Tuesday, April 2, 2013

Cure Today Magazine: Treatment Advances in Sarcoma

Bookmarking this article from CureToday magazine. Hopefully, more and more advances in Sarcoma treatments will be available soon.

Here's a link to the article. And posting the full text below (mainly for me to re-read in the future):

Group Therapy: Treatment Advances in Sarcoma

Soft tissue sarcoma has benefited from research in other cancers.

In 1991, 34-year-old Gina Lamons received a diagnosis of synovial sarcoma and was told that the prognosis for survival was five years. By 1994, her disease had metastasized to her chest and lungs. Now 56, Lamons has long outlived her initial prognosis and the statistical odds due to multiple surgeries, numerous rounds of chemotherapy and radiation, and participation in a clinical trial.

 Print this Article

 E-mail to a Friend

 Order a Reprint

After decades of dealing with metastatic disease, Lamons’ options have become increasingly limited. She completed seven cycles of a 14-day continuous infusion of ifosfamide in July 2012 and was then placed on Votrient (pazopanib) that August. Initially approved for kidney cancer, Votrient blocks the growth of blood vessels to the tumor, as well as certain proteins that promote cancer cell development, and is the only new drug approved for treating sarcoma in years.

In her first follow-up scan in November 2012, none of Lamons’ existing tumors had grown and no new ones had appeared. The scan report also noted there was a decrease in one of the metastatic

Gina Lamons has been dealing with sarcoma for more than two decades. Photo by Rob Snavely.

The Road to Diagnosis

Sarcomas are a diverse group of cancers that arise in the body’s supportive tissues, including bone, cartilage, fat, muscle and blood vessels. With roughly 14,000 new cases diagnosed each year, sarcomas are rare, accounting for approximately 1 percent of all cancers in adults. These tumors can be broadly divided into bone and soft tissue varieties, with soft tissue sarcomas (STS) further divided into more than 50 subtypes that get their names from the tissue of origin. Liposarcomas, for example, have malignant fat cells, and leiomyosarcomas have cancerous smooth muscle cells.

Although most cases have no known cause, the risk of developing certain sarcomas is slightly higher in people who have received radiation for other forms of cancer. Certain STS subtypes are also more prevalent in people with genetic disorders caused by mutations in genes that affect cell growth and death. For example, people with Li-Fraumeni syndrome, a rare disorder caused by mutations in the TP53 gene, have a greater incidence of STS along with several other malignancies. In addition, non-inheritable (acquired) mutations in the c-kit gene have been associated with a rare type of STS called gastrointestinal stromal tumor (GIST). These mutations provide clues to the causes of these rare cancers that can lead to better therapies in the future. As the most common early symptom of STS is a painless mass, patients are often unconcerned and delay seeking treatment. As a result, these tumors can grow very large or even metastasize by the time they’re diagnosed. Lamons’ initial symptom—pain in her right thigh—was unusual for STS. An initial X-ray revealed nothing. Physical therapy and pain relief efforts didn’t help. Eventually a lump appeared, and a magnetic resonance imaging (MRI) scan revealed a 6-centimeter mass.

In some cases, a close look at the tumor’s genetics can help clinch the diagnosis. Certain types of STS, including synovial sarcoma and rhabdomyosarcoma, often carry telltale abnormalities called translocations, genetic mix-ups that occur when pieces of one chromosome break off and fuse to another. As a result, rogue proteins can be formed that fuel uncontrolled cell growth.

Growth pathways that are activated as a result of translocations and mutations have revealed promising drug targets, many of which have been successfully disrupted in other types of cancer. However, tests to detect these genetic traits are not routinely performed, primarily because the cost is often not covered by insurance but also because genetic factors account for only a small percentage of cancers. Lamons’ tumor was tested in 2005 and did not demonstrate a translocation.

Evolution of Therapy

Initially, Lamons’ tumor was localized, and her surgeon was confident that he had removed the entire tumor with clean margins, sparing her from chemotherapy. “My diagnosis kind of went over my head,” she recalls. “I didn’t understand the gravity of it at the time. I just knew I didn’t want chemo because during that time I always heard about people dying from the treatment.”

Like Lamons, most patients with localized disease are treated with surgery, often in combination with radiation, an approach that results in an overall five-year survival rate of 50 to 60 percent. Some institutions also add adjuvant (post-surgery) chemotherapy to eliminate cancer cells that may have escaped into the bloodstream. But it’s debatable whether the benefits of chemotherapy in this setting outweigh the risks, as clinical trials have shown little, if any, effect.

My diagnosis kind of went over my head. I didn't understand the gravity of it at the time.

—Gina Lamons

Patients with metastatic STS who can’t be treated with surgery receive radiation or chemotherapy, and the go-to drugs are doxorubicin and ifosfamide. Other agents may prove more effective for certain STS subtypes though they are not curative for metastatic disease. New approaches and drugs are clearly needed, as these patients have a median overall survival of only about eight to 12 months, although this varies widely.

Lamons didn’t avoid chemotherapy for long. She developed a cough in 1994, and an X-ray showed a large mass in her mediastinum along with nodules in both lungs. After surgery to remove the lung masses, she received six cycles of the MAID (mesna, doxorubicin [Adriamycin], ifosfamide, dacarbazine) chemotherapy regimen, which she says was the most challenging of her treatments to date. Three years later, more lung masses appeared and were surgically removed followed by ifosfamide, which Lamons tolerated better, apart from extreme fatigue and nausea. “There were days that I couldn’t even lift my head off the pillow,” she recalls.

