Bone Sarcomas

Overview

• Most common primary bone sarcomas: osteosarcoma, Ewing sarcoma, chondrosarcoma.
• Workup: MRI of primary (T1, whole involved bone; better than CT), CT chest with contrast, bone scan or PET, biopsy at a sarcoma center.
• Most common metastatic site: lung, then other bones.
• Osteosarcoma and Ewing peak in adolescence; chondrosarcoma affects older adults.

Osteosarcoma

• Epidemiology: rare (~750 to 900 cases/yr US, <1% of all cancers); >50% are <20 y/o; M > F. Bimodal (10 to 25 yr, and >65 yr Paget-associated / post-RT).
• Location: metaphyses of long bones, most commonly around the knee (distal femur > proximal tibia > proximal humerus); if metastatic, usually lung-only.
• Risk factors: Paget disease, chronic osteomyelitis, benign fibrous dysplasia, prior RT, alkylating chemo. Genetic: hereditary retinoblastoma (RB1, ~1000× ↑ risk of secondary osteosarcoma), Li-Fraumeni (TP53), Rothmund-Thomson / RAPADILINO / Bloom / Werner (RECQL gene family). Avoid PTH/PTHrP analogs in osteoporosis pts at ↑ osteosarcoma risk.

• Osteosarcoma NOS (3 subtypes): conventional (~80 to 90%; osteoblastic ~50%, chondroblastic ~25%, fibroblastic ~25%); telangiectatic (high-grade vascular, "multicystic bag of blood," ↑ pathologic fracture); small cell (mimics Ewing).
• Surface / juxtacortical: parosteal (low-grade, older pts, good prognosis, surgery alone; dedifferentiated variant in 15 to 43% needs surgery plus chemo); periosteal (intermediate-grade chondroblastic, proximal tibia, ~20% metastasize so adjuvant chemo debated); high-grade surface (treated like conventional).
• Rare variants: multifocal (poor prognosis), craniofacial (older, indolent, ↑ recurrence), secondary (Paget / post-RT, worse prognosis), low-grade central (<1%, MDM2/CDK4 amplification, surgery alone, OS ~90%, 1/3 progress to high grade).
• UPS of bone (formerly MFH of bone): resembles osteosarcoma without osteoid; lower necrosis response to neoadjuvant chemo but same OS; treated like high-grade osteosarcoma.

• Codman triangle (aggressive periosteal reaction) and sunburst pattern; destructive sclerotic lesion with soft tissue mass. MRI better than CT; CT chest with contrast in all. Labs may show ↑ alkaline phosphatase and LDH.

• Subclinical metastases are present at diagnosis in most pts with local disease: ~80% relapse with surgery alone (~20% cured); adjuvant chemo raises 5-yr OS from ~15 to 20% (surgery alone) to ~60 to 75%. About 2/3 of pts <40 y/o with nonmetastatic extremity osteosarcoma achieve long-term survival.
• Neoadjuvant equals adjuvant for OS (POG 8651); neoadjuvant is preferred to enable limb-sparing surgery. Limb-sparing is as effective as amputation. Adjuvant RT only for R1 resection; conventional osteosarcoma is radioresistant (small cell more RT-sensitive).
• MAP (high-dose methotrexate, doxorubicin, cisplatin) is SOC, especially <40 y/o. Adding ifosfamide/etoposide does NOT improve outcomes (EURAMOS-1: switching poor responders to MAP-I/E gave no EFS benefit but much more febrile neutropenia and grade 4 toxicity; adding PegIFN to good responders did not help). MAP is preferred for children and younger patients and AP is an accepted option (particularly older adults); no RCT proves MAP superior to AP, and both are NCCN category 1.
• Percent necrosis after neoadjuvant chemo is the strongest prognostic factor: >90% necrosis gives 5-yr OS 71 to 80% vs 45 to 60% for <90% (chondroblastic necrosis does not correlate). There is no evidence that changing postoperative chemo for poor responders improves outcomes; continue MAP regardless of response.
• AP alone (no HDMTX) is reasonable for older adults (slower MTX clearance): doxorubicin 25 mg/m2 days 1 to 3, cisplatin 100 mg/m2 day 1, q3wk × 6. ICarboDox (carboplatin, ifosfamide, doxorubicin) if unable to tolerate cisplatin/HDMTX (St. Jude: 5-yr EFS 66%, OS 75%).
• Mifamurtide (liposomal MTP-PE, acts via NOD2/TLR4): improved 6-yr OS 78% vs 70% (HR ~0.71) across groups; adding ifosfamide did not improve survival; not approved in the US but approved in Europe.
• Pre-treatment plan: FDG-PET/CT and/or bone scan, echocardiogram and EKG, fertility preservation, genetics/NGS, CBC/CMP/Mg/Phos/LDH/ALP q2wk, repeat MRI of the extremity after neoadjuvant chemo.

