Chemotalk Newsletter

Chemotalk Newsletter, Vol. 60: April 1, 2013

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Experienced Surgeons Can Extend Lives

By Denise Grady

Most women with OVARIAN CANCER receive inadequate care and miss out on treatments that could add a year or more to their lives, a new study has found.

The results highlight what many experts say is a neglected problem: widespread, persistent flaws in the care of women with the disease, which kills 15,000 a year in the United States. About 22,000 new cases are diagnosed annually, most of them discovered at an advanced stage and needing aggressive treatment Worldwide, there are about 200,000 new cases a year.

Cancer specialists around the country say the main reason for the poor care is that most women are treated by doctors an hospitals that see few cases of the disease and lack expertise in the complex surgery and CHEMOTHERAPY that can prolong life.

"If we could just make sure that women get to the people who are trained to take care of them, the impact would be much greater than that of any new chemotherapy drug or biological agent," said Dr. Robert E. Bristow, the director o gynecologic oncology at the University of California, Irvine, and lead author of the new study presented at a meeting of the Society of Gynecologic Oncology in Los Angeles.

The study found that only a little more than a third of patients received the best possible care, confirming a troubling pattern that other studies have also documented.

Karen Mason, 61, from Pitman, N.J., had been a nurse for 28 years when she was found to have ovarian cancer in 2001. She scheduled surgery with her gynecologist, who was not a cancer surgeon.

But her sisters would not allow it. They ha gone on the Internet, an became convinced -- rightly, according to experts -- that she should go to a major cancer center.

"They too the reins out of my hands," Ms Mason said.

She wound up having a long, complicated an successful operation performed by a gynecologic oncologist, which she does not believe her gynecologist could have done.

Dr. Barbara A. Goff, a professor of gynecologic oncology at the University of Washington, in Seattle, who was not part of Dr. Bristow's study, said the problem with ovarian cancer care was clear: "We're not making the most use of things that we know work well."

What works best is meticulous, extensive surgery and aggressive chemotherapy. Ovarian cancer spreads inside the abdomen, an studies have shown that survival improves if women have surgery called debulking, to remove all visible traces of the disease. Taking out as much cancer as possible gives the drugs a better chance of killing whatever is left. The surgery may involve removing the spleen, parts of the intestine, stomach ad other organs, as well as the reproductive system.

The operations should be done by gynecologic oncologists, said Dr. Deborah Armstrong of Johns Hopkins University who is not a surgeon But many women, she said, are operated on by general surgeons and gynecologists.

Some women prefer the obstetricians who delivered their children. Many are desperate to start treatment and think there is no time to fin a specialist. Some do not now that gynecologic oncologists exist Some inexperienced doctors may find the cancer unexpectedly during surgery an try to remove it, but not do a thorough job.

"If this was breast cancer, and two-thirds of women were not getting guideline care that improves survival, you know what kind of hue and cry there would be," said Dr. Armstrong, who was not involved in the study. But in ovarian cancer, she said: "There's not as big an advocacy community. The women are a little older, sicker and les prone to be activists."

One patient advocacy group, the Ovarian Cancer National Alliance, ranks the availability of a gynecologic oncologist as one of its criteria in comparing the quality of care among states.

Surgeons who lack expertise in ovarian cancer should refer women to specialists if the women are suspected to have the disease, but often do not, Dr. Goff said.

Dr. Bristow's research, which has been submitted to a medical journal but not yet published, was based on the medical records of 13,321 women with ovarian cancer, diagnosed from 1999 to 2006 in California They had the most common type, called epithelial. Only 37% received treatment that adhered to guidelines set by the National Comprehensive Cancer Network, an alliance of 21 major cancer centers with expert panels, that analyze research and recommend treatments. The guidelines for ovarian cancer specify surgical procedures an chemotherapy, depending on the stage of the disease.

Surgeons who operated on 10 or more women a year for ovarian cancer, an hospitals that treated 20 or more a year, were more likely to stick to the guidelines, the study found. And their patients lived longer. Among women with advanced disease -- the stage at which ovarian cancer is usually first found -- 35% survived at least five years if their care met the guidelines, compared with 25% of those whose care fell short.

But most of the women in the study, more than 80%, were treated by what the researchers called "low-volume" providers -- surgeons with 10 or fewer cases a year, and hospitals with 20 or fewer.

Dr. Bristow said women should ask surgeons how often they operate on women with ovarian cancer and how often they achieve complete debulking. But he also acknowledged that many patients hesitate to ask for fear of offending the doctor who may operate on them.

