Rhabdomyosarcoma

by Leonard H. Wexler, MD
Also available in Chinese, French and Spanish

What is Rhabdomyosarcoma?

There are two kinds of muscle cells in the body: smooth muscle cells and skeletal muscle cells. Smooth muscles control involuntary activities; skeletal muscles control voluntary activities. Rhabdomyosarcoma (RMS) is a malignant tumor ("cancer") that arises from a normal skeletal muscle cell. Not very much is known about why normal skeletal muscle cells become cancerous. Because skeletal muscle cells are found in virtually every site of the body, RMS can develop in almost any part of the body.

RMS is a very rare cancer. There are only about 350 cases of RMS diagnosed each year in the United States in children under the age of 21 years. About four children per million healthy kids under the age of 15 will develop RMS each year. It is slightly more common in boys than in girls and it is most common in young children under the age of five.

Rhabdomyosarcoma is very uncommon in adults. There have been five "large" published series, totaling just over 400 cases of "adult" RMS (including some "children") seen at major cancer centers in the United States and Europe over the past 20-30 years.^1-5 Although "pleomorphic" histology is more common in the adult population (and rarely seen in children), treatment principles for managing adults with RMS are similar to those for children, and outcome is not intrinsically worse for adults treated with "modern", multi-modality therapy.

Although these tumors can arise almost anywhere, the most common locations for these tumors to develop are in the structures of the head and neck (nearly 40% of all cases), the male or female genitourinary tract (about 25% of all cases), and the extremities (about 20% of all cases).

Table 1: Incidence of RMS by site of primary tumor

Location	%
Parameningeal	16
Orbit	10
Head/Neck	10
GU (all)	23
Extremity	19
Other	22

Approximately 40% of newly diagnosed RMS arise in head and neck structures including parameningeal sites (16% of all cases, and almost half of all head and neck cases), the orbit or eyelid (10% of all cases), and other non-orbit, non-parameningeal sites (10% of all cases). Approximately 25% of cases arise in one of the structures of the genitourinary system including the paratesticular region, the female genitourinary tract (vulva, vagina, cervix, uterus), the urinary bladder, and the prostate. Approximately 20% of cases arise in an extremity. The remainder of cases ("other") arise in diverse sites including the chest wall and retroperitoneum.

Tumors that arise in the orbit, non-parameningeal head and neck sites (for example, the cheek or the ear lobe), and the male (paratesticular) or female (vagina, vulva, cervix, or uterus) genital tracts are considered "favorable." All other sites are considered "unfavorable."

Most children who develop RMS don’t have any clear risk factor for getting cancer. After taking a careful family history and doing a thorough physical examination, approximately one child in five to one child in ten will have an identifiable "genetic risk factor": the most common of these genetic "syndromes" include the Li-Fraumeni syndrome,⁶ neurofibromatosis,⁷ Beckwith-Wiedemann syndrome,⁸ and Costello syndrome.⁹

Rhabdomyosarcoma Symptoms

The symptoms that are associated with RMS can vary widely depending on where the tumor develops. Children with orbital RMS (about 10% of all cases of RMS), may present with a bulging or swollen eye (proptosis). Although this can sometimes be mistaken for a sinus infection, children with tumors in this location usually do not have the other symptoms that children with sinus infections experience (pain, fever, purplish discoloration of the eye).

Children with tumors arising in the one of the parameningeal sites (basically the sinuses, the middle ear, and the back of the throat) may complain for weeks or months of a stuffy nose, sometimes with nasal discharge; occasionally, a mass may be visible in the nostril or the back of the throat. Unlike sinus and throat infections, these tumors usually don’t spread to the lymph nodes in the neck. If they do, they usually are non-tender. If erosion of the skull base occurs, they may complain of headache or develop cranial neuropathies from infiltration or compression of affected cranial nerves.

Children with tumors arising in the genitourinary tract may present with a painless scrotal mass (paratesticular tumors), a protruding grape-like mass in the vagina ("botryoidal" rhabdomyosarcoma), blood in the urine (bladder tumors), or frequent urination, sometimes with burning or hesitancy. Occasionally, tumors that arise in the prostate gland (not the same as the more common type of prostate cancer that adult men get) can grow very large before they are diagnosed; these tumors may present as a visible mass in the pelvis or abdomen, sometimes with urinary frequency and urgency, sometimes with constipation, nausea and vomiting from compression of the bowels.

Tumors that arise in the legs or arms are usually amongst the most aggressive types of RMS. These tumors may grow from the size of a mosquito bite or a small marble to the size of a baseball or grapefruit in the course of only a few weeks. The tumors are usually hard, but only rarely are they painful unless they start pressing on nearby nerves. These tumors are the most likely to spread to nearby lymph nodes; it is not uncommon for a child with a RMS in the hand or arm to also have "swollen glands" in the armpit, or for a child with a RMS in the foot or calf to also have "swollen glands" in the groin.

Occasionally, children with RMS will also have unexplained fevers as one of the symptoms that are noticed at the time of diagnosis. Appetite may or may not be depressed. Fatigue and easy bruising are relatively uncommon symptoms unless the tumor has spread to the bone marrow.

Prognostic Factors

Although RMS is considered one disease, there are important differences in how these tumors behave depending on where they arise in the body, how they look under the microscope, how big the tumor is and whether it has spread anywhere, how much of the tumor remains after the initial operation, and the patient’s age at the time of diagnosis. These are called "prognostic factors." They describe "statistical probabilities" for cure but are never able to determine whether an individual child, regardless of how "favorable" or "unfavorable" her prognostic factors, will be cured.

