Radiation Oncology/Sarcoma/Osteosarcoma

Epidemiology

Represent 35% of bone sarcomas.
Primary distribution in adolescents
When it occurs in older patients, usually associated with pre-existing condition such as Paget's disease, prior irradiation of bones, multiple hereditary exostosis, or polyostotic fibrous dysplasia
Hereditary risk factors:
- Hereditary Retinoblastoma (Rb mutated in ~50% osteosarcomas)
- Li-Fraumeni syndrome (p53 mutated in 20-30%)
- Rothmund-Thomson syndrome
Distribution:
- Distal femur/knee joint ~50%
- Proximal humerus ~25%
- Long tubular bones ~80-90%
- Hands/feet <1%
Lab findings generally not helpful, though serum alkaline phosphatase elevated in ~50%
Clinical presentation:
- Night pain
- Typically no effusion in the adjacent joint
- Pathologic fractures rare
Metastatic disease:
- Approximately 15-20% at diagnosis
- Overwhelmingly in the lung

90% of osteosarcomas are conventional osteosarcomas; these are intramedullary high grade tumors. Subtypes include:
- osteoblastic
- chondroblastic
- fibroblastic
10% include osteosarcoma of the jaw, surface osteosarcomas (paraosteal and periosteal)
Radiation-induced osteosarcomas may be a linear function of radiation dose and alkylating agents. Risk for most childhood survivors <1%, but higher with genetic predisposition (Retinoblastoma 7%, Ewings' 5%, other bone tumors 2%)

Classic appearance on plain x-ray is sunburst pattern which is a mixed lytic sclerotic pattern (vs "onion skinning" in Ewing's sarcoma)
- Increased intramedullary density due to tumor bone or calcified cartilage
- Area of radiolucency due to nonossified tumor
- Cortical destruction
- Extraosseous elevation (Codman's triangle) when tumor lifts the periostium leading to a rim of subperiosteal bone.

Biopsy should be performed by an orthopedic surgeon who will ultimately perform the resection
Treatment is surgical resection, preferentially limb-sparing surgery (distal femur/proximal tibia, shoulder girdle/proximal humerus)
- Surgery alone historically leads to overall survival of <20%.
Adjuvant chemotherapy plays a key role in preventing distant mets; 4-agent regimens are favored
- Randomized trial by POG showed no difference between neoadjuvant chemotherapy -> surgery -> adjuvant chemotherapy and surgery -> adjuvant chemotherapy; 5-year ERS was ~60%
Adjuvant RT (including whole lung irradiation) does not appear to benefit survival
- Prior to advent of effective chemo, whole lung xrt was often administered b/c of high rate of pulmonary failure. Data is unclear as to whether there was any benefit to this practice
- Role for RT is mostly limited to life-threatening presentations where adequate surgical removal is unlikely, such as H&N, spine, or pelvis
Pelvic tumors are typically unresectable, and are treated with RT and chemotherapy
For metastatic disease, aggressive course is typically advocated, consisting of induction chemotherapy followed by maximal resection of primary and mets, followed by adjuvant chemotherapy

Blokhin Cancer Center, Russia; 2003 PMID 12583525 "Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the extremities," Mayo Clin Proc 2003; 78(2):147-55.
- 31 pts who refused surgery and underwent induction chemo + conventional xrt (median 60 Gy)
- Local control 56%, OS 61%
- Of pts who had local control, 86% had excellent limb function

UC San Francisco; 1976 PMID 1064887 "The role of radiation therapy in the treatment of osteosarcoma," Radiology. 1976; 120(1):163-5.
- 70 pts w/ osteosarcoma receiving either primary xrt or surgery b/w 1950-74
- Conclusion: xrt w/o chemo did not add palliative effect or improve OS in operative pt.

Harvard; 2005 (1980-2002) PMID 15667972 "Radiotherapy for local control of osteosarcoma" DeLaney TF, Int J Radiat Oncol Biol Phys. 2005; 61(2):492-8.)
- Retrospective. 41 patients with osteosarcoma (head/face 41%, extremity 20%, spine 20%, pelvis 17%). 5 were radiation-induced. Median age 29. GTR 66%, STR 22%, biopsy 12%. If GTR, received RT for close or +margins. Median 66 Gy delivered (If gross disease >=68 Gy; if SM+ 60-68 Gy, if close SM 55-60 Gy, if radiation-induced sarcoma 10-30 Gy). Some patients pre-op 20 Gy followed by post-op RT. Chemo 85%
- Outcome: 5-year LC 68%; GTR 78% vs. STR 78% vs. biopsy 22% (SS).
- RT: No definitive dose response seen, but doses >55 Gy w/ better local control (71% vs 54%)
- Conclusion: RT can help provide local control if widely negative margins not possible

Peru; 1986 PMID 3522504 "Postoperative whole lung irradiation with or without adriamycin in osteogenic sarcoma," Int J Radiat Oncol Biol Phys. 1986; 12(6):907-10.
- 36 patients w/ osteosarcoma of limbs tx'd b/w 1975-78 w/ radical surgery then 20 Gy whole lung irradiation. Most pts received adriamycin.
- All pts ultimately developed lung mets, but whole lung xrt appeared to increase the time to failure.

Mayo Clinic; 1976 PMID 824047 "Elective whole lung irradiation in the treatment of osteogenic sarcoma," Cancer. 1976 Aug;38(2):939-42.
- 53 pts w/o evidence of pulmonary mets; 2 cohorts (15 Gy prophylactic xrt to whole lung field, or no lung xrt).
- No differences in survival or interval b/w tx and development of pulmonary mets.

Palliative Radiotherapy

Milan; 1992 (1984-1990) PMID 1429102 -- "Hypofractionated accelerated radiotherapy in osteogenic sarcoma." (Lombardi F, Int J Radiat Oncol Biol Phys. 1992;24(4):761-5.)
- 14 pts receiving RT for palliation to either the primary site (n=6) or skeletal metastases (15 lesions). Received 6 Gy per fraction, 3 fractions per week, for 6 fractions = 36 Gy over 2 weeks.
- Radiographic response in 92%; no local recurrence. Toxicity was often severe.
- Conclusion: "Although effective in inducing remission of osteogenic sarcoma, this irradiation method produced severe damages to normal tissues in a high proportion of patients."