jueves, 7 de marzo de 2019

Childhood Rhabdomyosarcoma Treatment (PDQ®) 2/2 —Health Professional Version - National Cancer Institute

Childhood Rhabdomyosarcoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute





National Cancer Institute

Treatment of Previously Untreated Childhood Rhabdomyosarcoma





Because rhabdomyosarcoma can arise from multiple sites, surgical care decisions and radiotherapeutic options must be tailored to the specific aspects of each site, and should be discussed with a multidisciplinary team, including representatives of those specialties and pediatric oncologists. Surgical management of the more common primary sites is provided in the Local Control Management With Surgery and RT by Primary Sites of Disease section of this summary.


Surgery (Local Control Management)

In recent years, the predominant site of treatment failure in patients with initially localized rhabdomyosarcoma has been local recurrence. Both surgery and radiation therapy (RT) are primarily measures taken to produce local control, but each has risks and benefits. Surgical removal of the entire tumor should be considered initially, but only if functional and cosmetic impairment will not result.[1] With that stipulation, complete resection of the primary tumor, with a surrounding margin of normal tissue and sampling of possibly involved lymph nodes in the draining nodal basin, is recommended. Important exceptions to the rule of normal margins exist (e.g., tumors of the orbit and of the genitourinary region).[2,3] The principle of wide and complete resection of the primary tumor is less applicable to patients known to have metastatic disease at the initial operation, but it is an alternative approach if easily accomplished without loss of form (cosmesis) and function.
Patients with microscopic residual tumor after their initial excisional procedure appear to have improved prognoses if a second operative procedure (primary re-excision) to resect the primary tumor bed before beginning chemotherapy can achieve complete removal of the tumor without loss of form and function.[4]
There is little evidence that debulking surgery (i.e., surgery that is expected to leave macroscopic residual tumor) improves outcome, compared with biopsy alone; therefore, debulking surgery is not recommended for patients with rhabdomyosarcoma.[5][Level of evidence: 2A] In a retrospective study of 73 selected patients, second-look procedures (also called delayed primary excision) identified viable tumor that remained after initial chemotherapy; 65 of these patients had also received RT. Patients with viable tumor had shorter event-free survival (EFS) rates than did those without viable tumor, but there was no effect on overall survival (OS).[6] Thus, delaying surgery until after chemotherapy is preferred.
For children with low-risk rhabdomyosarcoma, local control was not diminished with reduced doses of RT after surgical resection.[7] Subsequently, delayed primary excision was evaluated by the Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG-STS) in 73 intermediate-risk rhabdomyosarcoma patients enrolled on D9803 (1999–2005).[8] Delayed primary excision was completed in 45% of Group III rhabdomyosarcoma patients with tumors of the bladder dome, extremity, and trunk; 84% of those who had a delayed primary excision with no gross residual disease remaining were eligible for modest radiation dose reduction (patients with no or only microresidual tumor after delayed primary excision). Local control outcomes were similar to IRS-IV results with RT alone.[6]

Radiation Therapy (RT) (Local Control Management)

Local control remains a significant problem in children with rhabdomyosarcoma. In IRS II, of patients who achieved a complete remission with chemotherapy and surgery, almost 20% of patients with Groups I to III disease relapsed locally or regionally, and 30% of patients with Group IV disease relapsed locally or regionally. Local or regional relapses accounted for 70% to 80% of all relapses in children with Groups I to III disease and 46% of all relapses in patients with Group IV disease.[9] RT is an effective method for achieving local control of the tumor for patients with microscopic or gross residual disease after biopsy, initial surgical resection, or chemotherapy.
  • Patients with completely resected embryonal rhabdomyosarcoma (Group I) do well without RT. However, because approximately 75% of embryonal rhabdomyosarcoma patients are Groups II to IV, RT is used in most patients with rhabdomyosarcoma.[10]
  • An earlier study of Group I patients with alveolar rhabdomyosarcoma and undifferentiated soft tissue sarcoma found that omission of RT was followed by decreased local control.[11] A subsequent review of patients with only alveolar rhabdomyosarcoma found that the improvement in outcome with RT did not reach statistical significance for patients with Stage 1 and Stage 2 tumors. There were very few patients (n = 4) with large tumors (Stage 3, >5 cm) who did not receive RT, but their outcome was poor.[12][Level of evidence: 3iiiDii]
In more than 50% of Group II rhabdomyosarcoma patients, local recurrence was the result of noncompliance with guidelines or omission of RT.[9] A review of European trials was conducted by the German Cooperative Weichteilsarkom Studiengruppe (CWS) between 1981 and 1998, in which RT was omitted for some Group II patients. This review demonstrated a benefit to using RT as a component of local tumor control for all Group II patient subsets, as defined by tumor histology, tumor size, and tumor site.[13]
The predominant type of relapse for patients with Group III disease is local failure. Approximately 35% of patients with Group III disease either fail to achieve a complete remission or relapse locally. Patients with tumor-involved regional lymph nodes at diagnosis also have a higher risk of local and distant failure than do patients whose lymph nodes are uninvolved.[14]

External-beam RT

As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the following:
  • Site of primary tumor.
  • Postsurgical amount of residual disease (none vs. microscopic vs. macroscopic), if surgery was performed.
  • Presence of involved lymph nodes.
For optimal care of pediatric patients undergoing radiation treatments, it is imperative that radiation oncologists, radiation technicians, and nurses who are experienced in treating children are available. An anesthesiologist may be necessary to sedate young patients. Computerized treatment planning with a 3-dimensional planning system should be available. Techniques to deliver radiation specifically to the tumor while sparing normal tissue (e.g., conformal radiation therapy, intensity-modulated radiation therapy [IMRT], volumetrical modulated arc therapy [VMAT], proton-beam therapy [charged-particle radiation therapy], or brachytherapy) are appropriate.[15-20]
Evidence (radiation delivery techniques):
  1. Dosimetric comparison of proton-beam RT and photon IMRT treatment plans has shown that proton-beam treatment plans can spare more normal tissue adjacent to the targeted volume than IMRT plans.[21,22] A prospective, phase II trial compared proton and IMRT in pediatric rhabdomyosarcoma.[23]
    • Target coverage was comparable between proton and IMRT plans. However, the mean integral dose for IMRT was 1.8 to 3.5 times higher than with proton therapy, depending on the site. Proton radiation lowers the radiation dose in the uninvolved tissues surrounding the tumor and, thus, improves normal tissue sparing when compared with IMRT.
    • Follow-up of treated patients remains short, and there are no data available to determine if the reduction in dose to adjacent tissue will result in improved functional outcome or reduce the risk of secondary malignancy.
  2. A retrospective review of patients with intermediate-risk rhabdomyosarcoma compared 3-dimensional conformal RT with IMRT.[24][Level of evidence: 2B]
    • IMRT improved the target coverage but did not show a difference in local failure rate or EFS.
  3. In a study on the patterns of failure in 11 of 66 children with nonmetastatic rhabdomyosarcoma who were treated with proton RT, the following was observed:[25]
    • A 2-year local control rate of 88%.
    • All 11 children with local recurrences were Group III (gross residual disease) and relapsed in the radiation field, suggesting that the conformality of the proton field did not lead to out-of-field failures. The radiation dose was 41.4 Gy (relative biological effectiveness [RBE]) to the prechemotherapy tumor volume and 50.4 Gy (RBE) to the visible disease at the time of RT.
    • Eight patients with local recurrences had tumors larger than 5 cm at diagnosis, and current guidelines escalate doses to 59.4 Gy for these patients.
    • This study does not delineate whether the recurrence was in the 41.4 Gy or 50.4 Gy irradiated volumes.
The radiation dose according to Group, histology, and disease site for children with rhabdomyosarcoma is described in Table 6:
Table 6. Radiation Therapy (RT) Dose According to Rhabdomyosarcoma Group, Histology, and Site of Disease (Children's Oncology Group [COG])
GroupTreatment
Group I
EmbryonalNo RT.
Alveolar36 Gy to involved (prechemotherapy) site.
Group II
N0 (microscopic residual disease after surgery)36 Gy to involved (prechemotherapy) site.
N1 (resected regional lymph node involvement)41.4 Gy to involved (prechemotherapy) site and nodes.
Group III
Orbital and nonorbital tumors45 Gy for orbital tumors in complete remission. For other sites and orbital tumors in partial remission, 50.4 Gy with volume reduction after 36 Gy if excellent response to chemotherapy (or complete remission after delayed re-excision) and noninvasive pushing tumors; no volume reduction for invasive tumors. 59.4 Gy boost to residual disease at 9 weeks for tumors >5 cm.
Group IV
As for other Groups and including all metastatic sites, if safe and possible.Exception: lung (pulmonary metastases) treated with 12 Gy to 15 Gy depending on age is under consideration.
The RT dose depends predominantly on the histology and amount of residual disease, if any, after the primary surgical resection.
  • Group II. In general, patients with microscopic residual disease (Group II) receive 36 Gy of RT if they do not have involved lymph nodes and 41 Gy in the presence of involved nodes.[11,26] Low-risk patients (embryonal histology and favorable sites with microscopic residual disease) treated on a COG study had excellent local control with 36 Gy, which was comparable to historic controls who received 41.4 Gy.[7] For Group II patients, 36 Gy to 41.4 Gy is recommended depending on nodal status.
  • Group III. IRS-II patients with gross residual disease (Group III) who received 40 Gy to more than 50 Gy had locoregional relapse rates greater than 30%, but higher doses of radiation (>60 Gy) were associated with unacceptable long-term toxic effects.[27,28] Group III patients on the IRS-IV standard treatment arm received 50.4 Gy to 59.4 Gy, with 5-year progression-free survival of 55% to 75% and a local control rate of 85% to 88%.[29] Select COG subgroups with Group III disease received somewhat reduced radiation doses of 36 Gy after delayed gross total resection with negative margins, and 41.4 Gy if the margins were microscopically involved or the nodes were positive. In the recent COG-D9602 study, a limited number of low-risk patients had a greater than 85% likelihood of local control with 36 Gy.[7] This approach is only appropriate for select site-specific subgroups.
In the D9803 study of patients with intermediate-risk rhabdomyosarcoma, local control was 90% in 41 patients with Groups I and II alveolar rhabdomyosarcoma, but was lower in 280 patients with Group III embryonal (80%) and alveolar (83%) rhabdomyosarcoma. Histology, regional lymph node status, and primary site were not related to the likelihood of local failure; however, the local failure rate for 47 patients with retroperitoneal tumors was 33% (probably caused by tumors ≥5 cm in diameter) compared with 14% to 19% for patients with bladder/prostate, extremity, and parameningeal tumors. Tumor size was the strongest predictor of local failure (10% for patients with primary tumors <5 cm vs. 25% for larger tumors; P = .0004).[30][Level of evidence: 3iiiDi]
The treated radiation volume should be determined by the extent of tumor at diagnosis before surgical resection and before chemotherapy. A margin of 2 cm is generally used, including clinically involved regional lymph nodes. However, with conformal plans and image-guided RT, a margin of 1 cm to 1.3 cm to a clinical target volume or planning target volume may be used.[11] While the volume irradiated may be modified because of considerations for normal tissue tolerance, gross residual disease at the time of radiation should receive full-dose radiation. A reduction in volume after 36 Gy is appropriate in chemoresponsive disease for patients with noninvasive displacement (T1) that have regressed in size, but not for invasive tumors (T2).
The timing of RT generally allows for chemotherapy to be given for 1 to 3 months before RT is initiated. RT is usually given over 5 to 6 weeks (e.g., 1.8 Gy once per day, 5 days per week), during which time chemotherapy is usually modified to avoid the radiosensitizing agents dactinomycin and doxorubicin.
  • The IRS-IV trial included a randomized study that reported that the administration of RT twice a day, 6 to 8 hours apart, at 1.1 Gy per dose (hyperfractionated schedule), 5 days per week, was feasible but difficult to accomplish in small children who required sedation twice daily. Patients with localized, gross residual tumors (Group III) were randomly assigned to receive conventional, once-daily RT (total dose of 50.4 Gy) or the twice-daily hyperfractionated schedule (total dose of 59.4 Gy). There was no demonstrated advantage in terms of local control, but increased acute toxicity was observed with the increased dose.[31]
Thus, conventional RT remains the standard for treating patients who have rhabdomyosarcoma with gross residual disease.[32]

Brachytherapy

Brachytherapy, using either intracavitary or interstitial implants, is another method of local control and has been used in selected situations for children with rhabdomyosarcoma, especially for patients with primary tumors at a vaginal site [33-37] and selected bladder/prostate sites.[38][Level of evidence: 3iiiA] In small series from one or two institutions, this treatment approach was associated with a high survival rate and with retention of a functional organ or tissue in most patients.[34,39]; [40][Level of evidence: 3iiDii] Other sites, especially head and neck, have also been treated with brachytherapy.[41] Patients with initial Group III disease, who subsequently have microscopic residual disease after chemotherapy with or without delayed surgery, are likely to achieve local control with RT at doses of 40 Gy or more.[42]

Treatment of children aged 3 years and younger

Very young children (aged ≤36 months) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk of treatment-related morbidity.[7] As suggested above, reduced radiation doses may be appropriate if delayed surgery can provide negative margins. However, for patients who are unable to undergo surgical resection, higher doses of RT remain appropriate.[43] Radiation techniques are designed to maximize normal tissue sparing and should include conformal approaches, often with intensity-modulated techniques.
Delayed primary excision and radiation dose reduction are appropriate for all ages. However, the youngest patients frequently do not get appropriate RT because of concerns about normal tissue toxicity, and these are ideal patients for whom surgical resection by delayed primary excision is a particularly important consideration. Local control can be achieved by both RT and surgery; it may be optimal if both treatments are used, but at least one approach is necessary in addition to chemotherapy.
One of the few studies of infants younger than 1 year included 77 patients with nonmetastatic rhabdomyosarcoma (median age, 7.4 months); 57% of patients had embryonal rhabdomyosarcoma. In this study, the 5-year failure-free survival (FFS) was 57%, and OS was 76%. Most failures were local, often because RT was withheld in violation of protocol guidelines. In contrast, for infants treated according to guidelines, both FFS and OS were clearly superior.[44]

Surgery and RT by Primary Site of Disease (Local Control Management)