Table 2: Risk-stratification for patients with newly diagnosed RMS

Risk	Stage	Group	Site	Size	Age	Histology	Metastasis	Nodes
Low A (D9602)	1	I	favorable	a or b	<21	EMB	M0	N0 or N1 or NX
	1	II	favorable	a or b	<21	EMB	M0	N0 or NX
	1	III	orbit only	a or b	<21	EMB	M0	N0 or NX
	2	I	unfavorable	a	<21	EMB	M0	N0 or NX
Low B (D9602)	1	II	favorable	a or b	<21	EMB	M0	N1
	1	III	orbit only	a or b	<21	EMB	M0	N1
	1	III	favorable (excluding orbit)	a or b	<21	EMB	M0	N0 or N1 or NX
	2	II	unfavorable	a	<21	EMB	M0	N0 or NX
	3	I or II	unfavorable	a	<21	EMB	M0	N1
	3	I or II	unfavorable	a	<21	EMB	M0	N0 or N1 or NX
Intermediate (D9803)	2	III	unfavorable	a	<21	EMB	M0	N0 or NX
	3	III	unfavorable	a	<21	EMB	M0	N1
	3	III	unfavorable	b	<21	EMB	M0	N0 or N1 or NX
	1 or 2 or 3	I or II or III	favorable or unfavorable	a or b	<21	ALV	M0	N0 or N1 or NX
	4	IV	favorable or unfavorable	a or b	<10	EMB	M1	N0 or N1 or NX
High (D9802)	4	IV	favorable or unfavorable	a or b	>=10	EMB	M1	N0 or N1 or NX
	4	IV	favorable or unfavorable	a or b	<21	ALV	M1	N0 or N1 or NX

The combination of Stage, Group, Site, Size, Age, Histologic Subtype, and the presence or absence of regional nodes or distant metastases is used to stratify patient into one of four "risk-groups."

Oncologists use a special set of short-hand terms to describe these factors. For children with RMS, there are two sets of terminology that are used to describe these factors. One is called Stage and the other is called Clinical Group (or "Group" for short). The Stage of RMS is dependent upon three factors:

1. What part of the body the tumor arose in
2. How big the tumor is
3. Whether or not the tumor has spread (see below) regionally or distantly

The Group of RMS is dependent upon how much tumor is still present after the initial surgery. There are four Stages (Stage 1, 2, 3, and 4) and four Groups (Groups I, II, III, and IV). Each patient with RMS is assigned a Stage and a Group based upon the combination of these factors.

Table 3: Site-modified Tumor, Nodes, Metastasis (TNM) Staging System for patients with newly diagnosed RMS

Stage	Site	T Status	Size	Node Status	Metastasis
1	Favorable	T1 or T2	a or b	N0, N1, or NX	M0
2	Unfavorable	T1 or T2	a	N0 or NX	M0
3	Unfavorable	T1 or T2	a	N1	M0
3	Unfavorable	T1 or T2	b	N0, N1, or NX	M0
4	Favorable or Unfavorable	T1 or T2	a or b	N0 or N1	M1

The combination of site (favorable versus unfavorable), size, and the presence or absence of regional nodes or distant metastases is used to classify patients into one of four Stages. This system is a Clinical staging system that relies upon physical examination and radiologic imaging to determine the extent of disease. T1 = tumor confined to anatomic site of origin; T2 = extension and/or fixation of tumor to surrounding tissues/structures; other abbreviations as above in the "Risk Stratification" table, Table 2).

Any tumor that is completely removed at the time of the initial operation is Group I. A tumor that has visibly spread to another "distant" part of the body is always Group IV. A tumor that is still visible (on scans or on physical examination) after the initial operation is Group III. Group II is when all of the visible tumor is removed but there is still "microscopic" amounts of tumor cells left behind - with or without spread to the regional nodes (as long as they are also removed). Half of all children with RMS have Group III tumors.

Table 4: Intergroup Rhabdomyosarcoma Group (IRSG) Clinical Group staging system for patients with newly diagnosed RMS

Clinical Group	Definition
I	Complete resection, (-) margins
IIa	Complete resection, (+) margins
IIb	Complete resection, (-) margins resected nodes positive
IIc	Complete resection, (+) margins resected nodes positive
III	Gross residual disease (includes unresected regional nodes)
IV	Distant metastases

This is the original "staging" system that was used to classify patients in the first three IRS studies. It is a staging system that relies upon the extent of initial surgical resection to determine Group. As such, it may be biased by such factors as the skill or aggressiveness of the local surgeon, and it does not take into account the differing recommendations for non-aggressive surgery for tumors arising in such "favorable" sites as the orbit or female genitourinary tract.

Patterns of Spread

RMS can spread locally, regionally, or distantly.

1. Local spread means that the tumor infiltrates or invades the tissues in the immediate vicinity of where it started.
2. Regional spread means that the tumor has traveled to the lymph nodes that drain the area where it arose. The highest chance that RMS will spread to the lymph nodes is for children with tumors that arise in the extremities and in older boys (ten years of age or older) with paratesticular tumors.
3. Distant spread means that the tumor has traveled through the bloodstream to another part of the body. The most common places that RMS travels to are the lungs, bones, and bone marrow.

It is very uncommon for RMS to spread to the brain or other organs such as the liver or spleen. When tumors have spread visibly to a "distant" location they are called "metastases." Only about one child in five with RMS will have distant metastases.

A variety of different tests are needed to evaluate the primary tumor and to look for signs that it may have spread to other parts of the body. The first test is always a thorough history and physical examination. Generally, the best imaging test to evaluate the primary tumor is a MRI. This provides 3-dimensional imaging and is frequently helpful for the purposes of planning radiation or surgery. CT scans of the chest are routinely done to look for the possibility of tumor having "metastasized" to the lungs. Depending on the location of the primary tumor, CT scans of the abdomen and pelvis are sometimes also done to look for spread of the tumor to lymph nodes. A bone scan is a nuclear medicine test that looks at the entire skeleton to determine if the tumor might have spread to the bones. Another nuclear medicine test that is being utilized increasingly is called a PET scan (Positron Emission Tomography). This test is relatively unique in that it images the entire body, both bones and soft tissues, can often be used to clarify an ambiguous finding on CT or MRI and can also be used to assess response to treatment. Because RMS can spread to the bone marrow, patients with RMS also undergo bone marrow aspirates and biopsies; a needle is placed into the hip bones and a specimen of the bone marrow is removed for testing; these tests are almost always done at the same time that anesthesia is being given for the biopsy of the tumor or insertion of the central venous catheter (CVC). Patients with tumors arising in one of the parameningeal locations must always have a lumbar puncture ("spinal tap") performed to obtain a sample of their cerebrospinal fluid (CSF) for testing to make sure that the lining of the brain has not become infiltrated by RMS.

