Volume 2 | Issue 1 | Jan-Apr 2016 | Page 33-35 Sangeeta Kakoti, Nehal Khanna, Siddhartha Laskar.
Authers: Sangeeta Kakoti Nehal Khanna, Siddhartha Laskar
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai. India
Address of Correspondence
Professor, Department of Radiation Oncology, Tata Memorial Hospital, Dr Ernest Borges Marg, Parel, Mumbai – 400012, India.
Osteosarcomas are known to be relatively radio-resistant, definitive radiotherapy has a role in cases that are unresectable or have poor prognostic factors. Neo-adjuvant Chemotherapy followed by local therapy (surgery alone and/or radiotherapy) and maintenance chemotherapy remain the current standard of care for treatment of non-metastatic high grade osteosarcoma. New technologies like particle beam therapy using proton and carbon ions and use of high precision radiation therapy techniques have further improved the results of definitive radiation therapy. Current review traces the advent of radiotherapy, its current role in management of osteosarcoma and future trends in the field.
Keywords: Osteogenic Sarcoma, Radiotherapy, Management.
Osteosarcoma (OGS), an osteoid-producing malignant mesenchymal tumour, accounts for 20-45% of all skeletal malignancies. It has a bimodal age distribution with peak incidence at 10-19 years and over 60 years (secondary to prior radiotherapy exposure, Paget’s disease etc). Male to female ratio is approximately 1.6:1. The most common sites of involvement are femur (50%), followed by tibia, humerus, pelvis, jaw, fibula and ribs. The major histological variants are conventional osteosarcoma (osteoblastic, fibroblastic or chondroblastic, according to the predominant type of matrix produced), teleangiectatic and small cell osteosarcoma. Patients commonly present with bony pain and local swelling. Patients may also present with symptoms of metastatic disease like dyspnoea, hemoptysis, or bone pain. Diagnostic investigations include Plain radiograph (characteristic ‘Sun burst’ appearance and ‘Çodman’s triangle’), MRI of local part, CT scan of chest, Bone scan (to look for skip lesions) and a histopathological examination. Tumors are staged according to either the AJCC or Enneking (MSTS) systems. Prognostic factors impacting survival  include presence of metastasis, response to Neoadjuvant chemotherapy (NACT), histologic type, age (each decade increases mortality rate by 7 fold), tumour location (tumours of tibia fare better than those of femur) and choice of therapy (post operative radiotherapy and amputation was associated with 92% and 76% increased relative risk of death respectively, may be confounded by advanced disease status). Prior to the extensive use of chemotherapy for treating patients with osteosarcoma, aggressive surgery was considered the treatment of choice, resulting in five year overall survival rate of 10-20% . A meta-analysis by Kassir et al  on head and neck Osteosarcoma showed that surgical cut margin status was the sole prognostic factor and there was no survival benefit by adding radiation therapy and/or chemotherapy. But subsequently there have been great leaps in the success of osteosarcoma management. Incorporation of highly active chemotherapeutic agents resulted in significant improvement in outcomes to the tune of 60-75% . The MIOS trial  reporting 5% versus 65% overall survival rates in patients randomised to surgery versus surgery and chemotherapy respectively, formed the basis for multimodality therapy in these tumours.
Role of Radiotherapy in management of Osteosarcoma
Osteosarcoma was always thought to be a radio-resistant tumour and hence radiotherapy was initially not included in the standard management regimens. Sir Stanford Cade a British surgeon radiotherapist in 1931 treated 133 patients with radiation therapy with an intention to avoid futile amputation in patients developing lung metastases in subsequent 6-9 months . Following completion of therapy (60 Gy over six weeks) the resected specimen revealed 100% tumour necrosis in all patients.
