February 15, 2006. Today’s New York Times runs a business section story by Alex Berenson about Genentech’s Avastin, A Cancer Drug Shows Promise, at a Price That Many Can’t Pay. Buried on the second page Berenson mentions this week’s news about deaths in a clinical trial of Avastin plus chemotherapy.

The patients were taking Avastin (bevacizumab) along with XELOX, an acronym for a therapy combining Roche’s pill Xeloda (capecitabine) plus IV infusion of the platinum chemotherapy drug Oxaliplatin. The trial is divided into three arms depending on what the patients take along with Avastin. Since the trial began in December 2004, Roche said in a press release, seven patients in the XELOX arm died, four of them suddenly. They were younger patients.

The Times already carried the AP’s report of the deaths in the business section when that news came across the wire yesterday, Deaths Halt Enrollments in a Drug Trial. The deaths were reported also by Paul Elias in the Miami Herald, Drug companies stop recruiting for cancer drug test after deaths. Bloomberg and the Herald Trib mentioned it and RedOrbit puts its own obliviously grotesque spin on things (Trial Delay Won’t Choke Avastin’s Growth).

So far Berenson is the one reporter I’ve seen leveraging the timing of the announcement of the deaths to slam the price of Avastin. Putting this story in the business pages instead of in the health section makes it a warning to investors not cancer patients. Is this smart? And will it help or hurt cancer patients?

I suppose the first impact is on the trial itself and any patients who were on the brink of entering it. Roche announced two days ago, February 13, that the AVANT trial is suspending recruitment of new patients for the next 60 days. This action was taken to review safety concerns.

The trial had been attracting patients at a phenomenal rate, 200 a month. Roche says patients who are already enrolled will be allowed to stay on treatment according to the study protocol throughout the 60-day review period.

Staying on treatment can be incredibly important to patients with advanced cancer. The last thing a patient needs is to be ripped off his treatment for no reason relevant to him or herself. Still and all, to select this somber moment to zero in on price indicates how gross and, in the long run, socially unbearable the price is.

“Doctors are excited about the prospect of Avastin,” Berenson writes, “a drug already widely used for colon cancer, as a crucial new treatment for breast and lung cancer, too. But doctors are cringing at the price the maker, Genentech, plans to charge for it: about $100,000 a year.”

That may be an overestimate but Genentech has hoped that Avastin might become the second-best selling drug in the world next to Lipitor. In 2005 some analysts were ecstatic at the prospect of a Genentech Avastin monopoly – “This drug is going to work in every single solid tumor,” said Sven Borho, a partner at Orbimed Advisors in New York. “What’s going to hold this drug back?”

Avastin is a monoclonal antibody with potent effects on the vascular system. It blocks the protein VEGF (Vascular Endothelial Growth Factor). VEGF stimulates the growth and survival of blood vessel cells that help cancer cells and tumors grow and spread to new locations in the body (metastasis). This growth of a network of blood vessels that supply nutrients and oxygen to cancerous tissues is called angiogenesis. Avastin is a VEGF targeting angiogenesis inhibitor.

This makes it an exciting novel drug but it is not without side effects; and drugs it may be taken with have side effects also.

XELOX is a pill plus chemotherapy. Roche’s pill, Xeloda, is a convenient replacement for the old IV hook-up chemotherapy 5-fluorouracil (5-FU)/oral leucovorin. FDA approved it only quite recently, 1998. The thousands of patients attracted by the “wonder” drug Avastin into joining this international trial are battling colon cancer. The protocol is not a cake walk. Xeloda and oxaliplatin have a similar range of side effects.

In most trials today measures are taken to prevent and alleviate side effects and not all patients by any means experience them; but side effects of these two drugs (without Avastin in the pictuire) may include: diarrhea, nausea, vomiting, mouth sores, stomach pain, decreased appetite, dehydration, hand-and-foot numbness, rash, dry or itchy skin, tiredness, dizziness, headache, fever.

