how the course of cancer will likely play out in an individual patient based on genetic factors is already changing the way certain cancers are approached, but it will take unprecedented levels of cooperation between researchers, federal regulators, drug developers, patient groups and clinical oncologists to continue advances in the field.

The collective knowledge of practicing oncologists is becoming increasingly important to advances in biomarker discovery, according to Shawnmarie Mayrand-Chung, PhD, JD, Program Director, representing the National Institutes of Health to the Biomarker Consortium (www.biomarkersconsortium. org). Dr. Mayrand-Chung explained the purpose of the Biomarker Consortium, formally launched in 2006, at the recent Biomarker World Conference in Philadelphia.

“Doctors are a frontline link to patients,” Dr. Mayrand-Chung said. “Involving practicing physicians in the process of biomarker research will provide insight into their day-to-day experiences with patients and contribute to designing effective clinical trials.” If individual clinical oncologists report discoveries in their patients to the Consortium, for example, collective results can provide the basis of new discoveries. “Research is inherently slow,” Dr. Mayrand-Chung said. “If we can speed it up by aggregating the observations we make through clinical interactions, it just makes sense.”

How Reliable Are Biomarkers in Cancer Treatment and Drug Development?

The discovery of how likely a cancer treatment will work in people with certain types of cancer based on the genetic makeup of either the person or the tumor has already changed how certain forms of aggressive breast cancer are treated, but many oncologists remain skeptical whether such predictors will eventually be 100% accurate in all patients and in all cancers.

Dr. Scott Patterson, executive director of medical sciences for Amgen, is a biomarker believer. He cited the Food and Drug Administration’s (FDA) “Critical Path Initiative”, which encourages researchers to utilize cutting-edge scientific tools and discoveries like biomarkers to measure the progress of a disease, or the effects of a particular treatment, quicker and more accurately than the traditional “phase 1-to-phase 4” method does.

Dr. Patterson cites the example of the KRAS biomarker to demonstrate the validity of using other biomarkers for targeted drug development and cancer therapy. Mutation of the KRAS gene can lead to overexpression of epidermal growth factor receptors (EGFR) and continued tumor growth.

“Even though biologists have known about the presence of a mutant KRAS gene in the tumors of patients with pancreatic, colon, and lung cancers, there has been a long standing-debate over whether this is indicative of a poor prognosis,” he said. Skeptics site preclinical studies in mice and studies conducted with relatively small patient samples, which seemed to indicate some patients with KRAS mutations may respond to chemotherapeutic agents that target EGFRs.

Amgen examined its archive of tumor samples from patients enrolled in their phase II studies with metastatic colorectal cancer (mCRC) in an attempt to come to a more definitive conclusion about the KRAS mutation’s role and then went on to conduct studies in more than 400 patients with metatastic colorectal cancer (mCRC) in its pivotal trial to compare their response to the best supportive care only (in this study it was FOLFIRI) and FOLFIRI combined with the Amgen drug panitumumab (Vectibix). 

“The best supportive care along with panitumumab gave people with the wild type (normal) KRAS gene the best chance of objective response,” Dr. Patterson said, citing data from the study. In patients with a wild-type KRAS gene, 34% achieved a stable disease state, 17% showed a partial response to the combination therapy, and 36% went on to progressive disease. In comparison, 70% of patients with mCRC and a confirmed KRAS mutation in the study saw their disease worsen and none had a partial response to therapy, although disease stabilized in 12% of the patients. 

Dr. Patterson said while these findings are promising, the treatment of individual patients is best left in the hands of their oncologists and he hopes for the day when there is a clearer understanding by patients and physicians on how and when to collect and interpret cancer-related biomarkers like KRAS. Amgen is preparing to study this subject further, Dr. Patterson said, to “ultimately generate a companion diagnostic for first- and secondline therapies.” 

The reality, according to Dr. Patterson, is the example of panitumumab and the KRAS genetic marker “will not be unique.” Indeed, he said, “oncologists on both sides of the Atlantic are hoping treatment can eventually be determined at primary diagnosis. That’s what I’m hearing, and that’s what we’re pushing for.”

