Introduction
Radiotherapy for bone sarcomas
Primary bone tumors are rare, accounting for < 0.2% of malignant neoplasms registered in the EUROCARE (European Cancer Registry-based study on survival and care of cancer patients) database [1].Osteosarcoma and Ewing Sarcoma are the most common malignant bone tumors affecting children and young adults. Osteosarcoma is a complex genomic sarcoma arising mainly in the medulla of long bones while Ewing Sarcoma of the bone (85% of the all the Ewing sarcoma) are high-grade sarcoma arising principally in the diaphysis or metaphysis of the pelvis, femur, or tibia. Osteosarcoma-driven mutations include TP53 and Rb1 while Ewing sarcoma is characterized by the fusion of genes of the FET and ETS family, the most renowned being EWS-FLI1. Chondrosarcoma and chordoma are the most common malignant bone tumors in adults and aging-populations. They affect cartilage cells of the upper arm, pelvis or femur for chondrosarcoma; and cervical, thoracic spine or sacrum for chordoma. Chondrosarcoma and chordoma are thought to arise from the malignant transformation of mesenchymal stem cells and of embryological remnants of the notochord, respectively. Both tumors are highly aggressive locally and present an abundant extracellular matrix. Adult bone sarcoma etiology is not clearly defined and driver mutations are not fully identified even if chondrosarcoma and chordoma initiation seem to be linked to the mutation of IDH genes and T gene, respectively [1, 18]. |
Role of radiotherapy in CD and CHS treatment
Citation | Nb of patients | Information | Treatment background | Overall Survival (OR) | Local control | level of evidence | Type of study | Toxicity | |
---|---|---|---|---|---|---|---|---|---|
[9] | Dial, et al | 1478 chordoma patients, 1401 patients were metastatic | 567 skull base, 551 sacral, 360 mobile spine | 116 without surgical resection (SR) and radiotherapy (RT), 680 with SR alone, 277 with SR and currative RT, 235 SR and non-currative RT, 59 SR and unknow dose of RT, 111 RT alone | SR + RT improve 5-year OR in patients with positive surgical margin, no effect on patients with negative surgical margin. High-dose RT and new RT model are associated with better outcome compared to standard RT | NA | 2b | retrospective analysis | NA |
[10] | Krochak et al | 38 chondro-sarcoma patients | 25 axial: 14 pelvic, 6 limb, 5 spine, 6 head and neck, 7 sternum and rib chondrosarcoma | no patients with complete surgery, 9 patients with chemotherapy combined with radiation | 1 death post treatment, 6 survived but very short follow up 8–80 month | 17 local failure, 4 distal failure | 2b/4 | retrospective analysis | NA |
[11] | Mc naney et al | 20 chondro-sarcoma patients | 11 RT alone, 3 with RT and positive SR, 3 RT with chemotherapy, 3 were reccurent tumor after a first surgery | 65% OR at 53 month | 9 local disease, 8 metastasis | 2b/4 | retrospective analysis | NA | |
[12] | Fujiwara et al | 48 chordoma, 11 with RT | 7 patients with tumor in S1, 7 in S2, 12 in S3, 12 in S4, 6 in S5, 4 in coxcis. Microsa-telite lesion in 3 tumor and vascular invasion in 2 tumors | 7 photon, 4 proton therapy | Local Recurrence FreeSurvival (LRFS) 5 years: -SR margin 0 without RT: 50% -SR margin < 1.5 mm without RT 32.8% -SR margin < 1.5 mm combined with RT 85.7% -SR margin > 1.5 mm without RT: 100% | 57% of local reccurence without RT, 18% with RT | 2b | retrospective analysis | NA |
