Monday, April 29, 2013

Dogs help fight sarcoma in humans

By Suzie Siegel

Dr. Stephen Withrow
By treating dogs with cancer, veterinarians gain important insights into improving treatments for humans.

This has special significance for people with sarcoma because "sarcoma is five times more common in dogs than humans," said Stephen Withrow, DVM, professor of surgical oncology at Colorado State University in Fort Collins and the founding director of its Flint Animal Cancer Center, the largest such center in the world.

The many sarcoma subtypes diagnosed in people are well represented in dogs, said Christina Mazcko, a biologist who manages the National Cancer Institute's Comparative Oncology Program. The subtypes include osteosarcoma, chondrosarcoma, synovial sarcoma, leiomyosarcoma, gastrointestinal stromal tumor (GIST), hemangiosarcoma (angiosarcoma) and other soft-tissue sarcomas.

Dr. Withrow is the only veterinarian admitted as a member of the Musculoskeletal Tumor Society. The surgeon also belongs to the Children’s Oncology Group. He's proud that he has served as a resource for surgeons who operate on humans.

"Physicians are not always aware of what's happening in animal studies, but some have realized we see more sarcoma cases than they do."

Colorado State's veterinary school is one of 20 across the United States and Canada that work with the NCI in the Comparative Oncology Trial Consortium, said Dr. Withrow, past president of the Veterinary Cancer Society.

"We can do so much more together than we can as single institutions."

Nine clinical trials have been completed, and two are underway. More than 150 pet owners have participated, and board-certified veterinary oncologists supervise the dogs' care. What veterinarians learn is then integrated into studies of cancer biology and therapy in humans, Mazcko said.

"Along the way, the dog has helped with imaging; the safety and efficacy of chemo delivery; radiation dose responses; and giving chemo in arteries," Dr. Withrow said. 

Treating dogs with cancer also has been useful in discovering what doesn't work or doesn't work as well as hoped, he said. "We proved hyperthermia had only mild improvement in local control.

"Fighting sarcoma is like slogging through mud. It's not a sprint. There are no home-runs but we've made progress.

"A major breakthrough in osteosarcoma was MTP-PE [mifamurtide], an immunotherapy popularized by a vet." Half of the dogs who received it benefited, but when it was tested in humans, only 15 percent got a response. "The drug was sold to a company in Europe, and it's no longer available in the U.S." He calls the stalemate between pharmaceutical companies and the FDA "sick."

"For pharmaceutical companies, the target is humans, where they can charge these inordinate prices." In general, people won't pay as much to treat their dogs. Plus, companies fear that, if they test their drugs in dogs first and side effects occur, the companies will have a harder time getting approval for clinical trials for humans.  

Clinical trials for dogs cost less money and give quicker results than those in humans, Dr. Withrow said. "It's money well spent."      

"Of the estimated 72 million dogs in the United States, up to 1 million are diagnosed with cancer each year," Mazcko said. Mice are commonly used to study cancer, and they are inbred to develop tumors. They are injected with cancer cells grown in the lab. In contrast, veterinarians are studying cancers that occur naturally in dogs and that "are very similar to those seen in human patients."

The strong genetic similarity has been demonstrated by the recent completion of the canine genome (the entire set of genetic material in dogs) and the increasing availability of biological and genomic reagents (substances used in a chemical reaction to analyze other substances), she said.

Like people, dogs experience recurrence, resistance and metastasis, she said. Dogs and humans are exposed to similar environmental risks. Dogs are large enough that their imaging studies can be compared to those of humans, and dogs can often tolerate multiple forms of treatment, such as chemotherapy and radiation.

When their cancers have not grown much or spread far, dogs can get experimental treatments not yet approved for humans -- even though the new drugs may be less harsh than conventional chemotherapy, she said. 

"Although the treatment options and approaches are comparable in dogs and humans, there is no requirement to pursue standard treatments as a first-line option for dogs."

This gives researchers a chance to answer questions about the drugs that could not be answered in conventional mouse studies or human clinical trials, Mazcko said.

In the 1970s, veterinarians had only crude treatments for animals with cancer, Dr Withrow said. In the next decade, vets began using imaging studies and treatments also used on humans.

In the mid-1980s, Colorado State partnered with the veterinary school at North Carolina State University and biostatisticians at Duke's cancer center. The National Cancer Institute awarded them a prestigious program-project grant to do clinical trials, and the funding continued for about 15 years, he said.

This partnership pioneered the idea that clinical trials in veterinary medicine would provide better information for cancer treatment in humans than mouse models, he said.