Pharma Companies Find Biomarker Research to Be a Lonely Road

Recognizing the multitude of hurdles researchers and pharmaceutical companies face in bringing biomarkers from discovery to clinical practice, and with hundreds of drugs with oncology indications in various stages of development, the National Institutes of Health (NIH) has partnered with both public and private groups to form “The Biomarker’s Consortium.” With an executive committee consisting of members from the Pharmaceutical Research and Manufacturers of America (PhRMA), the Biotechnology Industry Association as well as the FDA, Centers for Medicare & Medicaid Services (CMS) and the Foundation for the National Institutes of Health, one of the main goals of the Consortium is to create a “precompetitive environment” where the groups can pool resources for the “discovery development and regulatory acceptance” of biomarkers important to the treatment of cancer and several other disease states.

“Pharmaceutical companies’ investment in biomarker research is a difficult business model,” Dr. Mayrand-Chung said. “Clinical trials are expensive and difficult, and require high risk and input on the company’s part, so if we can share the risk and expense re- quired for biomarker development and qualification with other pharmaceutical companies and NIH and FDA, it just makes sense.” While members of the Consortium agree there will be no “intentional generation of intellectual property” Dr. Mayrand-Chung said companies are expected and encouraged to use the publicly available precompetitive information from the Consortium in product development and commercialization.

The oncology steering committee is co-chaired by Anna D. Barker, PhD, deputy directory of the National Cancer Institute of the NIH and Barbara Weber, MD, vice president, translational medicine, genetics and oncology for GlaxoSmithKline. Other committee members include representatives from pharmaceutical companies, academic research centers, and patient advocacy groups like the American Cancer Society.

Currently, the oncology committee is studying the use of Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) as a biomarker for clinical trials conducted in non-Hodgkin’s lymphoma and non—small cell lung cancer. The goal is to examine whether FDGPET imaging can help access the effect of traditional cytotoxic drugs in clinical outcomes and survival in lung cancer and lymphoma. This, according to the Committee, could have an “enormous affect on patient management by validating a tool that can measure responses to treatments and enable more rapid drug development.”

The studies hope to determine how effective FDG-PET imaging is in measuring the effect of conventional cytotoxic drugs in patients with either lung cancer or lymphoma. The qualification of the FDG-PET as a biomarker could, according to the Committee, potentially impact patient care by providing a tool to measure treatment response earlier and perhaps lead to more rapid drug development. Findings could also affect the regulatory review process for these cancers and “provide a basis on which CMS could make reimbursement decisions for cancer treatments,” Dr.Mayrand-Chung said.

Biomarkers Used to Predict Safety, Toxicity, and Dosage in Patients With Certain Genetic Markers

The correlation between certain genetic markers and specific cancer therapies is, in some cases, becoming strong enough to warrant relabeling of drugs from the FDA to reflect whether they are likely to work in an individual patient or not.

As pointed out by Dr. Alan H.B. Wu, professor of laboratory medicine at the University of California in San Francisco, the FDA has already changed the labeling on the colorectal cancer drug irinotecan (Campostar) instructing oncologists to test their patients for the presence of a UGT1A1 enzyme mutation before initiating the treatment. While the number is small, patients with this type of enzymatic mutation have a high risk of severe toxic reaction to the drug.

Breast cancer treatment and prophylactic tamoxifen (Nolvadex), taken orally, may be the next cancer drug to be relabeled. Increasing numbers of studies indicate the drug shows increased efficacy in women and men with a wildtype CYP2D6 enzyme, although survival rates between those without the wildtype 2D6 and those with the mutation are unknown. If a 2D6 mutation is detected, an oncologist may instead consider treating the patient with aromatase inhibitors such as Zoladex or Lupron, especially in pre-menopausal patients.

The University of California in San Francisco, where Dr. Wu is based, is running a study where people with breast cancer being treated with tamoxifen are invited to join an educational “tamoxifen pharmacogenomics program.” Participants are given the option of being genotyped in a certified lab; clinicians tell the patient’s oncologist if their patient has genetic indicators of an aggressive form of the disease. So far, 65 women have voluntarily enrolled in the program. Among other things, the study is examining whether oncologists change their management of a patient’s disease if they know their patient has a high-risk genotype.