[19] | Catanzano et al | 5427 chordoma, 680 RT | Tumor axial and apendicular: -without RT: 44% axial and 56% apendicular -With RT: 78% axial and 22 apendicular | 11% metastatic in patients treated with RT vs 4% in patients treated without. 75% with surgery and 44% with positive margin in the RT treated group vs 91% and 12% in the untreated. Chemotherapy in 14% of patients treated with RT vs 5% in the group without 245 patient received conventionnal RT, 245 received advanced | 5-year survival rate: -70% in RT treated with a dose > 60 gy, 57 in RT treated with a dosebetween 40 and 60 Gy -78% in advanced chordoma compared to 48% in conventionnal | NA | 2b | retrospective analysis | NA |
[20] | Zhou et al | clivus and non clivus tumor | -3 year OR: 70% with classical RT, 92% with stereotactic body therapy (SRT), 89% with proton, 93% with carvon ion therapy -5-year OR: 46% with classical RT, 81% with SRT, 78% with proton, 87% with carvon ion -10-year OR: 21%, 40%, 60% and 45% respectively | 2a | meta analysis of 25 study (non randomized) | NA | |||
[21] | Gao et al | 743 high grade chondrosarcoma | 212 axial, 326 extremite, 212 other | SEER stage: 224 localised, 335 regional, 149 distant, 35 unstaged -88% treated with SR, 212 with RT, 172 with RT and SR, 40 with RT alone, 482 with SR alone | 5-year OR: 48.5% in patients treated with RT compared to 56% in patients withour RT | NA | 2b | retrospective analysis | NA |
[22] | Kabolizadeh et al | 40 unresected chondrosarcoma | 9 cervical, 1 thoracic, 3 lombar, 27 sacral, | all definitive RT | OR at 3 years was 89.1% and 5 years 81.9% | 6 local failure, 2 with metastasis. One local and distal failure. 8 metastase (including the 2 with local) | 2b | retrospective analysis | acute side effects were grade 1 to 2 radiation-induced dermatitis and pain, nosea and vomiting n = 4, mucositis (n = 5), and diarrhea (n = 5). Long-term toxicities included 10 sacral insufficiency fractures, 2 foot drop, 1 erectile dysfunction, 1 perineal numbness, 2 worsening urinary/fecal inconti- nence, 1 bowel perforation/fistula formation, and 4 grade 2 rectal bleeding |
[23] | Palm et al | 863 chondrosarcoma, 715 chordoma, non-palliative RT or non-conventionnal RT | various location, skull, vertebra, imb, thorax | NA | Chondrosarcoma DRT: 5-year OR: Proton 75% vs 19.1% for conventional RT. High-dose (> 70 Gy) 40.6% vs 16.9 for low dose. Chondrosarcoma PRT: 5-year OR: proton 97.1% vs 69.4% for conventional RT. High-dose 86.3% vs 69.2% Chordoma DRT: 5-year OR:proton 100% vs 34.1% for conventional RT, and high-dose 79% vs 27% | NA | 2b | retrospective | NA |
[24] | Lu et al | 632 patient, 389 chordoma 243 chondrosarcoma | skull base | NA | OR 1, 5 and 10 years: Chordoma: 100%, 94% and 78% Chondrosarma: 99%, 95% and 79% | LC 1, 5 and 10 years: Chordoma: 99%, 80% and 56%. Chondrosarcoma: 97%, 89% and 88% | 2a | systematic meta analyse | Early complications: 24% mucositis, 17% skin irritation, 1% hearing loss Late complications: radiographic brain change 6%, hearing loss 6%, skin reaction 5% |
[25] | Imai et al | 73 patients, 75 tumor, unresectable chondrosarcoma | 26 spinal, 38 pelvic, 11 other | 70 conventionnal and 5 dedifferenciated chondrosaroma | 5-year OR: 53% Disease free Survival: 34% | 5-year Local Control: 53% | 2b | retrospective | NA |
[26] | wu et al | 16 chordoma, 5 chondrosarcoma | 19 saccrosigeal, 1 thoracic 1 pelvic. 8 primary and 13 reccurent tumors without metastasis | 1-year OR: 100% 2-year OR: 100% Progression-free survival 88.4% and 80.4% respectively | LC 1 and 2 years: 93.8% and 85.2% 5 patients develop lung metastasis | 2b | retros | Acute toxicity: 3 grade 1 skin toxicity and 7 grade 1 myelosuppression | |
[27] | Lockney et al | 12 patients included | Chordoma in mobile spine: 6 cervical, 4 thoracic, 2 lumbar | all stereotactic surgery radiation | 1 patient with disease progression | Group 1 LC: 80% Group 2 LC (10 month median follow up): 57% | 2b | retrospective | 4 mucositis, 4 vocal cord paralysis |