Head and neck

Primary sites for childhood rhabdomyosarcoma within the head and neck include the orbit; nonorbital head and neck and cranial parameningeal; and nonparameningeal, nonorbital head and neck. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed below.
  1. Orbit.
    Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[45,46] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[47,48] RT and chemotherapy are the standard of care, with survival in excess of 90% to 95%. For patients with orbital tumors, precaution should be taken to limit the RT dose to the lens, conjunctiva, and cornea.
    The COG studied administering less cyclophosphamide to reduce the risk of infertility. In the COG ARST0331 (NCT00075582) trial, only four cycles of therapy contained cyclophosphamide, for a total cyclophosphamide exposure of 4.8 g/m2. Sixty-two patients with Group III orbital embryonal rhabdomyosarcoma were treated. None of the 15 patients with radiographic complete response (CR) had local recurrences, compared with 6 of the 38 patients who had less than a CR after 12 weeks of vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy (P = .11). The authors concluded that for patients with Group III orbital embryonal rhabdomyosarcoma achieving a CR after VAC chemotherapy that includes modest-dose cyclophosphamide, 45 Gy of radiation may be sufficient for durable FFS. However, for patients with less than a CR who were treated with the ARST0331 systemic therapy, a different local therapy approach may be needed to achieve the control rate found in the IRS-IV trial (without the toxicity observed in the IRS-IV trial). At a minimum, this therapy can include radiation dose escalation to 50.4 Gy.[49][Level of evidence: 2Di]
  2. Nonorbital and cranial parameningeal.
    If the tumors are nonorbital and cranial parameningeal (arising in the middle ear/mastoid, nasopharynx/nasal cavity, paranasal sinus, parapharyngeal region, or pterygopalatine/infratemporal fossa), a magnetic resonance imaging (MRI) scan with contrast of the primary site and brain should be obtained to check for presence of base-of-skull erosion and possible extension onto or through the dura.[50-52] If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan with contrast of the same regions is indicated. Also, if there is any suspicion of extension down the spinal cord, an MRI scan with contrast of the entire cord should be obtained. The cerebrospinal fluid (CSF) should be examined for malignant cells in all patients with parameningeal tumors. Because complete removal of these tumors is difficult, owing to their location, the initial surgical procedure for these patients is usually only a biopsy for diagnosis.
    Nonorbital head and neck rhabdomyosarcomas, including cranial parameningeal tumors, are optimally managed by conformal RT and chemotherapy. Patients with parameningeal disease with intracranial extension in contiguity with the primary tumor and/or signs of meningeal impingement (i.e., cranial base bone erosion and/or cranial nerve palsy) do not require whole-brain irradiation or intrathecal therapy, unless tumor cells are present in the CSF at diagnosis.[50] Patients should receive RT to the site of primary tumor with a 1.5 cm margin to include the meninges adjacent to the primary tumor and the region of intracranial extension, if present, with a 1.5 cm margin.[51]
    The following studies have addressed the timing of RT. Both studies administered early irradiation to all patients with intracranial extension of the primary tumor.
    1. In a retrospective trial, starting RT within 2 weeks of diagnosis for patients with signs of meningeal impingement was associated with lower rates of local failure but was of borderline significance. When no signs of meningeal impingement were present, delay of RT for more than 10 weeks did not impact local failure rates.[51]
    2. A subsequent comparison of local control, FFS, and OS rates showed no statistical difference between early irradiation (day 0) for Group III patients in IRS-IV with cranial nerve palsy and/or cranial base erosion versus later initiation of RT (week 12) for Group III patients in D9803 who had similar evidence of meningeal involvement, suggesting that early RT for this group of patients is not necessary.[53][Level of evidence: 2A]
    3. A retrospective analysis of 47 patients with parameningeal primary sites suggested that the subgroup of adolescent patients with alveolar rhabdomyosarcoma (n = 13) might benefit from the addition of prophylactic irradiation (36 Gy) to bilateral cervical nodes.[54][Level of evidence: 3iiDii]
    4. A single-institution retrospective review identified 14 patients with head and neck alveolar rhabdomyosarcoma. All patients were treated with multiagent chemotherapy and radiation therapy to the primary site and clinically involved nodes.[55][Level of evidence: 3iiiDiii]
      • There were ten relapses in the cohort: seven regional nodal, one combination local and regional nodal, and two leptomeningeal.
      • In six of eight patients (75%) with no nodal disease at diagnosis, isolated regional nodal relapse developed.
      • The authors recommended elective nodal irradiation to treat at-risk draining lymph node stations relative to the primary tumor site for patients who present with head and neck alveolar rhabdomyosarcoma.
    An analysis of 1,105 patients with localized parameningeal rhabdomyosarcoma treated on protocols from 1984 to 2004 in North America and Europe found that several prognostic factors could be used to define subgroups of patients with significantly different survival rates. The OS rate at 10 years for the entire cohort was 66%. Patients with zero or one adverse factor (age <3 or >10 years at diagnosis, presence of meningeal involvement, tumor diameter >5 cm, unfavorable primary parameningeal site) had a 10-year OS rate of 80.7%; those with two factors had a 10-year OS rate of 68.4%; and those with three or four factors had a 10-year OS rate of 52.2%. Patients who did not receive RT as a component of their initial therapy had a poor prognosis, and their tumors were not salvaged with introduction of RT after relapse, establishing RT as a necessary component of initial treatment.[56][Level of evidence: 3iiiA]
    Children who present with tumor cells in the CSF (Stage 4) may or may not have other evidence of diffuse meningeal disease and/or distant metastases. In a review of experience from IRSG protocols II though IV, eight patients had tumor cells in the CSF at diagnosis; three of four without other distant metastases were alive at 6 to 16 years after diagnosis, as was one of four who had concomitant metastases elsewhere.[57] Patients may also have multiple intraparenchymal brain metastases from a distant primary tumor. They may be treated with central nervous system-directed RT in addition to treatment with chemotherapy and RT for the primary tumor. Craniospinal axis RT may also be indicated.[58,59]
  3. Nonparameningeal, nonorbital head and neck tumors.
    For nonparameningeal, nonorbital head and neck tumors, wide excision of the primary tumor (when feasible without functional impairment) and ipsilateral neck lymph node sampling of clinically involved nodes may be appropriate but requires postoperative RT if margins or nodes are positive.[60]; [61][Level of evidence: 3iiA] Narrow resection margins (<1 mm) are acceptable because of anatomic restrictions. Cosmetic and functional factors should always be considered, but with modern techniques, complete resection in patients with superficial tumors need not be inconsistent with good cosmetic and functional results. Specialized, multidisciplinary surgical teams also have performed resections of anterior skull-based tumors in areas previously considered inaccessible to definitive surgical management, including the nasal areas, paranasal sinuses, and temporal fossa. These procedures should only be considered, however, in children with recurrent locoregional disease or residual disease after chemotherapy and RT.
For patients with head and neck primary tumors that are considered unresectable, chemotherapy and RT with organ preservation are the mainstay of primary management.[47,52,62-65] Several studies have reported excellent local control in patients with rhabdomyosarcoma of the head and neck treated with IMRT, fractionated stereotactic radiation therapy, or proton RT, and chemotherapy. Further study is needed, but the use of IMRT and chemotherapy in patients with head and neck rhabdomyosarcoma may result in less severe late effects.[66-68]; [69][Level of evidence: 3iiiA]

Extremity sites

Delayed primary excision has been studied in the D9803 intermediate-risk rhabdomyosarcoma trial. (Refer to the Surgery (Local Control Management) section of this summary for more information.) Delayed primary excision may be most appropriate for infants because the late effects of RT are more severe than they are in older patients; thus, even a moderate reduction in radiation dose is desirable.
A pooled analysis of 642 patients from four international cooperative groups in Europe and North America was performed to identify prognostic factors in patients with localized extremity rhabdomyosarcoma. Regional lymph node involvement was approximately 2.5 times higher with alveolar rhabdomyosarcoma than with embryonal rhabdomyosarcoma. The overall 5-year survival rate was 67%. Multivariate analysis showed that decreased OS was correlated with age older than 3 years, T2 and N1 status, incomplete initial surgery, treatment before 1995, and treatment by European groups. This analysis also suggested that duration of chemotherapy might have an impact on outcome in these patients.[70]
IMRT can be used to spare the bone, yet provide optimal soft tissue coverage, and it is used for the management of extremity rhabdomyosarcoma. Complete primary tumor removal from the hand or foot is not feasible in most cases because of functional impairment.[71][Level of evidence: 3iiA] For children presenting with a primary tumor of the hands or feet, COG studies have shown 100% 10-year local control using RT along with chemotherapy, avoiding amputation in these children.[72][Level of evidence: 3iiiA] Definitive RT and chemotherapy for Group III tumors resulted in 90% to 95% local control in the IRS-IV trial.[31]
Primary re-excision before beginning chemotherapy (i.e., not delayed) may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is deemed resectable by a second procedure.[4] Chemotherapy and RT or delayed primary excision with or without RT results in comparable outcomes.[8]
Regional and in-transit lymph nodes
For patients enrolled in clinical trials, the COG-STS recommends biopsy of all enlarged or clinically suspicious lymph nodes. In the trunk and extremity, if no enlarged lymph nodes are identified in the draining nodal basin, a sentinel lymph node biopsy is recommended; this is a more accurate way of assessing regional lymph nodes, instead of random lymph node sampling. Positron emission tomography (PET) scanning is recommended for evaluation and staging of extremity primary tumors before initiation of therapy.[73] Techniques for sentinel lymph node biopsy are standardized and should be completed by an experienced surgeon.[74-81]
In a single-institution study of 28 patients aged 6 months to 32 years with soft tissue sarcomas, sentinel lymph node biopsy was prospectively compared with PET-CT scan for detection of lymph node metastases. Forty-three percent of patients (3 of 7) with proven malignant sentinel lymph nodes had negative cross-sectional and functional imaging (PET-CT). Also, PET-CT suggested nodal involvement in 14 patients, whereas only 4 of those were proven to have metastatic disease. The study does not mention relapse rate or follow-up in these patients. Therefore, the use of PET-CT staging to diagnose lymph node disease in soft tissue sarcomas is of uncertain utility.[82]
Because of the significant incidence of regional nodal spread in patients with extremity primary tumors (often without clinical evidence of involvement) and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment of regional (and also in-transit) nodes is warranted.[74,83-86]; [73][Level of evidence: 3iiDi] In-transit nodes are defined as epitrochlear and brachial for upper-extremity tumors and popliteal for lower-extremity tumors. Regional lymph nodes are defined as axillary/infraclavicular nodes for upper-extremity tumors and inguinal/femoral nodes for lower-extremity tumors.
  • In a review of 226 patients with primary extremity rhabdomyosarcoma, 5% had tumor-involved in-transit nodes, and over 5 years, the rate of in-transit node recurrence was 12%. Very few patients (n = 11) underwent in-transit node examination at diagnosis, but five of them, all with alveolar rhabdomyosarcoma, had tumor-involved nodes. However, the EFS rates were not significantly different among those evaluated initially and those not evaluated initially for in-transit nodal disease.[73]

Truncal sites

Primary sites for childhood rhabdomyosarcoma within the trunk include the chest wall or abdominal wall, intrathoracic or intra-abdominal area, biliary tree, and perineum or anus. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed below.
  1. Chest wall or abdominal wall.
    The surgical management of patients with lesions of the chest wall or abdominal wall should follow the same guidelines as those used for lesions of the extremities (i.e., wide local excision and an attempt to achieve negative microscopic margins if cosmetic and functional outcomes are acceptable). These resections may require use of prosthetic materials. Initial surgery is performed if there is a realistic expectation of achieving negative margins. However, most patients who present with large tumors in these sites have localized disease that becomes amenable to complete resection with negative margins after preoperative chemoradiation therapy; those patients may have excellent long-term survival.[87-90]
    Chest wall rhabdomyosarcoma, which is usually Group III, does not require R0 resection (no microresidual disease) at delayed primary resection. The COG data show equivalent survival for R0 and R1 (microresidual disease at the margin) resections in chest wall rhabdomyosarcoma, likely because of the addition of postoperative radiation therapy.[90] Aggressive resections at diagnosis before chemotherapy are not necessary because rhabdomyosarcoma is very chemosensitive and radiosensitive.
    Nodal involvement is difficult to predict, but pretreatment PET scanning may prove useful in staging.
  2. Intrathoracic or intra-abdominal sarcomas.
    Intrathoracic or intra-abdominal sarcomas may not be resectable at diagnosis because of the massive size of the tumor and extension into vital organs or vessels.[91]
    For patients with initially unresectable retroperitoneal/pelvic tumors, complete surgical removal after chemotherapy, with or without RT, offers a significant survival advantage (73% vs. 34%–44% without removal).[91]
    • The International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT) Group found that RT improved local control in patients with localized pelvic rhabdomyosarcoma whose initial surgical procedure was biopsy only, leaving macroscopic residual tumor. Age older than 10 years and lymph node involvement were unfavorable prognostic factors.[92][Level of evidence: 2A]
    • A German study found 100 patients with intra-abdominal nonmetastatic embryonal rhabdomyosarcoma larger than 5 cm in dimension; 61% had tumors larger than 10 cm and 88% were T2. Eighty-one patients were treated with chemotherapy and delayed primary excision, while 19 patients with emergency presentations (tumor rupture, ileus, hydronephrosis, oliguria, and venous congestion) underwent initial debulking surgery. EFS was 52% (± 10%), and OS was 65% (± 9%). Unfavorable factors were initial diagnosis at age older than 10 years, lack of achieving complete remission, and inadequate local control (incomplete secondary resection or no RT).[93][Level of evidence: 3iiA]
    • A small series of seven rhabdomyosarcoma patients with peritoneal dissemination and/or malignant ascites had good outcomes with whole-abdomen irradiation using IMRT with dose painting.[94][Level of evidence: 3iiA] This technique involves simultaneously irradiating the whole abdomen with a lower dose than that used for the primary tumor (or resection-bed); the larger volume receives a lower (fractional) daily dose than the high-dose target receives.
  3. Biliary tree.
    With rhabdomyosarcoma of the biliary tree, total resection is rarely feasible and standard treatment includes chemotherapy and RT. Outcome for patients with this primary site is good despite residual disease after surgery. External biliary drains significantly increase the risk of postoperative infectious complications. Thus, external biliary drainage is not warranted.[95]
  4. Perineum or anus.
    Patients with rhabdomyosarcoma arising from tissue around the perineum or anus usually have advanced disease. These patients have a high likelihood of regional lymph node involvement, and about half of the tumors have alveolar histology.[96] The high frequency of nodal involvement and the prognostic association between nodal involvement and poorer outcome suggest that nodal sampling is appropriate. The current recommendation is to sample the regional lymph nodes.[97] When feasible and without unacceptable morbidity, removing all gross tumor before chemotherapy improves the likelihood of cure.
    • In IRSG protocols I through IV, the OS rate after aggressive therapy for 71 patients with tumors in this location was 49%, best for patients with Stage 2 disease (small tumors, negative regional nodes), intermediate for those with Stage 3 disease, and worst for those with Stage 4 disease at diagnosis.[97]
    • In a subsequent report from the German CWS trials, 32 patients had an EFS and OS of 47% at 5 years; in addition, patients with embryonal histology fared significantly better than did patients with alveolar histology.[98][Level of evidence: 3iiiA]
      With the goal of organ preservation, patients with tumors of the perineum/anus are preferentially managed with chemotherapy and RT without aggressive surgery, which may result in loss of sphincter control.