General Principles of Rhabdomyosarcoma Treatment

All children with RMS are treated with chemotherapy. Depending upon the size and location of the primary tumor, and how much of it can be surgically removed, most children will also receive some combination of radiation therapy and surgery.

Surgery

The diagnosis of RMS can never be made without obtaining a specimen of the tumor for testing in the laboratory. The initial process for obtaining this specimen is called a biopsy. A biopsy is usually considered a "small" operation; most of the time it does not require an overnight stay in the hospital. There are different ways that a specimen of the tumor can be obtained:

1. A percutaneous needle biopsy: in this procedure, a needle is placed through the skin into the tumor and a small piece of the tumor is removed inside the needle. Sometimes this procedure is done using an ultrasound or CT scan to guide the person doing the biopsy. This procedure is usually not done with anesthesia, although intravenous sedation may be required depending on the site of the tumor and age of the child. Depending on the location of the tumor, this procedure may or may not be safer than one of the procedures discussed below. A needle biopsy is able to provide an adequate specimen to make a correct diagnosis about 90% of the time.
2. An open incisional biopsy: in this procedure, which is almost always done under anesthesia, a small cut is made in the skin through which a small piece of the tumor is removed. This procedure provides an adequate specimen to make a correct diagnosis about 100% of the time.
3. An open excisional biopsy: in this procedure, which is almost always done under anesthesia, a cut is made in the skin and an attempt is made to remove the entire tumor. This is a bigger operation than either of the two other procedures. This operation is appropriate for children whose tumors have been fully imaged if the surgeon believes that the entire tumor can be removed and doing so will not result in either a functional deficit (that is, if a calf tumor could be taken out without doing an amputation or otherwise compromising the ability to ambulate) OR a cosmetic defect (that is, if a tumor of the sinuses could be taken out without producing a big facial scar or facial deformity).

Because imaging studies can fail to detect many instances of tumor spread to regional lymph nodes, surgical evaluation of regional nodes is mandatory in two specific cases, children with extremity RMS and boys ten years of age or older with paratesticular tumors. In the former instance, surgical sampling of lymph nodes behind the knee or in the groin should be performed for lower extremity tumors, and sampling of lymph nodes behind the elbow or in the armpit should be performed for upper extremity tumors.¹⁵ The role of lymphoscintigraphy for identifying a sentinel node is under investigation. PET scanning may be helpful at identifying worrisome nodes not otherwise clearly seen on conventional imaging such as CT or MRI.

In the case of boys with paratesticular tumors, and ideally at the same time that the primary tumor is removed (an inguinal incision should be performed, as would be done for a hernia operation, and the tumor and testicle should both be extracted in contiguity from the scrotal sac and resected), surgical evaluation of ipsilateral (same side as the tumor) retroperitoneal regional lymph nodes should be performed; this latter procedure is increasingly being done laparoscopically, minimizing post-operative recovery and potentially shortening the time until chemotherapy is able to be initiated.¹⁶

It is important to remember that surgery by itself is never curative for children with RMS. It is also important to remember that the role of surgery is very dependent on the site of the tumor. While initial complete surgical removal of tumors arising in an extremity or in the pelvis may help improve the chance of cure, complete removal of a tumor arising in the orbit or vagina is almost never necessary to achieve a very high rate of cure (and is almost never appropriate). Although most families whose child is suspected of having RMS want the whole tumor taken out as quickly as possible, this initial surgical procedure is almost never an emergency and it is imperative that proper imaging of the tumor be obtained before a biopsy is performed if RMS is being considered. Failure to image the primary tumor before a biopsy can result in an irreversible loss of opportunity to properly plan critically needed radiation therapy. Similarly, it is important to ensure that the biopsy is obtained at a facility with experienced pathologists who will process the specimen in the appropriate fashion to ensure that all necessary testing is performed in a timely and thorough manner.¹⁷

Pathology

Once biopsied, the tumor is studied under the microscope in the laboratory. The defining characteristic of RMS is the demonstration of evidence of skeletal muscle lineage—either by its appearance under the microscope or by the pattern of chemical staining ("immunostaining"). There are two basic kinds of RMS – embryonal and alveolar. Approximately two-thirds of children with RMS have the more common embryonal type (or the spindle-cell or botryoid variants). These tumors are more common in younger children, particularly those with tumors arising in the head and neck sites (including parameningeal sites) and the genitourinary system (including the bladder and prostate). The tumor cells tend to be more elongated and less densely cellular.

About 20-25% of children with RMS have the less common alveolar type (or solid alveolar variant). These tumors are much more common in teenagers, and most commonly arise in the extremities. The tumor cells tend to be smaller and rounder, often with a denser cellularity, and are so named because of their resemblance to the appearance of the small air sacs in the lungs (the "alveoli"). Alveolar tumors are often considered more "aggressive", or "higher risk", than embryonal tumors – particularly for tumors that arise in one of the favorable locations.

About 5-10% of children will have tumors that cannot be more definitively categorized and are considered either "undifferentiated" sarcomas or "rhabdomyosarcoma, not otherwise specified."

When a tumor has been biopsied and the pathologist (the doctor who studies the tumor in the laboratory) suspects that it is RMS, she will usually order confirmatory tests called "immunostains." These are chemical reactions that stain different structures in the tumor cell. RMS tumors will usually stain "positively" for a number of different stains including desmin and myogenin. The demonstration of myogenin positivity is virtually diagnostic of RMS.

A final level of testing is sometimes done on RMS tumor cells. This is called "molecular diagnostic testing." Although not much is known about why a normal skeletal muscle cell becomes cancerous, there is quite a lot known about the genetic changes that occur in the cell once it does become a cancer cell. In virtually all cases of embryonal RMS, an abnormality can be found in the cancer cells (and only in the cancer cells – so this is not an inherited abnormality!) that causes an "over-dosage" of a gene that is important in the growth of normal muscle cells.