Standard EURAMOS-1 MAP: blocks: 2 preop MAP, 2 postop MAP, 2 postop MA (no cisplatin); cisplatin in 4 blocks only (cumulative 480 mg/m2, not 720); 2 neoadjuvant and 4 adjuvant cycles (6 total over ~29 to 30 weeks). HDMTX efficacy relies on a C-max of ~700 to 1000 micromol/L after a 4 to 6 h infusion; serial levels at 24, 48, 72 h guide leucovorin rescue. Adjuvant chemo should restart within 21 days of surgery.

• Lung-only mets have better outcomes than bone mets; ~20 to 30% long-term survival if mets are limited to lung (approaching 40 to 50% only in selected, completely resectable limited disease). Newly diagnosed metastatic: frontline MAP (age-appropriate) plus metastasectomy. Recurrent: no standard salvage regimen; HDMTX/doxorubicin/cisplatin/ifosfamide most active (ORR 20 to 40%). Pts >40 y/o get cisplatin and doxorubicin without HDMTX.
• Pulmonary metastasectomy (resection of all metastatic sites) is essential for long-term survival and can be curative.
• 2L: docetaxel/gemcitabine or pazopanib; E/I (etoposide plus lower-dose ifosfamide) is preferred if MAP already given; also high-dose ifosfamide, cyclophosphamide plus etoposide, samarium-153 for palliation.
• Relapse >2 yr is favorable (5-yr post-relapse OS 35% vs 15%); other favorable factors: ≤2 pulmonary nodules, unilateral involvement, no pleural disruption, second surgical remission.

• Cabozantinib phase 2 (Italiano Lancet Oncol 2020, PMID 32078813) post-chemo: osteosarcoma 6-mo non-progression 33%, ORR 12%; Ewing cohort ORR 26%. NCCN-listed for refractory osteosarcoma and Ewing.
• Follow-up: q3mo for 2 yr, q4mo yr 3, q6mo yr 4 to 5, then annually; lifetime surveillance; MUGA if anthracycline given. 5-yr OS: localized ~70%, metastatic ~30%, recurrent ~20%.

Ewing sarcoma

• Undifferentiated primary bone tumor (historically PNET, Askin tumor of chest wall). ~30% in <10 y/o; pelvis and the diaphysis or metadiaphysis of long bones (metaphyseal/growth-plate location is more typical of osteosarcoma).
• Histology: sheets of uniform small round blue cells, high nuclear-to-cytoplasmic ratio; rosettes in PNET. IHC: CD99 (MIC2) positive, NKX2.2 positive, FLI1, vimentin.
• Genetics: EWSR1 gene rearrangement; ~90% have t(11;22)(q24;q12) creating EWSR1-FLI1; EWSR1-ERG (~10%). EWSR1 rearrangement defines classic Ewing; distinct WHO 2020 entities include CIC-rearranged sarcoma (CIC-DUX4, aggressive) and BCOR-altered sarcoma; rare Ewing has a FUS-ETS fusion (FUS-ERG or FUS-FEV; EWSR1-negative). Not Ewing: CIC-DUX4 (t(4;19) or t(10;19), more aggressive than Ewing) and BCOR fusions such as BCOR-CCNB3 (males, chemosensitive, outcomes similar to Ewing). Other alterations: gains of 1q, 2, 8, 12; losses 9p, 16q; CDKN2A deletion, TP53, STAG2.
• Imaging: "onion skin" (onion peel) periosteal reaction, lytic destructive lesion, Codman triangle; CT chest and whole-body staging (FDG-PET/CT preferred; bone scan is an alternative or complementary test, not required in all) (PET may be more sensitive; bone scan better for sclerotic, PET better for lytic).