Genitourinary system

Primary sites for childhood rhabdomyosarcoma within the genitourinary system include the paratesticular area, bladder, prostate, kidney, vulva, vagina, and uterus. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed below.[99]
  1. Testis or spermatic cord.
    Lesions occurring adjacent to the testis or spermatic cord and up to the internal inguinal ring should be removed by orchiectomy with resection of the spermatic cord, utilizing an inguinal incision with proximal vascular control (i.e., radical orchiectomy).[100] Resection of hemiscrotal skin is required when there is tumor fixation or invasion.
    Hemiscrotectomy has been recommended by the COG, German groups, and Italian groups when a previous transscrotal biopsy had been performed. By contrast, a retrospective German CWS study of 28 patients with embryonal rhabdomyosarcoma found a 5-year EFS rate of 91.7% in 12 patients with an initial transscrotal excision followed by hemiscrotectomy, while the 5-year EFS in 16 patients without subsequent hemiscrotectomy was 93.8%. All of these patients also received chemotherapy with vincristine, dactinomycin, an alkylator, and other agents.[101][Level of evidence: 3iiiDi] This area is controversial, and more data are needed.
    For patients with incompletely removed paratesticular tumors that require RT, temporarily repositioning the contralateral testicle into the adjacent thigh before scrotal radiation may preserve hormone production, but again, more data are needed.[102][Level of evidence: 3iiiC] A retrospective review of 49 patients with paratestis rhabdomyosarcoma referred to Memorial Sloan Kettering Cancer Center found that 20 patients had scrotal violation as a part of their original surgery. Fifteen of these patients underwent salvage surgery or radiation therapy; 11 of these patients had continuous progression-free survival, whereas four of the five patients who were treated without a salvage procedure recurred.[103][Level of evidence: 3iiiDiii]
    Paratesticular tumors have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II),[83] and all patients with paratesticular primary tumors should have thin-cut abdominal and pelvic CT scans with IV contrast to evaluate nodal involvement. For patients who have Group I disease, are younger than 10 years, and in whom CT scans show no evidence of lymph node enlargement, retroperitoneal node biopsy/sampling is unnecessary, but a repeat CT scan every 3 months is recommended.[104,105] For patients with suggestive or positive CT scans, retroperitoneal lymph node sampling (but not formal node dissection) is recommended, and treatment is based on the findings of this procedure.[3,32,106]
    Staging ipsilateral retroperitoneal lymph node sampling is currently required for all children aged 10 years and older with paratesticular rhabdomyosarcoma on COG-STS studies. However, node dissection was not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. Many European investigators relied on radiographic, rather than surgical-pathologic assessment, for retroperitoneal lymph node involvement.[100,104] In the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumour (MMT) 89 and 95 studies, patients with paratesticular rhabdomyosarcoma were evaluated with imaging but did not undergo routine ipsilateral lymph node sampling.[107][Level of evidence: 2Di] Thirty-one percent of Stage N0 patients aged 10 years and older developed node relapse, compared with 8% of Stage N0 patients younger than 10 years (P = .0005). The SIOP MMT group subsequently recommended ipsilateral lymph node sampling for all patients aged 10 years and older. The North American and European cooperative groups performed a pooled analysis of 12 studies from five cooperative groups.[108][Level of evidence: 3iiA] For patients with paratesticular rhabdomyosarcoma (N = 842), age 10 years and older at diagnosis and tumor size larger than 5 cm were unfavorable prognostic features. At 7.5 years of median follow-up, EFS was 87.7%, and OS was 94.8% at 5 years. Surgical assessment of regional nodes is important in patients aged 10 years and older and in patients with N1 nodes because it affects EFS. Radiation therapy may be considered for those patients.
  2. Bladder or prostate.
    Bladder preservation is a major goal of therapy for patients with tumors arising in the bladder and/or prostate. Two reviews provide information about the historical, current, and future treatment approaches for patients with bladder and prostate rhabdomyosarcomas.[109,110]
    In rare cases, the tumor is confined to the dome of the bladder and can be completely resected. Otherwise, to preserve a functional bladder in patients with gross residual disease, chemotherapy and RT have been used in North America and some parts of Europe to reduce tumor bulk,[111,112] followed, when necessary, by a more limited surgical procedure such as partial cystectomy.[113] Early experience with this approach was disappointing, with only 20% to 40% of patients with bladder/prostate tumors alive and with functional bladders 3 years after diagnosis (3-year OS was 70% in IRS-II).[113,114] The later experience from IRS-III and IRS-IV, which used more intensive chemotherapy and RT, showed 55% of patients alive with functional bladders at 3 years postdiagnosis, with 3-year OS exceeding 80%.[112,115,116] Patients with a primary tumor of the bladder/prostate who present with a large pelvic mass resulting from a distended bladder caused by outlet obstruction at diagnosis receive RT to a volume defined by imaging studies after initial chemotherapy to relieve outlet obstruction. This approach to therapy remains generally accepted, with the belief that more effective chemotherapy and RT will continue to increase the frequency of bladder salvage.
    The initial surgical procedure in most patients consists of a biopsy, which often can be performed using ultrasound guidance or cystoscopy, or by a direct-vision transanal route. In selected cases in one series, bladder-conserving surgery plus brachytherapy for boys with prostate or bladder-neck rhabdomyosarcoma led to excellent survival, bladder preservation, and short-term functional results.[38][Level of evidence: 3iiiB] For patients with biopsy-proven, residual malignant tumor after chemotherapy and RT, appropriate surgical management may include partial cystectomy, prostatectomy, or exenteration (usually approached anteriorly with preservation of the rectum). Very few studies have objective long-term assessments of bladder function, and urodynamic studies are important to obtain accurate evaluation of bladder function.[117]
    An alternative strategy, used in European SIOP protocols, has been to avoid major radical surgery when possible and omit external-beam RT if complete disappearance of tumor can be achieved by chemotherapy and conservative surgical procedures. The goal is to preserve a functional bladder and prostate without incurring the late effects of RT or having to perform a total cystectomy/prostatectomy. From 1984 to 2003, 172 patients with nonmetastatic bladder and/or bladder/prostate rhabdomyosarcoma were accrued in a SIOP-MMT study. Of the 119 survivors, 50% had no significant local therapy, and only 26% received RT. The 5-year OS rate was 77%.[118][Level of evidence: 3iiA]
    Another alternative strategy in highly selected patients is to perform conservative surgery followed by brachytherapy at a specialized center.[119]; [120][Level of evidence: 3iiDiii]; [121][Level of evidence: 3iiiA] A prospective, nonrandomized analysis of this strategy reported the outcomes of 100 children. The 5-year disease-free survival rate was 84%, and the overall survival rate was 91%. At last follow-up, most survivors presented with only mild to moderate genitourinary sequelae and a normal diurnal urinary continence. Five patients required a secondary total cystectomy, three patients for a nonfunctional bladder and two patients for relapse.
    In patients who have been treated with chemotherapy and RT for rhabdomyosarcoma arising in the bladder/prostate region, the presence of well-differentiated rhabdomyoblasts in surgical specimens or biopsies obtained after treatment does not appear to be associated with a high risk of recurrence and is not an indication for a major surgical procedure such as total cystectomy.[115,122,123] One study suggested that in patients with residual bladder tumors with histologic evidence of maturation, additional courses of chemotherapy should be given before cystectomy is considered.[115] Surgery should be considered only if malignant tumor cells do not disappear over time after initial chemotherapy and RT. Because of very limited data, it is unclear whether this situation is analogous for patients with rhabdomyosarcoma arising in other parts of the body.
  3. Kidney.
    The kidney is rarely the primary site for sarcoma. Ten patients were identified from among 5,746 eligible patients enrolled on IRSG protocols, including six with embryonal rhabdomyosarcoma and four with undifferentiated sarcoma. The tumors were large (mean widest diameter, 12.7 cm), and anaplasia was present in four (67%) patients. Of the patients with embryonal rhabdomyosarcoma, three Group I and Group II patients survived, one Group III patient died of infection, and two Group IV patients died of recurrent disease; these children were 5.8 and 6.1 years old at diagnosis. This very limited experience concluded that the kidney is an unfavorable site for primary sarcoma.[124]
  4. Vulva/Vagina/Uterus.
    For patients with genitourinary primary tumors of the vulva/vagina/uterus, the initial surgical procedure is usually a vulvar or transvaginal biopsy. Initial radical surgery is not indicated for rhabdomyosarcoma of the vulva/vagina/uterus.[3] Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and adjunctive radiation (often brachytherapy) for residual disease (Group II or III), results in excellent 5-year survival rates.[125-127][Level of evidence: 3iA]
    In the COG-ARST0331 study, there was an unacceptably high rate of local recurrences in girls with Group III vaginal tumors who did not receive RT.[126][Level of evidence: 3iiiDiii] In 21 girls with genitourinary tract disease who were not treated with radiation therapy (mostly Group III vaginal primary tumors), the 3-year failure-free survival (FFS) rate was 57%, compared with an FFS rate of 77% in the other 45 patients with non–female genitourinary primary tumors (P = .02).[128][Level of evidence: 2Dii] Therefore, the COG-STS recommended that RT be administered to patients with residual viable vaginal tumor, beginning at week 12.[129][Level of evidence: 3iA]
    Because of the smaller number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision, but chemotherapy with or without RT is also effective.[125,130] Twelve of 14 girls with primary cervical embryonal (mainly botryoid) rhabdomyosarcoma were disease-free after vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy and conservative surgery. Of note, two girls also had a pleuropulmonary blastoma and another had Sertoli-Leydig cell tumor.[131] Exenteration is usually not required for primary tumors at these sites, but if needed, it may be done, with rectal preservation possible in most cases.
    For girls with genitourinary primary tumors who will receive pelvic irradiation, ovarian transposition (oophoropexy) before radiation therapy should be considered unless dose estimations suggest that ovarian function is likely to be preserved.[132] Alternatively, ovarian tissue preservation is under investigation and can be considered.[133]
    Four cooperative groups in the United States and Europe evaluated patients with localized vaginal/uterine tumors (N = 427). Some patients received initial RT for local control of residual disease after induction chemotherapy, while others had it later, or not at all if no demonstrable disease was found. The 10-year EFS rate was 74%, and the 10-year OS rate was 92%. Unfavorable factors were positive lymph node disease and uterine corpus primary site. There was no statistical difference in outcomes between patients who received early RT and patients who received later RT. About one-half of these patients were cured without radical surgery or systematic RT.[134][Level of evidence: 3iiA]

Unusual primary sites

Rhabdomyosarcoma occasionally arises in sites other than those previously discussed.
  1. Brain.
    Patients with localized primary rhabdomyosarcoma of the brain can occasionally be cured using a combination of tumor excision, RT, and chemotherapy.[135][Level of evidence: 3iiiDiii]
  2. Larynx.
    Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx.[136]
  3. Diaphragm.
    Patients with diaphragmatic tumors often have locally advanced disease that is not grossly resectable initially because of fixation to adjacent vital structures such as the lung, great vessels, pericardium, and/or liver. In such circumstances, chemotherapy and RT should be initiated after diagnostic biopsy; removal of residual tumor at a later date if clinically indicated should be considered.[137]
  4. Ovary.
    Two well-documented cases of primary ovarian rhabdomyosarcoma (one Stage III and one Stage IV) have been reported to supplement the eight previously reported patients. These two patients were alive at 20 and 8 months after diagnosis. Six of the previously reported eight patients had died of their disease.[138][Level of evidence: 3iiiDiii] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful.[138]

Metastatic sites

Primary resection of metastatic disease at diagnosis (Stage 4, M1, Group IV) is rarely indicated.
Evidence (treatment of lung-only metastatic disease):
  1. The CWS reviewed four consecutive trials and identified 29 patients with M1 embryonal rhabdomyosarcoma and metastasis limited to the lung at diagnosis.[139][Level of evidence: 3iiiA]
    • They reported a 5-year EFS of approximately 38% for the cohort and did not identify any benefit for local control of pulmonary metastasis, whether by lung irradiation (n = 9), pulmonary metastasectomy (n = 3), or no targeted pulmonary therapy (n = 19).
  2. The IRSG reviewed 46 IRS-IV (1991–1997) patients with metastatic disease at diagnosis confined to the lungs. Only 11 patients (24%) had a biopsy of the lung, including six at the time of primary diagnosis. They were compared with 234 patients with single non-lung metastatic sites or multiple other sites of metastases. The lung-only patients were more likely to have embryonal rhabdomyosarcoma and parameningeal primary tumors than the larger group of 234 patients, and were less likely to have regional lymph node disease at diagnosis.[140][Level of evidence: 3iiiB]
    • At 4 years, the FFS rate was 35% and the OS rate was 42%, better than for those with two or more sites of metastases (P = .005 and .002, respectively).
    • Age younger than 10 years at diagnosis was also a favorable prognostic factor.
    • Lung irradiation was recommended by the protocols for the lung-only group, but many did not receive it. Those who did receive lung irradiation had better FFS and OS at 4 years than those who did not (P = .01 and P = .039, respectively).

