Pediatrics

Rhabdomyosarcoma

OVERVIEW: What every practitioner needs to know

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. About 350 cases are diagnosed in the United States each year. RMS occurs in all age groups; the proportion of patients diagnosed in various age groups is: <1 year of age - 4%; 1 to 4 years - 34%; 5 to 9 years - 25%; 10 to 14 years - 22%; 15 to 21 years - 15%. The tumor occurs at many sites in the body, including orbit, parameningeal sites, other head and neck locations, extremity, and genitourinary sites. The presentation is dependent on the site of primary tumor. Most tumors are localized at diagnosis; only 15%-25% have distant spread of tumor.

Rhabdomyosarcoma is one of the small round blue cell tumors of childhood. The tumor is characterized by myogenic differentiation. Immunohistochemistry analysis is usually required for accurate diagnosis. The histologic subtypes of rhabdomyosarcoma are embyronal and alveolar histology. Embryonal tumors express loss of heterozygosity on chromosome 11p. Alveolar histology tumors express tumor-specific gene fusions associated with a poorer prognosis: PAX3-FOXO1 or PAX7-FOXO1, (FOXO1 was previously named FKHR). These fusions may be detected by PCR or FISH (fluorescent in situ hybridization).

Present Children's Oncology Group (COG) studies use both a Clinical Stage and Surgical Group to assess extent of disease and estimate prognosis. Risk is determined by age, the extent of disease, and histologic subtype, with alveolar histology having a less favorable outcome.

Curative treatment for rhabdomyosarcoma requires effective local disease control and multiagent chemotherapy. Complete surgical excision is recommended at diagnosis, if feasible for the patient. If surgical excision cannot be accomplished, children require local irradiation to maximize cure; however, irradiation can create irreversible long-term complications, particularly in very young children. All patients with rhabdomyosarcoma require multiagent chemotherapy. In the United States, the combination of vincristine, actinomycin and cyclophosphamide (VAC) is the mainstay of therapy. Studies are evaluating whether the addition of other chemotherapeutic agents will improve outcome in higher risk patients.

Are you sure your patient has rhabdomyosarcoma? What are the typical findings for this disease?

Rhabdomyosarcoma typically presents as a mass or lump; often this is painless. However, if the mass invades or obstructs other organs, it may cause pain or other symptoms. The clinical presentation is dependent on the anatomic site of the primary tumor. Biopsy of the tumor to obtain tissue for histopathologic diagnosis is required.

Head and neck region

Nearly 40% of RMS tumors arise in the head and neck region.

Orbit

Orbit primary tumors account for about one quarter of head and neck tumors, or 10% of all rhabdomyosarcomas. Tumors arising in this site typically cause proptosis, less commonly ophthalmoplegia. Orbital tumors typically occur in younger children. Most tumors arising in this site have embryonal histology. This site is considered a "favorable" site with overall good outcomes. Tumors in this site most often require only biopsy for diagnosis, with irradiation used for local control.

Parameningeal

Parameningeal tumors account for 50% of head and neck primaries, or about 16% of all rhabdomyosarcomas. These tumors present with nasal, aural, or sinus "congestion" and/or obstruction. Often children will also have mucopurulent or sanguineous discharge. Tumors may also cause cranial nerve palsies. Headache, vomiting, and systemic hypertension may occur if the tumor has extended intracranially. Common parameningeal sites include: nasal cavity, paranasal sinus, pterygopalatine/infratemporal fossa, nasopharynx, and middle ear. These sites have a propensity for involving the base of the skull and/or extending intracranially. Parameningeal tumors are classified as an "unfavorable" site. Few of these tumors are amenable to surgical resection and require local irradiation for local control.

Other head and neck

About 25% of head and neck primary tumors arise in non-orbital, non-parameningeal sites, including the scalp, face, buccal mucosa, oropharynx, larynx, and neck, accounting for about 10% of all rhabdomyosarcomas. Most often, these tumors present with a painless, progressively enlarging mass and remain localized. Often, these tumors can be surgically excised at diagnosis. Other head and neck sites are considered a "favorable" tumor site.

Genitourinary region

Tumors arising in the genitourinary region account for 23% of all rhabdomyosarcomas.