[28] | Ryugi Nakamura et al | 1 patient | Pulmonary metastases for extraskeletal mucinous chondrosarcoma | stereotactic body radiation therapy | healthy for another 4 years | NS | 5 | case report | pneumotitis |
[29] | Vasudevan et al | 20 patients | 16 chordoma and 4 chondrosarcoma (4 recurrences) | Fractionnated Stereotactic radiotherapy peri-operatively | 28-month OR: 90% | LC: 90% | 2b | retrospective | 9 patients with grade 1–3 acute toxicity, 2 patients with grade 4, 5 toxicity |
Radiotherapy is one of the most widely used therapies for tumors. Radiation is defined as “ionizing” if its energy load is enough to ionize a molecule of water (> 10 eV). There are two categories of ionizing radiations: particle beams (protons, neutrons, ions, α-particles) and photons radiations (X-rays, γ-rays). Ionizing radiations are characterized by their capacity to ionize a tissue, or Linear Energy Transfer (LET). Particle beams have high LET and photon radiations have low LET. External beams are generally used to deliver the maximum dose of radiation to the tumor and to spare surrounding healthy tissues. Different strategies of radiation delivery can be adopted depending on the patient and the type of tumor: 3D conformational radiation is adapted to the shape of the tumor by delivering beams from different directions. More recently, advances in imaging promoted the use of Intensity Modulated Radiation Therapy (IMRT). IMRT uses smaller beams with different intensities to deliver different doses of radiation to certain areas of the tumor. For example, higher doses can be delivered to hypoxic areas which are usually more radioresistant, while sparing healthy tissues near the tumor. Variable radiation intensity is generated across each beam, in contrast to the uniform intensity used in other RT technics. Stereotactic Body Radiation Therapy is a technique that uses precise imaging in conjunction with high-intensity radiations beams to deliver high radiation doses to tumors in three to five treatments. Extracorporeal radiation can also be used in the treatment of bone sarcoma and consists in excising the tumor bearing segment of bone, irradiate the tumor and reimplant it back into the body. |
Role of radiotherapy in the treatment of Ewing sarcoma and osteosarcoma
Citation | Nb of patients | Information | Treatment background | Overall Survival (OR) | Local control | level of evidence | Type of study | Toxicity | |
---|---|---|---|---|---|---|---|---|---|
[32] | Delaney et al | 41 osteosarcoma | unresected or incompletely resected. 27 primary disease, 10 local recurrence and 4 metastatic disease | photon and/or proton beam therapy | NA | LC at 5 years: 78.4% (total resection); 77.8% (subtotal resection), 40% (biopsy only) | NA | ||
[30] | Dubois et al | 465 bone Ewing sarcoma | All non-cranial: 124 distal extremity, 123 proximal, 98 pelvic, 95 chest wall, 25 spine | RT alone for 121 patients, SR alone for 241, RT and SR combined for 103 | Compared with surgery, radiation had a higher risk of local failure (HR, 2.41; 95% CI, 1.24–4.68. No difference in event-free survival (EFS) | 2a | retrospective of 3 combined study | NA | |
[31] | Haeusler et al | 120 Ewing sarcoma | For primary tumor, 26 patients SR alone, 21 SR and RT, 40 RT alone. For metastasis 6 SR, 9 SR and RT, 33 RT. All patients received chemotherapy. Almost all patients presented metastasis (82.2% bone, 43% Bone Marrow, 22% lymph node) | Forty-seven (39%) patients had local treatment of both the primary tumor and metastases, 41 (34%) patients of either the primary tumor or metasta- ses, and 32 (27%) received no local therapy. Primary tumor location: 82 central, 34 peripheral, 4 unknown | 3-year EFS was 25% with SR, 47% with SR and RT, 23% for RT, and 13% when no local therapy was admin- istered | 2b | retrospective | NA | |