Dr. Wu thinks it is still premature for the vast majority of clinical oncologists to routinely genotype their patients. “I don’t recommend [oncologists] go out and genotype their patients without a plan on how they’re going to use the information,” he said. “The tests are expensive, they are not widely available, and there are no guidelines to interpret the results.” Ultimately, Dr. Wu said, “implementation will only be successful if testing leads to clinically actionable decisions.”

Patients Weigh in on ‘Personalized’ Medicine, With an Emphasis on ‘Quality of Life’ Factors

People with cancer and their advocates, according to at least one genomic research company, are beginning to add their voices to the biomarker discovery debate. In some cases, they are already influencing how this information is discovered and applied to their current cancer treatment options.

Patrick Terry, co-founder and director of industry relations for Genomic Health, Inc., a developer of genomic-based clinical laboratory services, said time spent in “engagement mode” with patients with breast cancer and their advocates helped his company design their flagship genomic test, Oncotype DX. Given to patients with early-stage breast cancer, the test is credited with predicting whether the disease is likely to metastasize within 10 years of initial diagnosis.

“What we heard from the breast cancer community is that uncertainty has an impact on quality of life,” Mr. Terry said, “so the patient community helped us to apply the technology to measure this. We discovered it was not so much a ‘targeted therapy’ question they wanted answered, but a ‘likelihood of recurrence’ question. If we can tell patients the likelihood of disease recurrence they can make a much more informed care decision.”

Patients then wanted to take the information gathering even further: could a test be developed to ascertain a “mid-range” risk of recurrence?

“This is a difficult and highly controversial area,” Mr. Terry said. “But patient advocates said they wanted to help patients who were deciding whether to treat—or not to treat&mdash;their conditions.” In response to this demand, Genomic Health is now conducting trials to find that out.

“Whether we can spare women chemotherapy is the universal question behind this trial.” Bucking the trend of slow clinical trial enrollment, Mr. Terry anticipates this trial, which will be open for two years, will be ahead of schedule because of immense patient interest. 

Access to survival and quality-of-life information is changing the relationship between oncologists and their patients at a core level. “We’re seeing a wholesale shift where oncologists are ‘partnering’ with patients. Patients are demanding this type of information,” Mr. Terry said. “For the clinical oncologist, the dilemma is how to present this information so the patient can weigh [her] treatment options appropriately.”

However, patients and oncologists are not the only ones interested in their likelihood of surviving cancer or having to contend with recurrence somewhere down the road. Different ‘stakeholders’ may come to very different conclusions as to what is “appropriate” therapy based on a patient’s genetic makeup.

“There are some highly integrated care teams, along with the patient and the patient’s family, so you may have a highly interactive and dynamic situation,” Mr. Terry said. “Throw in the hospital administrator, insurance company and the lawyers and it complicates the mix even more.”

Mr. Terry predicted detailed conversations between oncologists and patients regarding which therapy to choose based on individual genetic findings may still be 10 to 20 years away, but said oncologists should start demanding rigorous data so they can have improved confidence in their decision making for patient care and who will be on the patient care team.

“Delegating these responsibilities to the cancer advocate community is another aspect of what clinicians can do,” he said. “There is the trauma of a cancer diagnosis, but there is also the empowerment of knowledge.”

Will the Pull Toward Biomarker Identification Push More People Out of Clinical Trials?

With more oncology drugs in the research pipeline than ever before, the need for clinical trial enrollment by both patients and control groups is reaching critical levels.

“Demand for patients is expected to increase, but problems in recruitment will cause delays in drug development,” said Geert Kolvenbag, MD, PhD, executive director of development for emerging oncology and infection brands at AstraZeneca. Although genotyping can mean the quicker development of more targeted therapies, the added step of preselecting groups on a molecular basis may exacerbate enrollment problems.

The ability to predict how the course of cancer will likely play
out in an individual patient based on genetic factors is already changing the way certain cancers are approached. As highlighted at the recent Biomarker World Conference in Philadelphia, clinical oncologists have an increasingly integral role. 

By Diane West