Bladder/prostate

Rhabdomyosarcomas arising in the bladder/prostate region typically present with signs and symptoms of bladder outlet obstruction and less commonly with bowel obstruction. Bladder tumors often grow intraluminally and have a polyploid (botryoid) appearance. Hematuria is common, and less often the tumor may present with extrusion of mucosanguineous tissue. Bladder tumors usually present in children under age 4. Prostate primary tumors may occur in older males, and may present with very large pelvic masses and signs of urinary obstruction. Bladder tumors tend to remain localized, but prostate tumors often disseminate. The bladder and prostate are considered "unfavorable" primary sites of presentation.

Male genital tract

Paratesticular rhabdomyosarcoma usually presents as a painless, unilateral scrotal mass. In young children, these tumors are most often embryonal histology, but in older boys tumors arising in this site may be alveolar histology. In those over the age of 10, there is higher risk of tumor spread to regional retroperitoneal lymph nodes. Modified retroperitoneal lymph node dissection is recommended in COG studies for accurate staging at this site for patients 10 years of age and older. Resection of primary scrotal tumors must be accomplished via an inguinal surgical approach.

Female genital tract

Vaginal tumors typically present with extrusion of polyploid (botryoid) mass and are most often embryonal histology. They arise almost exclusively in very young girls, presenting with mucosanguineous discharge similar to that seen with a foreign body. Regional lymph node involvement is uncommon. Vaginal and uterine primary tumors are considered a "favorable" site.

Extremity

Extremity rhabdomyosarcomas account for 20% of all RMS; they present with a mass in the affected body part. Pain, redness, and tenderness may occur. One-half to three-quarters of extremity tumors are alveolar histology, with up to one-half of these tumors presenting with regional lymph node spread. For this reason, regional lymph node sampling is required for accurate staging. These tumors may be locally extensive and not easily amenable to primary tumor resection. Extremity is an "unfavorable" tumor site.

Other sites

Among all rhabdomyosarcomas, 21% present in other body sites. Tumors arising in the trunk have a tendency for local recurrence despite wide local excision, and often are quite large at presentation. Primary intrathoracic and retroperitoneal/pelvis primary tumors may also be very large at diagnosis, because they are deep within the body and create few symptoms. There is a high rate of local recurrence at these sites. Perineal/perianal region tumors are rare; they may mimic abscesses or polyps and are often alveolar histology. Biliary tract tumors are even rarer, typically presenting with obstructive jaundice. Other rare sites of presentation include: liver, brain, trachea, heart, breast, and ovary.

Diagnosis: Pathologic and molecular

Rhabdomyosarcoma is one of the small round blue cell malignancies of childhood. The distinguishing feature of rhabdomyosarcoma is skeletal myogenic differentiation. On routine H&E staining, rhabdomyosarcoma may show cross-striations characteristic of skeletal muscle, or characteristic rhabdomyoblasts. Immunohistochemistry is typically required for accurate diagnosis, with specific staining for muscle-related genes or proteins, including muscle-specific actin and myosin, desmin, myoglobin, Z-band protein, MyoD, and myogenin. Recent studies have confirmed the utility and potential prognostic significance of the intensity and staining pattern of myogenin.

Present COG studies require central pathologic review, using the modified International Classification of Rhabdomyosarcoma. This system recognizes two main histologic subtypes of rhabdomyosarcoma: embyronal and alveolar histology.

Some rhabdomyosarcomas are classified as sclerosis subtype; some tumors may have anaplasia. Anaplastic tumors appear more aggressive histologically, but multivariate analysis has not shown anaplasia to be independently associated with an unfavorable outcome.

Rarely, tumors cannot be subclassified, usually because of inadequate specimen or suboptimal fixation. These are called rhabdomyosarcoma NOS (not otherwise specified). Sarcoma NOS and undifferentiated sarcomas are not rhabdomyosarcoma, and are treated on COG studies for non-rhabdomyosarcoma soft tissue sarcomas.

Embryonal rhabdomyosarcoma

Embryonal histology is most common and usually is associated with a more favorable prognosis. Tumors have a stroma-rich, less dense, spindle appearance, often with scattered large rhabdomyoblasts. Spindle cell RMS is a variant of embryonal RMS that shows more elongated leiomyomatous differentiation. Botryoid RMS is also a variant form of embryonal RMS that typically arises in bladder, vagina and nasopharynx; it grows as a polypoid mass under an epithelial surface. Histologically botryoid tumors have a dense tumor cell layer under the epithelial surface (cambium layer). The spindle cell and botryoid variants are associated with the most favorable prognosis of all embryonal histology tumors.