Additionally, Xeloda interacts with blood thinners like warfarin (Coumadin). “After Xeloda became available, there have been reports to the FDA of changes in blood clotting and/or bleeding in people taking Xeloda together with certain anticoagulants (blood thinners).” (FDA, Patient Information Sheet).

Three patients died in the non-Avastin arm, four in the Avastin arm — perhaps all those deaths might have been prevented by monitoring the effects of Xeloda on coagulation.

No one is saying much about that though, we’re all too jumped up about the price, with estimates like Berenson’s as high as $100,000 year:

That price, about double the current level as a colon cancer treatment, would raise Avastin to an annual cost typically found only for medicines used to treat rare diseases that affect small numbers of patients. But Avastin, already a billion-dollar drug, has a potential patient pool of hundreds of thousands of people — which is why analysts predict its United States sales could grow nearly sevenfold to $7 billion by 2009. Doctors, though, warn that some cancer patients are already being priced out of the Avastin market. Even some patients with insurance are thinking hard before agreeing to treatment, doctors say, because out-of-pocket co-payments for the drug could easily run $10,000 to $20,000 a year.

Studies have shown that Avastin can prolong the lives of patients with late-stage breast and lung cancer by several months when the drug is combined with existing therapies. Berenson says Genentech “expects to seek federal approval later this year to sell it specifically for those diseases. But even now, doctors, who are free to prescribe the drug as they see fit, are using Avastin for some breast and lung cancer cases — and finding its cost beyond the means of some patients.” How does the oncologist choose who is to receive it?

“Avastin is a superb drug, but its cost is already discouraging patients and doctors from using it,” said one oncologst Bereson interviewed, Dr. David Johnson, head of the cancer unit at Vanderbilt University and a former president of the American Society of Clinical Oncology. “I wish it were one-tenth the cost, and if it were I would be giving it to almost everybody.”

The price of other new cancer drugs, Berenson predicts, may shoot up to match Avastin’s. And patients may pay too much for the drug through Genentech’s failure to test whether lower doses are sufficient:

The higher cost of using Avastin in breast and lung cancer, compared with colon cancer, is a result of cancer drugs’ being priced on the basis of weight. In colon cancer, Genentech tested Avastin at a dose of 5 milligrams of the drug per kilogram . . . of the patient’s body weight. But in lung and breast cancer, the company tested the drug at a dose of 10 milligrams per kilogram of body weight.

Actual cost of producing Avastin is a fraction of what Genentech charges for it. Some analysts and doctors had expected the company to lower Avastin’s price per milligram for use in lung and breast cancer: Dr. Leonard Saltz, an oncologist at Memorial Sloan-Kettering Cancer Center in New York, “noted that Genentech had not tested Avastin at the dose level for colon cancer in large-scale trials of lung and breast cancer. As a result, no one really knows whether the lower dose might turn out to be equally effective in lung and breast cancer, he said. Besides costing less, he said, a lower dose might have fewer side effects. “There are no meaningful data to allow us to address that question,” he said.

It gets worse, almost a conspiracy theory — Dr. Desmond-Hellmann told Berenson that Genentech was assuming that some cancer doctors might, in fact, use Avastin at the lower dosage to treat breast and lung cancer. That is a reason the company does not want to lower Avastin’s per-milligram price, she said, because doing so would cut too deeply into revenues if doctors do not prescribe the higher doses that were used in the breast and lung cancer trials. “We don’t actually know whether physicians will actually use Avastin as was used in the clinical trials,” she said.

But Dr. Saltz and other doctors said that they would almost certainly stick to the higher Avastin dose that was tested in the clinical trials, for fear that a lower dose might not be as effective.

Clinical trials are supposed to establish the most effective dose with tolerable side effects. From Berenson’s account, it sounds like Genetech is so profit-driven that it may be using clinical trials to establish not the safest and most effective but the most profitable dose. The week’s reckoning of deaths is a signal that everyone needs to sober up.

