Why everyone should care about this uncommon disease

By Beverly A. Caley

“Sarcomas are basically cancers of the things that hold the body together.” George Demetri, MD, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston, adds that this includes cancers of muscles, blood vessels, bones, nerves, fat—“the infrastructure of the body.”

Sarcomas are a diverse group of diseases that are subclassified according to the type of normal cell they most closely resemble, the most common of which are those that occur in soft tissue and those that occur in bone. Sarcomas range from the “very curable” to the “more complicated,” says Dr. Demetri. It’s a bitter irony for some that despite the fact that sarcomas are being intensively studied, they may often go unrecognized in local physicians’ offices and therefore untreated at the most optimum time—early.

In 2004, more than 10,000 new soft tissue and bone sarcomas will be diagnosed in the United States, and about 5,000 people will die of sarcomas.
Indeed, sarcomas were some of the first cancers to show beneficial effects of Adriamycin^® (doxorubicin), but most physicians outside large specialty referral centers rarely see a sarcoma patient, meaning it may be challenging to keep up on the latest advances in diagnosis, treatment and strategies for optimal follow-up.

Jon Danos’ experience with Ewing’s sarcoma, a type of bone cancer, represents the curable end of the range. Two years out of college in 1992, Danos began having severe chest pain that his doctor first attributed to a muscle problem. Before long, though, Danos could feel a lump on his rib. Chemotherapy followed surgery to remove the tumor. Today, he is married with three children and has been sarcoma-free since surgery.

Marny Tobin’s experience with liposarcoma, cancer of the fat cells, represents the more challenging side of sarcoma. In 1998, at the age of 33, she remarried and moved with her daughter and new husband from Seattle to New York. The weeks after the move were filled with exhaustion and weight loss due to severe heartburn that made it difficult to eat. Yet she noticed fat accumulating around her midsection. She had surgery to remove the more than 5-pound tumor that proved to be a liposarcoma. About a year later, the tumor recurred and another tumor had to be removed along with parts of her intestines.

In December 2002, Tobin’s doctors found a third tumor. Her doctor told her that every time they operate in the same area, it becomes more difficult and dangerous because of accumulated scar tissue. “Realistically, they don’t think I can survive many more surgeries, maybe one or two more,” Tobin says. Today she is living with a recurrent tumor and considering her future treatment options.

Under-Diagnosis Common

Jody Cummings, MPH, executive director of the Sarcoma Foundation of America, says his work with patients has led him to believe that under-recognition and delayed diagnosis of sarcoma is frequent because it is so low on the list of possible causes for a patient’s problems.

Cummings, a survivor of a malignant peripheral nerve sheath tumor above his elbow, had initial symptoms that included a feeling similar to electric shock down his arm. He consulted a neurologist, an internist and an orthopedist, but none identified the sarcoma.

Cummings was treated with physical therapy to try to trick the arm into not reacting to every stimuli. “Then the bump started to grow before my very eyes,” Cummings recalls. The orthopedist recommended surgery, but, not suspecting cancer, he sewed the cancerous nerve back together after removing the lump, Cummings says. No one looked at the pathology report until Cummings asked for it at his two-week follow-up visit, which was when it was discovered he had cancer.

He consulted a surgeon with experience in sarcoma, had a second surgery to remove a wider area and underwent six weeks of radiation treatment. He has not had a recurrence.

Test-First, Cut Second

According to Robert Mennel, MD, associate chief of medical oncology at Baylor University Medical Center in Dallas, most lumps and masses noticed by patients in a primary care practice are benign tumors that surgeons remove with no problem. However, when a mass is actually a sarcoma, poorly planned surgery can contaminate the compartments, the anatomical areas where the sarcomas are located, Dr. Mennel says, making it crucial that the compartments be cleared in the initial surgery.

To do this, a surgeon needs to keep sarcoma on the list of possible diagnoses for any mass. If compartments are contaminated in the process of removing a sarcoma, any subsequent surgeries will have to remove a larger area (and have more risk of causing disability) than if the tumor had been properly identified and the course of treatment had been thoughtfully prepared before any surgery.

Neillie Kirk, 22, has been treated for five desmoid tumors, a tumor of the tissue type that is ordinarily responsible for healing wounds. With the first one, a lump on her hip, she had no symptoms, but within a short time the lump had grown so large that she couldn’t pull her pants up. She had an MRI, but doctors couldn’t identify the lump.

“That was a Tuesday and by Friday I was in an operating room and they were taking it out,” Kirk remembers. She had the surgery at a local hospital by a surgeon unfamiliar with treating sarcoma. No cancer was found in the areas surrounding the tumor, so her doctor decided it was “some kind of a fluke thing and left it at that,” she says.

Exactly one year later, three more tumors developed in the same hip. This time, Kirk sought treatment from an experienced team. The tumors were removed, along with the surrounding muscle, leaving Kirk “the bare minimum in my leg to allow me to walk.” She developed a staph infection, and a week later a hole was drilled near her knee to drain infected fluid. She also had seven weeks of radiation treatment.