• ~80 to 90% relapse with surgery alone; subclinical metastatic disease is presumed in nearly all, so systemic therapy is essential in localized disease (raises 5-yr OS to ~70%). Neoadjuvant chemo is given ~12 to 13 weeks (6 cycles of interval-compressed VDC/IE) before local control, up to ~18 weeks in some European schedules.
• VDC/IE is standard: alternating vincristine/doxorubicin/cyclophosphamide with ifosfamide/etoposide, given interval-compressed q2wk with growth factor. Neoadjuvant 4 to 6 cycles, then surgery, then adjuvant to complete 14 to 17 cycles; replace doxorubicin once 375 mg/m2 reached.
• EE2012: VDC/IE superior to VIDE (3-yr EFS 67% vs 61%, HR 0.71; 3-yr OS 82% vs 74%, HR 0.62), with shorter duration. AEWS0031 (pts <50 y): interval-compressed q2wk improved EFS vs q3wk (current standard for fit pediatric and adult pts when deliverable). AEWS1031: adding vincristine/topotecan/cyclophosphamide did not improve 5-yr EFS or OS. Euro-EWING 99/2008 (R2loc): high-dose busulfan-melphalan with autologous SCT after VIDE improved EFS (HR 0.64) and OS (HR 0.63) in localized high-risk pts (poor histologic response or volume ≥200 mL); no benefit in pulmonary-met pts (R2pulm); more acute toxicity, and applicability after VDC/IE is uncertain.
• Local control: surgery preferred when feasible; Ewing is more radiosensitive than osteosarcoma, but RT causes growth inhibition in the young, so RT is for incomplete (R1) resection or when surgery is not possible (positive margins after wide excision require RT plus chemo).
• Metastatic: VDC/IE (adding I/E to VAC gives no benefit in metastatic disease); autologous SCT investigational (no improvement in pulmonary-met pts). Whole-lung RT can benefit even after CR.

• Preferred: high-dose ifosfamide (rEECur). Also topotecan plus cyclophosphamide (TC), irinotecan plus temozolomide (IT), gemcitabine plus docetaxel (GD).
• rEECur (phase 2/3): compared HD-ifosfamide vs TC vs IT vs GD; IT and GD dropped in phase 2 for low efficacy. HD-ifosfamide vs TC: HD-ifosfamide significantly superior (EFS 5.7 vs 3.5 mo; OS 15.4 vs 10.5 mo) but with much higher grade ≥3 neuro-, nephro-, and infectious toxicity. Cabozantinib (CABONE) ORR 26%.
• 5-yr OS: localized ~70 to 80%, metastatic ~30%, recurrent <20%.