[33] | Brown et al | Stereotactic body radiotherapy: 14 patients: 9 osteosarcoma and 5 ewing | 13 metastatic patients, 27 lesions treated (19 osteosarcoma and 8 ewing) | 21 bone lesions and 6 pulmonary 1/3 of the case were co treated with chemotherapy | 4 | descriptive report of faisability | Two grade 2 and one grade 3 complication: myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy | ||
[34] | Mohamad et al | 26 unresectable pediatric osteosarcoma. Carbon ion radioterapy | 24 pelvic, 1 mediastinal and 1 paravertebral | 22 primary, 1 local reccurent, 3 meta | OR: 50% and 41.7% at 3 and 5 years | LC 69.9% and 62.5% at 3 and 5 years Progression-free survival was 34.6% at 3 and 5 years | 2b | retrospecive | 4 grade 3–4 CIRT-related late toxicities, 1 case of bone fracture and no treatment-related mortalities |
[35] | Seidensal et al | Combined ion-beam radiotherapy combined with carbon ion or proton | 20 patients with primary (N = 18), metastatic (N = 3), or recurrent (N = 2) tumor. Inoperable pelvic (70%) or craniofacial (30%) osteosarcoma treated with protons up to 54 Gy (RBE) and a carbon ion boost of 18 Gy (RBE) | 3 surgery before treatment, all r2. All patient with chemotherapy treatments. Three patients with metastatic disease (15%) received radiotherapy of their primary tumor only but not for the metas- tases | OR 75% at one year and 68% at two | Local progression-free survival 73% at 1 year and 55% at two Distal progression-free survival: 74% at 1 and 65% at two years. Global progression-free survival 60% and 45% respectively | 2b | retrospective | No acute toxicities > grade III were observed. One case of secondary acute myeloid leukemia (AML) seven months after CIBRT for recurrent disease and one case of hearing loss |
Potential target for combination with radiotherapy in bone sarcomas
X-rays have no mass and interact weakly with matter, depositing energy along their entire path until they exit the body. The highest doses are recorded just below the skin, and deep-seated tumors can be treated by focusing beams from many different angles. The energy deposited by X-rays is diffuse, hence X-ray radiation is characterized by low linear energy transfer (LET). Protons and carbon ions are charged particles with mass that have the important property of depositing low amounts of LET energy when traveling at high speed through tissue. Collision of these particles with tissue causes the particles to slow down and eventually stop, and they deposit the bulk of their energy at the very end of their path (Bragg Peak). Because no energy is delivered beyond the particle stopping point, normal tissue situated beyond the tumor receives almost no dose. While low LET radiations produce diffuse ionizations along their tracks, high LET radiations cause dense ionizations that create clustered DNA damage that is less easily repaired by tumor cells. This is reflected in the greater tumor cell killing per unit of dose of high LET radiations (carbon ions) compared to low LET radiations (photons, protons). This difference is termed Relative Biological Effectiveness. |
Sarcoma | Overall TP53 mutation rate | TP53 mutations | Other mutations affecting TP53 |
---|---|---|---|
OS | 80% | TP53 intron rearrangements | MDM2/MDM4 gene amplification |
EWS | 10% | C176F and R273X | Inhibition of WT TP53 by EWS-FL1 fusion protein |
CHS | 20% | TP53 intron rearrangements | MDM2 amplification Alterations in the TP53 pathway |
