According to an article written by Reuters some doctors have raised doubts about the efficacy of Provenge, known scientifically as sipuleucel-T. Prostate cancer vaccine Provenge has long incited passions unlike any other cancer therapy and the story seems to continue even to today.

The current issue has been raised by Marie Huber, a trained scientist and former hedge-fund analyst. Last year she analyzed what she believes are deadly flaws in the studies that led to the approval of Provenge by the FDA. She concluded that Provenge which showed that it extended survival was flawed. She claimed that older men in the study who did not receive Provenge, or received the placebo, died months sooner than similar patients in other studies.

She expressed concern is that the “placebo” they received was actually harmful and made Provenge look better by comparison or created a statistically false survival benefit.

Huber published her concerns in a February paper in the Journal of the National Cancer Institute.

Dendreon, the company responsible for the creation of Provenge, insists Huber’s analysis is flawed. “I’m looking forward to getting this to patients around the world,” said President and Chief Executive John Johnson.

In the pivotal trial called IMPACT, published in July 2010 Provenge extended median survival by 4.1 months to 25.8 months from 21.7 months. That was sufficient for FDA approval.

Each dose of Provenge is custom-made. A nurse or technician withdraws white blood cells from a man’s arm in a three-to-four hour procedure called leukapheresis.

The cells are then shipped to a Dendreon manufacturing facility, where for two days they are incubated with a “fusion protein:” One protein that stimulates the cells’ growth and maturation and another called PAP, or prostatic acid phosphatase.

Dendreon says the patients’ white blood cells take up the antigen and within hours their surfaces bristle with fragments of the telltale molecule. The cells are then shipped back to the physician and infused into the patient. A full treatment includes three such procedures, two weeks apart.

Steven Rosenberg of the National Cancer Institute, a leading tumor immunologist, says that raises doubts over whether Provenge helps patients live longer, as the IMPACT trial reported.

“We have a lot of data that supports the idea that the product works the way it was designed to,” said Dr. Mark Frohlich, Dendreon’s chief medical officer. “We’re seeing evidence of immune-system activation. The only question is whether the T cells are killing the tumor.”

Huber’s analysis comes from data showing that men who received the placebo had very different survival times based on their age. Men who were older than 65 lived 17.3 months when given a placebo and 23 months when given Provenge. Men who are younger than 65 lived 28 months after receiving placebo and 29 months after having Provenge.

Peter Iversen, a urologist and prostate-cancer surgeon at the University of Copenhagen and co-author of the paper with Huber said that other studies have shown that age generally does not affect how long a man survives with this form of prostate cancer.

Huber’s paper concluded that the four-month edge in median survival from Provenge for all patients was due to longer survival among older men who got the vaccine. Huber said, “There is no efficacy in the younger patients, the primary group where you would expect it.”

Huber said that since the immune system weakens with age, an immune-based therapy should work better in younger men. Huber is not alone in this analysis. “If it was really a vaccine, you’d think younger men would show more response, since they are more immunocompetent,” said NCI’s Rosenberg.

Huber argues that the placebo used in the trial may have actually harmed the older men, cutting months off their lives and inadvertently making Provenge seem beneficial.

Huber claims that it is possible that the problem occurred as a result of the leukapheresis. She said that the leukapheresis removed about 90 percent of certain kinds of circulating white blood cells, according to calculations by immunologist Laura Haynes of the Trudeau Institute, a co-author of the JNCI paper.

The Provenge men got back about 32 percent of those cells, which had been stored at body temperature. The placebo men got back 12 percent, which had been incubated at near-freezing temperatures. Cold storage has been reported to kill “most, if not all, of those cells,” notes the JNCI paper. Moreover, said Haynes, “if you return dead and dying cells to older men you are likely to cause inflammation,” which can stoke the growth of cancerous cells.

Younger men were better able to replace the lost white blood cells, argued Iversen. Older men could not, resulting in early death. “These cells are very specialized and there is research suggesting that removing them can harm older men,” he said.

Earlier this month, DynaMed, an online database used by physicians, added to its Provenge entry a note on the JNCI paper, but calls the concern “not substantiated.” ACS’s Lichtenfeld says the analysis “might inhibit some patients and doctors from going ahead with a very expensive drug.”

The critics of the new analysis argue the number of cells removed is too small to suppress the immune system. Dr. Charles Drake, an oncologist and immunologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said there is no evidence the placebo men in IMPACT suffered more infections or other effects of a depleted immune system than the Provenge men.

The scientist who led IMPACT, oncologist Philip Kantoff of Dana Farber Cancer Center, said colleagues in immunology “dismissed as nonsense the idea that leukapheresis could hurt individuals.” He takes issue, too, with the statistics. Dividing the men by whether they are older or younger than 65, he said, is “arbitrary” and to pick apart data retrospectively is a statistical no-no.

Dendreon’s Frohlich also criticizes the statistics: “If you do enough of these (post-hoc analyses) then by chance alone you’d expect to get one positive finding.” He went on to say that it is almost always possible to find a subset of patients who do better than others.

When Dendreon divided the men by whether they were older or younger than about 71, he added, they found no red flags.

The FDA has been very clear and agrees that such post-hoc statistical analyses “are exploratory” and their results “must be interpreted with caution, as acknowledged by the authors.” Yet a paid consultant to Dendreon before the IMPACT trial agreed with many of Huber’s concerns.

So, the Provenge controversy continues making the decisions we have to make even more complicated.

Joel T Nowak, M.A., M.S.W.