Abstract: Paediatric sarcomas are a heterogeneous group of disorders constituting bone sarcoma and various soft tissue sarcomas. Almost one-third of these presents with metastasis at baseline and another one-third recur after initial curative treatment. There is a huge unmet need in this cohort in terms of curative options and/or prolongation of survival. In this review, we have discussed the current treatment options, challenges and future strategies of managing relapsed/refractory paediatric sarcomas. Upfront risk-adapted treatment with multidisciplinary management remains the main strategy to prevent future recurrence or relapse of the disease. In the case of limited local and/or systemic relapse or late relapse, initial multimodality management can be administered. In treatment-refractory cases or where cure is not feasible, the treatment options are limited to novel therapeutics, immunotherapeutic approach, targeted therapies, and metronomic therapies. A better understanding of disease biology, mechanism of treatment refractoriness, identifications of driver mutation, the discovery of novel targeted therapies, cellular vaccine and adapted therapies should be explored in relapsed/refractory cases. Close national and international collaboration for translation research is needed to fulfil the unmet need.

Keywords: paediatric sarcoma, immunotherapy, targeted therapy, relapsed sarcoma, osteosarcoma, disease biology


Paediatric sarcoma constitutes a major group of disease that includes osteosarcoma (OGS), Ewing’s sarcoma/primitive neuroectodermal tumor (EWS/PNET), rhabdomyosarcoma (RMS), and heterogeneous group of soft tissue sarcoma (STS), mostly infantile fibrosarcoma, malignant peripheral nerve sheath tumour (MPNST), termed as non-rhabdomyomatous soft tissue sarcoma (NRSTS). With the introduction of multimodality treatment including poly-chemotherapy, surgery and/or radiotherapy, the outcome of localized paediatric sarcoma has improved drastically. However, 20–30% localized sarcoma recurs where cure seldom occurs. On the other hand, a sizeable number of bone1 and soft tissue sarcoma2 presents with metastasis at baseline, and the cure rate is still low with the current armamentarium of systemic anti-cancer therapies. In spite of progress in chemotherapeutic combinations, newer surgical approach and radiation techniques, local as well as distant recurrence is one of the major challenges in the management of paediatric sarcomas. The outcome remains dismal in recurrent or treatment-refractory (primary or secondary) setting with the currently available systemic therapies even with a better understanding of tumorigenesis and discovery of potential therapeutic targets.

In-depth understanding of disease biology, determination of molecular signature, identifications of potentially targetable driver mutation, newer immunotherapeutic approach, risk-adapted treatment strategies, and long-term maintenance therapy remains the optimal approach to treat recurrent and refractory paediatric sarcomas.

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In this review, we have discussed the current standard of care in recurrent bone sarcoma & STS in paediatric & young adult patients with emerging therapeutic options, unmet needs and future strategies.


Data regarding burden of refractory paediatric sarcoma can be estimated from the patients where cure is not possible as literature regarding the same is limited. There is no consensus regarding optimal treatment in second line as various regimens have been tried and there is no head-to-head comparison amongst the different regimens.

Survival in OGS has plateaued at 70% after the dramatic improvement in the 1980s and 1990s.3 In a large retrospective analysis of 1067 patients, there were 564 (52.85%) recurrences with a median time of 13 months. Post recurrence survival was 18% at 5 years. Approximately 35% had refractory disease.4

For localized EWS, the 5-year overall survival ranges from 65% to 75% whereas in metastatic setting it is less than 30%, except in isolated pulmonary metastasis (approximately 50%).5 The 5-year survival of relapsed EWS is 13%. Patients who relapse in the first 2 years from diagnosis have a 5-year survival of 7% compared to 29% who relapse after 2 years from diagnosis.6 At present, there is no standard protocol to treat relapsed EWS due to paucity of clinical trials.7

In pediatric populations, the most common soft tissue sarcoma is RMS, which accounts for one-half of all soft tissue sarcomas. Relapses occur in around 30% cases of RMS, with most relapses occurring before 2 years after initial diagnosis whereas late relapses (after 5 years of diagnosis) are rare and constitute less than 10% of relapsed cases. Most relapses (80%) occur at distant site and involve lungs, bones or bone marrow. Few patients (20%) relapse at the local site and have a more favourable prognosis.8–11 Prognostic factors associated with recurrent or progressive disease include factors at the time of initial diagnosis, including histological subtype, disease group, stage, age 10 years or younger, size, site, and lack of initial radiation therapy. Distant site of recurrence and time of relapse after diagnosis <18 months are important prognostic factors for survival at the time of relapse.8–10,12

In a retrospective analysis by Intergroup Rhabdomyosarcoma Study Group (IRSG), 605 (25.6%) patients out of 2364 treated on IRS-III, IRS-IV pilot, & IRS-IV experienced disease relapse or progression. Median OS was 9.6 months and 17% of patients survived till 5 years after relapse. Probability of survival after relapse was dependent on histologic subtype, disease group, and stage at initial diagnosis. At the time of relapse distant site recurrence have poor survival compared with local recurrence.8

Of 1398 patients with localized disease at diagnosis treated in International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumour/MMT 84, 89, and 95 studies, 474 (33.9%) had a relapse. Metastatic disease at relapse, prior treatment, initial tumour size >5 cm, and relapse within 18 months of diagnosis were associated with poor outcomes.10 Many other retrospective analyses have found similar prognostic factors for survival.12

NRSTS accounts for approximately 50% of paediatric STS (13). It is a heterogenous group of rare tumours, with common histologies being synovial cell sarcoma, infantile fibrosarcoma and malignant peripheral nerve sheath tumour. Five-year survival from synovial sarcoma has been approximately 77%.13 Survival of infantile fibrosarcoma ranges from 80% to 94%.14,15 Malignant peripheral nerve sheath tumour is relatively chemoresistant. The five-year survival has ranged from 23% to 69%.13

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