An experimental targeted drug could treat a rare type of cancer usually affecting the limbs


An experimental targeted drug could treat a rare type of cancer usually affecting the limbs, a clinical trial led by The Institute of Cancer Research, London, has shown.

The important trial could lead to a much-needed new treatment for patients with alveolar soft part sarcoma (ASPS), which tends to affect younger adults and does not respond well to existing treatments.

In the trial, a team led by The Institute of Cancer Research (ICR) researchers tested whether cediranib, which blocks blood vessel growth, was an effective treatment for ASPS.

8 percent reduction in tumor size

Some 48 patients from 10 hospitals across the UK, Spain and Australia took part in the phase II trial, called CASPS. The results were published in The Lancet Oncology.

The trial was funded by a range of sources including Cancer Research UK and the company AstraZeneca, which owns the rights to develop cediranib (brand name Recentin).

Patients in whom the disease had already spread to other parts of the body, and had recently progressed, were allocated to receive either cediranib or placebo for 24 weeks.

To measure whether cediranib was giving benefit to the patients, the researchers analyzed the change in the sum of diameters of selected tumors which had spread from the original site.

In the measurements of selected tumor size, patients taking cediranib had an average reduction of eight percent after 24 weeks, compared with an average increase of 13 percent for patients taking placebo.

Cediranib has a ‘significant clinical benefit’

Trial co-leader Professor Judith Bliss, Director of the Clinical Trials and Statistics Unit at the ICR, said:

“Our study set out to provide some answers to the question of whether cediranib provides any benefit to patients with alveolar soft part sarcoma (ASPS), which generally affects young patients.

It’s an important question because there are limited treatment options, and conventional chemotherapy is not effective for these cancers.

“Using a trial design which allowed us to monitor treatment effectiveness over 24 weeks, we showed cediranib does indeed have a significant clinical benefit for patients with ASPS, and could play an important role in the long-term management of the disease.

We hope our study also leads to further studies using cediranib in ASPS and other sarcomas, alongside other potential new treatments.”

Trial co-leader Professor Ian Judson, Professor of Cancer Pharmacology at the ICR and former Consultant at the ICR’s partner hospital The Royal Marsden NHS Foundation Trust, said: “There are too few treatments for many kinds of sarcoma and the development of new options for patients is all too rare.

This trial offers new hope for the mostly young adults with this rare sarcoma type, and it was gratifying to discover that cediranib offers a new possible option that could help in the management of their disease.”

Alveolar soft part sarcoma (ASPS) is a rare, slow growing soft tissue tumor of an unclear cause. It is among the least common sarcomas, representing 0.2-1 percent of large studies of soft tissue sarcomas. ASPS is characterized by a painless mass that most commonly arises in the leg or buttock, with a particular affinity to travel to the lungs as multiple nodules, presumably while the sarcoma itself is still small. This disorder is very rare because it involves a specific breaking and joining event between two chromosomes, called an “unbalanced translocation”. This finding is observed in essentially all people with ASPS examined so far. This finding cannot be passed on to children, however, as the finding occurs only in the tumor cells, not in the normal cells. In addition, there are no families in which multiple family members have the disorder. ASPS tends to occur more often in younger individuals, specifically adolescents and young adults.

Treatment is with surgery for the primary place where the sarcoma arises. Radiation therapy is sometimes considered as an adjunct to surgery depending on the tumor characteristics (size, location, microscopic appearance). For disease that travels to the lungs, sometimes surgery is possible to remove nodules, but often chemotherapy is the only option for treatment. However, this tumor tends to be resistant to traditional chemotherapy, so alternate approaches involving newer “targeted” chemotherapy drugs are also a reasonable option for treatment. Several new targeted therapies are being studied in clinical trials and hold promise, but more research on their safety and effectiveness is required.

ASPS is classified as a soft tissue sarcoma. Sarcomas are malignant tumors that arise from the connective tissue, which connects, supports, and surrounds various structures and organs in the body. Soft tissue includes fat, muscle, nerves, tendons, and blood and lymph vessels.

Signs & Symptoms

The typical clinical findings are of a painless thigh or buttock mass, although ASPS can occur in the trunk, arm or elsewhere. Sometimes these masses cause pain by stretching of the surrounding tissues, and cause limping or other difficulty with movement. These masses are usually soft and slow growing. In children, these masses most often occur in the head and neck, most commonly the tongue and the eye socket (orbit). In adults, the thighs and buttocks are most often affected.

Although ASPS is a slow growing tumor, it can spread (metastasize) to other areas of the body. Sometimes there is a significant delay of years after resection of the original tumor before sites of spread (metastases) are detectable. The lungs, brain and bone are most frequently affected when the cancer spreads. In the advanced stages, when nodules are found in the lung, the tumor nodules can cause cough, sharp chest pain, or fluid collections around the lungs (pleural effusions). Some people will develop headaches associated with metastases to the brain, or a fracture from metastases to the bones. The involvement of the lungs or brain by ASPS are potentially life-threatening complications, but people can live for several years despite lung nodules, since the nodules grow only very slowly for most people. In the people with brain metastases, surgery and radiation are the major ways to control the tumor and the side effects they cause in the brain.


There is no exposure or infection that is known to predispose to ASPS. It is known that two chromosomes break and rejoin is a certain way (unbalanced translocation) and bring together two genes, normally separated on chromosomes X (the sex chromosome) and 17.

Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The two genes involved in ASPS are the alveolar soft part sarcoma critical region 1 (ASPSCR1) gene on chromosome 17 and TFE3 gene on chromosome X. In an unbalanced translocation, one chromosome ends up with extra material while the other chromosome is missing material. In ASPS, the TFE3 gene breaks off from the X chromosome and attaches onto the ASPSCR1 gene on chromosome 17. This unbalanced translocation creates a new so-called “fusion” gene known as ASPSCR1-TFE3. This fusion gene creates an abnormal protein. Researchers believe that this abnormal protein plays a significant role in the development of ASPS. However, more research is necessary to determine the exact manner in how this abnormal protein functions.

Affected Populations

ASPS tends to affect younger people, especially those between 15 and 35 years of age. It is rare in children under 5 or in adults over 50. Women outnumber men, especially under age 25. There appears to be no link of this tumor to a particular ethnicity. ASPS accounts for about 0.2-1% of all soft tissue sarcomas. In turn, soft tissue sarcomas account for approximately 1% of all cancers.

Related Disorders

The exact same chromosomal changes are found in a rare form of kidney cancer, ASPSCR1-TFE3 translocation renal cell carcinoma in which the chromosomal translocation is “balanced” as opposed to the “unbalanced” translocation seen in ASPS. This is a cancer of an entirely different nature. Researchers are unsure as to why the ASPSCR1-TFE3 gene fusion causes ASPS in some people and a form of renal cell carcinoma in others.

Other tumors can resemble ASPS by the way they look under the microscope. These tumors include paraganglioma, granular cell tumors, adrenal cortical carcinoma, hepatocellular carcinoma, rhabdomyosarcoma, clear cell sarcoma of the soft tissue, hibernoma, and perivascular epithelioid cell neoplasm or PEComa. However, some of these tumors have signs and symptoms that differ from those of ASPS.


Biopsy is the fastest way to come to a diagnosis of soft-tissue sarcomas. A biopsy involves taking a small sample of affected tissue and examining it under a microscope. There are more than 50 different types of sarcomas, of which ASPS is only one rare subtype. Often times, a core needle biopsy of the leg mass is enough to make the diagnosis. If a core needle biopsy is not diagnostic, then an incisional biopsy that obtains more tissue will make the diagnosis.

Doctors can use a biopsy sample to check the cells to see if the characteristic chromosome change (an unbalanced translocation involving chromosomes 17 and X, resulting in the formation of the fusion gene, (ASPSCR1-TFE3) is present. Detection of this change, confirms a diagnosis of ASPS.

Because the tumor grows slowly and usually does not cause any pronounced symptoms, affected individuals often have ASPS for years before a diagnosis is made.

Typically, people will also undergo specialized imaging techniques such as computed tomography (CT) scans or magnetic resonance imaging (MRI) scans of the primary tumor site to determine if the mass is removable. A CT scan of the chest is typically performed to determine if there is disease in the lungs. Additional scans may also be considered to assess for the spread of cancer to other areas of the body. ASPS, generally does not move to lymph nodes, instead preferring to travel via the blood to get to the lungs or other parts of the body.

Standard Therapies

The therapeutic management of individuals with ASPS may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis (pathologists)and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists (depending upon the primary tumor site). Given the rarity of this disease, it is recommended that patients be treated at a high-volume referral center for sarcomas.

Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade), whether the tumor has spread to distant sites, individual’s age and general health; and/or other elements.

Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference, and other appropriate factors.

Surgery is a standard treatment option for ASPS. However, identification of the fusion gene ASPSCR1-TFE3, has opened new avenues for treatment. Researchers are studying targeted therapies designed to block the effects of this abnormal gene. Please see the Investigational Therapies section below for more information.

The prognosis is best if the tumor is small and localized (i.e. has not moved elsewhere in the body, such as the lungs), and can be completely removed by surgery. It is rare for amputation to be used as a surgical technique to attempt to cure sarcomas (it occurs less than 5% of the time at most major US sarcoma centers).

Typical surgery is called “limb-sparing”, trying to get around the tumor completely, without having to remove so much tissue that the limb (or another site) does not work well anymore.

Often, radiation is used before or after surgery to minimize the chance of the tumor coming back in the place where it started. This can be achieved by directing a radiation beam at the tumor (external beam radiation, or some variant of that) or can be achieved by placing temporary catheters (tubes) in the area where the tumor was resected.

These tubes stick out of the skin and can have radiation seeds placed in them to deliver a high dose of radiation to the area of the tumor in a very specific manner. This technique is called brachytherapy.

Either external beam radiation or brachytherapy are considered typically when the tumor is 5cm (approximately 2 inches) in size or greater. For smaller tumors, it is not clear that radiation helps decrease the risk of the tumor coming back.

Without evidence of disease in the lungs, or other spread of ASPS beyond where it started, chemotherapy is not recommended. Chemotherapy for ASPS after surgery (and radiation for some people) will not decrease the risk of the tumor from coming back, like it can for breast cancer or colon cancer.

If the tumor is advanced and has traveled elsewhere (metastasized) or recurred, surgery is still sometimes considered depending on the extent of disease, in particular the number of sites affected.

For patients in whom surgery is not an appropriate option, chemotherapy is the main consideration for therapy. However, traditional chemotherapies for metastatic disease have generally been ineffective.

Standard drugs for sarcoma include doxorubicin and ifosfamide, but do not work particularly well for ASPS. Few people have shrinking of tumor, and chemotherapy will not be curative if the tumor has spread beyond the tumor’s starting place. Given these limitations with traditional chemotherapy, most specialists in the field are quick to consider newer or investigational treatments.

More information: Ian Judson et al. Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial, The Lancet Oncology (2019). DOI: 10.1016/S1470-2045(19)30215-3

Journal information: Lancet Oncology
Provided by Institute of Cancer Research


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