Methodology

These guidelines have been developed by a multidisciplinary panel of specialists involved in the diagnosis and treatment of rhabdomyosarcoma (RMS) both in children and adults. A bibliographic search of published articles was performed in the PubMed database and international guidelines, such as EpSSG (European Pediatric Soft Tissue Sarcoma Study Group), were consulted [1]. In a telematic meeting, each section was presented by one expert to the entire group for discussion and consensus. The panel adopted the Infectious Disease Society of America levels of evidence/grades of recommendation [2].

As pleomorphic rhabdomyosarcoma’s behavior is more similar to other adult soft tissue sarcomas, we refer the reader to those specific therapeutic guidelines [3].

Incidence and epidemiology

RMS is the most frequent soft tissue sarcoma (STS) in children, representing 55% of these tumors in Spain [4]. It accounts for 3.7% of all pediatric cancers, with an annual incidence of 4.4 cases per million children younger than 14 years. These figures are similar to those reported by other series both in Europe and the US [5,6,7]; Asian countries report lower incidences [8, 9]. Incidence is higher among boys (1.5/1 ratio), and in the age group from 1 to 4 years (6.3 cases per million). Most frequently, histological subtypes are embryonal (55–60% of patients) and alveolar (20–25%), while fusocellular/sclerosing is rare [7]. Similar to other pediatric cancers, predisposing factors are identified only in a small fraction of patients. There are known associations with cancer predisposition syndromes (Li-Fraumeni, DICER1…) [10, 11]. Approximately 40% of RMS are diagnosed in patients over 20 years of age. This represents 1% of STS and 0.02% of cancer in adults [12]. Conversely to pediatric RMS, there is a high proportion of the pleomorphic variant [7].

Diagnostic procedures

RMS can appear anywhere on the body, but head and neck (35–50% of cases), genitourinary region (25%) and extremities (20%) are the most frequent sites. Moreover, some locations are more frequently associated with certain histological subtypes, such as the alveolar variant predominant in extremities [13, 14]. Lymph node involvement is common in RMS, mainly in older children and adults, and in the alveolar tumors [15].

Imaging

Ultrasound

It should be used as the first imaging test for any suspicious palpable mass, as well as for abdominal or genitourinary symptoms in children [16].

MRI

The technique of choice for the head and neck, as well as for local staging. With diffusion-MRI techniques, low ADC values are observed in areas with cellular predominance; and intermediate or high ADC values are seen in areas with myxoid and/or necrotic changes [17]. Alveolar RMS associates scattered foci of necrosis with a more heterogeneous enhancement involving muscle, fasciae, bone, and regional lymph nodes [18, 19].

CT

It is usually the first imaging test in older children and adults in head and neck, chest or abdomen locations.

PET/CT

The metabolic activity of RMS tends to be high, and has prognostic value in the baseline study [20]. High SUVmax, SUVpeak, metabolic tumor volume and total-lesion glycolysis are more prevalent among patients with less favorable clinical and pathological features, including unfavorable primary site, alveolar subtype, presence of regional or distant metastasis, and high-risk group.

Plain radiography

Of limited utility in evaluating soft tissue tumors, but it is useful for the initial assessment of calcifications or bone involvement.

Biopsy

Biopsies must be planned to ensure that the scar and the biopsy tract can be easily resected in the definitive surgery or included in the radiotherapy field, and must respect the compartmental anatomy. Endoscopic biopsies are accepted in certain anatomic locations (e.g., urinary tract, biliary tract). Regardless of the technique, hemostasis must be guaranteed to avoid tumor dissemination. Drains should be avoided if possible, and if needed, they should be placed in parallel to the surgical incision and as close as possible. To guarantee an adequate oncologic resection, crossing different anatomical compartments and compromising neurovascular structures should be avoided.

Core needle biopsy (CNB)

This is currently the preferred approach in most situations, as it is less invasive and tumor seeding is rare [22, 23]. If performed under image guidance (mostly ultrasound, but also CT) [24], it allows avoiding necrotic or cystic areas and prevents possible complications. The needle must be directed toward the peripheral areas of the lesion, those with high metabolism detected on PET/CT, or with clear contrast enhancement on MRI or CT. Usually, 14 or 16G needles, 10–20 mm long, are sufficient, with the number of passes necessary to obtain sufficient tissue to perform histological, immunohistochemical and molecular studies (minimum 4–5 cylinders). Coaxial needles are highly recommended to avoid tumor seeding.

