OGS is the most common primary bone tumor in the pediatric population.73 Two-third of patients present with localized disease and have good long-term survival. About 20% of cases have metastatic disease at diagnosis and have a poor outcome. However, about one-third of patients with localized OGS and about 80% of metastatic OGS patients relapse even after multimodality treatment. Most relapses (>50%) occur within 2 years of diagnosis and only a few relapses (<5%) after 5 years of initial diagnosis.74 The most common site of relapse is lung followed by bones and local sites. Pulmonary relapse occurs in 60–90% of cases, bone relapse in 10–20%, local relapse in 10–20% and other sites in <10%.75,76 Approach to treatment of relapsed OGS is based on sites of relapse (lungs, bones, local site or multiple), resectability and timing of relapse after the first diagnosis (Table 4).

Long-term survival in relapsed cases may be achieved in up to one-third of cases. Various factors that predict outcome in relapsed osteosarcoma include timing of relapse after initial diagnosis, sites of relapse, presence of initial metastasis, response to neo-adjuvant therapy, achievement of second complete remission (CR2) after relapse and age. Most important among these are timing of relapse and site of relapse.74

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Prognosis of locally recurrent OGS without systemic metastasis is poor with long-term survival reported in 10–40% patients in retrospective studies.4,76-82 No benefit was observed with chemotherapy administration after surgical salvage.83 So locally recurrent OGS should be managed by surgical resection whenever possible. The role of chemotherapy and radiotherapy is doubtful after complete surgical resection. Additional chemotherapy may be administered after surgery as followed in unresectable disease.

Osteosarcoma: Lung Metastasis

In the majority of patients with relapsed OGS, lungs are the only site of disease. Surgery (metastasectomy) is the mainstay of management in these cases, with many cases requiring repeated or staged lung resection.83–87 Five-year event-free survival (EFS) for patients after complete surgical resection of pulmonary metastasis ranges from 20% to 45%.84,85 Overall survival with unresectable metastatic disease is less than 5%.86

In the case of isolated lung metastases, the treatment of recurrent OS is primarily surgical. Even patients with subsequent relapses may be cured as long as recurrences are resectable, and repeated thoracotomies may be required.87 Surgical resection of all macroscopic disease should be attempted with thoracoscopy or thoracotomy with palpation of the collapsed lung. There is no comparative trial or clear recommendations for using different approaches viz. thoracoscopy, unilateral or bilateral thoracotomy. Unilateral multiple metastases are usually treated with the addition of chemotherapy but the benefit is less clear. Bilateral thoracotomy with chemotherapy is required for the management of bilateral metastases. Unresectable metastases are treated with chemotherapy with palliative intent. Whether the use of preoperative chemotherapy improves the respectability of bilateral metastases is yet to be defined.88,89 The role of chemotherapy after surgery is controversial.82,90 Limited success has been achieved using radiofrequency ablation and stereotactic radiotherapy as an alternative local treatment option for primary lung or bone metastases.91,92

Osteosarcoma: Bone Metastasis

Patients with bone metastases have a poor prognosis with a 5-year EFS of 11%. However, patients who have late solitary bone relapse have a 5-year EFS of 30%.93,94 Samarium-153 ethylenediamine tetramethylene phosphonate (Sm 153-EDTMP) is a beta-particle–emitting radiopharmaceutical agent, has been studied in patients with locally recurrent or metastatic OGS. Patients with recurrent OGS with bone-only involvement can be managed by surgical resection if feasible. Patients with multiple unresectable bone lesions, 153Sm-EDTMP with or without stem cell support provide good pain relief.95,96

Radium-223 dichloride (Ra 223) is alpha-particle–emitting radiopharmaceutical that is under trials for treating metastatic or recurrent OGS. Preliminary studies suggest that this agent is active in OGS and may have less marrow toxicity and greater efficacy than beta-particle–emitting radiopharmaceuticals such as Sm 153-EDTMP.97,98

Osteosarcoma: Palliative Chemotherapy

Patients with unresectable disease are treated with conventional chemotherapy with palliative intent. The role of chemotherapy for recurrent OS is much less well defined. The choice of chemotherapy depends on the prior disease-free interval and includes ifosfamide or cyclophosphamide, with etoposide and/or carboplatin, gemcitabine and docetaxel, sorafenib or regorafenib and radioactive agents. Various agents and their responses are summarised in Table 2.