Efforts are under way to test new chemotherapy drugs as well as new versions and different combinations of existing ones. One example is palifosfamide, a new and presumably less toxic derivative of ifosfamide, which improved progression-free survival by more than three months in patients with metastatic STS when used as first-line and second-line therapy in combination with doxorubicin. But Kristy Weber, an oncologist who directs the Johns Hopkins Sarcoma Center in Baltimore, describes these new regimens as “tweaks” rather than big changes.

A promising new chemotherapy agent, TH-302, appears beneficial in early studies of patients with advanced STS. It hones in on the low-oxygen region at the center of tumors. “Most chemotherapy drugs can only get into the periphery of the tumor because that’s where the blood vessels [and thus oxygen] are,” explains Richard Riedel, an oncologist who is associate director of clinical research for the Duke Sarcoma Research Program at Duke Cancer Institute in Durham, N.C., where he leads a TH-302 trial.

[Find clinical trials in soft-tissue sarcoma]

Researchers believe another drug, Halaven (eribulin mesylate), already approved for breast cancer, jams up the cell’s division machinery in patients with certain STS subtypes. Both TH-302 and Halaven are currently being tested in large, international phase 3 trials; Riedel estimates that preliminary results for TH-302 will be available by mid-2014.

The DNA-damaging agent trabectedin is approved in many European countries for patients with advanced STS. The drug is still being tested in the U.S., but phase 2 trials showed some benefit, particularly in those with liposarcomas and leiomyosarcomas. Trabectedin is also being tested as a front-line treatment in comparison to doxorubicin in all patients with translocation-related, advanced STS and to dacarbazine in those with liposarcomas and leiomyosarcomas.

Surgical advances are not going to cure more people. At the end of the day, if we don't have better drugs, we're not going to make progress.

—Kristy Weber

Letting the Tumor Lead the Way

For many years, the repertoire of drugs used to treat sarcoma was notably lacking targeted agents, drugs that block the growth of cancer cells by targeting specific molecules that promote cell growth and survival. But things began to change in 2002, when the targeted drug Gleevec (imatinib), was approved for patients who have GIST and a c-kit gene mutation.

Gleevec is primarily used to treat chronic myeloid leukemia, where it works by inhibiting an enzyme activated by the mutant BCR-ABL gene. In GIST, Gleevec inhibits the similar c-kit enzyme that is activated in more than 80 percent of GIST tumors. “For the first time ever, we had an outstanding response in STS,” says Katherine Thornton, an oncologist at Johns Hopkins, “and this tipped off a whole new interest in studying sarcoma and targeted therapy.”

Four years later, the Food and Drug Administration (FDA) approved a related drug, Sutent (sunitinib), for patients with GIST who failed to respond to Gleevec. In general, however, Gleevec and Sutent work poorly against other subtypes of STS. Lamons was treated with Gleevec in 2002 as a maintenance strategy, and her lung masses remained small and amenable to surgery for several years. But such “off-label” use often requires lengthy negotiations with insurance companies to cover the cost of these drugs, which haven’t yet passed the rigorous efficacy and safety tests required for an FDA approval in that indication.

After her cancer progressed in 2011, Gina Lamons switched to Votrient, a recently approved drug that inhibits blood vessel growth to the tumor. Photo by Rob Snavely.

By 2011, Lamons’ cancer had progressed further, and she had multiple nodules in her neck, requiring still more radiation and chemotherapy. Years of treatment had taken a toll on her body, and she needed a new approach. Fortunately, in April 2012, Votrient (pazopanib) was approved for treating her type of advanced STS, and her doctor suggested she try it. Votrient blocks the growth of blood vessels to the tumor by inhibiting the activation of the vascular endothelial growth factor (VEGF) receptor. Although she tolerated it well, her dose was reduced after she developed high blood pressure, a common side effect of the drug, and experienced frequent low white blood cell counts.

Other types of targeted agents being tested against advanced STS and bone sarcomas include Rapamune (sirolimus), Afinitor (everolimus) and Torisel (temsirolimus), all of which target a growth-promoting protein called mTOR. Avastin (bevacizumab), another VEGF receptor inhibitor, seems to work well in patients with angiosarcoma.

Some of the most promising drugs for STS block the insulin-like growth factor 1 (IGF1) receptor, which is activated in rhabdomyosarcomas and leiomyosarcomas. Unfortunately, many drug companies pulled back on development of anti-IGF1 agents (such as figitumumab) when larger clinical trials showed that they weren’t as effective in more prevalent cancers, such as breast and lung. “Even if they sold the drug to every kid with rhabdomyosarcoma on the planet, it wouldn’t budge their balance sheet,” says Paul Meyers, a pediatric oncologist specializing in sarcoma at Memorial Sloan-Kettering Cancer Center in New York. Indeed, the rarity of STS, as well as other rare or “orphan” cancers, means that it’s also a lower priority for funding agencies. “Even if we found a target and an agent that attacks that target, we fear that we would never attract the kind of resources needed to take that drug from pre-clinical testing all the way to an indication from the FDA,” Meyers says, noting the extraordinary expense of this process. The FDA is actively addressing this issue by funding clinical research on drugs used to treat orphan diseases and providing drug companies with financial incentives for the development of these agents.

Despite the considerable challenges, Meyers sees targeted drugs as the future of sarcoma therapy. “I think each one of these diseases is going to have a different point of attack,” he says, which will be revealed by the unique biology of each tumor.

Having battled recurrent disease for more than two decades, Lamons has witnessed the evolution of sarcoma therapy first-hand. She recalls thinking, “If only I can survive a little longer, perhaps there will be advancements in treatment where I can just take a pill. And, eventually, there was!” she says of Votrient. Lamons stays focused on the positive, hoping that Votrient will continue to work and that further advances in sarcoma treatment will stay one step ahead of her disease.