In March 2003, an MRI technician mistakenly imaged Kirk’s entire leg instead of just her hip area, a mistake that proved to be serendipitous because the MRI showed that another mass had appeared near the knee at the place the hole had been drilled. The mass was removed, and her December 2003 MRI was completely clear.

Identifying the Tumor

Experts agree that surgery for sarcoma must be carefully planned, which means the diagnosis must be suspected and, usually, confirmed before surgery.

Some of the tests commonly used to examine an undefined lump include ultrasound, which images the mass using sound waves; computed tomography (CT scan), a series of detailed pictures taken from different angles by an X-ray machine linked to a computer; magnetic resonance imaging (MRI), which uses magnetic fields instead of ionizing radiation and can show cross-sectional views in several different directions; and angiography, an X-ray of blood vessels that involves injecting dye into an artery.

Dr. Mennel warns that if a lump is causing significant pain or is growing very quickly, it should not be approached as a benign lesion. Even if these red flags are not present, he recommends that if a doctor decides not to perform a biopsy prior to surgery, patients should ask why. In some cases a biopsy is not necessary, Dr. Mennel acknowledges, but if the physician has any question about whether a mass is a sarcoma, the reasonable course is to biopsy it first, so that any subsequent surgery can be planned appropriately.

Dr. Demetri adds that even the biopsy must be carefully planned and implemented, since biopsies oriented the wrong way can cause problems for subsequent definitive surgery of a sarcoma.

It is also very important, says Dr. Mennel, to make sure the lungs are imaged in addition to the area around the tumor, because that is where many sarcomas are prone to metastasize (spread).

The National Cancer Institute recommends that all soft tissue lumps that persist or grow should be biopsied, because it’s the only reliable way to determine if the lump is sarcoma.

A simple outpatient biopsy called fine-needle aspiration is commonly performed for other forms of cancer, but the thin needle sometimes cannot remove enough tissue for pathologists to make a definitive diagnosis of sarcoma.

A core needle biopsy, also an outpatient procedure, uses a somewhat larger needle and usually removes enough tissue to allow expert pathologists to determine the type and grade of a tumor. Finally, for some patients with easily accessible tumors, such as a mass on the top of the thigh, it may make the most sense for a surgeon to do a conventional outpatient biopsy using a scalpel after numbing the area in and around the suspicious lump.

The experts agree that if a biopsy suggests a lump is a sarcoma, it is best for the patient to be evaluated by a multidisciplinary team at a major hospital with a department that specializes in sarcomas.

Choosing Treatment

Surgery remains the major treatment for a patient who presents for the first time with a sarcoma that has not spread. Dr. Mennel cautions that it is vitally important to get clean wide margins during the first surgery, meaning the border of the tissue removed does not contain cancer cells. Otherwise, “the chance of curing somebody of the sarcoma is lessened.”

While size of the tumor is the most important factor in determining appropriate treatment for many cancers, when dealing with soft tissue sarcoma, how “normal” (or well differentiated) the sarcoma cells look under the microscope becomes an important marker of how the cancer might behave.

Well-differentiated tumor cells more closely resemble normal cells, and they are easily identified when a pathologist looks at them under a microscope. For example, the pathologist might say with certainty that a tumor strongly resembles a type of smooth muscle tissue. If the pathologist cannot tell exactly what kind of sarcoma is present, the cells are termed “undifferentiated” and the tumor is called a high-grade sarcoma, meaning they are more likely to metastasize and recur quickly.

Other factors that influence treatment decisions include the extent of disease (localized versus metastatic) and tumor location (either close to the surface of the body or deep within the tissue). Sarcomas located in the superficial parts of the arm or leg are easier to remove surgically than those located deep within the abdomen or pelvis.

In Cumming’s case, exact tumor size and location of his peripheral nerve sheath tumor were not known since it had already been removed by the first surgeon. The treatment advice he received ranged from amputation to doing nothing because “everything will be fine.” With such a range of opinions, the experience of other sarcoma survivors helped Cummings decide on a course of action.

In most cases of adult soft tissue sarcoma, where the tumor cells are well differentiated or moderately differentiated, the treatment options are surgery alone or surgery with radiation therapy, given either before or after the surgery. Radiation decreases the risk of local recurrence of sarcomas but does not affect the risk for the tumor to metastasize. In cases where the cells are poorly differentiated or undifferentiated, some patients may receive chemotherapy in addition to surgery and/or radiation. If the cancer has metastasized, chemotherapy may be useful as the first treatment approach, followed by removal of all sites of disease, possibly followed by radiation therapy.

Chemotherapy

According to Dr. Mennel, there is a clear-cut role for chemotherapy in treating Ewing’s sarcoma, rhabdomyosarcoma, osteogenic sarcoma and gastrointestinal stromal tumor (GIST, see sidebar). He says that in other types of soft tissue sarcoma, such as smooth muscle tumors, fatty tumors, fibrous tissue tumors and large high-grade soft tissue tumors, the role of chemotherapy is much more debatable as is whether to give chemotherapy before surgery to shrink the tumor or after surgery to eradicate remaining cancer cells.