Dr. Chand Khanna
"It really was Khanna's brain child," he said, referring to Chand Khanna, DVM, PhD, now director of the Comparative Oncology Programwhich the NCI's Center for Cancer Research created in 2003. He also heads the Tumor and Metastasis Biology Section of the NCI's Pediatric Oncology Branch. "Fortunately, his boss was Lee Helman," who supported his work. 

About 10 years ago, federal grant money started drying up, and the vets doing the research had to look for money from  pharmaceutical companies, others health-care companies, foundations and nonprofits. It was a terrible blow, Dr. Withrow said.

"The Comparative Oncology Trial Consortium is limited only by funding. Great science is all around us."

Information on COTC clinical trials is available at:

Monday, April 22, 2013

Making sense of the palifosfamide failure

By Suzie Siegel

Sarcoma specialists mourn the loss of palifosfamide, a promising new drug that could have improved the quality of life for their patients.

Dr. Gina D'Amato
"It is such a shame that a great drug will not be approved," said Alliance board member Gina D'Amato, MD, a sarcoma medical oncologist at Georgia Cancer Specialists in Atlanta.

Ziopharm has reported that palifosfamide in combination with doxorubicin didn't show any significant difference from doxorubicin alone in a phase 3 clinical trial called PICASSO. Because FDA approval now appears impossible, the company has said it will no longer study its drug in sarcoma patients.

Dr. Charles Forscher
Soft-tissue sarcoma patients have gotten the chemotherapy drug ifosfamide for years, often combined with doxorubicin (also known by its brand name Adriamycin). Palifosfamide was developed to be as effective as ifosfamide, but not as toxic. 

In the randomized PICASSO trial, doctors didn't know if they were giving patients palifosfamide or a placebo, said Charles Forscher, MD, medical director of Cedars-Sinai Medical Center's sarcoma program in Los Angeles.

Dr. Scott Schuetze
Sometimes side effects give clues as to which patients are getting which drugs. But palifosfamide caused so few side effects that doctors couldn't tell which patients got that drug and which got saline injections, said Scott Schuetze, MD, PhD, Director of the Connective Tissue Oncology Program and medical director of the Clinical Trials Office of the University of Michigan Comprehensive Cancer Center in Ann Arbor.  

He and other sarcoma oncologists say they await the full study results.

Dr. Robin Jones
"The provisional results ... add to the evidence that doxorubicin alone could be considered standard systemic treatment for metastatic soft tissue sarcoma," said Robin Jones, MD, who directs the Gilman Sarcoma Research Program at the Fred Hutchinson Cancer Research Center in Seattle.

Last year, he said, a "European trial of doxorubicin versus doxorubicin and ifosfamide showed NO significant difference in overall survival. However, the combination of doxorubicin and ifosfamide had significantly longer progression-free survival and higher response rate compared to doxorubicin alone."

Dr. Robert Maki
Robert Maki, MD, PhD, medical director of the sarcoma program at Mount Sinai Medical Center in New York City, said an earlier,  smaller study of palifosfamide + doxorubicin showed a clear benefit, and the larger PICASSO trial was expected to do the same.

"With the failure of palifosfamide in this study, we continue to have no other option than to use ifosfamide, which causes significant side effects affecting the brain, kidney, bladder, and bone marrow," Dr. Maki said. "These side effects of ifosfamide appear to be worse in people over age 60."

Dr. D'Amato said: "This study was designed to show that doxorubicin + palifosfamide would improve the PFS [progression-free survival] by three months compared to doxorubicin. This is very difficult to do. Of course, hindsight is 20/20. They probably should have compared doxorubicin + ifosfamide vs. doxorubicin + palifosfamide and the endpoint should have been noninferiority, tolerability, Quality of Life (QoL). However, I suspect that the FDA encouraged the company to do the trial as the current design and not the latter."

"An even more ambitious design could have involved three randomized arms: doxorubicin + ifosfamide vs  doxorubicin + palifosfamide vs doxorubicin," Dr. Jones said.

It also should have focused on subtypes of sarcoma that had shown response in previous studies, he said.

Another alkylating agent like ifosfamide, TH-302 (glufosfamide), is in clinical trials now, and it also is less toxic than ifosfamide, Dr. Maki said.

"The trial is still enrolling patients," said Dr. D'Amato, "so it will take some time before we have any answers as to whether TH-302 has a chance to be approved."

"We can still hold out hope for TH-302," Dr. Jones added.