Surgical biopsy

A valid alternative, but currently reserved for those cases where CNB is not feasible, when after two attempts there is not sufficient/valid tissue, or when an excisional biopsy with negative margins can be achieved without mutilation. In the extremities, the incision must be longitudinal to the long axis of the limb.

Fine needle aspiration (FNA)

Not indicated for the initial histological study, however, it could be a valid option for the diagnosis of tumor relapses.

Pathology

RMS is classified into four histologic subtypes: embryonal (ERMS), alveolar (ARMS), spindle cell/sclerosing and pleomorphic, with different histological, immunohistochemical (IHC) and molecular characteristics [25] (Table 1).

Table 1 Histological and molecular classification of RMS
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1. ERMS: predominantly located in the head and neck and genitourinary area. Histologically, the classic form shows myxoid stroma and variable degrees of rhabdomyoblastic differentiation: 1.1 classic (includes botryoid); 1.2 ERMS with predominance of a spindle cell component; 1.3 densely cellular ERMS.

2. ARMS: frequently located in deep soft parts of the extremities. Histologically, it is an undifferentiated small, round blue cell tumor, with skeletal muscle differentiation markers: 2.1 classic; 2.2 solid.

3. Spindle cell/sclerosing RMS: composed of “herringbone” spindle cells with different components of sclerosis. Four variants have been described based on their molecular features: 3.1 congenital/infantile spindle cell RMS [26, 27]; 3.2 Myo-D1 mutant spindle cell/sclerosing RMS [28]; 3.3 intraosseous spindle cell RMS [29]; 3.4 spindle cell/sclerosing RMS without identifiable genetic alterations.

4. Pleomorphic RMS: tumor presenting in adults. It is characterized by a proliferation of spindle or rhabdoid cells with marked pleomorphism. They have complex karyotypes, comparable to undifferentiated pleomorphic sarcomas.

The term RMS N.O.S (not otherwise specified) is not a subtype; it indicates that diagnosis of RMS can be made but no further subtyping is possible. This usually occurs when the biopsy is very small or presents artefacts.

Anaplasia needs to be documented and is defined by the presence of cells with large, lobulated hyperchromatic nuclei (at least three times the size of neighboring nuclei) and atypical mitosis.

Reception and macroscopic study of the specimen

Biopsies and surgical specimens should be sent fresh and provide sufficient material for diagnosis and molecular characterization. All primary and post-chemotherapy resection specimens require evaluation of the margins by the pathologist. The specimen should be inked before incision, weighed, measured, orientated, photographed and, at least, one block per centimeter needs to be sampled. Percentage of necrosis must be documented and all lymph nodes processed.

Diagnostic report

  • Histological type and subtype (architectural pattern, cell type, stroma, number of mitoses/10HPF, % of necrosis and anaplasia).

  • In surgical specimens: anatomical location, type of surgical resection, resection margins and minimum distance to the tumor, signs of response to treatment if neoadjuvancy (percentage of necrosis/fibrosis or other regressive changes), vascular invasion, and metastatic lymph nodes.

  • IHQ stains: negative or positive, localization and extension.

  • Molecular techniques (FISH, PCR, RT-PCR, NGS) specifying reagents, results and evaluation criteria.

Diagnosis of RMS requires an integration of morphology, IHQ (myogenin, MyoD1 and desmin) and molecular analysis: rearrangements of FOXO1 (FOXO1-PAX3, FOXO1-PAX7, FOXO1-FGFR1) and PAX3 (PAX3-NCOA2) [30] using FISH, RT-PCR or NGS.

Staging and risk stratification

Staging

Local

The initial radiological evaluation (MRI or CT) should include the primary tumor and all anatomical landmarks that may compromise the surgical approach: vascular-nerve tracts, fascial involvement, and bone or adjacent organs [31]. It is important to include regional lymph node stations, especially when using MRI [32].