Cases of embryonal RMS typically demonstrate evidence of over-expression of the IGF-II gene located on the short arm of chromosome 11. This is believed to result from loss of the maternal allele and duplication of the paternal allele. It is thought that the expression of two copies of this gene leads to an "overdose" effect whereby too much IGF-II produces a constant proliferative signal that allows the pre-cancerous (or already transformed) muscle cell to grow in an unrestrained fashion and prevents it from dying in response to what would otherwise be lethal environmental stresses. This process is known as "loss of heterozygosity."

This process results in an "overdosage" of a "growth promoting gene", insulin-like growth factor Type II (IGF-II), that is located on chromosome 11. Normally, only one copy (usually the gene that is inherited from the father) of this gene is "active" and the other is "silent" (it’s believed that a chemical modification of the DNA structure near the gene, known as "methylation" is responsible for one gene being "on" and another nearby growth suppressing gene [H19] being "off"). In most cases of embryonal RMS, either both genes are activated or the copy of the mother’s gene is lost and the father’s gene is duplicated and both copies are "active." This is thought to lead to the production of a constant "proliferative" signal that tells the cell to continue to grow and prevents it from dying in response to the normal environmental stresses that cells face.

Many cases of childhood cancer are associated with specific translocations whereby a piece of one normal gene and a piece of another normal gene break apart and switch places. In approximately 90% of cases of alveolar RMS, a portion of one of the PAX genes (most commonly the PAX 3 gene located on chromosome 2, less commonly the PAX 7 gene located on chromosome 1) fuses with a portion of the FKHR gene (located on chromosome 13) to create a new "hybrid" gene (PAX-FKHR) that turns on growth-stimulatory genes that would otherwise be "inactive" and turns off growth-inhibitory genes that are normally active. Since this abnormal "hybrid" gene is found only in cases of alveolar RMS, it can be used for diagnostic purposes and, potentially in the future, as a target for immune-mediated cancer therapies.

This abnormality can often be detected using one of several specialized techniques for looking at the chromosomal content of the tumor cells.

Nearly 90% of cases of alveolar RMS will have a characteristic "translocation" involving one of the "PAX" genes (most commonly the PAX 3 gene, located on chromosome 2, less commonly the PAX 7 gene, located on chromosome 1) and the "forkhead" (FKHR) gene (located on chromosome 13).

A translocation is a fairly common "event" in childhood cancers in which a piece of a normal gene breaks away from its usual location and joins a piece of another normal gene. Specifically, by fusing the "paired box" (PB) and "homeodomain" (HD) DNA binding regions of the PAX 3 gene with the "transcriptional activation domain" (TAD) of the FKHR gene, a new "hybrid" gene is created that appears to play a critical role in the process by which the RMS cell becomes cancerous in two ways. First, it turns "off" other genes that are normally "active" and serve as "brakes" on cell growth; and, second, it turns "on" other genes that are normally "inactive" and serve as stimulators of cell growth, survival, and spread. This abnormality is never seen in embryonal RMS so if there is a question about which type of RMS a patient has based on how it looks under the microscope, the demonstration of a PAX-FKHR translocation proves conclusively that it is alveolar RMS. This abnormality is usually tested for using a technique known as RT-PCR (reverse transcriptase polymerase chain reaction), however, this test may only be available in specialized reference laboratories at large Cancer Centers or Children’s Hospitals.

Once all of the imaging studies have been completed, and the biopsy has been performed, and the diagnosis of RMS has been confirmed, it is possible to classify patients with RMS into one of four "risk groups" based on the combination of their Stage (site, size, nodal involvement), their Group (extent of residual tumor post-operatively), their age at diagnosis, their histologic sub-type (embryonal versus alveolar), and the presence or absence of distant metastases. These risk groups provide important information about the potential curability of the tumor with treatments of lesser or greater intensity:

1. Standard-risk, subgroup A: These patients, relatively few in number, have a survival of better than 85% using relatively non-intensive, 2-drug chemotherapy, with or without radiation therapy. This group is essentially comprised of patients with orbital tumors (as long as they have not metastasized), patients with "favorable" site tumors (Stage 1) that have been either completely removed surgically (Group I) or gross totally removed with only microscopic residual disease (Group II), and patients with small unfavorable site tumors (Stage 2) that have been completely resected (Group I).
2. Standard-risk, subgroup B: These patients, slightly more numerous, have a survival of better than 80% but need relatively more intensive, 3-drug chemotherapy, usually with radiation therapy (with one important exception, see below). This group is comprised of all patients with non-metastatic, non-orbital favorable site tumors (Stage 1) that are still visible (Group III) after initial surgery, patients with non-metastatic, small unfavorable site tumors without regional nodal spread (Stage 2) that have been gross totally resected (Group II), and patients with unfavorable site tumors that are large or have spread to regional nodes (Stage 3) but have been completely or gross totally resected (Groups I and II). Approximately 15-20% of all newly diagnosed RMS patients will be considered "standard-risk." Patients with alveolar RMS are never considered standard-risk.
3. Intermediate-risk: These patients comprise the majority of patients with newly diagnosed RMS and include those with unfavorable site tumors (Stages 2 and 3) that have not been completely resected (Group III), patients under the age of ten with embryonal RMS that has spread to other parts of the body (Stage 4, Group IV), and all patients with non-metastatic alveolar RMS. Although this is a diverse group of patients, the prognosis for cure with 3 (or more) drug chemotherapy and radiation therapy is usually better than 50%, and perhaps as high as 70% for certain sub-groups.
4. High-risk: These patients comprise approximately 10-15% of patients with newly diagnosed RMS. The prognosis for cure for these children is usually quite poor, generally between 20% and 35%, even with very aggressive chemotherapy, radiation, and surgery. This group includes all patients with metastatic alveolar RMS, patients ten years of age or older with metastatic embryonal RMS, and probably two other groups currently considered intermediate-risk: infants under one year of age with metastatic embryonal RMS, for whom the 5-year survival is less than 20%,³³ and children with extremity tumors with regional nodal spread, almost all of whom have alveolar RMS, for whom the 5-year survival is approximately 30%.¹⁵

Rhabdomyosarcoma Treatment

The treatment of patients with RMS is multi-disciplinary and begins even before the start of treatment with the availability of skilled radiologists who can accurately interpret the results of imaging studies, skilled pathologists who are familiar with the evaluation and testing of pediatric "small round blue cell tumors", and skilled surgeons who understand the role of initial surgery in the overall management of patients with RMS. It includes radiation oncologists and pediatric oncologists who are familiar with national (or institutional) treatment guidelines (also known as protocols) for treating this rare form of cancer. Ideally, treatment will be given at a facility where regular meetings of all of these disciplines (known as Tumor Boards) are held so that all of the health care providers involved in the child’s care can see the important imaging tests, biopsy results, and on-treatment evaluations that are necessary to give optimal care.