UPDATE: April 18, 2009:

The trial in which seven deaths occurred was formally suspended on Feb 14, 2006 and was allowed to start up again in May, 2006.

Roche said the data safety monitoring board had now concluded that the current safety profile and the death rates from all causes in AVANT were consistent with those seen in other adjuvant colon cancer trials and, therefore, no concerns were raised about continuing recruitment in AVANT.

However, trial procedures were changed to include additional cardiac testing before patients begin treatment and cardiac monitoring during treatment.

Avastin has side effects:
Avastin side effects, manufacturer’s patient brochure.

Xeloda interacts with blood thinners like warfarin (coumadin). In a press release Roche said changes in blood clotting and/or bleeding and death have been reported in other patients taking Xeloda.

Clinically significant increases in the time it takes blood clots to form –prothrombin time (PT) and INR — have been observed within days to months after starting Xeloda, and infrequently within one month of stopping Xeloda.

For patients receiving Avastin and Xeloda at the same time, frequent monitoring of INR or PT is recommended. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of trouble from blood clotting (coagulopathy).

LINKS

XELODA (capecetabine) FDA Patient Information Sheet

Recruitment Planned To Resume In AVANT International Phase III Trial In Adjuvant Colon Cancer 5/23/2006 Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2084-2091

Expert Interview – Medscape Hematology-Oncology. 2006;9(2) Posted 10/25/2006
Colorectal Cancer — Moving Biologics Into the Adjuvant Setting: An Expert Interview With Dr. John Marshall

Drug companies stop recruiting for cancer drug test after deaths
PAUL ELIAS
AP via Miami Herald reg Tue Feb 14 2006
SAN FRANCISCO – Biotechnology giant Genentech Inc. and its majority stockholder Roche Holding AG said they temporarily halted recruiting volunteers for a large human test of the blockbuster cancer drug Avastin after more patients than expected died.

The deaths occurred among colon cancer patients taking Avastin with a chemotherapy regimen called XELOX. Since the test was started in December 2004, seven patients taking that combination died, four of them suddenly, Roche said in a press release Monday.

“An occurrence of sudden deaths, especially in three younger patients, was noted,” Roche said, adding that the temporary suspension would allow “a full safety assessment.”

Those seven deaths compare to four deaths in another arm of the study that combined Avastin with a different chemotherapy called FOLFOX.

About 2,000 of the 3,450 patients planned for the test already receiving one of three combinations of Avastin and the chemotherapy regimens will continue to receive their drugs. The rest of the volunteers won’t be enrolled for at least 60 days while the companies try to find what caused the deaths.

The test is designed to see if Avastin can safely be used to prevent colon cancer from recurring in patients in remission. The Food and Drug Administration approved Avastin for patients with advanced colon cancer in 2004 and the drug accounted for $1.1 billion in sales for Genentech last year. Basel, Switzerland-based Roche owns sales rights in Europe, where it was approved last year.
Full story online:
http://www.miami.com/mld/miamiherald/13867271.htm

QLT says therapy fails Phase II trial

Canada’s QLT, a Vancouver-based developer of light-activated pharmaceuticals, says that it is suspending work on an experimental therapy for
enlarged prostate because the drug “did not meet the study’s primary efficacy objective at three months.”

Researchers announced that lemuteporfin failed to significantly decrease
symptoms of benign prostatic hyperplasia after three months of treatment
compared with a placebo.

“While the decrease in AUA (American Urological Association) Symptom Score was consistent with that seen after other minimally invasive therapies there was no significant difference between treatment and sham-control groups.”

“The preliminary result of this trial does not support initiation of Phase
III clinical trials of lemuteporfin in BPH at this time,” commented Bob
Butchofsky, QLT’s acting chief executive officer. “We intend to complete the
analysis of the data, including the six-month measurements, in order to
determine the best path forward.”

source: QLT’s press release, February 14, 2006.