Chemotherapy Treatment Options

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.[141] (Refer to Table 5 in the Stage Information for Childhood Rhabdomyosarcoma section of this summary for more information about Risk Groups.)
Adolescents treated with therapy for rhabdomyosarcoma experience less hematologic toxicity and more peripheral nerve toxicity than do younger patients.[142]

Low-risk Group

Low-risk patients have localized (nonmetastatic) embryonal histology tumors in favorable sites that have been grossly resected (Groups I and II), embryonal tumors in the orbit that have not been completely resected (Group III), and localized tumors in an unfavorable site that have been grossly resected (Groups I and II). (Refer to Table 4 in the Stage Information for Childhood Rhabdomyosarcoma section of this summary for more information.) Only approximately 25% of newly diagnosed patients are, by definition, low risk.
Certain subgroups of low-risk patients have achieved survival rates higher than 90% when treated with a two-drug chemotherapy regimen that includes vincristine and dactinomycin (VA) plus RT for residual tumor. (Refer to Table 7 below.)
Table 7. Characteristics of Low-Risk Patients With High Survival Rates Using Two-Drug Therapy With Vincristine and Dactinomycin With or Without Radiation Therapy (Subset A)
SiteSizeGroupNodes
N0 = absence of nodal spread.
FavorableAnyI, IIAN0
OrbitalAnyI, II, IIIN0
Unfavorable≤5 cmIN0
Evidence (chemotherapy for low-risk Group patients):
  1. Two-drug regimen.
    1. The COG-D9602 study stratified 388 patients with low-risk embryonal rhabdomyosarcoma into two groups.[143] Treatment for subgroup A patients (n = 264; Stage 1 Group I/IIA, Stage 2 Group I, and Stage 1 Group III orbit) consisted of VA for 48 weeks with or without RT. Patients with subgroup B disease (n = 78; Stage 1 Group IIB/C, Stage I Group III nonorbit, Stage 2 Group II, and Stage 3 Group I/II disease) received VAC (total cumulative cyclophosphamide dose of 28.6 g/m2). Radiation doses were reduced from 41.4 Gy to 36 Gy for Stage 1 Group IIA patients and from 50 Gy or 59 Gy to 45 Gy for Group III orbit patients.
      • For subgroup A patients, the 5-year overall FFS rate was 89%, and the OS rate was 97%.
      • For subgroup B patients, the 5-year FFS rate was 85%, and the OS rate was 93%.
    2. The Children's Oncology Group clinical trial COG-ARST0331 for subset 2 low-risk patients was designed to test the safety of reducing total cumulative cyclophosphamide dose to decrease the risk of permanent infertility.[128][Level of evidence: 2Dii]
      • Using reduced total cyclophosphamide, researchers observed suboptimal FFS rates among patients with subset 2 low-risk rhabdomyosarcoma. Eliminating RT for girls with Group III vaginal tumors in combination with reduced total cyclophosphamide appeared to contribute to the suboptimal outcome. However, the OS rate appeared to be similar to the OS rate in previous studies with higher-dose cyclophosphamide.
  2. Three-drug regimen.
    Other subgroups of low-risk patients have achieved survival rates of at least 90% with three-drug chemotherapy with VAC (total cyclophosphamide dose of 28.6 g/m2) plus RT for residual tumor. (Refer to Table 8 below.)
    Table 8. Characteristics of Low-Risk Patients With High Survival Rates Using Three-Drug Therapy With Vincristine, Dactinomycin, and Cyclophosphamide With or Without Radiation Therapy (Subset B)
    SiteSizeGroupNodes
    N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site.
    Favorable (orbital or nonorbital)AnyIIB, IIC, IIIN0, N1
    Unfavorable≤5 cmIIN0
    Unfavorable>5 cmI, IIN0, N1
  3. Treatment duration.
    The subsequent COG-ARST0331 trial evaluated a refinement of therapy for two subsets of low-risk patients. The study enrolled 271 newly diagnosed patients with Subset 1 low-risk rhabdomyosarcoma, defined as patients with Stage 1 or Stage 2 tumors; Group I or Group II embryonal tumors; or Stage 1, Group III orbital embryonal tumors, with a shorter duration chemotherapy regimen that included four cycles of VAC chemotherapy followed by 10 weeks of therapy with vincristine and dactinomycin.[129] Study results are pending for Subset 2.
    • The 3-year FFS rate was 89%, and the OS rate was 98%. Thus, shorter duration of therapy did not appear to compromise outcome in these patients.

Intermediate-risk Group

Approximately 50% of newly diagnosed patients are in the intermediate-risk category. VAC is the standard multiagent chemotherapy regimen used for intermediate-risk patients.
Evidence (chemotherapy for intermediate-risk Group patients):
  1. The IRS-IV study randomly assigned intermediate-risk patients to receive either standard VAC therapy or one of two other chemotherapy regimens using ifosfamide as the alkylating agent. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites (Stages 2 and 3) with gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma (Stages 2 and 3) at any site (Groups I, II, and III).[32]
    • Intermediate-risk patients had survival rates at 3 years from 84% to 88%.[32]
    • There was no difference in outcome between these three treatments, and the VAC regimen was easier to administer, confirming VAC as the standard chemotherapy combination for children with intermediate-risk rhabdomyosarcoma.[32]
    • Survival in patients with tumors of embryonal histology treated on IRS-IV (who received higher doses of alkylating agents) was compared with similar patients treated on IRS-III (who received lower doses of alkylating agents); a benefit was suggested with the use of higher doses of cyclophosphamide for certain groups of intermediate-risk patients. These included patients with tumors at favorable sites and positive lymph nodes, patients with gross residual disease, or patients with tumors at unfavorable sites who underwent grossly complete resections, but not patients with unresected embryonal rhabdomyosarcoma at unfavorable sites.[144] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[145]
  2. The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improved outcome for children with intermediate-risk rhabdomyosarcoma. Topotecan was prioritized for evaluation on the basis of its preclinical activity in rhabdomyosarcoma xenograft models as well as its single-agent activity in previously untreated children with rhabdomyosarcoma, particularly those with alveolar rhabdomyosarcoma.[146,147] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[148,149] The COG-D9803 clinical trial for newly diagnosed patients with intermediate-risk disease randomly assigned patients to receive either VAC therapy or VAC therapy with additional courses of topotecan and cyclophosphamide.
    • Patients who received topotecan and cyclophosphamide fared no better than those treated with VAC alone; 4-year FFS was 73% with VAC and 68% with VAC plus vincristine, topotecan, and cyclophosphamide (VTC).[148][Level of evidence: 1iiA]
  3. In a limited-institution pilot study, a combination of vincristine/doxorubicin/cyclophosphamide (VDC) alternating with ifosfamide/etoposide (IE) was used to treat patients with intermediate-risk rhabdomyosarcoma. The relative efficacy of this approach versus the standard approach requires further investigation.[150][Level of evidence: 3iiiA]
  4. In a European trial (SIOP-MMT-95), 457 patients with incompletely resected embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or soft tissue primitive neuroectodermal tumor, carboplatin, epirubicin, and etoposide was added to standard ifosfamide, vincristine, and dactinomycin (IVA) therapy.[151]
    • The addition of carboplatin, epirubicin, and etoposide did not improve outcome (3-year OS for IVA was 82%; 3-year OS for IVA plus carboplatin, epirubicin, and etoposide was 80%).
    • Toxicity was significantly worse in the six-drug arm.
  5. The COG reported a prospective randomized trial of two treatment strategies for patients with intermediate-risk rhabdomyosarcoma.[152][Level of evidence: 1iiA] Patients were randomly assigned to receive treatment with either VAC or VAC with half of the cyclophosphamide cycles replaced with vincristine/irinotecan (VAC/VI). All patients received a lower cumulative dose of cyclophosphamide and earlier introduction of RT than did patients who were treated in previous COG studies. Patients who were treated with VAC/VI received half as much cumulative cyclophosphamide than did patients who were treated with VAC.
    • At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI (P = .51), and the 4-year OS was 73% for VAC and 72% for VAC/VI (P= .80). The COG concluded that the addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk rhabdomyosarcoma.
    • However, VAC/VI produced less hematologic toxicity and had a lower cumulative cyclophosphamide dose, potentially making VAC/VI an alternative standard therapy for patients with intermediate-risk rhabdomyosarcoma.
Approximately 20% of Group III patients will have a residual mass at the completion of therapy. The presence of a residual mass had no adverse prognostic significance.[153,154] Aggressive alternative therapy is not warranted for rhabdomyosarcoma patients with a residual mass at the end of planned therapy unless it has biopsy-proven residual malignant disease. For Group III patients, best response (complete remission versus partial or no response) to initial chemotherapy had no impact on overall outcome.[154] While induction chemotherapy is commonly administered for 9 to 12 weeks, 2.2% of patients with intermediate-risk rhabdomyosarcoma on the IRS-IV and COG-D9803 studies were found to have early disease progression and did not receive their planned course of RT.[155]

High-risk Group

High-risk patients have metastatic disease in one or more sites at diagnosis (Stage IV, Group IV). These patients continue to have a relatively poor prognosis with current therapy (5-year survival rate of ≤50%), and new approaches to treatment are needed to improve survival in this group.[140,156,157] Two retrospective studies have examined patients who present with metastases limited to the lungs;[139,140] results are summarized in the Metastatic sites section of this summary.
The standard systemic therapy for children with metastatic rhabdomyosarcoma is the three-drug combination of VAC.
Evidence (chemotherapy for high-risk Group patients):
  1. A multinational pooled analysis included 788 high-risk rhabdomyosarcoma patients treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[158][Level of evidence: 3iiiA]
    Analysis identified several adverse prognostic factors (Oberlin risk factors):
    • Age at diagnosis younger than 1 year or 10 years and older.
    • Unfavorable primary site (all sites that are not orbit, nonparameningeal head and neck, genitourinary tract other than bladder/prostate, and biliary tract).
    • Bone and/or bone marrow involvement.
    • Three or more different metastatic sites or tissues.
    The EFS rate at 3 years depended upon the number of adverse prognostic factors:[158][Level of evidence: 3iiiA]
    • The EFS rate was 50% for patients without any of these adverse prognostic factors.
    • The EFS rates were 42% for patients with one adverse prognostic factor, 18% for patients with two adverse prognostic factors, 12% for patients with three adverse prognostic factors, and 5% for patients with four adverse prognostic factors (P < .0001).
Despite many clinical trials attempting to improve outcome by adding additional agents to standard VAC chemotherapy or substituting new agents for one or more components of VAC chemotherapy, to date, no chemotherapy regimens have been shown to be more effective than VAC, including the following:
  1. In the IRS-IV study, three combinations of drug pairs were studied in an up-front window—ifosfamide/etoposide (IE), vincristine/melphalan (VM),[159] and ifosfamide/doxorubicin (ID).[160] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12.
    • OS rates for patients treated with IE and ID were comparable (31% and 34%, respectively) and better than for those treated with VM (22%).[160]
      Results with VAC chemotherapy for Stage IV rhabdomyosarcoma in the North American experience are similar.
  2. Results from a phase II window trial of patients with metastatic disease at presentation and treated with topotecan and cyclophosphamide showed activity for this two-drug combination.[148,149]
    • Survival was not different from that seen with previous regimens.
    • An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma showed similar results.[147]
  3. Irinotecan and irinotecan with vincristine have also been evaluated as up-front window trials by the COG-STS.[161]
    • The response rates were better when irinotecan was administered with vincristine than without it, but survival in a preliminary analysis was not improved over previous experience.
  4. In a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses.[162]
    • Thirteen of 20 patients responded to therapy, and four patients had progressive disease.
  5. A study from the SIOP demonstrated continued poor outcome for patients with high-risk features such as age 10 years and older or bone/bone marrow involvement. This study compared a standard six-drug combination followed by VDC maintenance versus an arm that evaluated a window of single-agent doxorubicin or carboplatin followed by sequential high-dose monotherapy courses including cyclophosphamide, etoposide, and carboplatin followed by maintenance VAC.[163]
    • No benefit was seen for the high-dose therapy arm.
  6. A study of patients with previously untreated metastatic rhabdomyosarcoma from the COG-STS examined outcome of 109 patients with the disease.[158] Several treatment strategies, all given over 54 planned weeks, were used:
    1. A period of compressed (every 2 weeks) schedule of chemotherapy using vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide plus etoposide.
    2. The addition of vincristine and irinotecan including during RT.
    3. A period of vincristine, actinomycin, and cyclophosphamide therapy.
    The following results were observed:
    • Using Oberlin risk factors (age <1 or >10 years, unfavorable primary site, number of metastatic sites and presence or absence of bone/bone marrow involvement), the strategy improved outcome compared with historic controls for patients with lower-risk disease. Three-year EFS rates were 69% for those with Oberlin risk factor score of 0 or 1 and 60% for patients younger than 10 years of age with embryonal rhabdomyosarcoma.[164][Level of evidence: 3iiDi]
    • However, patients with more than 2 Oberlin risk factors had a 20% 3-year EFS, comparable to historic outcomes. This intensive protocol did not appear to improve outcome for the highest-risk patients.
  7. The European Paediatric Soft Tissue Sarcoma Study Group performed a randomized prospective phase III trial of patients with high-risk rhabdomyosarcoma. They compared a standard arm comprising nine cycles of ifosfamide, vincristine, and dactinomycin (IVA) with an investigational arm comprising four cycles of IVA plus doxorubicin followed by five cycles of IVA.[165][Level of evidence: 3iiA]
    • The investigational therapy was associated with increased toxicity, including treatment-related mortality, and was not associated with improvement in either EFS or OS.
  8. The COG performed two nonrandomized pilot trials in patients with high-risk rhabdomyosarcoma. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide.[166][Level of evidence: 3iiDi]
    1. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. Cixutumumab is a monoclonal antibody against the insulin-like growth factor 1 receptor.
    2. In pilot 2, patients received oral temozolomide (100 mg/m2) daily for 5 days with irinotecan.
    The following results were observed:
    • With a median follow-up of 2.9 years, the 3-year EFS rate was 16% (95% CI, 7%–25%) with cixutumumab and 18% (95% CI, 2%–35%) with temozolomide.
    • These results did not differ from the results observed in the ARST0431 (NCT00354744) trial that used the same chemotherapy regimen.

Other Therapeutic Approaches

  • High-dose chemotherapy with autologous and allogeneic stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[167-169] The use of this modality has failed to improve the outcomes of patients with newly diagnosed or recurrent rhabdomyosarcoma.[169]
  • The National Cancer Institute's intramural Pediatric Oncology Branch conducted a pilot study of cytoreductive treatment followed by consolidative immunotherapy incorporating T-cell reconstitution, plus a dendritic-cell and tumor-peptide vaccine that was given with minimal toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma (n = 37) and alveolar rhabdomyosarcoma (n = 15). Ten patients with alveolar rhabdomyosarcoma had improved survival compared with five patients who did not receive immunotherapy.[170][Level of evidence: 3iiiA]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.