Given the young age of these patients, the treatment team should also include anesthesiologists to sedate patients for scans and procedures (including sometimes for the entire 5-6 week course of radiation treatment), and nursing staff familiar with the unique medical needs and complications of children with cancer. Finally, it includes Social Work, Chaplaincy, and Child Life staff to help a family (and child) whose world has been shattered by the words "your child has cancer."

Treatment for children with RMS focuses on achieving "local control" and "systemic control." Local control refers to the permanent eradication of the "primary tumor." This is usually accomplished by surgical removal or irradiation of the tumor (or both) and any involved nearby areas, in addition to chemotherapy treatment. Systemic control refers to the permanent control of invisible "micrometastases" or visible "metastases", generally by chemotherapy (sometimes with additional surgery or radiation therapy). The risk that treatment will fail to be curative varies by "risk group." For most children with non-metastatic tumors (that is, Standard and Intermediate Risk), the greatest risk is that the primary tumor will not be permanently controlled. More than half of all treatment failures in these groups are "loco-regional" (that is, at or near the primary site). Failure to control the primary tumor is associated with a markedly increased risk of relapse at other parts of the body; this is probably a reflection of intrinsic or early-acquisition of resistance to chemotherapy and radiation therapy. For most children with metastatic tumors (that is, High Risk), the overwhelmingly greater risk of treatment failures is that the metastases will not be controlled even if the primary tumor is controlled. Although there are exceptions, because post-relapse survival is poor for the vast majority of children with recurrent RMS (less than 20% of patients who relapse will be cured), it is critical that optimal therapy be given at the time of diagnosis.

Chemotherapy

All patients with RMS require chemotherapy to maximize the chance for cure. Most children in the United States are treated on (or following) an International Clinical Trial formerly known as the "Intergroup Rhabdomyosarcoma Study" (now known as the Soft Tissue Sarcoma Committee of the Children’s Oncology Group). Over the past 30 years, four Intergroup Rhabdomyosarcoma Studies have been completed with over 4000 patients with RMS treated. The 5th generation of these studies will complete accrual this year. For select patients, usually those with Intermediate or High-Risk RMS, treatment on a "pilot" single- or limited-institution clinical trial may be available.

Chemotherapy treatments for RMS are always given through an intravenous line; generally, a special type of "permanent" intravenous line is placed prior to the start of treatment. Most patients with RMS receive chemotherapy treatments lasting 6-12 months (rarely longer, although depending on the severity of side effects, treatment that is scheduled to last ten months can sometimes last 15 months). Chemotherapy is generally given in two to five (or sometimes ten) day "pulses" or "cycles" every 3-four weeks. Some chemotherapy drugs can be given on a weekly basis.

Chemotherapy side effects can be "drug-specific" (that is, only seen with one or two drugs) or "general" (that is, seen with many drugs). The following is a list of the most common drugs that are used to treat RMS in the United States and in Europe:

• Vincristine
• Dactinomycin
• Cyclophosphamide
• Topotecan
• Irinotecan
• Etoposide
• Ifosfamide
• Doxorubicin
• Carboplatin

Common side effects that may be seen (to lesser or greater degrees) with virtually all of the chemotherapy drugs that are used to treat RMS include hair loss, nausea and vomiting, loss of appetite, fatigue, mouth sores, and the development of low-blood cell counts. These side effects typically develop because of the effects of chemotherapy on rapidly dividing cells. While tumor cells are usually the most rapidly dividing cells in the body, other normal cells, such as hair cells, "mucosal cells" (the cells that line the mouth and intestines), and blood cells, are also rapidly dividing. Fortunately, there is usually a greater supply of these normal cells than of tumor cells so these side effects are usually temporary.

The development of low blood cell counts is the side effect that most limits the ability to give chemotherapy all the time (the way an infection would be treated) and is one of the most dangerous side effects. There are three major kinds of blood cells: red blood cells, white blood cells, and platelets. Typically, about seven or eight days from the start of a "cycle" of chemotherapy, the blood cells drop to very low levels and may remain low for 5-10 days. Red blood cells carry oxygen from the lungs throughout the body; when the red blood cell count is low this is called anemia and may produce fatigue. White blood cells are the body’s infection fighting cells; when the white blood cell count is low this is called leukopenia and may increase greatly the risk of developing a serious infection from the "germs" that are already in/on one’s own body. When the most important infection-fighting white blood cell count is low, this condition is called neutropenia. Platelets are the cells that help the blood to clot; when the platelet count is low, this increases the risk of bleeding, either spontaneously or from a cut. When the red blood cell count is low, a transfusion can be given to help improve fatigue; when the platelets are low, a transfusion can be given to reduce the risk of bleeding. Most children with RMS, even those with Standard-Risk, Subgroup A tumors who receive relatively less-intensive 2-drug chemotherapy with vincristine and dactinomycin, will require transfusion support with red blood cells and/or platelets at some point during their treatment. The one type of blood cell that can’t be transfused is the infection-fighting white blood cell; however, a medicine (G-CSF, filgrastim, Neupogen®) is available that can help the white blood cells return to a safe level more quickly.

Inflammation of the liver, though an uncommon side effect, can occur and can be life-threatening, particularly in very young children, and requires a heightened level of awareness to monitor and evaluate promptly laboratory tests of "liver function."