Metastatic

Chest CT continues to be the technique of choice in the initial assessment of possible pulmonary metastases. PET-CT can increase the accuracy of initial staging, mainly in the detection of lymph node involvement, with high sensitivity (69–100%) and specificity (89–100%) [33]. Nevertheless, sentinel node biopsy detected by 99mTc-labeled-nanocolloid SPECT/CT remains the technique of choice in the definitive characterization of lymph node involvement [34]. The most recent RMS staging protocols from various cooperative groups include PET-CT as a recommended procedure (IIB) [35,36,37]. It is superior to conventional bone scintigraphy, detecting skeletal involvement thus replacing scintigraphy. Whole-body MRI is an equally valid alternative [38].

Lymph nodes

Adequate sampling of clinically or radiologically suspicious lymph nodes is mandatory at diagnosis and at relapse. Tissue samples can be obtained by FNA, CNB or surgically, depending on each clinical scenario. There is controversy regarding the histological study of non-suspicious lymph nodes, as radiological evaluation (US, MRI) in the case of negative or doubtful findings has been proven insufficient. In cases with high risk of lymph node invasion, PET/CT is recommended [39, 40] and/or biopsy with sentinel lymph node biopsy (SLNB) techniques. Biopsy is particularly recommended in cases of negative clinical and/or radiological examination, but with high risk of involvement. Current recommendations include dual SNLB techniques that should be performed in centers with experience in these procedures [41, 42]. Histological evaluation of the lymph nodes is particularly important in limb and paratesticular tumors > 5 cm in patients > 10 years. At the extremities, regional lymph nodes and “in transit” nodes must be evaluated, as positivity has an impact on treatment and prognosis. The new FaR-RMS Surgical Guidelines of the EpSSG provide a detailed orientation of the lymph nodes to explore depending on the different anatomic locations [43].

Bone marrow examination

Staging of metastatic disease also includes bilateral bone marrow aspirate and biopsy in alveolar tumors. Bone marrow examination may be omitted in patients with tumors < 5 cm, fusion-negative and no lymph node spread [44].

Lumbar puncture

Pre-treatment lumbar puncture is recommended in parameningeal tumors if there is evidence of intracranial/meningeal invasion on imaging studies.

Other studies

Include complete blood counts, biochemistry, echocardiography and hormonal evaluation prior to starting treatment.

Risk group assignment

Risk stratification for RMS is based on both the pretreatment (TNM) staging system and post-surgical grouping system established by the Intergroup Rhabdomyosarcoma Clinical Grouping System (IRS) [44, 45]. The clinical subgroup is determined after the initial surgical procedure, prior to systemic therapy, and is primarily based on the extent of residual tumor after surgery with consideration of regional lymph node involvement. Assignation of the final risk group is completed considering pathology, site and age. Some cooperative groups consider FOXO1 fusion instead of pathology as a risk stratification marker [46].

Table 2 shows final risk group assignment according to the EpSSG guidelines considering all the mentioned risk factors.

Table 2 Risk groups
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Treatment of localized disease

Systemic treatment

Systemic therapy is a cornerstone in the multimodal approach of these patients. With the current multidisciplinary therapy, 5-year overall survival (OS) rates are around 80% in localized disease [47]. Systemic therapy has to be integrated with local therapy (surgery ± radiotherapy) and is adapted, both in duration and regimen, to the patient’s risk group (Table 3).

Table 3 Local and systemic treatment
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Vincristine, dactinomycin and alkylating agents (ifosfamide or cyclophosphamide) are the main drugs for rhabdomyosarcoma therapy, IVA being the current standard regimen in Europe. More intensive regimens with the addition of other drugs failed to show an improvement in outcome [48, 49].

Regimens without alkylating drugs (VA) or reduced doses of ifosfamide (IVA/VA), can be administered to patients with low or standard risk, without impairing prognosis and with a better toxicity profile [50] (IIA) (Table 4).

Table 4 Treatment schedules (first line and relapse)
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The addition of anthracyclines did not improve the prognosis of high-risk patients in a randomized study [51], and thus is not recommended (IA), although it can be added to the induction chemotherapy in those patients with very high-risk disease (alveolar rhabdomyosarcoma with nodal involvement) [52].