References
  1. Leaphart C, Rodeberg D: Pediatric surgical oncology: management of rhabdomyosarcoma. Surg Oncol 16 (3): 173-85, 2007. [PUBMED Abstract]
  2. Lawrence W Jr, Hays DM, Heyn R, et al.: Surgical lessons from the Intergroup Rhabdomyosarcoma Study (IRS) pertaining to extremity tumors. World J Surg 12 (5): 676-84, 1988. [PUBMED Abstract]
  3. Lawrence W Jr, Neifeld JP: Soft tissue sarcomas. Curr Probl Surg 26 (11): 753-827, 1989. [PUBMED Abstract]
  4. Hays DM, Lawrence W Jr, Wharam M, et al.: Primary reexcision for patients with 'microscopic residual' tumor following initial excision of sarcomas of trunk and extremity sites. J Pediatr Surg 24 (1): 5-10, 1989. [PUBMED Abstract]
  5. Cecchetto G, Bisogno G, De Corti F, et al.: Biopsy or debulking surgery as initial surgery for locally advanced rhabdomyosarcomas in children?: the experience of the Italian Cooperative Group studies. Cancer 110 (11): 2561-7, 2007. [PUBMED Abstract]
  6. Raney B, Stoner J, Anderson J, et al.: Impact of tumor viability at second-look procedures performed before completing treatment on the Intergroup Rhabdomyosarcoma Study Group protocol IRS-IV, 1991-1997: a report from the children's oncology group. J Pediatr Surg 45 (11): 2160-8, 2010. [PUBMED Abstract]
  7. Breneman J, Meza J, Donaldson SS, et al.: Local control with reduced-dose radiotherapy for low-risk rhabdomyosarcoma: a report from the Children's Oncology Group D9602 study. Int J Radiat Oncol Biol Phys 83 (2): 720-6, 2012. [PUBMED Abstract]
  8. Rodeberg DA, Wharam MD, Lyden ER, et al.: Delayed primary excision with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. Int J Cancer 137 (1): 204-11, 2015. [PUBMED Abstract]
  9. Maurer HM, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71 (5): 1904-22, 1993. [PUBMED Abstract]
  10. Maurer HM, Beltangady M, Gehan EA, et al.: The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 61 (2): 209-20, 1988. [PUBMED Abstract]
  11. Wolden SL, Anderson JR, Crist WM, et al.: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol 17 (11): 3468-75, 1999. [PUBMED Abstract]
  12. Raney RB, Anderson JR, Brown KL, et al.: Treatment results for patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III and IV, 1984-1997: a report from the Children's Oncology Group. Pediatr Blood Cancer 55 (4): 612-6, 2010. [PUBMED Abstract]
  13. Million L, Anderson J, Breneman J, et al.: Influence of noncompliance with radiation therapy protocol guidelines and operative bed recurrences for children with rhabdomyosarcoma and microscopic residual disease: a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (2): 333-8, 2011. [PUBMED Abstract]
  14. Wharam MD, Meza J, Anderson J, et al.: Failure pattern and factors predictive of local failure in rhabdomyosarcoma: a report of group III patients on the third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 22 (10): 1902-8, 2004. [PUBMED Abstract]
  15. Hug EB, Adams J, Fitzek M, et al.: Fractionated, three-dimensional, planning-assisted proton-radiation therapy for orbital rhabdomyosarcoma: a novel technique. Int J Radiat Oncol Biol Phys 47 (4): 979-84, 2000. [PUBMED Abstract]
  16. Yock T, Schneider R, Friedmann A, et al.: Proton radiotherapy for orbital rhabdomyosarcoma: clinical outcome and a dosimetric comparison with photons. Int J Radiat Oncol Biol Phys 63 (4): 1161-8, 2005. [PUBMED Abstract]
  17. Laskar S, Bahl G, Ann Muckaden M, et al.: Interstitial brachytherapy for childhood soft tissue sarcoma. Pediatr Blood Cancer 49 (5): 649-55, 2007. [PUBMED Abstract]
  18. Yang JC, Dharmarajan KV, Wexler LH, et al.: Intensity modulated radiation therapy with dose painting to treat rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 84 (3): e371-7, 2012. [PUBMED Abstract]
  19. Ladra MM, Szymonifka JD, Mahajan A, et al.: Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J Clin Oncol 32 (33): 3762-70, 2014. [PUBMED Abstract]
  20. Folkert MR, Tong WY, LaQuaglia MP, et al.: 20-year experience with intraoperative high-dose-rate brachytherapy for pediatric sarcoma: outcomes, toxicity, and practice recommendations. Int J Radiat Oncol Biol Phys 90 (2): 362-8, 2014. [PUBMED Abstract]
  21. Cotter SE, Herrup DA, Friedmann A, et al.: Proton radiotherapy for pediatric bladder/prostate rhabdomyosarcoma: clinical outcomes and dosimetry compared to intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 81 (5): 1367-73, 2011. [PUBMED Abstract]
  22. Leiser D, Calaminus G, Malyapa R, et al.: Tumour control and Quality of Life in children with rhabdomyosarcoma treated with pencil beam scanning proton therapy. Radiother Oncol 120 (1): 163-8, 2016. [PUBMED Abstract]
  23. Ladra MM, Edgington SK, Mahajan A, et al.: A dosimetric comparison of proton and intensity modulated radiation therapy in pediatric rhabdomyosarcoma patients enrolled on a prospective phase II proton study. Radiother Oncol 113 (1): 77-83, 2014. [PUBMED Abstract]
  24. Lin C, Donaldson SS, Meza JL, et al.: Effect of radiotherapy techniques (IMRT vs. 3D-CRT) on outcome in patients with intermediate-risk rhabdomyosarcoma enrolled in COG D9803--a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 82 (5): 1764-70, 2012. [PUBMED Abstract]
  25. Vern-Gross TZ, Indelicato DJ, Bradley JA, et al.: Patterns of Failure in Pediatric Rhabdomyosarcoma After Proton Therapy. Int J Radiat Oncol Biol Phys 96 (5): 1070-1077, 2016. [PUBMED Abstract]
  26. Mandell L, Ghavimi F, Peretz T, et al.: Radiocurability of microscopic disease in childhood rhabdomyosarcoma with radiation doses less than 4,000 cGy. J Clin Oncol 8 (9): 1536-42, 1990. [PUBMED Abstract]
  27. Heyn R, Ragab A, Raney RB Jr, et al.: Late effects of therapy in orbital rhabdomyosarcoma in children. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 57 (9): 1738-43, 1986. [PUBMED Abstract]
  28. Tefft M, Lattin PB, Jereb B, et al.: Acute and late effects on normal tissues following combined chemo- and radiotherapy for childhood rhabdomyosarcoma and Ewing's sarcoma. Cancer 37 (2 Suppl): 1201-17, 1976. [PUBMED Abstract]
  29. Donaldson SS, Asmar L, Breneman J, et al.: Hyperfractionated radiation in children with rhabdomyosarcoma--results of an Intergroup Rhabdomyosarcoma Pilot Study. Int J Radiat Oncol Biol Phys 32 (4): 903-11, 1995. [PUBMED Abstract]
  30. Wolden SL, Lyden ER, Arndt CA, et al.: Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys 93 (5): 1071-6, 2015. [PUBMED Abstract]
  31. Donaldson SS, Meza J, Breneman JC, et al.: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma--a report from the IRSG. Int J Radiat Oncol Biol Phys 51 (3): 718-28, 2001. [PUBMED Abstract]
  32. Crist WM, Anderson JR, Meza JL, et al.: Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19 (12): 3091-102, 2001. [PUBMED Abstract]
  33. Curran WJ Jr, Littman P, Raney RB: Interstitial radiation therapy in the treatment of childhood soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 14 (1): 169-74, 1988. [PUBMED Abstract]
  34. Flamant F, Gerbaulet A, Nihoul-Fekete C, et al.: Long-term sequelae of conservative treatment by surgery, brachytherapy, and chemotherapy for vulval and vaginal rhabdomyosarcoma in children. J Clin Oncol 8 (11): 1847-53, 1990. [PUBMED Abstract]
  35. Flamant F, Chassagne D, Cosset JM, et al.: Embryonal rhabdomyosarcoma of the vagina in children: conservative treatment with curietherapy and chemotherapy. Eur J Cancer 15 (4): 527-32, 1979. [PUBMED Abstract]
  36. Nag S, Shasha D, Janjan N, et al.: The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas. Int J Radiat Oncol Biol Phys 49 (4): 1033-43, 2001. [PUBMED Abstract]
  37. Magné N, Haie-Meder C: Brachytherapy for genital-tract rhabdomyosarcomas in girls: technical aspects, reports, and perspectives. Lancet Oncol 8 (8): 725-9, 2007. [PUBMED Abstract]
  38. Martelli H, Haie-Meder C, Branchereau S, et al.: Conservative surgery plus brachytherapy treatment for boys with prostate and/or bladder neck rhabdomyosarcoma: a single team experience. J Pediatr Surg 44 (1): 190-6, 2009. [PUBMED Abstract]
  39. Magné N, Oberlin O, Martelli H, et al.: Vulval and vaginal rhabdomyosarcoma in children: update and reappraisal of Institut Gustave Roussy brachytherapy experience. Int J Radiat Oncol Biol Phys 72 (3): 878-83, 2008. [PUBMED Abstract]
  40. Hentz C, Barrett W: Efficacy and morbidity of temporary (125)I brachytherapy in pediatric rhabdomyosarcomas. Brachytherapy 13 (2): 196-202, 2014 Mar-Apr. [PUBMED Abstract]
  41. Nag S, Fernandes PS, Martinez-Monge R, et al.: Use of brachytherapy to preserve function in children with soft-tissue sarcomas. Oncology (Huntingt) 13 (3): 361-69; discussion 369-70, 373-4, 1999. [PUBMED Abstract]
  42. Regine WF, Fontanesi J, Kumar P, et al.: Local tumor control in rhabdomyosarcoma following low-dose irradiation: comparison of group II and select group III patients. Int J Radiat Oncol Biol Phys 31 (3): 485-91, 1995. [PUBMED Abstract]
  43. Puri DR, Wexler LH, Meyers PA, et al.: The challenging role of radiation therapy for very young children with rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 65 (4): 1177-84, 2006. [PUBMED Abstract]
  44. Malempati S, Rodeberg DA, Donaldson SS, et al.: Rhabdomyosarcoma in infants younger than 1 year: a report from the Children's Oncology Group. Cancer 117 (15): 3493-501, 2011. [PUBMED Abstract]
  45. Wharam M, Beltangady M, Hays D, et al.: Localized orbital rhabdomyosarcoma. An interim report of the Intergroup Rhabdomyosarcoma Study Committee. Ophthalmology 94 (3): 251-4, 1987. [PUBMED Abstract]
  46. Oberlin O, Rey A, Anderson J, et al.: Treatment of orbital rhabdomyosarcoma: survival and late effects of treatment--results of an international workshop. J Clin Oncol 19 (1): 197-204, 2001. [PUBMED Abstract]
  47. Raney RB, Anderson JR, Kollath J, et al.: Late effects of therapy in 94 patients with localized rhabdomyosarcoma of the orbit: Report from the Intergroup Rhabdomyosarcoma Study (IRS)-III, 1984-1991. Med Pediatr Oncol 34 (6): 413-20, 2000. [PUBMED Abstract]
  48. Mannor GE, Rose GE, Plowman PN, et al.: Multidisciplinary management of refractory orbital rhabdomyosarcoma. Ophthalmology 104 (7): 1198-201, 1997. [PUBMED Abstract]
  49. Ermoian RP, Breneman J, Walterhouse DO, et al.: 45 Gy is not sufficient radiotherapy dose for Group III orbital embryonal rhabdomyosarcoma after less than complete response to 12 weeks of ARST0331 chemotherapy: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatr Blood Cancer 64 (9): , 2017. [PUBMED Abstract]
  50. Raney RB, Meza J, Anderson JR, et al.: Treatment of children and adolescents with localized parameningeal sarcoma: experience of the Intergroup Rhabdomyosarcoma Study Group protocols IRS-II through -IV, 1978-1997. Med Pediatr Oncol 38 (1): 22-32, 2002. [PUBMED Abstract]
  51. Michalski JM, Meza J, Breneman JC, et al.: Influence of radiation therapy parameters on outcome in children treated with radiation therapy for localized parameningeal rhabdomyosarcoma in Intergroup Rhabdomyosarcoma Study Group trials II through IV. Int J Radiat Oncol Biol Phys 59 (4): 1027-38, 2004. [PUBMED Abstract]
  52. Hawkins DS, Anderson JR, Paidas CN, et al.: Improved outcome for patients with middle ear rhabdomyosarcoma: a children's oncology group study. J Clin Oncol 19 (12): 3073-9, 2001. [PUBMED Abstract]
  53. Spalding AC, Hawkins DS, Donaldson SS, et al.: The effect of radiation timing on patients with high-risk features of parameningeal rhabdomyosarcoma: an analysis of IRS-IV and D9803. Int J Radiat Oncol Biol Phys 87 (3): 512-6, 2013. [PUBMED Abstract]
  54. Yang JC, Wexler LH, Meyers PA, et al.: Parameningeal rhabdomyosarcoma: outcomes and opportunities. Int J Radiat Oncol Biol Phys 85 (1): e61-6, 2013. [PUBMED Abstract]
  55. Ludmir EB, Paulino AC, Grosshans DR, et al.: Regional Nodal Control for Head and Neck Alveolar Rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 101 (1): 169-176, 2018. [PUBMED Abstract]
  56. Merks JH, De Salvo GL, Bergeron C, et al.: Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups. Ann Oncol 25 (1): 231-6, 2014. [PUBMED Abstract]
  57. Raney B, Anderson J, Breneman J, et al.: Results in patients with cranial parameningeal sarcoma and metastases (Stage 4) treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols II-IV, 1978-1997: report from the Children's Oncology Group. Pediatr Blood Cancer 51 (1): 17-22, 2008. [PUBMED Abstract]
  58. Wharam MD Jr: Rhabdomyosarcoma of Parameningeal Sites. Semin Radiat Oncol 7 (3): 212-216, 1997. [PUBMED Abstract]
  59. Raney RB: Soft-tissue sarcoma in childhood and adolescence. Curr Oncol Rep 4 (4): 291-8, 2002. [PUBMED Abstract]
  60. Raney RB, Chintagumpala M, Anderson J, et al.: Results of treatment of patients with superficial facial rhabdomyosarcomas on protocols of the Intergroup Rhabdomyosarcoma Study Group (IRSG), 1984-1997. Pediatr Blood Cancer 50 (5): 958-64, 2008. [PUBMED Abstract]
  61. Affinita MC, Ferrari A, Milano GM, et al.: Long-term results in children with head and neck rhabdomyosarcoma: A report from the Italian Soft Tissue Sarcoma Committee. Pediatr Blood Cancer 65 (3): , 2018. [PUBMED Abstract]
  62. Wharam MD, Beltangady MS, Heyn RM, et al.: Pediatric orofacial and laryngopharyngeal rhabdomyosarcoma. An Intergroup Rhabdomyosarcoma Study report. Arch Otolaryngol Head Neck Surg 113 (11): 1225-7, 1987. [PUBMED Abstract]
  63. Pappo AS, Meza JL, Donaldson SS, et al.: Treatment of localized nonorbital, nonparameningeal head and neck rhabdomyosarcoma: lessons learned from intergroup rhabdomyosarcoma studies III and IV. J Clin Oncol 21 (4): 638-45, 2003. [PUBMED Abstract]
  64. Meazza C, Ferrari A, Casanova M, et al.: Evolving treatment strategies for parameningeal rhabdomyosarcoma: the experience of the Istituto Nazionale Tumori of Milan. Head Neck 27 (1): 49-57, 2005. [PUBMED Abstract]
  65. Defachelles AS, Rey A, Oberlin O, et al.: Treatment of nonmetastatic cranial parameningeal rhabdomyosarcoma in children younger than 3 years old: results from international society of pediatric oncology studies MMT 89 and 95. J Clin Oncol 27 (8): 1310-5, 2009. [PUBMED Abstract]
  66. Wolden SL, Wexler LH, Kraus DH, et al.: Intensity-modulated radiotherapy for head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 61 (5): 1432-8, 2005. [PUBMED Abstract]
  67. Combs SE, Behnisch W, Kulozik AE, et al.: Intensity Modulated Radiotherapy (IMRT) and Fractionated Stereotactic Radiotherapy (FSRT) for children with head-and-neck-rhabdomyosarcoma. BMC Cancer 7: 177, 2007. [PUBMED Abstract]
  68. McDonald MW, Esiashvili N, George BA, et al.: Intensity-modulated radiotherapy with use of cone-down boost for pediatric head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 72 (3): 884-91, 2008. [PUBMED Abstract]
  69. Curtis AE, Okcu MF, Chintagumpala M, et al.: Local control after intensity-modulated radiotherapy for head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 73 (1): 173-7, 2009. [PUBMED Abstract]
  70. Oberlin O, Rey A, Brown KL, et al.: Prognostic Factors for Outcome in Localized Extremity Rhabdomyosarcoma. Pooled Analysis from Four International Cooperative Groups. Pediatr Blood Cancer 62 (12): 2125-31, 2015. [PUBMED Abstract]
  71. Casanova M, Meazza C, Favini F, et al.: Rhabdomyosarcoma of the extremities: a focus on tumors arising in the hand and foot. Pediatr Hematol Oncol 26 (5): 321-31, 2009 Jul-Aug. [PUBMED Abstract]
  72. La TH, Wolden SL, Su Z, et al.: Local therapy for rhabdomyosarcoma of the hands and feet: is amputation necessary? A report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (1): 206-12, 2011. [PUBMED Abstract]
  73. La TH, Wolden SL, Rodeberg DA, et al.: Regional nodal involvement and patterns of spread along in-transit pathways in children with rhabdomyosarcoma of the extremity: a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (4): 1151-7, 2011. [PUBMED Abstract]
  74. Neville HL, Andrassy RJ, Lobe TE, et al.: Preoperative staging, prognostic factors, and outcome for extremity rhabdomyosarcoma: a preliminary report from the Intergroup Rhabdomyosarcoma Study IV (1991-1997). J Pediatr Surg 35 (2): 317-21, 2000. [PUBMED Abstract]
  75. Neville HL, Andrassy RJ, Lally KP, et al.: Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 35 (6): 961-4, 2000. [PUBMED Abstract]
  76. Neville HL, Raney RB, Andrassy RJ, et al.: Multidisciplinary management of pediatric soft-tissue sarcoma. Oncology (Huntingt) 14 (10): 1471-81; discussion 1482-6, 1489-90, 2000. [PUBMED Abstract]
  77. Kayton ML, Delgado R, Busam K, et al.: Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer 112 (9): 2052-9, 2008. [PUBMED Abstract]
  78. Dall'Igna P, De Corti F, Alaggio R, et al.: Sentinel node biopsy in pediatric patients: the experience in a single institution. Eur J Pediatr Surg 24 (6): 482-7, 2014. [PUBMED Abstract]
  79. Alcorn KM, Deans KJ, Congeni A, et al.: Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging. J Pediatr Surg 48 (9): 1903-6, 2013. [PUBMED Abstract]
  80. Wright S, Armeson K, Hill EG, et al.: The role of sentinel lymph node biopsy in select sarcoma patients: a meta-analysis. Am J Surg 204 (4): 428-33, 2012. [PUBMED Abstract]
  81. Parida L, Morrisson GT, Shammas A, et al.: Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int 28 (6): 571-8, 2012. [PUBMED Abstract]
  82. Wagner LM, Kremer N, Gelfand MJ, et al.: Detection of lymph node metastases in pediatric and adolescent/young adult sarcoma: Sentinel lymph node biopsy versus fludeoxyglucose positron emission tomography imaging-A prospective trial. Cancer 123 (1): 155-160, 2017. [PUBMED Abstract]