CD | 1–2% | TP53 missense mutations | / |
Drug | Drug target | RT technic used | Models | Combination effects | Citation |
---|---|---|---|---|---|
Osteosarcoma | |||||
Zoledronic acid | Osteoclasts | γ radiation | KHOS/NP, U-2, MG63, HOS OS cells | Increased cell death, increased levels of ROS, increased DNA damage, decreased proliferation | [41] |
Sulforaphane | Multiple targets: survivin, NFKB, Bcl-2, VEGF, MMP-2 | X-rays | LM8 murine OS cells | Cell cycle arrest, increased DNA damage, increased apoptosis, decreased cell proliferation | [42] |
Ginseng polysaccharide | Multiple targets | γ radiation | MG63 cell line | Decreased cell viability, increased apoptosis and autophagy, | [43] |
BI6727, GSK461364 | PLK1, key regulator of mitosis | X-rays | HOS and MG63 | Cell growth arrest, apoptosis induction | [44] |
KU60648 | DNA-PKcs, serin/threonine kinase, sensor of DNA damage | γ radiation | 143B, U2OS, Saos-2, Hos | Altered cell cycle distribution, increased DNA damage, decreased survival fraction | [45] |
SAHA | HDAC, histone deacetylase | X-rays | KHOS-24OS, SAOS2 cell lines, xenogrqfted mice | Increased cell death | [46] |
Hydrogen peroxide | ROS induction | X-rays | HS-Os-1 cell line | Oxidative DNA damage induction | [47] |
Valproic acid | HDAC, histone deacetylase | X-rays | U2OS cells | Decreased cell survival, increased chromosomal abberations | [48] |
SAHA, M344, PTACH | HDAC | Proton therapy | U2OS | Decreased survival fraction, increased DNA damages | [49] |
SAHA, M344, valproate | HDAC | X-rays | KHOS-24OS, SAOS2 | Decreased survival, cell cycle arrest, enhanced apoptosis | [50] |
Demethylating agent 5-Aza-CdR | Methylation, regulation of genic expression | X-rays | SaOS, HOS, U2OS | Enhanced apoptosis, arrest in G2/M | [51] |
Berberine, isoquinoline alkaloid | Multiple targets | γ radiation | MG63 | Increased cell death, induced cell cycle arrest in G2/M, induced apoptosis | [52] |
DTCM-g | Activator Protein 1 | X-rays | HOS MG63 | Decreased cell proliferation | [53] |
BI2536 | PLK1, key regualtor of mitosis | X-rays | U2OS | Cell cycle arrest, increased cell death | [54] |
Wortmannin | PI3K, proliferation and survival | X-rays | MG-63 | Decreased cell survival fraction, decreased DNA repair | [55] |
Ewing sarcoma | |||||
Mithramycin | Inhibitor of transcription | X-rays | 4 EWS:Fli1 + and 3 EWS:Fli- cells in vitro and in vivo | Reduced tumor growth in vivo, increased apoptosis | [56] |
Olaparib | PARP-1 | γ radiation | RD-ES, SK-N-MC EWS cell lines + tumor xenografts SK-N-MC | Decreased proliferation, increased cell death | [57] |
Curcumin | Multiple targets | γ radiation | SK-N-MC cell lines | Increased apoptosis and DNA fragmentation, increased cytotoxicity | [58] |
Taxol | Multiple targets | X-rays | Cell line HTB-166 | Blockade in G2/M, decreased colony formation rate | [59] |
Chondrosarcoma | |||||
Olaparib | PARP | X-rays, proton, hadron therapy | CHS2879 cell line | Decreased cell survival, decreased proliferation | [60] |
Disulfiram + copper | ALDH1A1 | X-rays | SW1353 and CS1 cell lines, Orthotopic CHS model, | Decreased survival, increased apoptosis, decreased colonies, decreased cancer stem cells | [61] |
Chordoma | |||||
Hyperthemia | X-rays | U-CH2 and MUG-Chor1 cell lines | Reduced colony formation | [62] | |
Ribavirin | Anti-viral drug | X-rays | U-CH1 cell line in vitro and in vivo | Decreased cell growth in vitro and in vivo | [63] |
LB100 | Protein Phosphatase 2A | X-rays | U-CH1, JHC7, UM-ChOR1 in vitro + in vivo | Accumulation in G2/M, growth inhibition, in vivo tumor growth delay | [64] |