Ovarian cancer has unusual traits that make it more treatable than some other cancers. It is less likely to spread through the bloodstream and lymph system to distant organs like the lungs and brain. The tumors do spread, but usually within the abdomen and pelvis where they tend to coat other organs but not eat into them and destroy them, said Dr. Matthew A. Powell, a gynecologic oncologist and associate professor at Washington University School of Medicine in St. Louis.

And most ovarian cancers are extremely sensitive to chemotherapy, experts said.

In 2006, a study was published that many doctors thought would change the field forever. It compared standard intravenous chemotherapy with a regimen that pumped the drugs directly into the abdomen. The test regimen was highly toxic, and not all patients could tolerate it. But median survival on it was 65.6 months, compared with 49.7 months on the standard treatment -- a survival difference of 15.9 months.

The gain was huge, almost unheard of. New cancer drugs are often approved if they buy patients just a few months. The test treatment -- called intraperitoneal, or IP therapy -- did not even use new drugs. It just gave the old ones in a different way. Several previous studies had had similar findings for IP therapy, but the 2006 study, led by Dr Armstrong, had the most definitive results.

The National Cancer Institute took a rare step, one it reserves for major advances. It issued a "clinical announcement" to encourage doctors to use the IP treatment, and to urge patients to ask about it. Cancer specialists predicted that the announcement would lead to widespread changes in treatment. Expert guidelines said it should be offered to every patient considered strong enough to endure it.

Seven years later, Dr. Armstrong and other physicians said, IP therapy still has not caught on.

Part of the reason may involve money, Dr. Armstrong said. With IP chemotherapy, patients also need a lot of intravenous fluids, which means unusually long treatment sessions.. Oncologists are paid for treatments, not for time, so for those in private practice, long sessions can eat away at income.

"You don't make a lot of money with somebody in the chair getting IV fluids," Dr. Armstrong said. "Chair time is money. I'm being a cynic here, but I think that is part of the issue."*

Dr. Goff said: "Where I live, in the Pacific Northwest, IP chemotherapy is pretty much only being done in the major medical centers, and by very few private-practice oncologists. Many say it's too difficult, and they don't even offer it to patients, which I think is unethical."

Ms. Mason had six hours of surgery at the Fox Chase Cancer Center in Philadelphia, with a gynecologic oncologist. The cancer had spread to lymph nodes, and was Stage 3. The surgeon remove her ovaries, fallopian tubes, various lymph nodes, uterus, cervix and omentum (part of the tissue that lines the inside of the abdomen).

"Ovarian cancer looks like Rice Krispies all over the place," Ms. Mason said. "She spent most of the time picking out each little visible Rice Krispy, and left nothing behind that she could see with her naked eye."

Then, Ms. Mason had chemotherapy (not IP, because it was not being done at the time). The disease has not recurred. Had she stuck with the first doctor, she believes, "I would be gone."

" feel so strongly about letting women know that you need to get to a center of excellence," Ms Mason said. "It's shocking to think it's still not happening."

*EDITOR'S NOTE: I want to believe that it's more a matter of training more gynecological oncologists, than of current doctors looking at their bottom lines.

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by Jessica Stoller-Conrad

A simple switch of ingredients made a big difference in how mice responded to experimental CANCER vaccines.

In the quest for better cancer medicines, vaccines that treat rather than prevent disease are getting lots of attention. More than 90 clinical trials have tested therapeutic vaccines in cancer patients, but the results have been a mixed bag. A recent study in mice suggests that changing a traditional ingredient in the vaccines could make a big difference.

A typical therapeutic vaccine against cancer contains a cancer-specific peptide, or protein fragment, that is injected under a patient's skin. The peptide serves as a red flag for the immune system. If all goes well, the patient's immune system recognizes the peptide as something to be attacked and boosts the population of cancer-fighting T-cells in the bloodstream.

For such vaccines to work against the cancers, though, these cells have to find their way to tumors. This migration might not be happening as expected in traditional human cancer vaccines, says Willem Overwijk, an author of the study in the latest Nature Medicine and an assistant professor at MD Anderson Cancer Center in Houston.

Cancer vaccines typically include a substance called IFA, short for "incomplete Freund's adjuvant." Adjuvants are chemicals added to vaccines to stimulate an immune response.