Ifosfamide with etoposide/carboplatin has shown some response in retrospective and Phase 2 trials. Responses have been observed in about one-third of cases. Higher responses were observed in high dose ifosfamide.99,100 The combination of gemcitabine and docetaxel has an overall response rate of less than 20%. A 900 mg/m2 dose of gemcitabine was associated with a higher response rate and longer survival than 675 mg/m2 dose.101,102 Cyclophosphamide and etoposide have shown some activity in recurrent OGS in two phase 2 trials.103,104

Targeted inhibition of molecular pathways viz. mTOR, SRC kinases, and vascular endothelial growth factor receptors (VEGFRs) are currently under clinical trials in relapsed or refractory OGS. The Italian Sarcoma Group reported a poor response rate with sorafenib alone or in combination with everolimus. However, disease stabilization was observed in half of the cases at 6 months.105,106 Two phase 2 double-blind, placebo-controlled have evaluated the efficacy of regorafenib in OGS whose disease had progressed after treatment with at least one previous line of chemotherapy for metastatic disease. Responses were observed in 8–13% cases; however, at least stable disease was seen in up to 64% cases at 8 weeks.107,108

In the Italian Sarcoma Group study, carboplatin and etoposide followed by peripheral blood autologous stem cell transplantation, the 3-year OS and DFS rates were 20% and 12%, which is similar to that achieved with the conventional chemotherapeutic approach.109,110 So currently HDT followed by AHSCT is not recommended. Current approaches for treating OGS using novel therapeutics are given in Table 5.

Osteosarcoma: Newer Advances

Immunotherapy targeting the PD1-PDL1 axis has shown only modest activity in relapsed and refractory OGS patients. In the SARC28 study of pembrolizumab, in advanced bone and soft tissue sarcoma patients, only one partial response was observed among 22 patients with OGS, and median progression-free survival was 8 weeks.111 Prospective data from trials involving other immune checkpoint inhibitors are pending. Novel immunotherapeutic agent for the lung metastases includes inhalation of aerosolized granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF stimulates the proliferation and differentiation of hematopoietic progenitor cells and augments the function of neutrophils, monocytes, macrophages, and dendritic cells. However, no significant benefit was observed in 43 patients with pulmonary relapse from OGS in the American Osteosarcoma Study Group (AOST) protocol 0221.112

Osteosarcoma: Ongoing Studies

AOST1421 (NCT02484443) is currently studying combination dinutuximab (anti-GD2 antibody) with sargramostim (GM-CSF) in patients after complete surgical resection of pulmonary metastasis at recurrence.

NCI-COG Paediatric Molecular Analysis for Therapeutic Choice (MATCH) in patients between 1 and 25 years of age is next-generation sequencing-based study in refractory and recurrent solid tumours.Children and adolescents aged 1 to 21 years are eligible for the trial.AOST1321 (NCT02470091) is a single-arm, phase II trial of RANKL inhibitor denosumab, in patients with relapsed or refractory OGS post resection of any measurable disease.

Ewing Sarcoma [EWS]/Primitive Neuroectodermal Tumor [PNET]

EWS is the second most common primary bone tumour after OGS.113 With currently available therapeutic modalities good outcomes have been achieved; however, relapses occur in about 30–40% of localized disease and up to 80% with advanced disease.114 Most of the relapses, about 70–80% occur early (within 2 years of diagnosis). Late (2–5 years) and very late (after 5 years of diagnosis) relapses occur in about 20–30% and 5 −10% patients, respectively.115,116 At relapse, most patients have metastatic disease or combined distant and local disease (75−85%). About 15–25% of relapses occur only at the local site, and these are more common with initially localized disease. Lungs are the most common sites of distant relapse followed by bones.6,114 At the time of relapse, about 52% of patients have symptoms, while remaining patients are diagnosed during follow-up imaging.117

The most important prognostic factors are interval between initial diagnosis and subsequent relapse, and site of relapse. Other prognostic factors for poor survival at relapse include high LDH at relapse, age >15 years, non-pulmonary metastasis and symptomatic relapse.114,117,118

No standard approach is available for the treatment of recurrent EWS. Multimodality treatment including surgery, radiation, and chemotherapy is required and depends on previous therapy, duration from diagnosis to relapse, and site of relapse. Relapsed cases are considered a systemic disease and chemotherapy is recommended in all cases. Survival with only local recurrence is better compared with distant and combined recurrences.118 If operable, the patient should undergo surgery and systemic chemotherapy. Radiotherapy may be used in case of inoperable cases, and if margin positivity after surgery. In cases of metastatic disease, chemotherapy is administered with palliative intent. Accepted approach is summarized in Table 4.

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