Embryonal histology tumors show loss of the maternal allele (loss of heterozygosity) at 11p15 with duplication of the paternal allele, leading to higher IGF-2 expression.

Alveolar rhabdomyosarcoma

Alveolar RMS is characterized by densely packed, small round cells lining stromal septations, reminiscent of pulmonary alveoli. A solid variant of alveolar RMS with these same dense small round tumor cells, but lacking the septations, is also recognized. Typically, alveolar RMS stains very strongly with myogenin. Many studies have reported worse outcome for patients with alveolar RMS.

Two reciprocal chromosomal translocations occur in alveolar histology tumors. The t(2;13)(q35;q14) translocation fuses the PAX3 gene at chromosome 2q35 to the FOXO1 (previously called FKHR) gene at chromosome 13q14. Less common, a (t(1;13)(p36;q14) translocation fuses the PAX7 gene at chromosome 1p36 to FOXO1. Both translocations are detected by PCR and FISH techniques. The significance of the specific gene fusion type is uncertain, with some studies suggesting that patients with PAX7 fusions have a more favorable prognosis than those with PAX3 fusions. Gene expression profiling studies demonstrate unique gene signatures for these translocations that may be useful for classification and estimating prognosis. Some rhabdomyosarcomas have the histologic appearance of alveolar RMS but lack either gene fusion; these tumors typically have gene expression profiles indistinguishable from embyronal RMS.

What other disease/condition shares some of these symptoms?

Depending on the site of presentation, rhabdomyosarcoma may be confused with some benign lesions. However, usually initial imaging studies will clearly delineate an aggressive tumor mass consistent with malignancy. Histologically, rhabdomyosarcoma must be differentiated from the other common small round blue cell malignancies that occur in children, including lymphoma, Ewing sarcoma, and neuroblastoma.

What caused this disease to develop at this time?

  • Most rhabdomyosarcomas occur sporadically.

  • Some familial syndromes are associated with increased risk for development of rhabdomyosarcoma, including: neurofibromatosis (NF-1), Li-Fraumeni syndrome (germline mutations of the p53 tumor suppressor gene), Beckwith-Wiedemann syndrome (abnormalities of 11p15) and Costello syndrome (point mutations in the H-ras gene).

  • Epidemiological studies have noted that use of marijuana and cocaine in parents is associated with a higher risk of rhabdomyosarcoma in offspring. A case-control study noted an association between prenatal X-ray exposure and development of rhabdomyosarcoma.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Routine CBC, comprehensive chemistry profiles, and urinalysis should be obtained in all patients. Unless the tumor has spread to marrow and widely replaced normal bone marrow function, the CBC is usually normal. Very rarely, the marrow is completely replaced by tumor and may be confused for leukemia. The chemistry profile is usually also normal unless tumor obstruction has caused organ dysfunction. Occasionally with widespread disease the lactate dehydrogenase (LDH) may be elevated.

  • Biopsy or resection of tumor is required for accurate diagnosis.

  • Bone marrow aspirate and core biopsy is required on COG studies for complete staging. In lower risk patients without other evidence of metastatic disease, involvement of the bone marrow at diagnosis is rare.

Would imaging studies be helpful? If so, which ones?

  • Imaging is required to assess the extent of the primary tumor and to evaluate the patient for metastatic disease. The specific imaging modalities are dependent on the primary tumor site.

  • In many sites, magnetic resonance (MR) imaging is superior for delineating the extent of primary tumor. Sites best imaged by MR include head and neck sites, including orbit and parameningeal primary tumors and extremity sites. MR is the best modality for assessing possible intracranial extension of tumor. For genitourinary sites, depending on the exact tumor site, either double contrast computed tomography (CT) imaging and/or MR imaging is required. For many tumor sites, particularly GU and trunk, complete imaging of the abdomen and pelvis are required for assessment of disease extent and possible retroperitoneal lymph node involvement.

  • Computed tomography (CT) imaging of the chest is required for accurate assessment of pulmonary metastatic disease.