The Lowdown on Sweet?
February 12, 2006
By MELANIE WARNER

note — This New York Times article was published today, Feb 12, in the business section, not in the health section. I have edited the links so that you can get hold of Dr. Soffritti’s full text article in .pdf

WHEN Dr. Morando Soffritti, a cancer researcher in Bologna, Italy, saw the results of his team’s seven-year study on aspartame, he knew he was about to be injected into a bitter controversy over this sweetener, one of the most contentiously debated substances ever added to foods and beverages.

Aspartame is sold under the brand names Nutra-Sweet and Equal and is found in such popular products as Diet Coke, Diet Pepsi, Diet Snapple and Sugar Free Kool-Aid. Hundreds of millions of people consume it worldwide. And Dr. Soffritti’s study concluded that aspartame may cause the dreaded “c” word: cancer.

The research found that the sweetener was associated with unusually high rates of lymphomas, leukemias and other cancers in rats that had been given doses of it starting at what would be equivalent to four to five 20-ounce bottles of diet soda a day for a 150-pound person. The study, which involved 1,900 laboratory rats and cost $1 million, was conducted at the European Ramazzini Foundation of Oncology and Environmental Sciences, a nonprofit organization that studies cancer-causing substances; Dr. Soffritti is its scientific director.

The findings, first released last July, prompted a flurry of criticism from the Calorie Control Council, a trade group for makers of artificial sweeteners that has spent the last 25 years trying to quell fears about aspartame. It said Dr. Soffritti’s study flew in the face of four earlier cancer studies that aspartame’s creator, G. D. Searle & Company, had underwritten and used to persuade the Food and Drug Administration to approve it for human consumption. “Aspartame has been safely consumed for more than a quarter of a century and is one of the most thoroughly studied food additives,” read one news release from the council.

2006-02-10 10:16:19 -0400 (Reuters Health)

NEW YORK (Reuters Health) – Adding arachidonic acid, an omega-6 fatty acid, to culture media causes prostate cancer cells to grow twice as fast as usual, according to a report in the February 1st issue of Cancer Research.

“Investigating the reasons for this rapid growth, we discovered that the omega-6 was turning on a dozen inflammatory genes that are known to be important in cancer,” lead author Dr. Millie Hughes-Fulford, from the San Francisco VA Medical Center, said in a statement.

Further analysis indicated that arachidonic acid was activating these genes through a PI3-kinase pathway known to play a key role in the pathogenesis of cancer.

Adding an NSAID or a PI3-kinase inhibitor to the culture media blocked the arachidonic acid-induced proliferation of prostate cancer cells, the findings indicate.

In light of the current findings, Dr. Hughes-Fulford said she now avoids cooking with corn oil, which is known to be high in omega-6 fatty acids. “I’m not a physician, and do not tell people how to eat, but I can tell you what I do in my own home. I use only canola oil and olive oil.”

Cancer Research, Feb 1, 2006.
Arachidonic Acid Activates Phosphatidylinositol 3-Kinase Signaling and Induces Gene Expression in Prostate Cancer
Millie Hughes-Fulford1,2,3, Chai-Fei Li, Jim Boonyaratanakornkit and Sina Sayyah
Department of Veterans Affairs Medical Center; Northern California Institute for Research and Education; and University of California, San Francisco, California

News Source: Reuters Health

Responding to news reports of a large US study published in JAMA, which showed that women who began eating a lower-fat diet at over age 50 were not significantly protected from cancer and heart disease, Sarah Keating M.D., a Canadian doctor, wrote to the Toronto Star to say these women’s diets were not strict enough:

The latest study on low-fat diets is further indication that only truly significant changes to our eating habits can reduce our risk of disease.

As a physician, I know that eliminating meat and other animal products from the diet — a step the low-fat dieters in this study did not take — is proven to reduce the risk of heart disease, obesity, and some forms of cancer.