Vincristine is a drug that is given to virtually all children with RMS. Uniquely, it can cause pain in the hands and feet or in the jaw or abdomen. It can also produce weakness in the hands and feet due to (usually reversible) nerve damage (peripheral neuropathy). Presently, there are no proven "protective" medications to prevent this nerve damage, but there is some evidence that nerve damage that is caused by other chemotherapy drugs (not typically used to treat RMS), specifically cisplatin and paclitaxel, may be ameliorated by the use of Vitamin E and glutamine, respectively.

Irinotecan is a newer drug that was found to be very effective at treating RMS in newly diagnosed patients with metastatic tumors and in patients with recurrent RMS (that is, RMS that relapsed after treatment finished or that never disappeared completely with initial treatment). Uniquely, it is given for ten days every three weeks and although it only infrequently causes severe nausea or vomiting, low blood cell counts, or hair loss, it can produce very severe diarrhea.

Cyclophosphamide (usually given in combination with vincristine and dactinomycin, or vincristine and doxorubicin) and ifosfamide (usually given in combination with etoposide) can cause damage to the urinary bladder resulting in blood in the urine. Both drugs are given with a "protective" medication, called "mesna" that is effective at reducing the risk of this specific side effect.

Doxorubicin can cause damage to the heart, particularly at higher total (cumulative) doses. Increasingly, in RMS and other types of cancer, it is given with a "protective" medication, called "dexrazoxane", that is effective at reducing the risk of this potentially quite serious complication.

Radiation Therapy

All patients with alveolar RMS – even those whose tumors have been completely removed prior to the start of chemotherapy – and almost all patients with Group II (microscopic residual disease) and Group III (gross residual disease) embryonal RMS – require radiation to maximize their chance for cure. Girls with embryonal RMS of the genital tract (vagina, vulva, cervix, and uterus), for whom initial conservative surgical management is the rule of thumb, can often be managed with serial biopsies, beginning after approximately 12 weeks of chemotherapy treatment, without radiation. Radiation treatments are generally given after 4-5 cycles of chemotherapy have been given (that is, after about 12 weeks), although in selected cases (generally limited to children with parameningeal RMS that has eroded through the base of the skull to extend intracranially) radiation may begin at the same time (or as shortly thereafter as possible) as chemotherapy.

Depending on the site and size and Group of the tumor, between 20 and 28 radiation treatments are given. Ideally, treatment should be planned based on 3-dimensional imaging of the pre-biopsy, pre-chemotherapy tumor. The skill of the Radiation Oncologist in the successful treatment of RMS cannot be overemphasized. Because these are rare tumors, and because most children with RMS are treated on protocols that specify the details of their therapy, the Radiation Oncologist must not only be able to accurately interpret relevant imaging studies to design an appropriate "treatment field" that encompasses all of the original tumor, plus a "margin" of normal surrounding tissue, but to do so at the time specified in the protocol and with an awareness of the "normal tissue tolerance" of surrounding normal structures and the risks of long-term complications of irradiating growing tissue in a young child.

Some of the European cooperative groups that treat children with RMS have tried to reduce or eliminate the use of radiation in very young children or in children whose tumors have disappeared completely after a period of chemotherapy or that were gross totally resected prior to the start of chemotherapy. Unfortunately, although some children can be cured in this fashion, the risk of relapse is significantly greater and it is unclear whether the chance for subsequent cure is as good. Consequently, with the exception of girls with genital tract embryonal RMS, radiation is recommended for all patients with Group III RMS, for all patients with Group II RMS, and for all patients with Group I alveolar RMS. The role of radiation to sites of metastatic disease in children with Stage 4 (or Group IV) RMS is less clear, although children with lung metastases that have disappeared after chemotherapy may have an improved prognosis following low-dose (usually eight treatments) whole-lung irradiation (WLI).

Delayed (Second-Look) Surgery

Some children with RMS undergo "delayed" or second-look surgery after their tumor has shrunk following chemotherapy. The reasons for doing this type of operation include trying to eliminate the need for radiation therapy (infrequent) or to allow a "clinically significant" lower dose of radiation to be given post-operatively (common), or to maximize the chance that post-operative radiation will work effectively (particularly for tumors that were very large at the time of diagnosis). Occasionally, a child whose tumor has been treated with radiation will have imaging results that are worrisome and suggest that the tumor has not been killed by the radiation. In these instances, if feasible, surgery may be necessary to remove the residual cancer that has survived the radiation to try to prevent a recurrence at the primary site.

Newer Treatments

Post-relapse survival for the majority of patients with recurrent RMS remains dismal. 95% of recurrences occur within three years of diagnosis. With the exception of a small "favorable risk" group (approximately 20% of relapsing patients) whose 5-year survival approaches 50%, half of patients with recurrent RMS will die of their disease within one year of relapse and 90% of patients will die within five years of relapse.⁶¹

Novel therapies are desperately needed for this group of patients.

As greater insights are gained into the basic biology of RMS, novel treatment approaches are being developed to try to exploit these "Achilles’ heels" of the tumor cells. Because of the dependency of RMS on IGF-II, promising new drugs have been developed that either block the interaction of the type I IGF receptor with IGF-II, or that block the downstream biological effects that occur after IGF-II binds to its receptor. These agents, though not yet clinically available, offer great promise as both "stand-alone" treatments, or in combination with chemotherapy.

Finally, because of the presence of the unique, tumor-cell specific "translocation" gene in cases of alveolar RMS, the potential exists to utilize immune-based therapies to recognize and kill cells that contain this abnormal gene. Pilot clinical trials are ongoing to evaluate the ability to "vaccinate" patients with alveolar RMS to develop immunity against their own tumors; simultaneously, pilot clinical trials are also ongoing to evaluate the ability of a "genetically matched" sibling’s immune system to control a patient’s alveolar RMS tumor following a "mini"- allogeneic stem cell transplant.

