ATC codes: L01CA04
Rhabdomyosarcoma primary site ICD11 code: 2C25.Z
Medicine type
Chemical agent
List type
Parenteral > General injections > IV: 10 mg per mL in 1 mL vial ; 50 mg per 5 mL in 5 mL vial
Oral > Solid: 20 mg ; 30 mg ; 80 mg
EML status history
First added in 2021 (TRS 1035)
Also recommended for children
Therapeutic alternatives
The recommendation is for this specific medicine
Patent information
Patents have expired in most jurisdictions
Expert Committee recommendation
The Expert Committee noted that maintenance treatment with oral and intravenous vinorelbine in combination with oral cyclophosphamide was associated with relevant survival benefits in children with rhabdomyosarcoma at high risk of relapse in a randomized clinical trial. Although maintenance treatment for 6 months after induction chemotherapy was associated with more severe toxicity, the overall benefit-to-risk profile of vinorelbine was favourable, with limited related costs. The Committee therefore recommended the addition vinorelbine on the complementary list of the EML and EMLc for the treatment of rhabdomyosarcoma in children and adolescents at high risk of relapse.
A comprehensive review of treatment protocols for rhabdomyosarcoma was considered by the Expert Committee in 2015. The Committee noted that the use of multidrug chemotherapy regimens comprising vincristine, dactinomycin and cyclophosphamide (VAC) and ifosfamide, vincristine and dactinomycin (IVA), in conjunction with local control measures for the primary tumour, was associated with survival rates of around 70%. The Committee recommended the inclusion of these medicines, along with the cytoprotectant mesna (to be administered with ifosfamide) on the EMLc. As rhabdomyosarcoma also affects children older than 12 years and adolescents, the same medicines were also recommended for inclusion on the EML for this indication (1). Vinorelbine injection is currently included on the EML for use as part of chemotherapy protocols for the treatment of non-small-cell lung cancer and metastatic breast cancer in adults.
Public health relevance
Soft tissue sarcomas are the fourth biggest group of malignancies in children after leukaemias/lymphomas, brain tumours and bone sarcomas. They account for about 7.4% of all paediatric malignancies. Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents, accounting for 3% of all paediatric cancers (2). The incidence is greatest in people younger than 20 years, with an incidence of 4.4 cases per million a year. The incidence decreases with age, with rhabdomyosarcoma responsible for 1% of solid cancers in adults (3). Rhabdomyosarcomas are divided into four main subtypes: embryonal, alveolar, pleomorphic and sclerosing/spindle cell (4–6). Embryonal and alveolar are the two most common subtypes of rhabdomyosarcomas with frequencies of 60–70% and 20%, respectively (6). The outcome for children with embryonal rhabdomyosarcoma is much more favourable than the outcome for children with alveolar rhabdomyosarcoma (5-year event free survival 73% versus 29%) (7). Patients newly diagnosed with rhabdomyosarcoma are assigned to a risk group that takes into account fusion status, clinical group (based on Intergroup Rhabdomyosarcoma Studies), site, nodal stage, tumour size and patient age. Treatment is subsequently adapted to risk groups. The prognosis for paediatric patients with high-risk and metastatic rhabdomyosarcoma is still unsatisfactory. In a pooled analysis of 788 patients with metastatic (high-risk) rhabdomyosarcoma, treated with multiagent chemotherapy regimens (VAC), VAC with addition of doxorubicin and cisplatin, or VAC with addition of doxorubicin, cisplatin and etoposide, the 3-year event-free survival rate was 34% and the 3-year overall survival rate was 27% (8).
A pilot study was conducted to define the optimal dose of vinorelbine when used in combination with oral low-dose cyclophosphamide in 18 children with high-risk refractory or recurrent sarcoma who had received prior induction therapy (9). Vinorelbine was administered at a dose of 25 mg/m2. Overall, seven objective responses to treatment were observed (one complete remission and six partial remissions). Three of the eight assessable patients with rhabdomyosarcoma had responses to treatment. Combination therapy with oral cyclophosphamide and intravenous vinorelbine as maintenance treatment was evaluated as part of a multicentre, open-label, randomized, controlled phase III trial in 371 patients aged 6 months to 21 years with non-metastatic, high-risk rhabdomyosarcoma (10). After completion of standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery and radiotherapy), patients in remission were randomly assigned to either stop treatment (n = 185) or to continue maintenance chemotherapy (n = 186) with six cycles of intravenous vinorelbine 25 mg/m2 (days 1, 8 and 15) and daily oral cyclophosphamide 25 mg/m2 (days 1–28). Median follow-up was 60.3 months. The 5-year disease-free survival rates were 77.6% with maintenance chemotherapy versus 69.8% without (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.45 to 1.02). The 5-year overall survival rates were 86.5% with maintenance chemotherapy versus 73.7% without (HR 0.52, 95% CI 0.32 to 0.86). The addition of vinorelbine 25 mg/m2 to standard IVA chemotherapy (the so-called VIVA regimen) for patients with high-risk metastatic rhabdomyosarcoma was subsequently evaluated in a small prospective study (11). Preliminary results reported that after three cycles, a major partial response was seen in four (of four) cases on radiological assessment. All four patients remained alive after a median follow-up of 11 months, two in radiological complete remission and two in partial remission.