In detail, in patients with initial complete resection (IRS I Group), 8–9 cycles of chemotherapy will be administered based on risk group. Patients in IRS groups II and III, should receive nine cycles of chemotherapy, with local treatment after the first four cycles.

After completing consolidation chemotherapy, in patients with high-risk disease, maintenance chemotherapy with daily oral cyclophosphamide and weekly vinorelbine, for 6 months, proved to increase disease-free survival (DFS) and OS, in a randomized trial [53], and is part of the standard therapy in this risk group (IA). The use of maintenance chemotherapy is also recommended in those patients with very high-risk disease after completion of consolidation chemotherapy if there is evidence of disease remission (IIA).

Local treatment

Surgery

Local disease control, with surgery and/or radiotherapy, is the keystone of multimodal treatment in patients with RMS. The type of treatment depends on: patient’s age, histological subtype, tumor biology, anatomical location, tumor size and response to chemotherapy. Surgical principles for the treatment of pediatric RMS can be extrapolated to adult patients. The post-surgical grouping system is an independent risk factor for every tumor location. However, in most cases, definitive surgery will take place after neoadjuvant chemotherapy (four cycles in localized disease and six in metastatic). Surgical consultation to reference centers is highly advised, given its impact on prognosis and the possible functional and technical implications. The treating surgical team must be able to predict the quality of resection, and whether it will imply the resection of anatomical structures or organs, or even, mutilating procedures. If so, the appropriate reconstructive procedures must be foreseen and scheduled at optimal timing.

When surgical resection carries a high probability of mutilation, other treatment options must be explored, mainly radiotherapy. However, mutilating procedures might be preferable or necessary in certain situations. A list of the procedures considered mutilating can be consulted [43].

The surgical report must reflect the quality of resection achieved. For the correct evaluation of the surgical specimen by the pathologists, the surgeon must make an orientative drawing of the tumor and mark the critical points with sutures. The quality of the resection will be determined by the worst surgical margin:

  1. 1.

    R0 or microscopically complete resection. This can be “Wide” (en bloc resection surrounded by healthy tissue) or “Compartmental” (en bloc resection with the entire anatomical compartment). R0 resection should be the goal.

  2. 2.

    R1 or microscopically incomplete resection. This happens when the tumor or its pseudocapsule is exposed on the resection surface, or when the surgical margins present microscopic involvement, without residual macroscopic remains. In the event of a pseudocapsule rupture and tumor leakage, the field must be thoroughly washed, margins widened and reported by the surgeon, since it will require the addition of local radiotherapy.

  3. 3.

    R2 or macroscopically incomplete resection. It occurs when a macroscopic residual tumor is left in situ.

The timing of the definitive tumor resection defines a series of conditions:

Primary resection: complete resection with curative intent (R0) performed at the time of diagnosis, as long as this does not imply a vital risk or mutilation, always in the absence of lymph node or metastatic disease. Debulking is not recommended as initial treatment [54]. In the vast majority of cases, particularly in children, an R0 resection at diagnosis will be impossible, so obtaining biopsies and initiating neoadjuvant treatment would be the most adequate route.

Pre-treatment re-excision: refers to a second resection performed after a R1 or R2 primary resection, with the aim of reaching negative margins (R0). It can serve to avoid overstaging the patient, thus reducing the intensity of subsequent treatment.

Delayed excision: the definitive surgery that is carried out after completing the neoadjuvant treatment (chemotherapy ± radiotherapy). Its objective is to achieve a R0/R1 resection of the residual mass. These are mainly conservative surgeries generally combined with radiation therapy, although in some patients, R0 resection can avoid it. If all neoadjuvant options have been exhausted, “mutilating” procedures may be warranted. Brachytherapy, which can offer enormous benefits in individual patients (e.g., bladder or vaginal tumors), should be considered when planning surgery [55, 56]. Debulking surgery does not appear to afford benefits, so preoperative radiation therapy should be considered instead. In the case of preoperative radiotherapy, possible surgical complications must be taken into account, recommending scheduling the surgery in the window between the 4th and 6th weeks after the last session.