  • Technitium-99m diphosphonate bone scanning is used to assess for the presence of bony metastatic disease.

  • In many centers, positron emission tomography (PET or PET/CT) imaging is preferred for assessment of metabolic disease activity and for assessment of metastatic disease. Its utility in assessing response to therapy is being evaluated.

Assessing extent of disease: Rhabdomyosarcoma Stage and Group

Assessing extent of disease is crucial. In COG studies, both a Clinical Staging system and Surgical Grouping system is used to classify patients into risk groups and assign therapy. The Surgical/Pathological Group has been used since the development of the first cooperative group trials for rhabdomyosarcoma initiated by the Intergroup Rhabdomyosarcoma Study Group (IRSG) in the 1970's. Because Group assignment is dependent on local surgical expertise, and to make comparisons with other international studies, the IRSG developed a pretreatment, site-modified TNM staging system.

TNM Clinical Stage

Table I shows the pretreatment, site-modified TNM clinical staging system for rhabdomyosarcoma developed by the IRSG.

Table I.

TNM Clinical Staging System
Stage Sites T-invasivness T-size N M
1 Orbit,Head/neck (non-parameningeal);Genitourinary (non-bladder prostate);Biliary tract/liver T1 or T2 a or b Any M0
2 Bladder/prostate;Extremity;Cranial parameningeal;Other T1 or T2 a N0 or Nx M0
3 Bladder/prostate;Extremity;Cranial parameningeal;Other T1 or T2 ab N1Any M0
4 All T1 or T2 Any Any M1

IRS Group

Clinical Group I: Localized disease, completely resected (requires microscopic confirmation of complete resection). Any nodes must be negative for tumor.

a. Confined to muscle or organ of origin

b. Contiguous involvement

Clinical Group II: Total gross resection with evidence of regional spread

a. Grossly resected tumor with microscopic margins

b. Regional disease with involved nodes, completely resected

c. Regional disease with involved nodes, grossly resected but with evidence of microscopic residual disease

Clinical Group III: Incomplete resection with gross residual disease

a. Biopsy only

b. Gross resection of primary (>50%)

Clinical Group IV: Distant metastatic disease present at onset

Metastases may occur in lung, liver, bone, bone marrow, brain, and distant muscle and lymph nodes. Presence of positive cytology in CSF, pleural or abdominal fluid or implants on pleural or peritoneal surfaces place the patient in Group IV.

If you are able to confirm that the patient has rhabdomyosarcoma, what treatment should be initiated?

  • Treatment paradigms for rhabdomyosarcoma are complicated and typically multidisciplinary, because curative therapy requires both control of the local tumor and systemic chemotherapy. Patients who are eligible for cooperative group or institutional research studies should be encouraged to enroll. For the active COG therapy studies, patients are required to enroll on the D9902 Soft Tissue Sarcoma Diagnosis, Biology and Banking Protocol. This study facilitates the collection and banking of tumor tissue and other biologic specimens, and provides for central pathology review of all tumors and assessment of tumor biologic characteristics. Present COG studies triage patients to one of three treatment approaches, based on stratification of prognostic factors.

  • Complete surgical excision of the primary tumor at diagnosis – defining the patient as Group I – is recommended for small and relatively easily excised tumors. For patients with embyronal RMS, complete excision obviates the need for local irradiation. Almost all patients with paratesticular tumors undergo primary excision, as do many with head and neck (non-orbit, non-parameningeal sites) tumors. Some vaginal primary tumors can be primarily excised. However, for tumors in many common primary sites, the appropriate initial approach is tumor biopsy, including most orbit, parameningeal, many bladder/prostate and extremity primary tumors, as well as larger tumors arising in the trunk. Regional lymph node excision for staging is required for all extremity tumors and for paratesticular tumors in patients over 10 years of age. Delayed surgical excision was tested in the COG D9803 studies, but many patients were not amenable to complete local excision even after chemotherapy.

  • The favorable or lower risk group is restricted to patients with embryonal histology tumors. This group has overall excellent outcome. Subset 1 of the favorable risk group includes patients with embryonal RMS that are either Stage 1 or 2, Clinical Group I or II; or with Stage 1 Clinical Group III orbit primary tumors. Subset 2 includes patients with embryonal RMS that are either Stage 1, Clinical Group III non-orbital tumors or Stage 3 Clinical Group I or II tumors. The most recently completed COG study, ARST0331, provided four cycles of cyclophosphamide (VAC) therapy, followed by dactinomycin (VA) (Subset 1 patients 24 weeks of therapy; Subset 2 patients 48 weeks of therapy). All Group II or III patients received irradiation at week 13.