The China Healthy study and other research on populations around the world have already shown that people on plant-based diets have strikingly low cancer rates. This is because vegetarians typically eat less saturated fat, more fibre and are, on average, slimmer than meat eaters. A 2003 study showed that a vegetarian diet lowers serum cholesterol concentrations about as effectively as cholesterol-lowering statin drugs, a key to preventing heart disease.

By choosing a meatless diet rich in naturally low-fat foods, such as beans, whole grains, fruits, and vegetables, we can significantly reduce our intake of artery-clogging saturated fat and protect ourselves from a number of chronic illnesses.

Toronto Star, Letters, Feb 10, 2006

Although headlines claim that the study has shown no benefit for women on the lower-fat diet, comments from some of the researchers themselves indicate that despite the size and cost of this study, the results are far from definitive.

Why? The women switched to a low fat diet relatively late in life. At 8 years out, the study has not run long enough. By today’s standards, the women received inadequate guidance on types of fat to avoid (especially, they were not advised to avoid trans fats). And many of the women on the supposedly “low-fat” diet drifted away from the relatively moderate target levels of fat back to close to a normal US diet. Even so,the women on the low-fat diet actually did develop less cancer. As reported by The Baltimore Sun,

[The study recruited] 48,835 healthy women with an average age of 62 were enrolled. Forty percent of them were given what is descriobed as intensive counseling to help them reduce their fat intake, while the remainder continued with their normal diet.

Even with the counseling, most women were not able to reduce fat consumption from the average of 35 percent of their calories at the beginning of the study to the target of 20 percent.

At the end of the first year, their fat consumption was 24 percent of calories; by the sixth year it had inched back up to 29 percent.

That lower adherence to the diet than planned was, in part, “why we don’t have definitive results yet,” said biostatistician Ross Prentice of the Fred Hutchinson Cancer Research Center in Seattle.

The study did not differentiate between different types of fat.

Prentice cautioned that the subjects were all “very healthy women who were already following most of the [government’s] dietary guidelines,” so their ability to decrease risk by lowering fat might have been low.

“Unhealthy women may gain more benefit.”

The Mercury News presents a Q&A with one of the study leaders, Marcia Stefanick of Women’s Health Initiative:

Best bet: Eat more fruits, veggies

Q What did the Women’s Health Initiative diet study find?

A The study of 48,835 women found that a low-fat diet alone does not prevent breast cancer, colorectal cancer or heart disease in women over 50. However, there were some signs that a low-fat diet might improve health.

Q What were those signs?

A Women who dramatically lowered the amount of fat they ate and increased their consumption of fruits and vegetables had lower rates of breast cancer than women in a comparison group who did not change their diets. Fewer polyps, a potential sign of colon cancer, were found in women who ate a low-fat diet. Women who ate less saturated fat or trans fats and more fruits and vegetables appeared to have a lower risk of cardiovascular disease.

Q Does this mean that I should abandon my low-fat diet?

A Not necessarily. The women in the low-fat group did not reduce their fat intake as much as researchers had hoped. As a result, they say more study of a truly low-fat diet is needed to determine whether it can prevent cancer. More benefits of a low-fat diet may emerge as the women are studied for another five years. In addition, reducing saturated fat and trans fats have been shown to help improve heart health.

Q If a low-fat diet isn’t going to help, what else can I do to prevent heart disease and cancer?

A Researcher Marcia Stefanick of Stanford University recommends following a diet that’s low in saturated and trans fats, and rich in vegetables and fiber, rather than a generic “low-fat” diet. Pay attention to total calories and strive to get your weight to a healthy level. Exercise regularly. Women should also get routine mammograms and screenings for colorectal cancer and heart disease risk. Routinely check your cholesterol profile, blood pressure, blood sugar and body weight.