Radiotherapy

Treatment recommendations are based on the best current evidence and these guidelines apply to all ages. A retrospective study reported that treatment according to pediatric schedules could improve outcomes in adult patients [57]. Good local control requires the combination of surgery and radiotherapy and outcomes are better when both modalities are used. If it is decided to reduce the radiotherapy dose to minimize the long-term effects, the surgeon should plan the surgery according to the absence or reduced irradiation. Stratification in different risk groups is the basis for determining treatment intensity. It was applied in the EpSSG study (RMS 2005) which reported a significant improvement in outcome. Eighty-five percent of patients with localized high-risk RMS received radiotherapy and the 3-y EFS was 67%. For very high-risk patients the EFS was 56%, significantly better than those obtained in historical controls [51, 52] (Table 3).

Time of administration: according to EpSSG RMS2005, local treatment, either second surgery or radiotherapy, is administered at week 13 after the 4th cycle of induction chemotherapy.

Technique: the EpSSG RMS2005 study recommended a 3D technique, but the high rates of significant long-term morbidity in pediatric patients and the evolution of irradiation techniques available today make it advisable to use highly conformal techniques, such as single or rotational intensity modulated radiotherapy (IMRT). Proton therapy (excluding extremity localization) should be considered as an option, provided that adequate treatment times can be met and there is a dosimetric benefit to organs at risk. Brachytherapy should be considered as the preferred option in patients with genito-urinary, bladder, prostate, vaginal or perineal tumors, as long as the volume to be irradiated can be treated with this technique. This assessment should be carried out by a radiation oncologist together with a surgeon with experience in brachytherapy treatments.

Dose for the primary tumor: the dose is determined by histology, tumor response to induction chemotherapy and IRS staging group (Table 5).

Table 5 Radiotherapy dose for primary tumor by histology and IRS group (age > 3 years)
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Dose for the lymph nodes involved: only patients with positive lymph nodes at diagnosis should be irradiated. In those cases where lymph node involvement achieved a complete response, or in case of complete resection, the dose to be administered over the area of initial involvement is 41.4 Gy in 23 fractions. In cases of persistent disease at the time of irradiation, a boost dose of 9 Gy in five fractions should be administered to the residual macroscopic disease, with a total dose of 50.4 Gy, regardless of the histology.

Treatment of metastatic disease

Systemic treatment

The prognosis of these patients is clearly worse, with an OS at 3 and 5 years of 34% and < 20% respectively, according to a combined multivariate analysis of European and American groups [58]. In this study, age (< 1 year or > 10 years), unfavorable location, bone or bone marrow involvement and the presence of three or more metastatic sites were defined as poor prognostic factors. The 3-year EFS was 50%, 42%, 18%, 12% and 5% for patients without any, one, two, three or four of these adverse prognostic factors, respectively. In adults, a 5-year OS of 4.3% [59] has been reported, but could be improved when pediatric treatment protocols are applied [7].

In metastatic RMS, the combination of systemic and local treatment may also achieve complete remissions, although local and distant relapses are frequent. Despite many clinical trials attempting to improve outcomes by adding new agents to standard VAC/IVA chemotherapy, or substituting one or more components of VAC/IVA chemotherapy, to date, no chemotherapy regimens have been shown to be more effective [60, 61]. Thus, the standard systemic treatment in metastatic RMS would be IVA or VAC (IIA) adding anthracyclines [62] (IIIC) (e.g., IVADo regimen in induction followed by IVA in consolidation). If the disease is controlled at the end of consolidation chemotherapy, maintenance treatment with daily oral cyclophosphamide and weekly intravenous/oral vinorelbine seems indicated, since it has shown significant improvement in overall survival in high-risk RMS [53] (IIIB). However, to date, intensification with high doses of chemotherapy has not been shown to be beneficial [63] (IVB).

Local treatment

Radiotherapy

With scant evidence, international recommendations support the use of systematic irradiation of all sites that are technically feasible and where the risk/benefit analysis is appropriate. It is not known whether there are subgroups that may benefit more than others, given the prognostic differences also in metastatic disease [64]. Retrospective analyses suggest adequate disease control with irradiation of all metastatic lesions, mainly in the pediatric population (IVB). Therefore, according to a retrospective series, aggressive local treatment of metastatic disease, including surgery and radiotherapy in combination when feasible, may have an impact on EFS (35% vs. 16–20%) and OS (44% vs. 18%) [65]. The survival benefit of total lung irradiation with a dose of 15 Gy in 10 fractions in patients with pulmonary metastases is also unclear, although it seems to improve local lung control [66, 67] (IIIC). Prognostic group stratification in metastatic disease could modulate treatment intensity, as it does in localized disease [58].