DIMATE | ALDH1, ALDH3 | X-rays | U-CH1, U-CH12, CH22 3D | Decreased proliferation, decreased colony formation, increased cell death | [65] |
DNA damage recognition
P53 activation
Cell cycle arrest
DNA damage repair (DDR)
Cell death
Hypoxia
Other potential therapeutic targets with pre-clinical efficacy
Target | Method of inhibition | Models | Results | Citation |
---|---|---|---|---|
Osteosarcoma | ||||
CRIF1 | Knock down | U2OS cells + xenografts | Increased sensitivity to irradiation, delayed DDR, inactivated G1/S checkpoint, mitochondrial dysfunction. Tumor regression in vivo | [82] |
miR-513a-5p | Treatment with miR-513-5p | Decreased survival, decreased redox and DNA repair, stimulated apoptosis | [104] | |
miR-328-3p | Treatment with miR-328-3p | HOS-2R, U2OS + HOS xenograft mice | Decreased survival, increased apoptosis, decreased DNA repair | [105] |
iNOS, Nitric Oxide Synthase | Plasmid iNOS | D17 canine OS cell line | Decreased cell survival under hypoxic conditions | [106] |
UBE2T, Fanconi anemia gene, ubiquitine ligase | shRNA | U-2OS MG63, xenograft | Decreased survival fraction, induced cell cycle arrest in G2/M, promote apoptosis | [107] |
AKT2, serin/threonin kinase | miR-203a-3p | MG-63 | Promoted apoptosis | [108] |
IGF1R, Insulin-Growth Factor Rceptor | siRNA | U2, MG63, LM-8, SaOS-2, murine xenograft model | Suppressed growth, arrested cells in G0/G1, induced apoptosis, increased cell death, | [109] |
Ewing Sarcoma | ||||
Survivin, anti-apoptotic protein | SiRNA | 4 EWS cell lines RM-82, CADO-ES-1, VH-64, STA-ET-1 | Increased number of radiation-induced DSBs, reduced repair, increased apoptosis, reduced proliferation | [95] |
Chordoma | ||||
RAD51, recombinase | shRNA | U-CH1, U-CH2 | Decreased cell viability, increased apoptosis | [69] |
Combination of radiotherapy and pharmacological/genetic inhibition of targets in bone sarcoma in clinical trials
Clinical trials | Patients included | Drug | Radiation | Phase | Status | Evidence level |
---|---|---|---|---|---|---|
NCT03595228 | 29 avanced CD | BN-Brachyury | Fractionated radiation | 2 | Active, Not recruiting | 1c |
NCT01407198 | 29 advanced CD | Nilotinib (BCR-Abl, c-kit, and PDGF) | Fractionated radiation | 1 | Active, not recruiting | 1c |
NCT02383498 | 55 advanced CD | GI-6301 brachyury vaccine | 70 Gy fractionated radiation | 2 | Unknown | 1b |
NCT02802969 | 64 advanced CD after incomplete surgery | Hypoxia: 18F FAZA, proton boost | Proton therapy | 2 | Recruiting | 1c |
NCT02989636 | 33 recurrent, advanced or metastatic CD | Nivolumab (anti PD-1 antibody) | Stereotactic radiosurgery | 1 | Recruiting | 1c |
NCT01696669 | 43 EWSs | Chemotherapy: vincristine, doxorubicine, ifosfamide-etoposide, dexrazoxane-cyclophosphamide | Radiotherapy after incomplete resection | 2 | Completed | 1c |
NCT00023998 | 80 metastatic OSs | Trastuzumab (HER2) | radiotherapy | 2 | Completed | 1c |
NCT01886105 | 4 metastatic OSs | Sm-EDTMP | Radiotherapy | 2 | Terminated | 1c |
NCT03612466 | 20 OSs bone metastases | 153Sm-DOMTP Calcium carbonate Mozobil Neupogen | Radiotherapy | 1 | Not yet recruiting | 1c |
NCT00002466 | Bone sarcoma | Cyclophosphamide, doxorubicin hydrochloride, etoposide, ifosfamide, vincristine sulfate, surgery | Radiotherapy | 2 | Completed | 1c |
NCT00245011 | 11 OSs | Samarium-153 | Radiation | 2 | Completed | 1c |
NCT00544778 | 7 recurrent bone sarcomas | Filgrastim, dexrazoxane, doxorubicin, ifosfamide, irinotecan, conventional surgery | Radiotherapy | 2 | Terminated | 1c |
NCT03539172 | 61 bone sarcomas of head and neck | Apatinib mesylate | radiotherapy | 2 | Unknown | 1c |
NCT04398095 | 20 radiation-induced bone sarcomas | Hyperthermia | Radiotherapy | 2 | Recruiting | 1c |