  • The intermediate risk group comprises about one-half of all patients with rhabdomyosarcoma. About 2/3 of this group can be cured with present therapy approaches. This group includes patients with embryonal RMS that are Stage 2 or 3, Group III disease and all patients with non-metastatic alveolar RMS. The intermediate risk group has been the subject of most randomized prospective studies of chemotherapy combinations. A large series of studies over the last four decades has not shown any combination chemotherapy to be superior to VAC (although exact doses, schedules and length of therapy have varied substantially in these studies). The open COG study for intermediate risk patients randomly allocates patients to every-three-week VAC (with cyclophosphamide dose at 1.2 g/m2/dose) vs. alternating VAC and vincristine irinotecan (a two-drug combination with high activity in both previously untreated patients and those with recurrent rhabdomyosarcoma). This protocol also tests early delivery of local irradiation at week 4.

  • Patients with metastatic rhabdomyosarcoma comprise the high-risk group, about 15%-20% of patients. This group of patients has a predicted survival of about 20%-30%. Patients under age 10 years at diagnosis with embryonal RMS and those with a single-organ site of metastatic disease have the most favorable outlook; the under-age-10 embryonal patients are sometimes excluded from research studies of high-risk patients for this reason. The recently completed COG ARST0431 study evaluated initial therapy with vincristine plus irinotecan, followed by dose-compressed therapy using cycles of vincristine, cyclophosphamide and doxorubicin alternating with cycles of ifosfamide/etoposide. The very early outcome was encouraging with this approach; final analysis of this study is pending. A new study has been activated in COG (ARST08P1) using this same backbone of therapy, adding either an IGF-1R antibody (IMC-A12) to the entire therapy that evaluates increased doses of the antibody, or temozolomide to the vincristine and irinotecan phases of therapy.

  • Radiation therapy dose varies depending on Clinical Group, Stage, and site of primary tumor. The COG study recommendations are: Clinical Group I embryonal RMS patients do not require irradiation; Clinical Group I alveolar RMS patients - 3600 cGy; Clinical Group II patients without nodal involvement - 3600 cGY, with nodal involvement - 4140 cGY; Clinical Group III, orbit primary - 4500 cGy, non-orbit primary and all other Group III patients - 5040 cGy. Radiation modalities including external beam, intensity-modulated radiation therapy (IMRT), brachytherapy, or proton therapy, depending on the site and local expertise. Several centers now favor proton irradiation in selected sites to minimize irradiation exposure to normal tissues.

  • The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) study is presently evaluating in a prospective trial the addition of doxorubicin to a backbone of ifosfamide, vincristine and actinomycin, with a second randomization evaluating a maintenance phase of therapy with vinorelbine and cyclophosphamide.

What are the adverse effects associated with each treatment option?

The immediate adverse effects of surgery are usually limited to the immediate perioperative period. Only in rare circumstances is ablative surgery that reduces normal organ function indicated for treatment of rhabdomyosarcoma.

Most chemotherapy agents share many common side effects, including myelosuppression, nausea and vomiting, and hair loss. Myelosuppression often results in severe neutropenia, with increased risk for infection and need for growth factor support (granulocyte colony-stimulating factor [G-CSF] or Neupogen®), and the possible need for RBC and platelet transfusion support. Other common adverse reactions are specific for individual chemotherapy agents. Vincristine may cause jaw pain, peripheral nerve dysfunction, and constipation. Cyclophosphamide may rarely cause hemorrhagic cystitis, and may cause sterility at higher cumulative doses. Actinomycin may cause increased sensitivity to irradiation, and doses are typically omitted during the radiation therapy phase of treatment. In rare situations, high doses of actinomycin may cause sinusoidal liver dysfunction.

Irradiation often causes mild to moderate skin reactions at higher doses. If mucosal surfaces are in the radiation field, mucositis may cause significant pain and require intravenous fluid support and enteral or parenteral nutritional support.

Late effects of therapy are discussed below.

What are the possible outcomes of rhabdomyosarcoma?