Response assessment

Response assessment, before and after a specified number of chemotherapy cycles or radiotherapy, is based on imaging criteria. These criteria can evaluate the decrease or increase in size of the selected target lesions (morphological criteria); or can evaluate changes in various biological features of the tumor (functional criteria): glycidic metabolism (PET/CT), vascular permeability (DCE-MRI, DCE-CT), necrosis (PET/CT, diffusion MRI). Morphological criteria are the most commonly used, due to their greater simplicity and easy standardization. They can be one-dimensional (RECIST 1.1), two-dimensional (OMS) or three-dimensional (3D). Some publications show discrepancies in up to 20% of cases between them, without any clear advantages [68]. In the pediatric RMS response assessment, both EpSSG and the Children’s Oncology Group (COG) preferred volumetric quantification as standard criteria, by estimating 3 orthogonal axes: in the axial plane of maximum length (a), its perpendicular (b) and the skull axis [(π/6) × a × b × c]. Computer-assisted volumetric assessment offers more accurate and reproducible values, although it is more cumbersome for routine clinical practice [69]. The EpSSG RMS2005 protocol included a first assessment of response after three cycles of chemotherapy that required at least a minimal partial response (mPR) to continue with the same line of treatment. However, the COG group does not recommend any change in treatment unless progressive disease is identified at this timepoint [70]. In adults, RECIST 1.1 is more common as a reference for response assessment. Although the evidence is still limited, PET/CT plays an important role in the assessment of tumor metabolic response after chemotherapy induction, being a better predictor of response than morphological criteria [71]. Data published by a single Institution demonstrated that a complete metabolic response on FDG-PET after induction chemotherapy was associated with improved progression-free survival (PFS; 72% vs. 44%, p = 0.01). Similarly, high SUVmax values appear more prevalent in patients from high-risk groups, with unfavorable localization, alveolar RMS histology, or presence of metastases [21]. The current trend in RMS is to use morphological and functional criteria (PET/CT, dynamic-enhancement MRI, diffusion MRI) in a combined way to evaluate the response to treatment [72, 73].

Treatment at relapse

Patients refractory to first-line treatment or those who relapse after initial treatment have a dismal prognosis. Patients with ERMS initially treated with alkylating agents (IVA or VAC) and patients with ARMS constitute the group with the worst prognosis at relapse (5-y EFS 10%), while patients with ERMS stage I who did not receive alkylating agents (VA only) constitute a group with better prognosis (5-y EFS 50%). Moreover, relapses that occur within the first 3 years after diagnosis and metastatic relapses have less chance of cure than later local relapses [74].

Systemic treatment

Treatment differs depending on the time of relapse and previous treatment (Table 4). Reported schemas of chemotherapy include doxorubicin, ifosfamide, and etoposide [75], as well as different schedules with the combination of vincristine and irinotecan (VI) [76].

In a recent study conducted by the EpSSG group [77], the combination VI with temozolomide (VIT) demonstrated superiority over VI alone. The majority of patients included in the study had had relapses (89%) compared with those with refractory disease (11%). The objective response rate was 44% in the VIT arm vs. 31% in the VI arm. The VIT arm achieved a significantly better OS than VI, although toxicity, mainly hematological, was higher in the VIT arm.

The VIT scheme is considered the new standard of treatment of the EpSSG group for these patients. (III, B). If there is no response to VIT, or a new progression occurs, the following combinations are proposed:

1. Consider including the patient in a clinical trial.

2. In patients who did not receive doxorubicin previously: VCDE (vincristine, cyclophosphamide, doxorubicin, etoposide) or TVD (topotecan, vincristine, doxorubicin) [63, 78].

3. In patients who did not receive maintenance previously: vinorelbine–cyclophosphamide [79].

4. Other options in patients previously treated with anthracyclines: topotecan/carboplatin alternating with cyclophosphamide/etoposide (EpSSG RMS2005, second line) or cyclophosphamide/topotecan [80].