"IFA is a mineral oil that is not biodegradable by the body," says Overwijk. This was thought to be helpful in cancer vaccines because the longer the vaccine sticks around in the body, the greater the immune response and the more T-cells that can be produced, Overwijk says. But when mice were injected with an IFA vaccine against MELANOMA, the study reports that most of the T-cells in the bloodstream went to the site of the vaccine injection ‹ not the tumor.

"The body doesn't know how to deal with the mineral oil [in IFA], and the body cannot get rid of that big blob of vaccine ... that sits under the skin. The T-cells go back and try to kill the oil, but they can't," he says. When the oily IFA was replaced with water or saline ‹ substances easily processed by mice and men ‹ the T-cells migrated to the tumors and began to destroy them. If these results hold up in humans, they could lead to a shift in the approach to making therapeutic cancer vaccines because most clinical trials now are testing vaccines that use peptides and IFA. "This finding applies to all of those ‹ it's not limited to a certain cancer type," Overwijk says.

The results of this study confirm the findings of others in the field, and could be an important addition to cancer vaccine research, says Dr. Jeffery Weber, a tumor immunologist at the Moffitt Cancer Center in Tampa, Florida, who wasn't associated with the study. "Though, one word of caution is that obviously the skin and the subcutaneous tissue of a mouse is a lot different than in a human, so it's a little hard to extrapolate. But within the reasonable limits I have some confidence," Weber told Shots.

Overwijk and collaborators at the University of Virginia expect to start a human clinical trial using saline or water-based cancer vaccines sometime this year. But, he says, these non-IFA vaccines have problems, too. "While it is better than the IFA, we think water may actually be a little too ephemeral. Too short, and you don't get the activation of the immune system." Overwijk says. Another barrier is the difficulty in tracking human T-cells via biopsy ‹ a process that wasn't necessary in mice, where the cells could be fluorescently labeled.

Though there are plenty of unresolved issue in cancer vaccine research, Overwijk says that these results could be important for improving future clinical trials. It's "an eye-opener," he says, a kind of "'Aha!' moment after years of using these same vaccines."

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By Andrew Pollack

Celgene's drug Abraxane prolonged the lives of patients with advanced PANCREATIC CANCER by almost two months in a clinical trial, researchers reported, signifying an advance in treating a notorious difficult disease but not as big a leap as some doctors and investors had hoped.

"It was not the breakthrough we were anticipating," said Dr. Andrea Wang-Gillam, an assistant professor and pancreatic cancer specialist at Washington University in St Louis, who was not involve in the trial.

Still, Dr. Wang-Gillam and others said any progress was welcome against metastatic pancreatic cancer which has defied most treatments, with patients tending to live only about six months after diagnosis.

Pancreatic cancer is the fourth most common cause of cancer death, with 38,000 Americans expected to die this year, almost as many deaths as from BREAST CANCER, according to the American Cancer Society. Yet there are only 45,000 new cases of pancreatic cancer a year compared with more than 230,000 new breast cancer cases.

"This is a disease that gave oncology a bad name," said Dr. Robert Mayer, a professor at Harvard and the Dana-Farber Cancer Institute in Boston, who was not involved in the study. Now, he said, Abraxane, as well as another treatment combining four generic drugs, are showing some promise.

In Celgene's trial, patients who received Abraxane plus gemcitabine, the standard drug for pancreatic cancer, lived a median of 8.5 months, compared with 6.7 months for those who received gemcitabine alone.

At the end of one year, 35% of those getting Abraxane were alive, compared with 22% of those getting only gemcitabine. After two years, the figures were 9% for those getting Abraxane and 4% for those who received gemcitabine

The results of the study, which involved 861 patients, were released by Celgene and by the American Society of Clinical Oncology I advance of a presentation of the data at the Gastrointestinal Cancers Symposium in San Francisco.

The results were roughly in line with investors' expectations, according to a recent survey.

Abraxane is a novel form of the widely used cancer drug paclitaxel, also known by the brand name Taxol. In Abraxane the paclitaxel is bound to albumin, a human protein in tiny particles. That is said to enhance delivery of the drug to tumors and reduce side effects.

Abraxane was approve to treat advanced breast cancer in 2005 and to treat NON-SMALL-CELL LUNG CANCER in October. Sales the first nine months of 2012 were $320 million, a small percentage of Celgene's revenues of the $41 billion in that period, much of it from the MULTIPLE MYELOMA drug Revlimid.

A big impediment to future Abraxane sales in pancreatic cancer could be that its median survival was almost three months less than that of Folfirinox, a combination of four generic cancer drugs.