Patients with favorable risk as defined above typically have good to excellent cure rates, with 85%-90% or more patients cured. Research efforts have been focused on tailoring therapy to lessen late effects of therapy. However, attempts to eliminate or minimize cyclophosphamide exposures and to avoid use of irradiation have typically led to poorer outcomes.

About 2/3 of intermediate risk patients will be cured with present multidisciplinary therapy. As discussed above, no chemotherapy regimen has been shown superior to VAC chemotherapy. Typically, patients will need relatively high doses of local irradiation to maximize cure rates.

Only 20%-30% of patients with metastatic rhabdomyosarcoma will be cured with present multiagent therapy approaches. The present COG trial is investigating two new agents in an attempt to improve outcome. High-dose therapy with stem cell reinfusion has not improved outcome.

What causes this disease and how frequent is it?

  • Rhabdomyosarcoma is the single most common histology of soft tissue sarcoma occurring in children and adolescents. There are 4.3 cases per million children 20 years of age or younger. Among the extracranial solid tumors of childhood, RMS is the third most common neoplasm after neuroblastoma and Wilms' tumor.

    • About 350 cases of rhabdomyosarcoma are diagnosed in the United States each year. RMS occurs in all age groups: <1 year of age - 4%; 1 to 4 years - 34%; 5 to 9 years - 25%; 10 to 14 years - 22%; 15 to 21 years - 15%. There is a slight male predominance.

    • Epidemiological studies have noted that use of marijuana and cocaine in parents is associated with a higher risk of rhabdomyosarcoma in offspring. A case-control study noted an association between prenatal X-ray exposure and development of rhabdomyosarcoma.

  • Most cases of rhabdomyosarcoma are sporadic, without any predisposing features. Patient with neurofibromatosis (NF-1) are at increased risk for development of RMS. Patients with Li-Fraumeni syndrome (loss of normal p53 tumor suppressor gene function) are at increased risk for rhabdomyosarcoma, as well as early onset breast cancer, other sarcomas, and adrenocortical carcinoma. RMS is associated with Beckwith-Wiedemann syndrome, a fetal overgrowth syndrome associated with abnormalities on 11p15, where the IGF-2 gene is located. Costello syndrome, caused by heterozygous de novo point mutations in the Harvey rat sarcoma (H-ras) gene, is also associated with increased risk for development of RMS. Of the 268 cases of Costello syndrome reported, 19 have developed RMS.

How do these pathogens/genes/exposures cause the disease?

  • It is unknown how exposure to marijuana or cocaine may influence the development of rhabdomyosarcoma. For the associations with genetic disorders, loss of normal cell cycle control (germline p53 mutations), or increased activation of the IGF pathway may lead to loss of normal cellular growth or increased cell stimulation and proliferation.

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

Late effects of therapy depend on the specific primary chemotherapy regimen, dose, tissues treated with irradiation, and surgical defects created.

Children and adolescents who receive high-dose cyclophosphamide therapy are at high risk for sterility and some risk for development of bladder cancer.

Patients treated with doxorubicin may experience late cardiac events, including cardiac failure.

Patients who receive etoposide are at risk for development of secondary acute myeloid leukemia (AML), and those that receive high doses of alkylators and doxorubicin may also be at risk for secondary leukemias.

Children receiving moderate to high doses of irradiation will have somatic growth problems. This is particularly concerning for very young children with substantial growth potential.

Irradiation to the pelvis may result in substantial bladder dysfunction.

If irradiation involves the pituitary gland, patients are at risk for growth hormone deficiency and other endocrinopathies.

Irradiation also poses a long-term risk for second malignant neoplasms, including radiation-induced sarcomas.

Are additional laboratory studies available; even some that are not widely available?

N/A

How can rhabdomyosarcoma be prevented?

Rhabdomyosarcoma cannot be prevented.

What is the evidence?

Malempati, S, Hawkins, DS. "Rhabdomyosarcoma: review of the Children's Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies". Pediatr Blood Cancer. vol. 59. 2012. pp. 5-10.

(This is an up-to-date and concise review of the patient allocation by risk group and present treatment and research philosophy of the Soft Tissue Sarcoma Committee of the COG.)

Parham, DM, Alaggio, R, Coffin, CM. "Myogenic tumors in children and adolescents". Pediatr Dev Pathol. vol. 15. 2012. pp. 211-38.