1) Radiotherapy in definitive setting
There are no randomized trials comparing surgery versus radiotherapy (RT) as primary local therapy for osteosarcoma and is unlikely to be one in future due to ethical issues. However there are a few single arm series showing encouraging results. Machak et al  treated 31 patients with extremity osteosarcomas with definitive radiotherapy to a median dose of 60 Gy (range, 40–68 Gy). The 5-year local control (LC), metastasis-free and overall survival (OS) rates were 56%, 62%, and 61%, respectively. Similarly, Caceres et al  also noted a complete pathological response in 80% patients with limb OGS treated by chemotherapy and 60 Gy of RT. Excellent functional outcomes was noted in 86% of the patients. In 13 patients treated with definitive RT to median dose of 60 Gy, at a median follow up of 161 months, 3 year LC and OS was 70% and 75% respectively . Subsequently, in the COSS registry of 175 patients  treated from 1980 to 2007, at a median follow up of 1.5 years (0.2-23 years), the overall survival rates after RT for treatment of primary tumors, local recurrence, and metastases were 55%, 15%, and 0% respectively. Local control rates for combined surgery and RT were significantly better than those for RT alone (48% vs. 22%). Feasibility of Stereotactic body radiotherapy (SBRT) for recurrent OGS lesions was evaluated by Brown et al . Median dose delivered was 40 Gy in 5 fractions (range, 30-60 Gy in 3-10 fractions; total of 14 patients). Two grade 2 and 1 grade 3 late toxicities occurred (in the setting of concurrent chemotherapy and reirradiation); consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy . Efficacy and long term toxicity are yet to be determined. Gaitan-Yanguas showed a dose-response relationship with no lesion controlled at doses of 30 Gy, and all lesions controlled with doses of >90 Gy .
Approximately 25% of pelvic and 10% of head and neck osteosarcomas are not resectable and hence are candidates for definitive radiotherapy. In our institute, we prescribe 70.2 Gy in 39 fractions over 8 weeks.
2) Radiotherapy in preoperative setting
Preoperative radiotherapy is gradually evolving to facilitate function preserving less mutilating surgeries. Dincsbas et al  treated 44 patients with preoperative RT to a dose of 35 Gy in 10 fractions followed by limb sparing surgery. The tumor necrosis rate was 90% in 87% of the patients. At a median follow-up of 44 months, the 5-year LC and OS were 97.5% and 48.4% respectively. They documented subcutaneous fibrosis in 16%, joint movement restriction in 20%, and osteo-radionecrosis and pathologic fracture in 4% patients. Chambers et al  reported an OS of 73% at 5 years of 33 patients treated with preoperative RT and resection for craniofacial OGS.
3) Radiotherapy in adjuvant setting
Delaney et al  reported 41 patients with osteosarcoma involving various sites (primary, recurrent as well as metastatic) in different settings to a dose of 10 to 80 Gy (median 66 Gy) preceded by gross total tumor resection in 65.8%, subtotal resection in 21.9% and biopsy only in 12.2%. The local control rates according to the extent of resection were 78.4%, 77.8% and 40% respectively. The overall survival rates in corresponding groups were 74.45%, 74.1% and 25% respectively. The authors concluded that adjuvant RT can help provide local control of osteosarcoma for patients in whom surgical resection with widely negative margins is not possible. Dose response relationship was not found to be significant. Caveat of the study was that the patient population as well as the treatment parameters including dose and timing of radiation (some received preoperative followed by postoperative RT) was very heterogeneous.
Guadagnolo et al  reported that the addition of adjuvant RT in head and neck osteosarcoma definitely improves local control for those with positive or uncertain margins. Laskar et al reported the outcomes of patients with head and neck osteosarcomas treated at the Tata Memorial Hospital, Mumbai . The authors highlighted the impact of post-operative adjuvant radiotherapy, even after R0 resection or in patients with adverse prognostic factors (large tumour size, lymphovascular invasion, soft tissue infiltration etc). The patients receiving adjuvant RT at TMH were prescribed a dose of 64.8 Gy in 36 fractions over 7 weeks. The authors reported local control rate of 36%. High dose intra-operative EBRT with kV X rays or electrons is emerging as yet another experimental option. Hong et al reported outcome of extracorporeal irradiation (ECI) in the management of 16 pts with a variety of tumours (OGS being in 4 of them) to a dose of 50 Gy in single fraction. At a median follow-up of 19.5 months, there were no cases of local recurrence or graft failure. One patient required amputation due to chronic osteomyelitis . Puri et al reported the outcomes of patients treated at the Tata Memorial Hospital, Mumbai, using extracorporeal irradiation . Thirty-two patients (16 Ewing’s sarcoma and 16 OGS) with a mean age of 15 years (2 to 35 years) underwent this procedure. There were three local recurrences. All were associated with disseminated disease and the recurrences were in soft- tissue remote from the irradiated graft. There were no local recurrences involving the irradiated bone. The OS for patients with osteosarcoma was 65% with excellent functional outcome.