Results of a clinical trial published in 2011 showed that pancreatic cancer patients getting Folfirinox ha a median survival of 11.1 months compared with 68 months for those getting gemcitabine.

Experts cautioned that it was difficult to draw conclusions since Abraxane and Folfirinox were not compared directly in the same trial Nonetheless, doctors are going to make treatment decisions based on the separate results.

Abraxane, which Celgene says will cost $6,000 to $8,000 a month for pancreatic cancer patients, is likely to be more expensive than Folfirinox. However, Folfirinox is hard to tolerate and requires the patient to wear an infusion pump.

"The simplicity of Abraxane plus gemcitabine may be attractive to physicians and patients," said Dr. Neal J. Meropol chief of hematology and oncology at University Hospitals an Case Western Reserve University in Cleveland. Abraxane does cause low white blood cell counts and nerve damage.

How much of an extension of life is meaningful to patients is a matter of some debate, especially with cancer drugs costing thousands of dollars a month.

In 2005 the Food an Drug Administration approved Tarceva, now sold by Roche and Astellas, to treat pancreatic cancer. In a clinical trial, those who got Tarceva plus gemcitabine had a median survival only 12 days longer than those who received a placebo plus gemcitabine.

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By Ryan McBride

The FDA has opened the inside track to Novartis' experimental lung cancer drug, which gained "Breakthrough Therapy" designation that speeds the development and review schedules for new treatments. The Swiss drug giant plans to file for approval the drug, now in mid-stage clinical trials, in early 2014. Since clinical development began in 2011, the program has advanced with lightning speed compared with those that take 10 years or so to trial before submitted for approval.

While there are no guarantees of an FDA approval for Novartis' compound, code-named LDK378, the "breakthrough" tag provides an early nod to the potential of the candidate to improve treatment for patients with METASTATIC NON-SMALL CELL LUNG CANCER with anaplastic lymphoma kinase (ALK) mutations. The Novartis compound could offer another option for these patients whose cancer progresses despite treatment with Pfizer's approved drug Xalkori (crizotinib).

The "breakthrough" designation is also important because Novartis' compound and others with the coveted status have a shot to be approved by the FDA without completing all three phases of clinical trials typically required before an approval decision. The FDA began awarding the new status this year to promising treatments, including the experimental LYMPHOMA drug ibrutinib.

Novartis' LDK378 joined the "breakthrough" club after showing an 80% response rate in patients studied in Phase I trial of 88 subjects with advanced cases of ALK-positive NSCLC. The company has already begun a pair of Phase II studies of the compound for patients with the same kind of ALK-positive cancers, which account for about 3% to 8% of cases of NSCLC. Plans call for kicking off Phase III development of the new drug later this year.

Alessandro Riva, Novartis' global head of oncology development, said "This Breakthrough Therapy designation will allow us to collaborate more closely with the FDA and potentially to expedite the availability of an important new treatment option for patients with ALK+ NSCLC." Despite the small percentage of NSCLC patients with ALK mutations, pharma outfits are advancing multiple new drugs for this population.

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By Denise Grady

A treatment that genetically alters a patient's own immune cells to fight cancer has, for the first time, produce remissions in adults with an ACUTE LEUKEMIA that is usually lethal, researchers are reporting.

In one patient who was severely ill, all traces of leukemia vanished in eight days.

"We had hoped, but couldn't have predicted that the response would be so profound and rapid" said Dr Renier J. Brentjens, the first author of a new study of the therapy and a specialist in leukemia at Memorial Sloan-Kettering Cancer Center.

The treatment is experimental, has been used in only a small number of patients and did not work in all of them. But experts consider it a highly promising approach for a variety of malignancies, including other blood cancers and tumors in organs like the prostate gland.

The new study, in five adults with acute leukemia in whom CHEMOTHERAPY had failed, was published in the journal Science Translational Medicine.

The treatment is similar to one that pulled a 7-year-old girl, Emma Whitehead, from death's door into remission nearly a year ago, and that has had astounding success in several adults with chronic leukemia in whom chemotherapy had failed. The treatment regimen that save Emma and those adults was developed at the University of Pennsylvania. Related studies have also been done at the National Cancer Institute.

But this cell-therapy approach had not been tried before in adults with the disease that Emma had, ACUTE LYMPHOBLASTIC LEUEMIA. This type of blood cancer is worse in adults than in children, with a cure rate in adults of only about 40%, compared with 80% in children. The disease is not common. Each year in the United States, it affects about 2,400 people older than 20, and 3,600 younger. Though there are fewer cases in adults, there are more deaths: about 1,170 adults die each year compared with 270 deaths in people under 20.