Late Effects of Rhabdomyosarcoma Treatment

The adoption of risk-based therapy for children with RMS is intended to maximize the chance for cure while minimizing the development of short-, intermediate-, and long-term complications. Treatment related late-effects may develop anywhere from months to years after the completion of therapy. Individual chemotherapy agents may have unique toxicities that may not become manifest until many years after the end of therapy, or that may steadily worsen with increased length of follow-up. Damage from radiation therapy, and late complications from surgery, may not become apparent for many years, particularly in growing children. Select well-described complications of treatment include:

1. Infertility (associated especially with the use of alkylating agents such as cyclophosphamide and ifosfamide): The risk of chemotherapy-induced infertility is much greater for boys than for girls.⁷⁶ Whenever feasible, even for boys on the cusp of pubertal development, an evaluation should be made of the possibility of sperm cryopreservation.⁷⁷ Although the subject of intensive laboratory investigation, neither cryopreservation of ovarian tissue nor of ova is currently available as a routinely effective means of fertility preservation for girls;⁷⁸ fortunately, the risk of infertility appears to be much lower in girls. For girls undergoing pelvic irradiation, or for boys undergoing scrotal irradiation, surgical transposition of the gonad(s) out of the radiation field may be helpful at preserving hormonal function and/or fertility.
2. Bladder dysfunction: Although "non-mutilating" conservative surgery and full-dose irradiation has become the treatment of choice for bladder preservation in children with bladder/prostate RMS, approximately half of children with "intact" bladders will have one or more symptoms of bladder dysfunction including dribbling, incontinence, and enuresis.⁶⁰
3. Radiation damage of head and neck structures: The use of radiation to treat tumors arising in head and neck structures is frequently unavoidable due to the lack of "non-essential" surrounding structures that could be "sacrificed" if complete surgical resection were attempted. Well described complications of radiation include cataract formation after doses to the globe as low as 1000 cGy;⁷⁹ asymmetric facial growth as a result of permanently arrested bone development and fibrosis ("scarring") of surrounding tissues; chronic sinus infections; growth failure due to pituitary damage;⁸⁰ and complex and multiple dental abnormalities.⁸¹ It is unknown whether more precisely targeted, newer radiation techniques such as Intensity Modulated Radiation Therapy (IMRT), will reduce the risk of late complications from irradiation of head and neck structures.⁵³
4. Secondary cancer: Perhaps the most devastating late complication of treatment for any type of cancer, not just RMS, is the development of a second form of cancer. The use of chemotherapy and radiation can cause second cancers to develop. Chemotherapy-associated secondary cancers are most commonly leukemias (typically Acute Myeloid Leukemia [AML]), and may be associated with the use of alkylating agents (cyclophosphamide and ifosfamide), and topoisomerase II inhibitors (etoposide and doxorubicin). The risk of secondary leukemia is, fortunately, quite low (generally between 1 and 2%). Radiation is also associated with the development of second cancers, most commonly other sarcomas (either in bone or soft tissue). At the doses of radiation that are currently used to treat children with RMS, the risk of secondary sarcomas is approximately 5% at 20 years.⁸² Unlike the situation with secondary leukemias, which typically develop within four years of treatment, most cases of secondary sarcomas do not develop until 5+ years after the end of treatment.⁸² The contribution of underlying "genetic risk factors" to the development of treatment-induced cancers is being actively investigated.

Stories and Support

Will you share your story?

We would like to fill this page with survival stories that offer hope and encouragement to everyone learning about rhabdomyosarcoma. Please consider sharing your story.

Grant writes about finding support

I’m surviving sarcoma first and foremost because of fellow sarcoma survivors. When diagnosed with rhabdomyosarcoma in the head and lungs at age 26, a dear friend mine, a survivor of osteosarcoma, guided me through the beginning steps of treatment. Suggesting what doctors to see and what measures to take, my friend gave me the initial tools to fight my battle, including a few tricks to enduring the hell of chemotherapy. Websites like the Sarcoma Initiative and list-serves like ACOR’s Rhabdo list gave me the medical resources and information to further educate myself on the best options available.

Sarcoma, because it is so rare, can be an extremely isolating disease, so finding others in similar battles was very important to me. Their courage added to mine. Their successes gave me hope. They wanted me to learn from their mistakes and their triumphs. I joined a virtual army with a very real enemy. We know we can’t win every battle, but we plan to eventually win the war.

Recently, I met a scared young man who had just been diagnosed with rhabdomyosarcoma. I took off my blue sarcoma bracelet, handed it to him, and was able to proudly say, "You are not alone."

Len introduces us to Andrew

I would like to introduce you do my hero, my son Andrew. He was diagnosed with orbital rhabdomyosarcoma when he was 9 years old. His initial protocol was for nine months of chemotherapy and five weeks of radiation. He unfortunately relapsed shortly after completing his treatments, and after more chemotherapy and surgeries, his medical team decided to perform a very radical surgery, which had only been performed once in the history of SickKids, and that was the removal of his entire orbit.

Andrew never once complained or cried or asked "why me?" Even while going through all his treatments and surgeries, including the loss of his left eye, he continued to play rep hockey as a goalie. He led his team to the city championship the following year and he had the best goals against in the entire league. He has continued to persevere and inspire many; he excels at most sports including basketball and golf.

In 2003, Andrew was named an Ontario Junior Citizen of the year, and in 2004, Today’s Parent Magazine named him as one of the top five individuals in Canada that are making a difference in the lives of Canadian children. He has a cancer research fund at SickKids which, to date, has raised $350,000 for this worthy cause.

Today Andrew is 18 years old, and a straight "A" student in college. He is also pursuing his real estate license, which he plans on having before his 19th birthday. He is a gifted song writer and performer who is currently in studio recording an album. He coaches minor basketball and continues to inspire many, including his dad. Most important, he is cancer free!

John shares a moment in his journey

I remember the moment when I realized that we had entered the cancer realm, which no one enters voluntarily. The doctors had ruled out our initial suspicion that my son had an inflamed appendix. Instead they had confirmed that he had a stage 3 or 4 rhabdomyosarcoma. We were told that a course of radiation and chemotherapy would be prescribed, and that this treatment would in all likelihood have a negative impact on my son’s reproductive fertility. It was recommended that he "bank" a sperm specimen in the event that his treatment rendered him sterile. We were referred to a sperm bank near our house.