4) Radiotherapy in palliative setting
There is little data regarding dose fractionation and efficacy of radiotherapy for palliation of advanced osteosarcoma. Considering the similar mechanisms of pain and inflammation like bony metastases, data from the later are often extrapolated  and single fraction or protracted fractionation have both been equally used. Oligo-metastatic OGS is treated with curative intent. Metastatectomy is the gold standard as a component of the curative regimen with a documented 5 year OS of approx 22%. Stereotactic body radiotherapy (SBRT) to limited lung metastases is an equally efficacious emerging non invasive option. In a series of 46 patients with oligometastatic disease to lungs from sarcomas, at a median follow up of 22 months after median dose of 10-48 Gy in 1-5 fractions, 31% of patients survived for more than 3 years . In a multicentric phase I/II trial treating 38 patients with oligometastases to a median dose of 38-60 Gy in 3 fractions, LC at two years was 96% and median survival was 19 months. Incidence of grade III-IV toxicity was 8% .
5) Particle therapy for osteosarcoma
Ciernik et al, treated 55 patients (42% received definitive RT) with osteosarcoma of all sites  using combination of photons and protons to a mean dose of 68.4 Gy. With a median follow-up of 27 months, LC at 3 and 5 years were 82% and 72% respectively. The 5-year DFS and OS was 65% and 67% respectively. Prognostic factors found to have a significant impact on disease control were grade and bulk of the tumour. The extent of surgical resection did not correlate with outcome. Grade 3 to 4 late toxicity was seen in 30.1 % of patients. In another series of 30 patients with unresectable OGS of the trunk treated with definitive Carbon ion therapy to a dose of 52.8–73.6 Gy, the 3 and 5 year LC at a median follow up of 33 months was 62% and 49% respectively. The corresponding OS was 53% and 29%. Severe skin/soft tissue reaction was reported in 5 patients . With neutrons, local control rates of 55% were documented in patients with unresectable OGS of different sites . A median prescribed dose of 66 Gy has been tried in a series to patients with paraspinal osteosarcomas with a resultant LC of 74%. There were no reported late toxicities .
6) Role of brachytherapy
There is very limited role of brachytherapy in osteosarcomas. A new treatment strategy based on direct injections of 90Y-hydroxide into the tumor bed is under preclinical trial .
Neo-adjuvant Chemotherapy followed by local therapy (surgery alone and/or radiotherapy) and maintenance chemotherapy remain the current standard of care for treatment of non-metastatic high grade osteosarcoma. Although osteosarcomas are considered to be relatively radio-resistant, definitive radiation therapy results in significant long term disease control in patients with inoperable disease and postoperatively in patients with poor prognostic factors. The outcomes of definitive treatment using radiation therapy has further been improved by the use of particle beam therapy like protons & carbon ions & escalated doses of photon therapy using modern high precision radiation therapy techniques. Hence, Radiotherapy remains an important option for local treatment of unresectable tumors, following incomplete resection, or as an effective tool for palliation of symptomatic metastases
1. Prognostic factors and outcomes for osteosarcoma: An international collaboration. Emil-ios E. Pakos, Andreas D. Nearchou, Robert J. Grimer et al. European Journal of Cancer. 2009; 4 5: 2 3 6 7 –2 3 7 5
2. Osteogenic sarcoma: a study of 600 cases. Dahlin DC, Coventry MBBoneJoint Surg 1967; 49: 101-l 10.
3. Osteosarcoma of the Head and Neck: Meta-analysis of Nonrandomized Studies. Laryn-goscope, 1997; 107: 56-61.
4. Dana-Farber Cancer Institute/The Children’s Hospital adjuvant chemotherapy trials for osteosarcoma: three sequential studies, A. M. Goorin, M. Delorey, and R. D. Gelber, Cancer Treatment Symposia. 1985; 3: 155–159.
5. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosar-coma of the extremity. M. P. Link, A. M. Goorin, and A. W. Miser. The New England Journal of Medicine. 1986; 314: 1513
6. Osteogenic sarcoma. A study based on 133 patients. Cade S. J R Coll Surg Edinb. 1955; 1: 79-111.
7. Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the ex-tremities. Machak GN, Tkachev SI, Solovyev YN et al Mayo Clin Proc. 2003;78:147-155
8. Local control of osteogenic sarcoma by radiation and chemotherapy. Caceres E, Zaharia M, Valdivia S, et al. Int J Radiat Oncol Biol Phys . 1984;10:35-39
9. Patrick Hundsdoerfer et al, European Journal of Cancer 4 5 (2009) 24 47 –2451
10. Craniofacial osteosarcoma Experience of the cooperative German–Austrian– Swiss osteosarcoma study group. Sven Jasnau, Ulrich Meyer, Jenny Potratz et al. Oral Oncology (2008) 44, 286– 294
11. Stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosar-coma. Brown LC, Lester RA, Grams MP et al, Sarcoma. 2014:418270
12. A study of the response of osteogenic sarcoma and adjacent normal tissues to radiation. Gaitan-Yanguas M. IJROBP. 1981; 7: 593-595
13. The role of preoperative radiotherapy in non metastatic high-grade osteosarcoma of the extremities for limb-sparing surgery. Dincbas FO, Koca S, Mandel NM et al. Int J Radiat Oncol Biol Phys 2005;62:820-828
14. Osteogenic sarcoma of the mandible, current management. Chambers RG, Mahoney WD. Am Surg . 1970;36:463-471
15. Radiotherapy for local control of osteosarcoma. Thomas F. Delaney, Lily Park, Savelli I Goldberg et al, IJROBP, 2005; 61(2): 492-498.
16. Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment. Guadagnolo BA, Zagars GK, Raymond AK, et al, Cancer 2009;115: 3262-70.
17. Osteosarcoma of the head and neck region: lessons learnt from a single institutional expe-rience of 50 patients, Siddhartha Laskar, Ayan Basu, Mary Ann Muckaden et al, Head & Neck, 2008: 1020-1026.
18. Extracorporeal irradiation for malignant bone tumors. Hong A, Stevens G, Stalley P, et al. Int J Radiat Oncol Biol Phys . 2001;50:441-447
19. The outcome of the treatment of diaphyseal primary bone sarcoma by resection, irradia-tion and re-implantation of the host bone. A Puri, A Gulia, N Jambhekar, S Laskar. J Bone Joint Surg Br 2012;94-B:982–8.
20. Randomized trial of short versus long-course radiotherapy for palliation of painful bone metastases. Hartsell WF, Scott CB, Bruner DW, et al. J Natl Cancer Inst 2005;97:798–804
21. A retrospective study of SBRT of metastases in patients with primary sarcoma. Christina Linder Stragliotto, Kristin Karlsson, Ingmar Lax et al. Med Oncol. 2012; 29:3431–3439
22. Multi-Institutional Phase I/II Trial of Stereotactic Body Radiation Therapy for Lung Me-tastases, Kyle E. Rusthoven, Brian D. Kavanagh, Stuart H. Burri. J Clin Oncol 2009; 27:1579-1584.
23. Proton-Based Radiotherapy for Unresectable or Incompletely Resected Osteosarcoma: I. Frank Ciernik, MD1,2; Andrzej Niemierko, PhD1,3,4; David C. Harmon et al, cancer 2011; 117: 4522–30.
24. Impact of Carbon Ion Radiotherapy on Outcome in Unresectable High-grade Osteosar-coma of the Trunk, T. Kamada, R. Imai, S. Sugawara et al, I. J. Radiation Oncology d Biology d Physics Volume 75, Number 3, Supplement, 2009
25. Fast neutron radiotherapy for sarcomas of soft tissue, bone, and cartilage: Laramore GE, Griffith JT, Boespflug M et al, Am J Clin Oncol, 1989, vol 12, pp 320-326
26. Image-guided intensity-modulated photon radiotherapy using multifractionated regimen to paraspinalchordomas and rare sarcomas. Terezakis SA, Lovelock DM, Bilsky MH et al. Int J RadiatOncolBiol Phys. 2007;69(5):1502-8
27. Dosimetry of a 90Y-hydroxide liquid brachytherapy treatment approach to ca-nine osteosarcoma using PET/CT. Jien Jie Zhou, Arnulfo Gonzalez, Mark W. Lenox. Ap-plied Radiation and Isotopes. 2015; 95: 193-200.
|How to Cite this article:Kakoti S, Khanna N, Laskar S. The Current Role of Radiation Therapy for Osteogenic Sarcoma. Journal of Bone and Soft Tissue Tumors Jan-Apr 2016;2(1): 33-35.|