What your doctor may be reading according to Doctors Guide listing of top abstracts in prostate cancer for past 14 days:

1. Randomized Phase II study comparing paclitaxel and carboplatin versus mitoxantrone in patients with hormone-refractory prostate cancer. Cabrespine A, et al. Urology. 2006 Feb

2. First- and second-line chemotherapy with docetaxel or mitoxantrone in patients with hormone-refractory prostate cancer: does sequence matter? Michels J, et al.
Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

3. Gynecomastia in patients with prostate cancer: update on treatment options.
Autorino R, et al. 1Clinica Urologica, Seconda Universita degli Studi, Napoli, Italy.

4. Insulin Sensitivity During Combined Androgen Blockade for Prostate Cancer.
Smith MR, J Clin Endocrinol Metab. 2006 Jan 24. Massachusetts General Hospital, Boston, MA.
Free Full text in .pdf

5. Prospective comprehensive assessment of sexual function after retropubic non nerve sparing radical prostatectomy for localized prostate cancer. Trinchieri A,et al. Urology Unit Ospedale A. Manzoni Lecco, Italy. Arch Ital Urol Androl. 2005 Dec. “CONCLUSION: Severe erectile dysfunction was observed in most patients after retropubic radical non nerve sparing prostatectomy, but 50% of candidates for radical treatment presents with abnormal erectile function before surgery when appropriately studied. Patients who will recover erectile function could be identified by NPT test before surgery. Depression associated with the fear for intervention is related with erectile dysfunction measured by IIEF scores before surgery, but depression index scores improve after surgery showing that the role of depression in the maintenance of erectile dysfunction is marginal. Sexual counselling and oral treatment facilitate recovery after surgery in patients with optimal erectile function before treatment.”

For 3 month ratings see Doctors Guide Top Abstracts

Reported by Reuters, Feb 9, We add the abstract from the article, below this report

By Megan Rauscher

NEW YORK (Reuters Health) – Men with recurrent or advanced prostate cancer may be put on hormone therapy to block testosterone production in an effort to halt or slow the growth of the tumor. However, new research shows, this may put them at increased risk for developing insulin resistance and elevated blood sugar levels, which can affect heart health.

These complications of what doctors call androgen-deprivation therapy or ADT may contribute to the high rate of heart disease in men with prostate cancer, Baltimore-based investigators report in the journal Cancer.

Starting a low-fat diet in mid-life does not, by itself, decrease a woman’s risk of heart disease or stroke or dramatically reduce her risk of breast or colorectal cancer, according to three studies published today of almost 50,000 healthy, post-menopausal women. But don’t break out the ice cream just yet. Once you get into the nitty gritty of the study, the investigators stress, the findings still support the general idea that you need to pay attention to how much fat — and particularly what kinds of fat — you eat.

By GINA KOLATA
Published: February 7, 2006

The largest study ever to ask whether a low-fat diet keeps women from getting cancer or heart disease has found that the diet had no effect.

The $415 million federal study involved nearly 49,000 women aged 50 to 79 who were followed for eight years. In the end, those assigned to a low-fat diet had the same rates of breast cancer, colon cancer, and heart attacks and strokes as those who ate whatever they pleased, researchers are reporting today.

Those who ate the higher-fat diets also had no more diabetes, no higher blood glucose or insulin levels, no higher blood pressure. And the different diets did not make much difference in anyone’s weight. By the end of the study, women in the two groups weighed about the same. But women in the low-fat group had slightly lower levels of low density lipoprotein cholesterol, or LDL, which increases heart disease risk.

The results should put an end to more than two decades of speculating that a low-fat diet is protective, said Dr. Michael Thun, who directs epidemiological research for the American Cancer Society. The new study, he said, “was the Rolls Royce of studies that would answer this question.”

Considering the time, effort, and money it takes to do such a study, Dr. Thun and others added, it is unlikely that anything like it will ever be attempted again. “We usually have only one shot at a very large-scale trial on a particular issue,” Dr. Thun said.
Study Finds Low-Fat Diet Won’t Stop Cancer or Heart Disease – New York Times