  83. Lawrence W Jr, Hays DM, Heyn R, et al.: Lymphatic metastases with childhood rhabdomyosarcoma. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 60 (4): 910-5, 1987. [PUBMED Abstract]
  84. Mandell L, Ghavimi F, LaQuaglia M, et al.: Prognostic significance of regional lymph node involvement in childhood extremity rhabdomyosarcoma. Med Pediatr Oncol 18 (6): 466-71, 1990. [PUBMED Abstract]
  85. Andrassy RJ, Corpron CA, Hays D, et al.: Extremity sarcomas: an analysis of prognostic factors from the Intergroup Rhabdomyosarcoma Study III. J Pediatr Surg 31 (1): 191-6, 1996. [PUBMED Abstract]
  86. Rodeberg DA, Garcia-Henriquez N, Lyden ER, et al.: Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 29 (10): 1304-11, 2011. [PUBMED Abstract]
  87. Saenz NC, Ghavimi F, Gerald W, et al.: Chest wall rhabdomyosarcoma. Cancer 80 (8): 1513-7, 1997. [PUBMED Abstract]
  88. Beech TR, Moss RL, Anderson JA, et al.: What comprises appropriate therapy for children/adolescents with rhabdomyosarcoma arising in the abdominal wall? A report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Surg 34 (5): 668-71, 1999. [PUBMED Abstract]
  89. Chui CH, Billups CA, Pappo AS, et al.: Predictors of outcome in children and adolescents with rhabdomyosarcoma of the trunk--the St Jude Children's Research Hospital experience. J Pediatr Surg 40 (11): 1691-5, 2005. [PUBMED Abstract]
  90. Hayes-Jordan A, Stoner JA, Anderson JR, et al.: The impact of surgical excision in chest wall rhabdomyosarcoma: a report from the Children's Oncology Group. J Pediatr Surg 43 (5): 831-6, 2008. [PUBMED Abstract]
  91. Cecchetto G, Bisogno G, Treuner J, et al.: Role of surgery for nonmetastatic abdominal rhabdomyosarcomas: a report from the Italian and German Soft Tissue Cooperative Groups Studies. Cancer 97 (8): 1974-80, 2003. [PUBMED Abstract]
  92. Réguerre Y, Martelli H, Rey A, et al.: Local therapy is critical in localised pelvic rhabdomyosarcoma: experience of the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT) committee. Eur J Cancer 48 (13): 2020-7, 2012. [PUBMED Abstract]
  93. Dantonello TM, Lochbühler H, Schuck A, et al.: Challenges in the local treatment of large abdominal embryonal rhabdomyosarcoma. Ann Surg Oncol 21 (11): 3579-86, 2014. [PUBMED Abstract]
  94. Casey DL, Wexler LH, LaQuaglia MP, et al.: Favorable outcomes after whole abdominopelvic radiation therapy for pediatric and young adult sarcoma. Pediatr Blood Cancer 61 (9): 1565-9, 2014. [PUBMED Abstract]
  95. Spunt SL, Lobe TE, Pappo AS, et al.: Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J Pediatr Surg 35 (2): 309-16, 2000. [PUBMED Abstract]
  96. Casey DL, Wexler LH, LaQuaglia MP, et al.: Patterns of failure for rhabdomyosarcoma of the perineal and perianal region. Int J Radiat Oncol Biol Phys 89 (1): 82-7, 2014. [PUBMED Abstract]
  97. Blakely ML, Andrassy RJ, Raney RB, et al.: Prognostic factors and surgical treatment guidelines for children with rhabdomyosarcoma of the perineum or anus: a report of Intergroup Rhabdomyosarcoma Studies I through IV, 1972 through 1997. J Pediatr Surg 38 (3): 347-53, 2003. [PUBMED Abstract]
  98. Fuchs J, Dantonello TM, Blumenstock G, et al.: Treatment and outcome of patients suffering from perineal/perianal rhabdomyosarcoma: results from the CWS trials--retrospective clinical study. Ann Surg 259 (6): 1166-72, 2014. [PUBMED Abstract]
  99. Wu HY, Snyder HM 3rd, Womer RB: Genitourinary rhabdomyosarcoma: which treatment, how much, and when? J Pediatr Urol 5 (6): 501-6, 2009. [PUBMED Abstract]
  100. Stewart RJ, Martelli H, Oberlin O, et al.: Treatment of children with nonmetastatic paratesticular rhabdomyosarcoma: results of the Malignant Mesenchymal Tumors studies (MMT 84 and MMT 89) of the International Society of Pediatric Oncology. J Clin Oncol 21 (5): 793-8, 2003. [PUBMED Abstract]
  101. Seitz G, Dantonello TM, Kosztyla D, et al.: Impact of hemiscrotectomy on outcome of patients with embryonal paratesticular rhabdomyosarcoma: results from the Cooperative Soft Tissue Sarcoma Group Studies CWS-86, 91, 96 and 2002P. J Urol 192 (3): 902-7, 2014. [PUBMED Abstract]
  102. Grüschow K, Kyank U, Stuhldreier G, et al.: Surgical repositioning of the contralateral testicle before irradiation of a paratesticular rhabdomyosarcoma for preservation of hormone production. Pediatr Hematol Oncol 24 (5): 371-7, 2007 Jul-Aug. [PUBMED Abstract]
  103. Hammond WJ, Farber BA, Price AP, et al.: Paratesticular rhabdomyosarcoma: Importance of initial therapy. J Pediatr Surg 52 (2): 304-308, 2017. [PUBMED Abstract]
  104. Ferrari A, Bisogno G, Casanova M, et al.: Paratesticular rhabdomyosarcoma: report from the Italian and German Cooperative Group. J Clin Oncol 20 (2): 449-55, 2002. [PUBMED Abstract]
  105. Ferrari A, Casanova M, Massimino M, et al.: The management of paratesticular rhabdomyosarcoma: a single institutional experience with 44 consecutive children. J Urol 159 (3): 1031-4, 1998. [PUBMED Abstract]
  106. Wiener ES, Lawrence W, Hays D, et al.: Retroperitoneal node biopsy in paratesticular rhabdomyosarcoma. J Pediatr Surg 29 (2): 171-7; discussion 178, 1994. [PUBMED Abstract]
  107. Rogers T, Minard-Colin V, Cozic N, et al.: Paratesticular rhabdomyosarcoma in children and adolescents-Outcome and patterns of relapse when utilizing a nonsurgical strategy for lymph node staging: Report from the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumour 89 and 95 studies. Pediatr Blood Cancer 64 (9): , 2017. [PUBMED Abstract]
  108. Walterhouse DO, Barkauskas DA, Hall D, et al.: Demographic and Treatment Variables Influencing Outcome for Localized Paratesticular Rhabdomyosarcoma: Results From a Pooled Analysis of North American and European Cooperative Groups. J Clin Oncol : JCO2018789388, 2018. [PUBMED Abstract]
  109. Ferrer FA, Isakoff M, Koyle MA: Bladder/prostate rhabdomyosarcoma: past, present and future. J Urol 176 (4 Pt 1): 1283-91, 2006. [PUBMED Abstract]
  110. Rodeberg DA, Anderson JR, Arndt CA, et al.: Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee. Int J Cancer 128 (5): 1232-9, 2011. [PUBMED Abstract]
  111. Hays DM, Raney RB, Wharam MD, et al.: Children with vesical rhabdomyosarcoma (RMS) treated by partial cystectomy with neoadjuvant or adjuvant chemotherapy, with or without radiotherapy. A report from the Intergroup Rhabdomyosarcoma Study (IRS) Committee. J Pediatr Hematol Oncol 17 (1): 46-52, 1995. [PUBMED Abstract]
  112. Lobe TE, Wiener E, Andrassy RJ, et al.: The argument for conservative, delayed surgery in the management of prostatic rhabdomyosarcoma. J Pediatr Surg 31 (8): 1084-7, 1996. [PUBMED Abstract]
  113. Pappo AS, Shapiro DN, Crist WM, et al.: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 13 (8): 2123-39, 1995. [PUBMED Abstract]
  114. Raney RB Jr, Gehan EA, Hays DM, et al.: Primary chemotherapy with or without radiation therapy and/or surgery for children with localized sarcoma of the bladder, prostate, vagina, uterus, and cervix. A comparison of the results in Intergroup Rhabdomyosarcoma Studies I and II. Cancer 66 (10): 2072-81, 1990. [PUBMED Abstract]
  115. Heyn R, Newton WA, Raney RB, et al.: Preservation of the bladder in patients with rhabdomyosarcoma. J Clin Oncol 15 (1): 69-75, 1997. [PUBMED Abstract]
  116. Arndt C, Rodeberg D, Breitfeld PP, et al.: Does bladder preservation (as a surgical principle) lead to retaining bladder function in bladder/prostate rhabdomyosarcoma? Results from intergroup rhabdomyosarcoma study iv. J Urol 171 (6 Pt 1): 2396-403, 2004. [PUBMED Abstract]
  117. Raney B, Anderson J, Jenney M, et al.: Late effects in 164 patients with rhabdomyosarcoma of the bladder/prostate region: a report from the international workshop. J Urol 176 (5): 2190-4; discussion 2194-5, 2006. [PUBMED Abstract]
  118. Jenney M, Oberlin O, Audry G, et al.: Conservative approach in localised rhabdomyosarcoma of the bladder and prostate: results from International Society of Paediatric Oncology (SIOP) studies: malignant mesenchymal tumour (MMT) 84, 89 and 95. Pediatr Blood Cancer 61 (2): 217-22, 2014. [PUBMED Abstract]
  119. Fuchs J, Paulsen F, Bleif M, et al.: Conservative surgery with combined high dose rate brachytherapy for patients suffering from genitourinary and perianal rhabdomyosarcoma. Radiother Oncol 121 (2): 262-267, 2016. [PUBMED Abstract]
  120. Chargari C, Martelli H, Guérin F, et al.: Pulsed-dose rate brachytherapy for pediatric bladder prostate rhabdomyosarcoma: Compliance and early clinical results. Radiother Oncol 124 (2): 285-290, 2017. [PUBMED Abstract]
  121. Chargari C, Haie-Meder C, Guérin F, et al.: Brachytherapy Combined With Surgery for Conservative Treatment of Children With Bladder Neck and/or Prostate Rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 98 (2): 352-359, 2017. [PUBMED Abstract]
  122. Godbole P, Outram A, Wilcox DT, et al.: Myogenin and desmin immunohistochemistry in the assessment of post-chemotherapy genitourinary embryonal rhabdomyosarcoma: prognostic and management implications. J Urol 176 (4 Pt 2): 1751-4, 2006. [PUBMED Abstract]
  123. Arndt CA, Hammond S, Rodeberg D, et al.: Significance of persistent mature rhabdomyoblasts in bladder/prostate rhabdomyosarcoma: Results from IRS IV. J Pediatr Hematol Oncol 28 (9): 563-7, 2006. [PUBMED Abstract]
  124. Raney B, Anderson J, Arndt C, et al.: Primary renal sarcomas in the Intergroup Rhabdomyosarcoma Study Group (IRSG) experience, 1972-2005: A report from the Children's Oncology Group. Pediatr Blood Cancer 51 (3): 339-43, 2008. [PUBMED Abstract]
  125. Arndt CA, Donaldson SS, Anderson JR, et al.: What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract? Cancer 91 (12): 2454-68, 2001. [PUBMED Abstract]
  126. Walterhouse DO, Meza JL, Breneman JC, et al.: Local control and outcome in children with localized vaginal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma committee of the Children's Oncology Group. Pediatr Blood Cancer 57 (1): 76-83, 2011. [PUBMED Abstract]
  127. Kirsch CH, Goodman M, Esiashvili N: Outcome of female pediatric patients diagnosed with genital tract rhabdomyosarcoma based on analysis of cases registered in SEER database between 1973 and 2006. Am J Clin Oncol 37 (1): 47-50, 2014. [PUBMED Abstract]
  128. Walterhouse DO, Pappo AS, Meza JL, et al.: Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer 123 (12): 2368-2375, 2017. [PUBMED Abstract]
  129. Walterhouse DO, Pappo AS, Meza JL, et al.: Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 32 (31): 3547-52, 2014. [PUBMED Abstract]
  130. Corpron CA, Andrassy RJ, Hays DM, et al.: Conservative management of uterine pediatric rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study III and IV pilot. J Pediatr Surg 30 (7): 942-4, 1995. [PUBMED Abstract]
  131. Dehner LP, Jarzembowski JA, Hill DA: Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations. Mod Pathol 25 (4): 602-14, 2012. [PUBMED Abstract]
  132. Fernandez-Pineda I, Davidoff AM, Lu L, et al.: Impact of ovarian transposition before pelvic irradiation on ovarian function among long-term survivors of childhood Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study. Pediatr Blood Cancer 65 (9): e27232, 2018. [PUBMED Abstract]
  133. Jensen AK, Kristensen SG, Macklon KT, et al.: Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark. Hum Reprod 30 (12): 2838-45, 2015. [PUBMED Abstract]
  134. Minard-Colin V, Walterhouse D, Bisogno G, et al.: Localized vaginal/uterine rhabdomyosarcoma-results of a pooled analysis from four international cooperative groups. Pediatr Blood Cancer : e27096, 2018. [PUBMED Abstract]
  135. Guilcher GM, Hendson G, Goddard K, et al.: Successful treatment of a child with a primary intracranial rhabdomyosarcoma with chemotherapy and radiation therapy. J Neurooncol 86 (1): 79-82, 2008. [PUBMED Abstract]
  136. Kato MA, Flamant F, Terrier-Lacombe MJ, et al.: Rhabdomyosarcoma of the larynx in children: a series of five patients treated in the Institut Gustave Roussy (Villejuif, France). Med Pediatr Oncol 19 (2): 110-4, 1991. [PUBMED Abstract]
  137. Raney RB, Anderson JR, Andrassy RJ, et al.: Soft-tissue sarcomas of the diaphragm: a report from the Intergroup Rhabdomyosarcoma Study Group from 1972 to 1997. J Pediatr Hematol Oncol 22 (6): 510-4, 2000 Nov-Dec. [PUBMED Abstract]
  138. Cribbs RK, Shehata BM, Ricketts RR: Primary ovarian rhabdomyosarcoma in children. Pediatr Surg Int 24 (5): 593-5, 2008. [PUBMED Abstract]
  139. Dantonello TM, Winkler P, Boelling T, et al.: Embryonal rhabdomyosarcoma with metastases confined to the lungs: report from the CWS Study Group. Pediatr Blood Cancer 56 (5): 725-32, 2011. [PUBMED Abstract]
  140. Rodeberg D, Arndt C, Breneman J, et al.: Characteristics and outcomes of rhabdomyosarcoma patients with isolated lung metastases from IRS-IV. J Pediatr Surg 40 (1): 256-62, 2005. [PUBMED Abstract]
  141. Mandell LR: Ongoing progress in the treatment of childhood rhabdomyosarcoma. Oncology (Huntingt) 7 (1): 71-83; discussion 84-6, 89-90, 1993. [PUBMED Abstract]
  142. Gupta AA, Anderson JR, Pappo AS, et al.: Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. Cancer 118 (4): 1130-7, 2012. [PUBMED Abstract]
  143. Beverly Raney R, Walterhouse DO, Meza JL, et al.: 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 29 (10): 1312-8, 2011. [PUBMED Abstract]
  144. Baker KS, Anderson JR, Link MP, et al.: Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: results from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 18 (12): 2427-34, 2000. [PUBMED Abstract]
  145. Spunt SL, Smith LM, Ruymann FB, et al.: Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: a report from the soft tissue sarcoma committee of the children's oncology group. Clin Cancer Res 10 (18 Pt 1): 6072-9, 2004. [PUBMED Abstract]
  146. Houghton PJ, Cheshire PJ, Myers L, et al.: Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 31 (3): 229-39, 1992. [PUBMED Abstract]
  147. Pappo AS, Lyden E, Breneman J, et al.: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol 19 (1): 213-9, 2001. [PUBMED Abstract]
  148. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PUBMED Abstract]
  149. Walterhouse DO, Lyden ER, Breitfeld PP, et al.: Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study. J Clin Oncol 22 (8): 1398-403, 2004. [PUBMED Abstract]
  150. Arndt CA, Hawkins DS, Meyer WH, et al.: Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS-IV in intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 50 (1): 33-6, 2008. [PUBMED Abstract]
  151. Oberlin O, Rey A, Sanchez de Toledo J, et al.: 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 30 (20): 2457-65, 2012. [PUBMED Abstract]
  152. Hawkins DS, Chi YY, Anderson JR, et al.: Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol : JCO2018779694, 2018. [PUBMED Abstract]
  153. Arndt CA, Stoner JA, Hawkins DS, et al.: 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 27 (31): 5182-8, 2009. [PUBMED Abstract]
  154. Rodeberg DA, Stoner JA, Hayes-Jordan A, et al.: Prognostic significance of tumor response at the end of therapy in group III rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 27 (22): 3705-11, 2009. [PUBMED Abstract]
  155. Minn AY, Lyden ER, Anderson JR, et al.: Early treatment failure in intermediate-risk rhabdomyosarcoma: results from IRS-IV and D9803--a report from the Children's Oncology Group. J Clin Oncol 28 (27): 4228-32, 2010. [PUBMED Abstract]
  156. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [PUBMED Abstract]
  157. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003. [PUBMED Abstract]
  158. Oberlin O, Rey A, Lyden E, et al.: Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 26 (14): 2384-9, 2008. [PUBMED Abstract]
  159. Breitfeld PP, Lyden E, Raney RB, et al.: Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: a report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol 23 (4): 225-33, 2001. [PUBMED Abstract]
  160. Sandler E, Lyden E, Ruymann F, et al.: Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37 (5): 442-8, 2001. [PUBMED Abstract]
  161. Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. J Clin Oncol 25 (4): 362-9, 2007. [PUBMED Abstract]
  162. Bergeron C, Thiesse P, Rey A, et al.: Revisiting the role of doxorubicin in the treatment of rhabdomyosarcoma: an up-front window study in newly diagnosed children with high-risk metastatic disease. Eur J Cancer 44 (3): 427-31, 2008. [PUBMED Abstract]
  163. McDowell HP, Foot AB, Ellershaw C, et al.: Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer 46 (9): 1588-95, 2010. [PUBMED Abstract]
  164. Weigel BJ, Lyden E, Anderson JR, et al.: Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol 34 (2): 117-22, 2016. [PUBMED Abstract]
  165. Bisogno G, Jenney M, Bergeron C, et al.: Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet Oncol : , 2018. [PUBMED Abstract]
  166. Malempati S, Weigel BJ, Chi YY, et al.: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children's Oncology Group. Cancer : , 2018. [PUBMED Abstract]
  167. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010. [PUBMED Abstract]
  168. Peinemann F, Kröger N, Bartel C, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review. PLoS One 6 (2): e17127, 2011. [PUBMED Abstract]
  169. Thiel U, Koscielniak E, Blaeschke F, et al.: Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment. Br J Cancer 109 (10): 2523-32, 2013. [PUBMED Abstract]
  170. Mackall CL, Rhee EH, Read EJ, et al.: A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin Cancer Res 14 (15): 4850-8, 2008. [PUBMED Abstract]