Evaluation of response should be performed every two cycles and local treatment (surgery and/or radiotherapy) delivered as soon as possible.

Duration of treatment: with the VIT scheme, if there is an objective response and toxicity is tolerable, up to a total of 12 cycles are administered. With the VCDE and TVD regimens, the duration of treatment is not established.

Late relapses (> 3 years from diagnosis): these patients have a better prognosis and the use of standard first-line chemotherapy type IVA or VAC can be considered.

Local treatment

Surgery

Depending on the previous treatments, different therapeutic options can be considered. If cure is still a possibility and radiotherapy is not feasible, surgery is the most effective treatment, and even mutilating procedures can be justified [81, 82] On the contrary, when cure is not a realistic possibility, but it is feasible to prolong survival or improve the quality of life of the patient, interventional radiology offers a wide range of minimally invasive procedures [83, 84].

Radiotherapy

Recommendations of local treatment with radiotherapy cannot be established. Cases must be evaluated individually to reach a consensus on the options.

Follow-up

There is no evidence for a standard follow-up policy, but we propose some general recommendations (Table 6). The same techniques used at diagnosis should be consistently applied and by criteria of radioprotection, we recommend reducing the use of CT in favor of plain X-ray. The prognosis of patients with localized RMS is generally favorable with an OS of 80%. However, for patients with unfavorable prognostic factors the figures are not so positive. When planning the monitoring strategy, the kinetics of events is relevant. In general, the mean time for relapse is 1.43 years (range 0.13–13.5 years) [85]; while in paratesticular tumors, the mean is 0.9 (range 0.1–6.2 years) [86], and in alveolar parameningeal tumors it is 0.5 years (range 0.2–2.1 years) [87]. Therefore, it seems prudent to establish a follow-up calendar that ranges from the end of treatment to up to 5–10 years after completion. However, relapses beyond 5 years are very rare and, as recently published [88], the detection of incidental relapses in planned controls does not seem to affect subsequent survival. In addition, the risk associated with any of the routine tests (anesthesia, radiation) should also be considered. It is, therefore, essential to educate the patients/parents about the warning signs/symptoms.

Table 6 Follow-up evaluations
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Patient-centered care

Patients diagnosed of RMS should be attended at reference centers with expert multidisciplinary teams (MDT) available. Reference sarcoma centers should provide a discussion panel to assess the better treatment option and to offer potential enrolment in active clinical trials [89, 90]. Moreover, they should be able to offer a second opinion when required. MDT must be patient and family-centered, considering their physical, psychosocial and spiritual needs.

Once the cancer has been overcome, patients are at a higher risk of developing health issues many years after initial diagnosis, due either to the disease or as result of treatment-related toxicity [91]. Once treatment has ended, potential long-term effects will rely on different risk factors such as type of treatment received and age at the time of therapy. Scheduling an end-of-treatment clinic could be of valuable help. Also, an individualized follow-up treatment-plan (IFUTP) should be designed with the following aims:

1. Early detection of relapse.

2. Screening and early detection of second primary tumors.

3. Shared care with the Local Community Care Team to assure a continuous medical surveillance that guarantees health and long-term wellbeing [92], by developing prevention strategies and health promotion.

4. Early diagnosis and appropriate treatment of unforeseen events and long-term treatment sequelae including:

Neuro cognitive assessment and tailored academic curriculum in schools. There is a higher risk of developing learning difficulties and issues about being accepted by equals [93].

Psychosocial assessmentPsychosocial assessment since diagnosis. Continuous monitoring should be undertaken to detect potential disfunction or learning and psychosocial morbidity.

Cardiotoxicity monitoring. Main cardiac risk factors are represented by previous treatment including anthracyclines, radiation therapy and some medical conditions such as obesity, high blood pressure, hypercholesterolemia and diabetes. High-risk patients would require a cardiological assessment i.e., EKG, Echo performed yearly, or every 2–5 years based on dose of cardiotoxic therapy received.

Fertility. Patients with fertility potential must agree to use appropriate contraception during treatment period. Those patients at high risk of infertility based on the treatment planned, should be offered an age-appropriate fertility preservation technique.