Table 21.1 describes initial diagnostic work-up and information needed before proceeding to treatment. Ultrasonogram is often the first instrumental assessment to be used. Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the primary site is mandatory for the local extension assessment before any treatment (MRI could be considered superior in defining soft tissue extension). Distant assessment requires chest CT scan, Technetium bone scan, abdominal ultrasound, and bone marrow aspiration plus trephine biopsy, to identify lung, bone, abdominal, and bone marrow dissemination, respectively. Special sites may require particular evaluations, i.e., cerebrospinal fluid cytology in parameningeal RMS, to assess meningeal dissemination; regional lymph node biopsy in extremity RMS; retroperitoneal lymph node sampling in paratesticular RMS older than 10 years [7–9].

The initial biopsy (incisional biopsy or tru-cut) has the aim to define the histological diagnosis and should be the initial surgical procedure in all patients, also when a subsequent primary excision is planned. Initial biopsy must be carefully planned by experienced surgeons, taking into account the possible subsequent definitive surgery, which must include the scar and the biopsy tract (for example, in RMS of the extremities, the incision must be longitudinal to the limb and not traverse multiple compartment; very careful hemostasis must be ensured to avoid postsurgical hematoma and drains).

The prognosis of RMS depends on multiple factors, including age, primary tumor site and size, lymph node involvement, histology, surgical resection, and distant metastasis. In the past 30 years, the cure rates for RMS have improved dramatically from 25 to 30 % (before the modern chemotherapy-era) to approximately 70 %, due to the development of multidisciplinary and risk-adapted treatment approaches conducted by International cooperative groups. Of course, not all patients with RMS fare well with modern therapies. Patients with alveolar histology continue to have less than optimal outcome. Most patients with distant metastasis do not achieve long-term cure and may benefit of more intensive treatment and are candidates for experimental treatment with novel agents [10].

With the identification of different prognostic factors [11–16], risk assessment has now become more complex, but also more accurate. The approaches of Children Oncology Group (COG) (Table 21.2) and European pediatric Soft Tissue Sarcoma Study Group (EpSSG) (Table 21.3) for risk stratification use similar principles but with different approaches. The EpSSG, for example, identifies low, standard, high, and very high-risk groups (with eight subgroups) for localized RMS, plus the group of metastatic RMS cases; the EpSSG high-risk group grossly corresponds to the COG intermediate-risk group.

RMS is a rare tumor and its treatment is necessarily multidisciplinary and complex. The overall multimodality treatment strategy involves surgery, radiotherapy, and chemotherapy, and it is important that the optimal intensity and timing of these treatment modalities should be planned with regard to the patients’ risk stratification and late effects of treatment. In particular, radiotherapy needs to be used with caution in children, given the important sequelae of these treatments. For example, survivors after parameningeal RMS (requiring full doses and large volume of radiotherapy) have a high risk of facial growth retardation (bone and soft tissue hypoplasia, facial asymmetry), but also dental abnormalities, neuroendocrine dysfunctions (growth hormone deficiency, hypothyroidism), visual problems, hearing loss.

The VAC regimen (vincristine, actinomycin-D, cyclophosphamide, given at 1.2 mg/m²/cycle) is the gold standard for chemotherapy for RMS in North America. On the other hand, the standard in Europe is considered the IVA regimen (ifosfamide, given at 6 g/m²/cycle, vincristine, actinomycin-D), which differs only in the choice of alkylating agent—probably producing a slightly different pattern of hematological, renal, and gonadal toxicity. The Intergroup Rhabdomyosarcoma Study (IRS)-IV study found no differences in survival rates in a randomized comparison between VAC and IVA [17]. The duration of treatment is currently 6–12 months according to different protocols.

As mentioned above, the risk stratification as adopted by the collaborative groups directs the treatment direction. In the COG most recent low-risk RMS trial (ARST0331), patients with subset I (Table 21.2) had an excellent outcome (2 year EFS, 88 %; OS, 98 %) with short therapy duration (22 weeks) and a low cumulative dose (4.8 g/m²) of cyclophosphamide. On the other hand, subset 2 had a 3-year EFS of 66 % using low dose of cyclophosphamide [18]. This group had better outcome on the previous protocols with standard doses of cyclophosphamide.

The COG intermediate-risk/EpSSG high-risk RMS category is currently treated with the standard VAC or IVA regimen. Adding other agents to these regimens by collaborative groups did not result in significant impact to survival, so far. Among other drugs that were tested, camptothecin derivatives (topoisomerase I inhibitors) showed the best outlook. Addition of topotecan to the standard VAC regimen for intermediate-risk RMS failed to show benefit [19]. Nevertheless, the more promising drug, irinotecan, combined with vincristine is being evaluated in combination with the VAC regimen in the same population of patients.