Adriamycin^®, Ifex^® (ifosfamide) and DTIC-Dome^® (dacarbazine) are the drugs most often used to treat soft tissue sarcoma. There is evidence that Gemzar^® (gemcitabine) may be helpful in several kinds of soft tissue sarcoma in combination with Taxotere^® (docetaxel), says Robert Maki, MD, co-director of the sarcoma program at Memorial Sloan-Kettering Cancer Center in New York. Current studies are comparing how effective the two drugs are in combination compared with Gemzar alone.

These chemotherapy drugs can cause severe side effects, which was the main factor in Tobin’s decision to forego chemotherapy treatment for now. She has been treated with Cytoxan^® (cyclophosphamide), which was not effective for her, and then with Gemzar, which stopped the tumor’s growth for about nine months. Her doctors recommended that she begin therapy with Adriamycin, but “I felt very strongly that I didn’t want to take the drug because I didn’t want to feel sick,” she says.

Researchers are hard at work to reduce the toxicity of chemotherapy and prolong patients’ lives, especially for metastatic sarcoma. “It is very much an incremental process,” Dr. Maki says, as a variety of drugs must be studied in different combinations and at different doses.

One new drug being tested for the treatment of sarcoma is Yondelis^® (ET-743), which in early studies shrank tumors in about 10 percent of previously treated patients. “These were tumors that had already been treated with standard chemotherapy, which could no longer be given or was no longer working,” says Dr. Demetri, adding, “A 10 percent rate may not seem like a lot, but if you are the one who responds to the drug, it’s 100 percent effective for you. We were also struck by the cessation of tumor growth in patients.” ET-743 stopped tumor progression, sometimes for many months, in nearly 20 percent of patients.

ET-743 can temporarily irritate the liver, and it has side effects similar to those of conventional chemotherapy drugs. However, “it doesn’t make people lose their hair, people generally feel reasonably well and the quality of life is pretty good,” Dr. Demetri says. “We’ve been quite pleased, and—more importantly—our patients have been very pleased, with the tolerability.”

Dr. Maki reports that a new drug known as SU11248 has been promising in very early studies of a variety of cancers, including GIST. This drug works by cutting off tumor blood vessel growth, which may help people live longer even though the tumor remains.

Immunotherapy

Immunotherapy, an experimental approach to sarcoma treatment, is a general term for any method of producing immunity to a disease or enhancing the immune system’s resistance. With cancer, the big issue is that the body probably recognizes the tumor more as part of itself than as something that is foreign, Dr. Maki explains. “The idea is to teach the immune system to attack the tumor cells and not attack normal cells.

“There’s been a search on for a long time for particular proteins that you would find only on cancer cells, not on normal cells, because then it would be safe to vaccinate against those,” he continues, referring to the potential for a therapeutic vaccine (not the more familiar kind that protects against infectious disease).

Recently, he says, scientists have identified a group of proteins called “cancer-germ cell” antigens, which are found only on tumors and on the testes or ovaries. The thinking is that a vaccine could be developed that would stimulate the immune system to attack tumors by homing in on these proteins on tumors, leaving vital organs such as the heart, kidney, liver and lungs unaffected. Researchers are just beginning to study whether such vaccinations will actually jumpstart the immune system and whether the immune system response, if any, will translate into prolonged survival.

Risk Factors for Sarcoma

Certain family syndromes predispose individuals to sarcoma, but these are very rare. In the vast majority of cases, the children of people with sarcoma are not at increased risk of developing the disease.

Something that does increase the risk of hereditary sarcoma is a mutation in a gene called p53. Normally, p53 helps regulate cell division, and when it is mutated, the individual is apt to develop sarcoma, breast cancer, leukemia and/or a rare tumor called adrenal cortical carcinoma, says Dr. Maki. The mutation can be passed along from one generation to another.

“If you find three people in a family with the same sort of cancer occurring, typically at an early age, you should be highly suspicious of a genetic event,” Dr. Maki says. He advises such families seek genetic counseling.

A Model for Other Cancers

The amount of basic research into sarcoma is relatively disproportionate to the number of cases, Dr. Demetri says, because sarcoma is a good model for the study of other cancers. Most sarcomas are simpler to examine than common solid tumors of the breast, prostate or lung, he notes, in that sarcomas often have less complex disorder of the genetic material in the chromosomes of the tumor cells.

In fact, many sarcomas have highly specific rearrangements of genes within chromosomes, and these are giving important clues as to what is wrong with the tumor cells and how new therapies might be developed to fix them. Dr. Maki says that in less than one-fourth of patients, “the sarcoma is based on just two chromosomes breaking apart and coming together again.” He adds that over the past 20 years, researchers have identified the exact genes that break apart in 12-15 different types of sarcoma. Dr. Mennel says knowledge of the genes involved can help identify the type of tumor and can suggest what treatment will be best. In addition, better knowledge of genetic translocations is helping researchers develop new treatments.

But Dr. Mennel cautions that progress in treating sarcoma may not be rapid, since the tumors are uncommon and the various types of sarcomas are very different from each other. But with more attention focused on this rare disease, proper diagnosis and appropriate treatment from the onset can become increasingly better.