(A very recent review outlining the pathologic and genetic features of rhabdomyosarcoma, written by the leading pediatric pathologists who provide central review for soft tissue sarcomas in the COG.)

Missiaglia, E, Williamson, D, Chisholm, J. "PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification". J Clin Oncol. vol. 30. 2012. pp. 1670-7.

(Newly published data further substantiating the importance of gene fusion as a key prognostic marker in rhabdomyosarcoma.)

Raney, RB, Walterhouse, DO, Meza, JL. "Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group". J Clin Oncol. vol. 29. 2011. pp. 1312-8.

(The definitive research report for results of patients with lower risk rhabdomyosarcoma treated on the D9602 study, showing excellent long-term outcome. A more recent low-risk trial has been completed by COG (ARST0331), but these results have not yet been published.)

Arndt, CA, Stoner, JA, Hawkins, DS. "Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803". J Clin Oncol. vol. 27. 2009. pp. 5182-8.

(The most recently completed prospective, randomized phase III study conducted by the COG for patients with intermediate-risk rhabdomyosarcoma. The study again confirmed that vincristine, actinomycin and cyclophosphamide remain the standard therapy for this patient group.)

Oberlin, O, Rey, A, Sanchez de Toledo, J. "Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 Study". J Clin Oncol. vol. 30. 2012. pp. 2457-65.

(The most recent prospective, randomized study from the European MMT Group that also shows vincristine, actinomycin and an alkylator (in this case ifosfamide) continues to provide the best outcome for patients with more advanced-stage non-metastatic rhabdomyosarcoma.)

Ongoing controversies regarding etiology, diagnosis, treatment

The proportion of patients diagnosed with alveolar histology tumors has evolved both in COG and European clinical trials. During the Intergroup Rhabdomyosarcoma Study Group (IRSG) D-series of COG trials conducted from the late 1990s until 2005, the presence of any alveolar component histologically was sufficient to make a diagnosis of alveolar RMS. This evolution of histologic diagnosis resulted in a higher proportion of patients with alveolar histology tumors, and with a higher proportion of alveolar tumors that lacked a specific gene fusion. The ongoing COG trials now require a predominance of alveolar histology to make a diagnosis of alveolar RMS. Recent convenience cohorts collected from both the European and IRS cooperative groups show that fusion status (presence of either PAX3 or PAX7 translocation), rather than histology, best correlates with gene signatures and with patient outcome.

The best approach for local control, particularly in some selected sites, and risk benefit ratio for local irradiation continues to be a difficult and complicated decision. COG studies have assigned risk group at diagnosis in part dependent on resectability of the primary site. In certain sites, particularly bladder, female vaginal, and extremity sites, studies have attempted to evaluate delayed surgical excision and/or reduced or complete avoidance of irradiation. In the D9803 COG study, delayed surgical resection was an option for local control, but only a minority of patients were treated in this manner, confounding the analysis of this therapy approach. For vaginal primary tumors, attempts at avoidance of complete surgical excision and irradiation have resulted in an unacceptably high rate of local recurrence. European investigators have generally favored local control approaches that avoided or minimized irradiation in certain selected tumor sites, generally noting higher rates of local tumor recurrence. However, when rhadbomyosarcoma occurs in very young children (particularly those less than 3 years of age) irradiation has devastating long-term effects that have substantially limited the enthusiasm for using local irradiation.

The optimal approach for patients with lower risk rhabdomyosarcoma is not clearly delineated. The COG study D9602 reported overall excellent survival outcome, but many of these patients received multiple courses of VAC with high-dose cyclophosphamide (2.2 g/m2/dose), dose levels expected to cause sterility. The most recent COG trial, ARST0331, used only four cycles of VAC (with a lower cyclophosphamide dose of 1.2 g/m2/dose), but early analysis suggests a less favorable outcome, particularly in Subset 2 patients.

For patients with intermediate-risk rhabdomyosarcoma, no COG trial has demonstrated that any therapy combination is better than VAC, despite several decades of prospective controlled trials. The present COG study, ARST0531, is evaluating whether substitution of vincristine and irinotecan for some VAC cycles will improve outcome. This trial is also evaluating the use of early (week 4) local irradiation for local tumor control.

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