Doxorubicin is an effective drug in RMS, but the role of anthracyclines as part of a multidrug regimen remains somewhat controversial. For that reason doxorubicin is being evaluated in the current EpSSG trial (Table 21.3). It was also added to the COG high-risk RMS trial ARST0431 which is currently used as a backbone for future trials in high-risk patients [10]. Of note, this regimen incorporated irinotecan/vincristine and ifosfamide/etoposide and used an approach of “dose-compression”—increase of chemotherapy dose intensity and dose density by administering chemotherapy cycles at 2-week interval instead of the usual 3-week interval—similar to that used successfully for Ewing sarcoma [20]. In fact, the prognosis of metastatic RMS remains poor and their management is the subject of ongoing trials. The limited pool of these patients makes it difficult to conduct randomized trials to answer critical questions, but it is agreed that treatment intensification is warranted for this group of patients. High-dose, myeloablative chemotherapy, followed by autologous stem cell rescue, has been variously attempted in metastatic RMS patients. Weigel et al. reviewed 389 patients reported in the literature who underwent myeloablative chemotherapy for metastatic or recurrent RMS [21] and found the outcome much the same as in reports on metastatic patients given conventional therapy [22, 23]. This approach remains experimental and should not be considered as a standard approach for patients with high-risk RMS.

Finally, a potentially interesting option is that of maintenance therapy (metronomic therapy, i.e., regular, frequent administration of low doses of drug with the aim to achieve an anti-angiogenic effect). Currently, the approach of a 6-month maintenance therapy comprising a combination of vinorelbine and low-dose oral cyclophosphamide is under investigation in the EpSSG RMS trial for high-risk patients [24] (Table 21.3).

Possible complications of chemotherapy should be always taken into account. The VAC regimen has serious toxicity that might be exploited in malnourished and very young population. Some of these toxicities are tolerable, including neuropathy that is commonly observed after weekly administration of vincristine. Neutropenia is often observed but is less expected if lower doses of cyclophosphamide are used [25]. A very serious complication is hepatopathy, in the form of veno-occlusive disease (VOD) [26]. This potentially fatal complication is observed mainly in children less than 3 years of age and warrants careful dosing of vincristine and actinomycin-D in this group. Acute and late cardiotoxicity is a known complication of doxorubicin.

Radiotherapy is the mainstay of treatment in RMS, since local progression or relapse continues to represent the major cause of treatment failure. Radiotherapy is generally delivered to the pretreatment tumor volume with doses generally ranging between 40 and 55 Gy [17, 27–35]. Three-dimensional conformal radiotherapy—if available—may reduce the long-term toxicity by avoiding unnecessary exposure to vital structures. Similarly, intensity-modulated radiotherapy (IMRT), proton radiotherapy, and interstitial brachytherapy may provide adequate local control with better delineation of the treatment area, and hence, decreased toxicity.

Various issues on radiotherapy in RMS remain to be clarified: should all patients with RMS receive radiotherapy? Can the dose of treatment be modified based on response to treatment and delayed surgical resection? Is it possible to reduce the volume of radiotherapy based on new tumor volume following treatment with chemotherapy and/or surgery?

As for the first question, there is a general consensus that radiotherapy may be omitted in IRS group I patients (initial complete resection) with favorable histology, whereas it must be always required for alveolar histotypes. COG protocols suggest radiotherapy for all RMS patients except for IRS group I embryonal RMS [30], while in European groups it is more debated the indication of radiotherapy in IRS group III patients (patients with initially unresected tumor) after delayed complete surgery or after complete remission to initial chemotherapy, for those tumors arising in particularly favorable sites (i.e., orbit or vagina), especially for young children.

As for the second question, COG recently published its experience with dose reduction (up to 36 Gy) in patients with low-risk embryonal RMS, based on completeness of surgical resection of the primary tumor. Local control was adequate when cyclophosphamide was given (patients treated with VAC regimen), but the analysis suggested that radiotherapy dose reduction should be avoided in patients treated with two drugs only (VA) [34].

The third question remains unanswered: it has been suggested that volume reduction (from the pre-chemotherapy to the post-chemotherapy volume) may be potentially safe (but not for parameningeal cases) [35], but to date the standard treatment volume should remain the pre-chemotherapy one, except for very selected situations (e.g., large pelvic or chest wall tumors where pretreatment volume radiation exposes normal structures to untolerable doses of radiation).

Surgery for RMS has evolved over the years from the primary treatment modality (prior to the introduction of effective antineoplastic agents) to one component of a multidisciplinary approach, and from an aggressive surgery to a more conservative organ-sparing procedures, to the point that chemotherapy and radiotherapy may permit in some cases to cure the disease without any surgery (i.e., patients with parameningeal RMS).

Surgery with risk of anatomic or functional impairment is not recommended as first surgical approach and should be considered only as salvage treatment, after the failure of other procedures (special circumstances must be considered, however, e.g., a lower extremity RMS in a toddler, the choice between amputation and radiotherapy, with its long-term effects on limb growth, may pose a difficult dilemma). Tumors considered unresectable at diagnosis can be conservatively and completely resected in a large percentage of cases after tumor shrinkage achieved by primary chemotherapy. Wide resections are generally considered adequate to obtain local control, differently from adult STS that in general should require compartmental resection. In case of primary marginal resection, primary re-operation (prior to any other treatment) is recommended when feasible, hoping to achieve clear margins and proving the absence of microscopic residue in order to avoid radiotherapy [36].

Recently, a possible role for debulking procedure has been suggested for huge retroperitoneal and pelvic RMS [37]. This issue remains, however, controversial, particularly when these surgeries necessitate mutilation. What to do in cases of masses that remain after finishing treatment is debatable; biopsy may cause difficulty in interpreting results, in particular when mature rhabdomyoblasts are detected [38, 39].

Finally, surgery of positive regional lymph nodes is generally considered a diagnostic procedure: any involved lymph nodes warrant radiotherapy, so initial radical lymphadenectomy (which carries a high risk of morbidity) is unnecessary.