At the appointed time we pulled into the neighborhood where the facility was located, parked our car, and located the office on the upper floor of a two story building. While my son was filling out forms I walked to the window overlooking the street below. Across the street was a luxury hotel. A professional basketball team from the NBA was staying at the hotel and a line of about a dozen boys, close to my son’s age, had formed on the sidewalk outside the hotel’s entrance. These boys were waiting to intercept some of the players and plead for them to autograph their basketballs.

I suddenly had the feeling that I was looking at a world that we previously inhabited, but no longer do inhabit. I was looking at that world from a new one that we had suddenly and reluctantly been inducted into. The window separated these very different worlds, and we would probably never again be part of that other world.

Sarah writes about bonding with other parents

A woman was sitting in the surgical waiting room while my son was having an MRI. We thought the plastic surgeon had made a mistake and nicked an artery in the last cleft surgery. I cried and this woman reached out and said, "My daughter is here having back surgery. She has cancer." "Poor woman," I thought, "at least my son is not that bad."

Ten minutes later, we were exchanging numbers, bonding. My son was that bad. Rhabdomyosarcoma — a word we could not pronounce. One we had never heard before. A word for a 7 cm tumor that could kill my son. This woman became my rock, my best friend, my world on my ward.

I could tell you about the 11 month rollercoaster journey through chemo and radiation. I could tell you about the children throwing up, screaming, and begging the pokes to stop. It all has been said before. That crushing feeling when your world is stopped completely. A life that was secure suddenly seems hopeless. The feeling of not knowing if your baby will live or die. This woman’s daughter did pass away, and my son was saved, now cancer free.

Instead, I will tell you about the moment you realize that you have become part of a world you can never fully leave, where you bond with parents on the ward despite race or status. You fall in love with strangers; you share great scans, devastation, elation and death. A friend dies and your son lives and even though both are extremes at opposite ends of the spectrum, neither parent will ever leave the cancer world nor return to normal. You end up fighting until all the little faces become recognized, until there is hope, and through hope you save the fate of one more child.

The Online Rhadomyosarcoma Support Group at ACOR

This group provides a network of friends who are dealing with issues related to rhabdomyosarcoma. An ACOR "Mailing List" is a free, non-moderated discussion mechanism for patients, caregivers, researchers, and medical professionals to exchange messages with each other. Messages are "posted" by someone on the list (i.e., a member of the support group) and cover a wide range of topics, e.g., patient experiences, research articles, clinical trials, current treatment practices and alternative treatments. A posting often results in an "online discussion" of the topic. Sometimes, one or more medical professionals are members of a support group and may comment on a posting.

Focus on Rhabdo

The website of a community-anchored, multi-disciplinary consortium of “Rhabdo Activists.”

Connect on Facebook

The following Facebook groups provide opportunities to exchange messages with others who are dealing with rhabdomyosarcoma.

• Rhabdo Kids
• Team Sarcoma

Find Treatment and Support

We maintain listings of sarcoma treatment centers, local support groups and organizations that provide financial assistance to sarcoma patients and their loved-ones.

Rhabdomyosarcoma Cancer Research

The Liddy Shriver Sarcoma Initiative has funded more than $190,000 in rhabdomyosarcoma research grants. Rhabdomyosarcoma often strikes very young children, older children and adolescents, and treatment can involve aggressive chemotherapy, radiation therapy and surgery. It is our hope that research will lead to newer and better treatments for those who are diagnosed with rhabdomyosarcoma.

The following research studies were funded by the Initiative after sarcoma experts agreed that they were clinically relevant and scientifically sound:

Modeling Treatment Response of NF1-Deleted Sarcoma

$69,000 Grant: In this study, investigators from Duke University will use their mouse model of NF1-deleted sarcomas to explore the role of NF1 mutations in the development and therapeutic response of rhabdomyosarcoma, undifferentiated pleomorphic sarcoma, and malignant peripheral nerve sheath tumor.

This grant was co-funded by the Liddy Shriver Sarcoma Initiative in April 2013. It was made possible by a generous gift from the Thumbs Up For Lane Goodwin Childhood Cancer Foundation and by donations made in honor of Brett Reed, Craig Dion, Denise Grove, Michael Cretella, and Samara Sheller.

Immunotherapy for Pediatric Sarcomas

$50,000 Grant: In this study, investigators from the National Cancer Institute will alter T cells so that they recognize and kill osteosarcoma and rhabdomyosarcoma cells as if they were virus-infected cells. They will then use blocking antibodies to prevent the cancer from dampening the T cells' immune reaction. The investigators hope that the research will improve current immunotherapies and make them more effective in treating sarcomas.

This grant was funded by the Liddy Shriver Sarcoma Initiative in December 2012.

The Hippo Pathway in Alveolar Rhabdomyosarcoma

$50,000 Grant: In this study, investigators at Duke University Medical Center are working to provide a platform for designing new mouse models and therapeutic approaches for Alveolar Rhabdomyosarcoma. The researchers hope that they might ultimately find new therapeutic strategies for rhabdomyosarcoma and additional childhood sarcomas.

This grant was awarded by the Liddy Shriver Sarcoma Initiative in August 2012. It was made possible by generous gifts from the Jordan Paganelli Sarcoma Foundation and from the families and friends of Timothy "Tim" Yeates, Anna Rogotzke, Dillon Wolford, Ashley Miller, Harper Creek and Teri Marriage-Kuespert.

Study of Tissue Samples

$25,000 Grant: This tissue study was performed in conjunction with a clinical trial on several types of sarcoma, including Rhabdomyosarcoma.

Elizabeth Shriver Memorial Research Award

$25,000 Grant: In June 2004, Dr. Frederic Barr of the University of Pennsylvania was the recipient of a $25,000 Elizabeth Shriver Memorial Research Award. He is well known for his work on gene fusions in rhabdomyosarcoma (RMS), so he is well familiar with the complex genes in this tumor. Most of the alveolar type of RMS, a childhood tumor, form when two genes are abnormally stuck together (PAX and FKHR genes). For unknown reasons, some alveolar RMS lack this finding and yet still form and grow. In this grant, Dr. Barr tried to determine how and why some rhabdomyosarcomas do not have the usual gene fusion, which causes abnormal growth. Dr. Barr published an ESUN article based on his work.