A home run for rhabdomyosarcoma after 30 years: What now?

Rhabdomyosarcoma is a rare tumor, with an annual incidence of 4 in 1 million population. Around 400 cases are diagnosed among 0to 19-year-olds in Europe each year,1 50–60 of them in Italy.2,3 It is nonetheless the most common soft tissue sarcoma in children and adolescents. This highly malignant tumor has a strong propensity to metastasize, but also a good chance of responding to conventional chemotherapy. Recent pediatric oncology studies report overall survival rates exceeding 70% for patients with localized rhabdomyosarcoma given risk-adapted multidisciplinary treatments, including surgery, radiotherapy, and multiagent chemotherapy in particular.4 The outcome is unsatisfactory for some patient categories, however, such as adolescents and young adults with rhabdomyosarcoma, patients with an alveolar histology, and those with distant metastases or relapsing disease. In September 2019, the European pediatric Soft Tissue Sarcoma Study Group (EpSSG) published the results of a rhabdomyosarcoma study (EpSSG RMS 2005), particularly reporting on the efficacy of maintenance therapy.5 When the study findings were presented at the plenary sessions of the congresses held by the American Society of Clinical Oncology in June 2018 and by the European Society of Paediatric Oncology in May 2019, the media described them as a “home run” for the treatment of rhabdomyosarcoma. Here we retrace the story of this important study to glean useful hints and explore what to do next in clinical research on rhabdomyosarcoma. The phase III randomized EpSSG RMS 2005 trial was tailored to patients under 21 years old with localized rhabdomyosarcoma. The protocol paid special attention to the so-called high-risk patients, i.e., those with incompletely resected embryonal rhabdomyosarcoma arising at unfavorable sites and age ⩾10 years and/or tumor size >5 cm, any embryonal rhabdomyosarcoma with nodal involvement, or any alveolar rhabdomyosarcoma without nodal involvement. This high-risk group was believed to represent 55%–60% of all patients with localized rhabdomyosarcoma, whose 5-year event-free survival (EFS) and overall survival (OS) rates were estimated at around 50%– 55% and 60%, respectively. For these patients, the protocol included 2 randomizations (Figure 1). The first, applied at the time of diagnosis, was used to investigate whether patients with rhabdomyosarcoma might benefit from a higher doxorubicin dose intensity in the initial period of their treatment. The results were published in 2018: with 484 patients treated, the 3-year EFS rate was 63.3% for patients in the standard arm (ifosfamide, vincristine, and actinomycin-D; IVA), and 67.5% for those in the experimental arm (ifosfamide, vincristine and actinomycin-D plus doxorubicin; IVADo) (p = 0.33). The study showed that adding dose-intensified doxorubicin to the standard IVA chemotherapy did not significantly improve the outcome for patients with high-risk nonmetastatic rhabdomyosarcoma. Acute toxicity was significantly more common in the IVADo group.5 The second randomization used in EpSSG RMS 2005 concerned maintenance therapy, and the results have been published recently.6 The trial investigated whether treating patients for longer with a less intensive, but continuous chemotherapy regimen (maintenance therapy) could improve the outcome of those with high-risk rhabdomyosarcoma in complete remission at the end of the standard 9 courses of therapy (Figure 1). This trial was prompted by the results of a small study conducted many years earlier (between 1998 and 2001) at the Istituto Nazionale dei Tumori in Milan on 33 patients with heavily treated, refractory sarcomas, who were given vinorelbine as a single-agent therapy—not based on any preclinical findings or promising previous data, but rather as a last effort to treat them. There was a somewhat unexpected good response rate among the patients with rhabdomyosarcoma: 6 partial responses out of 12 cases with measurable disease (Table 1).7 Thus the physicians in Milan conducted another A home run for rhabdomyosarcoma after 30 years: What now?