Treatment of Refractory or Recurrent Childhood Rhabdomyosarcoma



Prognosis and Prognostic Factors

Although patients with recurrent or progressive rhabdomyosarcoma sometimes achieve complete remission with secondary therapy, the long-term prognosis is usually poor.[1,2] Rhabdomyosarcoma may relapse locally or in the lung, bone, or bone marrow. Less commonly, the site of first recurrence can be the breast in adolescent females or the liver.[3]
The following studies reported on the prognostic factors associated with recurrent or progressive disease:
  • In a 1999 study of 605 children, the prognosis was most favorable (5-year survival rates, 50%–70%) for children who initially presented with Stage 1 or Group I disease and embryonal/botryoid histology with small tumors and for those with local or regional nodal recurrence. Patients with Group I alveolar rhabdomyosarcoma or undifferentiated sarcoma had a 5-year overall survival (OS) of 40% to 50%. Only 20% of the relapsed patients were in these groups.[1][Level of evidence: 3iiiA]
  • In a 2014 study of 24 children, 22 (82%) children with initially localized orbital sarcoma survived at least 5 years after relapse following re-treatment with curative intent.[4][Level of evidence: 3iiA]
  • A 2005 study of 125 patients with nonmetastatic rhabdomyosarcoma who recurred after previous complete remission observed that favorable factors at initial diagnosis included: nonalveolar histology, primary site in the orbit, genitourinary/nonbladder-prostate or head/neck nonparameningeal regions, tumor size of 5 cm or smaller, local relapse, relapse after 18 months from the primary diagnosis, and lack of initial radiation therapy.[2]
  • A report of 337 patients with nonmetastatic rhabdomyosarcoma in 2008 observed that favorable factors at initial diagnosis were age 10 years or younger, embryonal histology, tumor size of 5 cm or smaller, favorable site, and lack of initial radiation therapy.[5]
  • In a 2009 study of 234 patients who relapsed after achieving complete remission and completing primary treatment, the favorable prognostic factors for 3-year OS were reported; the factors were favorable primary site, local relapse, time to relapse more than 12 months, tumor size of 5 cm or smaller, and no previous radiation therapy.[6][Level of evidence: 3iiB]
  • A study of 474 patients in 2011 with nonmetastatic rhabdomyosarcoma who had complete local control at the primary site noted the unfavorable factors for survival 3 years after first relapse. These unfavorable factors included relapse with metastatic disease, previous (initial) radiation therapy, tumor size more than 5 cm, time to relapse less than 18 months, regional lymph node involvement, alveolar histology, and unfavorable disease at primary diagnosis.[7]
  • In 2013, 90 patients with nonmetastatic alveolar rhabdomyosarcoma were re-treated with additional chemotherapy with or without local re-excision of the primary site (if indicated) with or without radiation therapy. The four most important factors for survival after relapse were no lymph node involvement, no metastases, adequate local therapy, and achieving a second complete remission. OS at 5 years was 21%.[8][Level of evidence: 3iiA]
  • A single-institution, retrospective review identified 23 patients with central nervous system (CNS) relapse after initial treatment for rhabdomyosarcoma.[9][Level of evidence: 3iiA] High-risk features at initial presentation included 16 alveolar patients, 13 stage IV patients, and 13 patients with primary tumor in parameningeal locations. All of the patients died. Twenty-one patients died because of CNS disease and two died because of metastatic disease at other sites. Median survival post-CNS relapse was 5 months (range, 0.1–49 months).

Treatment Options for Recurrent Childhood Rhabdomyosarcoma

The selection of further treatment depends on many factors, including the site(s) of recurrence, previous treatment, and individual patient considerations.
Treatment options for recurrent childhood rhabdomyosarcoma include the following:
  1. Surgery. Treatment for local or regional recurrence may include wide local excision or aggressive surgical removal of tumor, particularly in the absence of widespread bony metastases.[10,11] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[10] A review of 108 Italian children with bladder or prostate tumors who did not achieve tumor eradication after chemotherapy with or without RT found that only two factors correlated with inability to achieve progression-free survival at 5 or more years: initial histology showing undifferentiated sarcoma (P = .008) and diameter of the surgically removed tumor exceeding 5 cm. Positive tumor margins at the salvage operation did not predict ultimate failure.[12][Level of evidence: 3iiiDiii]
  2. Radiation therapy. Radiation therapy should be considered for patients with embryonal rhabdomyosarcoma who have not already received radiation therapy in the area of recurrence, or rarely for those who have received radiation therapy but for whom surgical excision is not possible.
  3. Chemotherapy. A German study found that treatment with multiagent chemotherapy incorporating carboplatin and etoposide, plus RT, was efficacious for patients with embryonal rhabdomyosarcoma (5-year event-free survival [EFS], 41%), but it was less effective for patients with alveolar rhabdomyosarcoma (5-year EFS, 25%).[13] Previously unused, active, single agents or combinations of drugs may also enhance the likelihood of disease control.