Chondrosarcoma

• 2nd most common primary bone sarcoma (~800 to 1000/yr US); >60 y/o, slight M > F; axial skeleton (pelvis), proximal extremities; more aggressive in the pelvis.
• Grades: 90% low to intermediate. Atypical cartilaginous tumor (ACT / grade 1) in appendicular bones is often indolent; grade 1 axial (pelvis, scapula, skull). Grade 2 (10-yr OS 64 to 85%). Grade 3 highly cellular, metastasis in 30 to 70% (10-yr OS 30 to 55%).
• Molecular: IDH1/IDH2 in 40 to 56% of enchondromas and primary chondrosarcomas; Indian hedgehog (central); PTHrP (enchondroma); CDKN2A/p53 in progression. Mesenchymal chondrosarcoma has HEY1-NCOA2 (or IRF2BP2-CDX1). No recurrent alteration in clear cell.
• Subtypes: conventional (central ~75%, peripheral ~10%, periosteal <1%); rare (dedifferentiated ~10%, IDH1/2 in ~50%, highly aggressive (5-yr OS ~10 to 25%, lower at 10 yr); mesenchymal, chemosensitive, Ewing-like; clear cell, low-grade, ↑ alkaline phosphatase; myxoid of bone). Extraskeletal myxoid chondrosarcoma is a soft tissue sarcoma (NR4A3), not cartilaginous.
• Benign cartilaginous: osteochondroma (most common; multiple hereditary exostoses EXT1/EXT2, ~5% malignant transformation) and enchondroma (~1% transformation; Ollier disease and Maffucci syndrome, IDH1/2 mosaicism, ~50% chondrosarcoma risk).
• Staging: Enneking system (IA/IB low grade, IIA/IIB high grade, III metastatic; compartmental status by cortical breach).
• Treatment: surgery is the mainstay (chemo and RT generally ineffective in conventional chondrosarcoma due to slow growth, poor vascularity, anti-apoptotic activity). Observe small central ACT/CS1 in extremity; intralesional curettage with local adjuvant if progression; wide resection for grade 2 to 3 or axial grade 1. RT (>60 Gy) for R1 high-grade or palliation.
• Chemo-directed subtypes: dedifferentiated treated like osteosarcoma (doxorubicin plus cisplatin, unclear benefit); mesenchymal treated like Ewing (10-yr OS ~53 to 67%). Advanced conventional: no standard cytotoxic chemo; prioritize clinical trials, consider IDH1 inhibitor if IDH-mutant (doxorubicin/cisplatin is for dedifferentiated, benefit uncertain).
• Chemo-refractory: pazopanib for conventional chondrosarcoma (phase 2, disease control 43% at 16 wk, mOS 18 mo, mPFS 8 mo; off-label). Immunotherapy for dedifferentiated (PD-L1 in 41%; SARC028 signal). IDH inhibitors (ivosidenib) investigational; mTOR inhibitors, imatinib/dasatinib, and aromatase inhibitors have not shown meaningful activity.

Other bone tumors

• Giant cell tumor of bone: osteolytic, usually benign but locally aggressive; epiphyseal in young adults; osteoclasts plus RANKL-expressing stromal cells. Denosumab (anti-RANKL) tumor response ~86% by composite histologic/no-progression criteria (modified RECIST ORR ~25%): FDA Jun 13, 2013 (XGEVA, GCT-specific) for unresectable GCT or where surgical resection would cause severe morbidity; long-term risks include atypical femoral fracture and osteonecrosis of the jaw. Surgery (curettage with phenol/cryosurgery/cement) for resectable; treat like osteosarcoma if malignant transformation.
• Chordoma: rare notochordal remnant tumor, midline (sacrum, spine, clivus/skull base); brachyury positive. Imaging of primary plus MRI spinal axis and CT chest/abdomen/pelvis. Standard tx is wide resection with or without RT (proton); IO / erlotinib emerging.
• Adamantinoma: rare, tibia; surgery. Osteochondroma, enchondroma, osteoid osteoma, fibrous dysplasia: benign, observe unless symptomatic.

Bone metastases (general principles)

• Common primaries: breast, prostate, lung, kidney, thyroid.
• Bone-modifying agents: zoledronic acid 4 mg IV q3 to 4wk (or q12wk per OPTIMIZE-2, non-inferior); denosumab 120 mg SC q4wk (preferred in renal insufficiency). Dental clearance before starting (osteonecrosis of jaw risk); supplement calcium and vitamin D for hypocalcemia.
• Spinal cord compression: dexamethasone 10 mg IV then 4 mg q6h, urgent MRI, then RT and/or surgery.
• Painful bone met RT: 8 Gy × 1 fraction equals 30 Gy in 10 fractions for pain control. Radium-223 for symptomatic bone-only mCRPC (ALSYMPCA).

High-yield bone sarcoma pearls

• Osteosarcoma: MAP regimen; percent necrosis is key; RB1 and Li-Fraumeni associations; adding ifosfamide/etoposide does not help (EURAMOS-1).
• Ewing: EWSR1-FLI1, CD99 positive, "onion skin"; interval-compressed VDC/IE; HD-ifosfamide preferred in relapse (rEECur).
• Chondrosarcoma: surgery is key; chemo/RT ineffective except mesenchymal (treat like Ewing) and dedifferentiated (treat like osteosarcoma); pazopanib off-label for refractory conventional.
• GCT of bone: denosumab (FDA 2013). Chordoma: midline notochordal, brachyury positive, surgery plus proton RT.
• Pulmonary metastasectomy for osteosarcoma can be curative. Bone met pain: 8 Gy × 1 RT. IDH1 inhibitor (ivosidenib) investigational for chondrosarcoma.