In the multicentre, phase III study, haematological toxicities and infections were the most commonly reported adverse events among patients in the maintenance chemotherapy group (10). Grade 4 neutropenia was the most commonly reported event (45% of patients), followed by grade 3 infection (31%). Grade 3–4 leukopenia was reported in 75% of patients and grade 3–4 neutropenia in 82%. Two serious treatment-related adverse events occurred, one case of inappropriate antidiuretic hormone secretion which resolved with treatment discontinuation, and one case of severe steppage gait with limb pain which resolved without treatment discontinuation. In the VIVA regimen study, grade 4 neutropenia occurred in all four study participants (11). Grade 3 anaemia, requiring red blood cell transfusion, occurred in two patients. Infection or febrile neutropenia requiring intravenous antibiotics was seen in two patients. No grade 3 or 4 non-haematological toxicity was reported. In general, toxicities associated with vinorelbine are well known and manageable and overall tolerance is acceptable.
Cost / cost effectiveness
The application estimates that one vial of generic intravenous vinorelbine 50 mg/5 mL costs between € 120 and € 150. At the recommended dose of 25 mg/m2, six cycles of treatment for a child with body surface area of 1 m2 would cost € 1350. No cost information was presented for the oral vinorelbine formulation.
WHO guidelines
WHO guidelines for the treatment of rhabdomyosarcoma are not available.
Intravenous vinorelbine formulations are widely available in generic brands. A generic brand of oral vinorelbine was launched in European markets in 2019. Intravenous vinorelbine has been included on the EML since 2015, and is included on numerous national essential medicines lists globally.
Other considerations
The EML Cancer Medicines Working Group advised that it supported the addition of oral and intravenous vinorelbine to the EMLc for the maintenance treatment of rhabdomyosarcoma. Vinorelbine, used in combination with oral cyclophosphamide, has relevant survival benefits in children with rhabdomyosarcoma, with a manageable toxicity profile. The Working Group noted that the use of vinorelbine in rhabdomyosarcoma is now established in current European and American treatment protocols and is considered the standard of care. Noting that rhabdomyosarcoma also affects older children and adolescents, the Working Group also supported the inclusion of vinorelbine on the EML for this indication and age group. Comments were received from the WHO Department Noncommunicable Diseases. The technical unit advised that it supported the inclusion of vinorelbine on the Model Lists for the new indication of rhabdomyosarcoma. Its inclusion would also be in line with the WHO Global Initiative for Childhood Cancer that seeks to improve childhood cancer patient survival by up to 60% by 2030, with access to essential medicines as a main foundation of the initiative. The unit highlighted that consideration should be given to patient selection (high-risk disease) and capacity for toxicity management (haematological and infections rate).
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2015 (including the 19th WHO Model List of Essential Medicines and the 5th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization; 2015 (WHO Technical Report Series, No. 994; https://apps.who.int/iris/handle/10665/189763, accessed 16 May 2021). 2. Arndt CAS, Bisogno G, Koscielniak E. Fifty years of rhabdomyosarcoma studies on both sides of the pond and lessons learned. Cancer Treat Rev. 2018;68:94–101. 3. Amer KM, Thomson JE, Congiusta D, Dobitsch A, Chaudhry A, Li M, et al. Epidemiology, incidence, and survival of rhabdomyosarcoma subtypes: SEER and ICES database analysis. J Orthop Res. 2019;37(10):2226–30. 4. Parham DM, Barr FG. Classification of rhabdomyosarcoma and its molecular basis. Adv Anat Pathol. 2013;20(6):387–97. 5. Fletcher CDM, Hogendoorm PCW, Bridge JA, Mertens F. WHO classification of tumours of soft tissue and bone. Fourth edition. Lyon: International Agency for Research on Cancer; 2013. 6. Rudzinski ER, Anderson JR, Hawkins DS, Skapek SX, Parham DM, Teot LA. The World Health Organization classification of skeletal muscle tumors in pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group. Arch Pathol Lab Med. 2015;139(10):1281–7. 7. Rudzinski ER, Anderson JR, Chi YY, Gastier-Foster JM, Astbury C, Barr FG, et al. Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2017;64(12). 8. Oberlin O, Rey A, Lyden E, Bisogno G, Stevens MC, Meyer WH, et al. Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol. 2008;26(14):2384–9. 9. Casanova M, Ferrari A, Bisogno G, Merks JH, De Salvo GL, Meazza C, et al. Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. Cancer. 2004;101(7):1664–71. 10. Bisogno G, De Salvo GL, Bergeron C, Gallego Melcón S, Merks JH, Kelsey A, et al. Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(11):1566–75. 11. Ferrari A, Chiaravalli S, Zecca M, Recupero S, Pascale S, Bergamaschi L, et al. VIVA (vinorelbine, ifosfamide, vincristine, actinomycin-D): a new regimen in the armamentarium of systemic therapy for high-risk rhabdomyosarcoma. Pediatr Blood Cancer. 2020;67(11):e28649.