The following chemotherapy regimens have been used to treat recurrent rhabdomyosarcoma:
  1. Carboplatin/etoposide.[13]
  2. Ifosfamide, carboplatin, and etoposide.[14,15]
  3. Cyclophosphamide/topotecan.[16]
  4. Irinotecan with or without vincristine.[17-20]
    • A Children's Oncology Group (COG) prospective, randomized, up-front window trial, COG-ARST0121, showed no difference between vincristine plus irinotecan (20 mg/m2/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m2/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma. At 1 year after initiation of treatment for recurrence, the failure-free survival (FFS) rate was 37% and the OS rate was 55% for Regimen 1A; the FFS rate was 38% and OS rate was 60% for Regimen 1B. The Soft Tissue Sarcoma Committee of the COG recommended the more convenient Regimen 1B for further investigation.[21][Level of evidence: 1iiA]
  5. Single-agent vinorelbine.
    • In one phase II trial, four of eleven patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[22]
    • In another trial, 6 of 12 young patients (aged 9–29 years) had a partial response.[23]
  6. Vinorelbine and cyclophosphamide.
    • In a pilot study, three of nine patients with rhabdomyosarcoma had an objective response.[24]
    • In a phase II study in France (N = 50), children with recurrent or refractory rhabdomyosarcoma were treated with vinorelbine and low-dose oral cyclophosphamide. Four complete responses and 14 partial responses were observed, for an objective response rate of 36%.[25][Level of evidence: 3iiiDiv]
  7. Gemcitabine and docetaxel.
    • In a single institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[26]
  8. Sirolimus.[27]
  9. Topotecan, vincristine, and doxorubicin.[28][Level of evidence: 3iiiDiv]
  10. Vincristine, irinotecan, and temozolomide.
    • One of four patients with recurrent alveolar rhabdomyosarcoma had a complete radiographic response sustained for 27 weeks with no grade 3 or 4 toxicities.[29]; [30][Level of evidence: 3iiiDiii]
    • In a group of 15 patients with relapsed rhabdomyosarcoma who were treated with vincristine, irinotecan, and temozolomide, there were no complete or partial remissions; 4 patients had stable disease, and 11 patients had progressive disease. Many of the patients had received previous relapse therapy.[31][Level of evidence: 3iiiA]
  11. Temsirolimus, irinotecan, and temozolomide.
    • In a phase I trial of these agents, four patients had rhabdomyosarcoma. The regimen was well tolerated, and one patient had a partial response and another had stable disease.[32]
  12. Temsirolimus, cyclophosphamide, and vinorelbine.
    • In a COG randomized, phase II, selection-design study in patients with relapsed rhabdomyosarcoma that compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine, the temsirolimus arm had a superior 6-month EFS (65%; 95% CI, 44%–79%) compared with the bevacizumab arm (50%; 95% CI, 32%–66%; P = .0031). The complete response rate (complete remission plus partial remission) was higher on the temsirolimus arm (47%) than on the bevacizumab arm (28%).[33]
Very intensive chemotherapy followed by autologous bone marrow reinfusion is also under investigation for patients with recurrent rhabdomyosarcoma. However, a review of the published data did not determine a significant benefit for patients who underwent this salvage treatment approach.[34-36]
Treatment options under clinical evaluation for recurrent rhabdomyosarcoma:
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
  • ADVL1412 (NCT02304458) (Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas): This phase I/II trial is studying the side effects and best dose of nivolumab when given with or without ipilimumab to see how well they work in treating younger patients with solid tumors or sarcomas that have come back (recurrent) or do not respond to treatment (refractory). Monoclonal antibodies such as nivolumab and ipilimumab may block tumor growth in different ways by targeting certain cells. It is not yet known whether nivolumab works better alone or with ipilimumab in treating patients with recurrent or refractory solid tumors or sarcomas.
  • ADVL1621 (NCT02332668) (A Study of Pembrolizumab [MK-3475] in Pediatric Participants With Advanced Melanoma or Advanced, Relapsed, or Refractory PD-L1-Positive Solid Tumors or Lymphoma [MK-3475-051/KEYNOTE-051]): This is a two-part study of pembrolizumab (MK-3475) in pediatric participants who have either advanced melanoma or a programmed cell death ligand 1 (PD-L1)-positive advanced, relapsed, or refractory solid tumor or lymphoma. Part 1 will find the maximum tolerated dose/maximum administered dose, confirm the dose, and find the recommended phase II dose for pembrolizumab therapy. Part 2 will further evaluate the safety and efficacy at the pediatric recommended phase II dose.
  • ADVL1312 (NCT02095132) (WEE1 Inhibitor MK-1775 and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors): This phase I/II trial is studying the side effects and best dose of WEE1 inhibitor MK-1775 and irinotecan hydrochloride in treating younger patients with solid tumors that have come back or that have not responded to standard therapy. WEE1 inhibitor MK-1775 and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. A rhabdomyosarcoma stratum is open in the phase II portion of this trial.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
  • ADVL1622 (NCT02867592) (Cabozantinib-S-Malate in Treating Younger Patients with Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors): This is an open-label, two-stage, phase II trial of cabozantinib in selective solid tumors, including rhabdomyosarcoma. Cabozantinib is an oral small molecule inhibitor of multiple tyrosine kinases including MET, VEGFR2, and RET, which are potential therapeutic targets in many pediatric and adult solid tumors.
  • New agents under clinical evaluation in phase I and phase II trials should be considered for relapsed patients.


Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.


References
  1. Pappo AS, Anderson JR, Crist WM, et al.: Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. J Clin Oncol 17 (11): 3487-93, 1999. [PUBMED Abstract]
  2. Mazzoleni S, Bisogno G, Garaventa A, et al.: Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma. Cancer 104 (1): 183-90, 2005. [PUBMED Abstract]
  3. Audino AN, Setty BA, Yeager ND: Rhabdomyosarcoma of the Breast in Adolescent and Young Adult (AYA) Women. J Pediatr Hematol Oncol 39 (1): 62-66, 2017. [PUBMED Abstract]
  4. Raney B, Huh W, Hawkins D, et al.: Outcome of patients with localized orbital sarcoma who relapsed following treatment on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-III and -IV, 1984-1997: a report from the Children's Oncology Group. Pediatr Blood Cancer 60 (3): 371-6, 2013. [PUBMED Abstract]
  5. Dantonello TM, Int-Veen C, Winkler P, et al.: Initial patient characteristics can predict pattern and risk of relapse in localized rhabdomyosarcoma. J Clin Oncol 26 (3): 406-13, 2008. [PUBMED Abstract]
  6. Mattke AC, Bailey EJ, Schuck A, et al.: Does the time-point of relapse influence outcome in pediatric rhabdomyosarcomas? Pediatr Blood Cancer 52 (7): 772-6, 2009. [PUBMED Abstract]
  7. Chisholm JC, Marandet J, Rey A, et al.: Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J Clin Oncol 29 (10): 1319-25, 2011. [PUBMED Abstract]
  8. Dantonello TM, Int-Veen C, Schuck A, et al.: Survival following disease recurrence of primary localized alveolar rhabdomyosarcoma. Pediatr Blood Cancer 60 (8): 1267-73, 2013. [PUBMED Abstract]
  9. De B, Kinnaman MD, Wexler LH, et al.: Central nervous system relapse of rhabdomyosarcoma. Pediatr Blood Cancer 65 (1): , 2018. [PUBMED Abstract]
  10. Hayes-Jordan A, Doherty DK, West SD, et al.: Outcome after surgical resection of recurrent rhabdomyosarcoma. J Pediatr Surg 41 (4): 633-8; discussion 633-8, 2006. [PUBMED Abstract]
  11. De Corti F, Bisogno G, Dall'Igna P, et al.: Does surgery have a role in the treatment of local relapses of non-metastatic rhabdomyosarcoma? Pediatr Blood Cancer 57 (7): 1261-5, 2011. [PUBMED Abstract]
  12. Angelini L, Bisogno G, Alaggio R, et al.: Prognostic factors in children undergoing salvage surgery for bladder/prostate rhabdomyosarcoma. J Pediatr Urol 12 (4): 265.e1-8, 2016. [PUBMED Abstract]
  13. Klingebiel T, Pertl U, Hess CF, et al.: Treatment of children with relapsed soft tissue sarcoma: report of the German CESS/CWS REZ 91 trial. Med Pediatr Oncol 30 (5): 269-75, 1998. [PUBMED Abstract]
  14. Kung FH, Desai SJ, Dickerman JD, et al.: Ifosfamide/carboplatin/etoposide (ICE) for recurrent malignant solid tumors of childhood: a Pediatric Oncology Group Phase I/II study. J Pediatr Hematol Oncol 17 (3): 265-9, 1995. [PUBMED Abstract]
  15. Van Winkle P, Angiolillo A, Krailo M, et al.: Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer 44 (4): 338-47, 2005. [PUBMED Abstract]
  16. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PUBMED Abstract]
  17. Cosetti M, Wexler LH, Calleja E, et al.: Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol 24 (2): 101-5, 2002. [PUBMED Abstract]
  18. Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. J Clin Oncol 25 (4): 362-9, 2007. [PUBMED Abstract]
  19. Vassal G, Couanet D, Stockdale E, et al.: Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol 25 (4): 356-61, 2007. [PUBMED Abstract]
  20. Furman WL, Stewart CF, Poquette CA, et al.: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17 (6): 1815-24, 1999. [PUBMED Abstract]
  21. Mascarenhas L, Lyden ER, Breitfeld PP, et al.: Randomized phase II window trial of two schedules of irinotecan with vincristine in patients with first relapse or progression of rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 28 (30): 4658-63, 2010. [PUBMED Abstract]
  22. Kuttesch JF Jr, Krailo MD, Madden T, et al.: Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children's Oncology Group study. Pediatr Blood Cancer 53 (4): 590-3, 2009. [PUBMED Abstract]
  23. Casanova M, Ferrari A, Spreafico F, et al.: Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer 94 (12): 3263-8, 2002. [PUBMED Abstract]
  24. Casanova M, Ferrari A, Bisogno G, et al.: Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. Cancer 101 (7): 1664-71, 2004. [PUBMED Abstract]
  25. Minard-Colin V, Ichante JL, Nguyen L, et al.: Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: good tolerance profile and efficacy in rhabdomyosarcoma--a report from the Société Française des Cancers et leucémies de l'Enfant et de l'adolescent (SFCE). Eur J Cancer 48 (15): 2409-16, 2012. [PUBMED Abstract]
  26. Rapkin L, Qayed M, Brill P, et al.: Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas. Pediatr Blood Cancer 59 (5): 854-8, 2012. [PUBMED Abstract]
  27. Houghton PJ, Morton CL, Kolb EA, et al.: Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer 50 (4): 799-805, 2008. [PUBMED Abstract]
  28. Meazza C, Casanova M, Zaffignani E, et al.: Efficacy of topotecan plus vincristine and doxorubicin in children with recurrent/refractory rhabdomyosarcoma. Med Oncol 26 (1): 67-72, 2009. [PUBMED Abstract]
  29. McNall-Knapp RY, Williams CN, Reeves EN, et al.: Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood Cancer 54 (7): 909-15, 2010. [PUBMED Abstract]
  30. Mixon BA, Eckrich MJ, Lowas S, et al.: Vincristine, irinotecan, and temozolomide for treatment of relapsed alveolar rhabdomyosarcoma. J Pediatr Hematol Oncol 35 (4): e163-6, 2013. [PUBMED Abstract]
  31. Setty BA, Stanek JR, Mascarenhas L, et al.: VIncristine, irinotecan, and temozolomide in children and adolescents with relapsed rhabdomyosarcoma. Pediatr Blood Cancer 65 (1): , 2018. [PUBMED Abstract]
  32. Bagatell R, Norris R, Ingle AM, et al.: Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children's Oncology Group Study. Pediatr Blood Cancer 61 (5): 833-9, 2014. [PUBMED Abstract]
  33. Mascarenhas L, Meyer WH, Lyden E, et al.: Randomized phase II trial of bevacizumab and temsirolimus in combination with vinorelbine (V) and cyclophosphamide (C) for first relapse/disease progression of rhabdomyosarcoma (RMS): a report from the Children’s Oncology Group (COG). [Abstract] J Clin Oncol 32 (Suppl 5): A-10003, 2014. Also available online. Last accessed January 29, 2019.
  34. Weigel BJ, Breitfeld PP, Hawkins D, et al.: Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol 23 (5): 272-6, 2001 Jun-Jul. [PUBMED Abstract]
  35. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010. [PUBMED Abstract]
  36. Peinemann F, Kröger N, Bartel C, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review. PLoS One 6 (2): e17127, 2011. [PUBMED Abstract]

Changes to This Summary (01/29/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Treatment of Previously Untreated Childhood Rhabdomyosarcoma
Added text about the results of a single-institution retrospective review that identified 14 patients with head and neck alveolar rhabdomyosarcoma who were treated with multiagent chemotherapy and radiation therapy to the primary site and clinically involved nodes (cited Ludmir et al. as reference 55 and level of evidence 3iiiDiii).
Added text about the results from a pooled analysis of North American and European cooperative groups of patients with paratesticular rhabdomyosarcoma, including prognostic features, survival outcomes, and treatment options (cited Walterhouse et al. as reference 108 and level of evidence 3iiA).
Added Fernandez-Pineda et al. and Jensen et al. as references 132 and 133, respectively.
Added text about the results of two Children's Oncology Group pilot trials in patients with high-risk rhabdomyosarcoma who were treated with intensive multiagent chemotherapy plus cixutumumab or temozolomide (cited Malempati et al. as reference 166 and level of evidence 3iiDi).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary



Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood rhabdomyosarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Rhabdomyosarcoma Treatment are:
  • Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
  • Holcombe Edwin Grier, MD
  • Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
  • R Beverly Raney, MD (Consultant)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Rhabdomyosarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/soft-tissue-sarcoma/hp/rhabdomyosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389243]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.


  • Updated: January 29, 2019



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