In adults, this type of leukemia is a "devastating, galloping disease," said Dr. Michel Sadelain, the senior author of the new study and director of the Center for Cell Engineering an the Gene Transfer an Gene Expression Laboratory at Memorial Sloan-Kettering Cancer Center in Manhattan.

Patients like the ones in the study, who relapse after chemotherapy, usually have only a few months left, Dr. Sadelain said. But now, three of the five have been in remission for 5 to 24 months. Two others died: one was in remission but died from a blood clot, and the other relapsed. The survivors have gone on to have bone-marrow transplants. Their prognosis is good, but relapse is still possible, and only time will tell.

Experts not connected with the study said it was an important advance in an emerging field. Dr. Carl June of the University of Pennsylvania, who led the team that treated Emma and the other patients, said, "This is the first report showing some real, clinically beneficial activity in adult acute lymphoblastic leukemia." He said his team was also starting to test its version of the cell therapy on patients with the disease.

Dr. Richard M Stone, the program director for adult leukemia at the Dana-Farber Cancer Institute in Boston, called the research exciting an said he hoped to begin collaborating with the team at Sloan-Kettering. He has already sent them a patient.

The treatment uses patients' own T-cells, type of white blood cell that normally fights viruses and cancer. The patient's blood is run through a machine that extracts T-cells and returns the rest of the blood to the body. Researchers then do some genetic engineering: they use a disabled virus as a "vector" to carry new genetic material into the T-cells, which reprograms them to recognize an ill any cell that carries a particular protein on its surface.

The protein, called CD19, is found on B-cells, which are part of the immune system. This target was chosen because the patients ha a type of leukemia that affects B-cells, so the goal was to train the patients' T-cells to destroy B-cells. Healthy B-cells -- which make antibodies to fight infection -- would be killed along with cancerous ones but that side effect was treatable.

"We're creating living drugs," Dr. Sadelain, said. "It's an exciting story that's just beginning.

One of the sickest patients in the study was David Aponte, 58, who works on a sound crew for ABC News. In November 2011, what he thought was a bad case of tennis elbow turned out to be leukemia. He brace himself for a long, grueling regimen of chemotherapy.

His oncologist, Dr Brentjens, suggested that before starting the drugs, Mr. Aponte might want to have some of his T-cells removed and stored (chemotherapy would deplete them). That way, if he relapse, he might be able to enter a study using the cells. Mr. Aponte agreed.

At first, the chemotherapy worked, but by the summer of 2012, while he was still being treated, tests showed that the disease was back. "After everything I ha gone through, the chemo, losing hair, the sickness, it was absolutely devastating," Mr. Aponte recalled.

He joined the T-cell study. For a few days, nothing seemed to be happening. Then, his temperature began to rise. He has no memory of what took place during the next week or so, but the journal article -- where he is Patient 5 -- reports that his fever spiked to 105 degrees. He was in the throes of a "cytokine storm", meaning that the T-cells, in a furious battle with the cancer, were churning out enormous amounts of hormones called cytokines. Besides fever, the hormonal rush can make a patient's blood pr4essure plummet an his heart rate shoot up. Mr. Aponte was taken to intensive care and treated with steroids to quell the reaction.

Eight days later, his leukemia was gone. Even the doctors were shocked, Dr. Brentjens said. They repeated the lab tests just to make sure there was no mistake.

Once he was in remission, Mr. Aponte had a bone-marrow transplant, as did three of the other patients in the study. Another had medical problems that made a transplant impossible and it was he who relapsed an died. The researchers think he may have relapsed because the steroids he needed to treat the cytokine storm may have wipe out the T-cells before they could do their job.

For the other patients, it is not known whether the transplants were really needed; in theory, the T-cells alone might have produce a long-term remission or even a cure. Patients treated at the University of Pennsylvania were not given transplants, and most have stayed in remission. But the technique used there involves a different viral vector an different genetic programming from the one at Sloan-Kettering.

In any case, Dr. Brentjens said, the T-Cells are still experimental, whereas transplants are the standard of care in acute leukemia because they have been shown to give many patients the best odds of survival. So the transplants were one for ethical reasons. The study is continuing, an as ore patients are treated, answers may emerge as to whether the T-cells alone will be enough for some patients.

Mr. Aponte, who had the transplant in December, is still recovering, and trying to gain back some of the 40 pounds he lost while he was ill. But he hopes to return to work soon.

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Until May ...

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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