While radiation therapy (RT) has an integral role in the management of soft-tissue sarcoma, it has a limited role in that of bone sarcoma, with few exceptions (ie, Ewing sarcoma). In keeping with the rarity of these tumors, it has been demonstrated that patients treated at high-volume centers have significantly better survival and functional outcomes.1–3 Accordingly, treatment should be delivered by a multidisciplinary team including orthopedic, medical, and radiation oncologists, as well as plastic and reconstructive surgeons, physical therapy specialists, and pathologists and radiologists with expertise in musculoskeletal sarcomas.4 As the preceding articles in this supplement have addressed the major modalities in the treatment of sarcomas other than RT, this article will focus on how RT fits into the overall management mix, with a focus on soft-tissue sarcomas, where it figures most prominently.
BONE SARCOMAS: A LIMITED ROLE FOR RADIATION
The role of RT in the management of bone sarcomas is limited. Its primary application appears to be in Ewing sarcoma, for which curative treatment requires combined local and systemic therapy. For definitive therapy, limb-salvage surgery is preferable over amputation, but amputation may be an option for younger patients with lesions of the fibula, tibia, and foot. Based on the available data, postoperative RT is probably of benefit for all patients with Ewing sarcoma with close margins and/or those with a poor histologic response.5 Further discussion of Ewing sarcoma management is beyond the scope of this article (see the second and fifth articles in this supplement).
For osteosarcoma, the current standard of care is surgical resection combined with neoadjuvant and adjuvant chemotherapy. RT had been used years ago, prior to the advent of effective chemotherapy regimens, but its use for osteosarcoma has now been relegated to a few select situations. These include lesions not amenable to surgical resection and reconstruction, cases in which the patient refuses surgery, cases where there are positive margins after resection, and cases where palliation is needed for symptomatic lesions.
SOFT-TISSUE SARCOMAS: RADIATION HAS A CLEAR ADJUVANT ROLE
The primary management of localized soft-tissue sarcomas is surgical resection to achieve a negative margin when feasible. Historically, local excision of soft-tissue sarcomas resulted in local failure rates of 50% to 70%, even when a margin of normal tissue around the tumor was excised. As a result, amputation became standard treatment.6 In a landmark National Cancer Institute study 3 decades ago, patients were randomized to amputation or to limb-sparing surgery with the addition of RT.7 Notably, disease-free and overall survival were not compromised by limb-sparing surgery plus RT, demonstrating that although lesser surgery in the absence of RT may be insufficient, limb-sparing surgery with RT was equal to amputation. Consequently, limb-sparing approaches have become the favored surgery for the majority of cases of soft-tissue sarcoma, as advocated in a consensus statement from the National Institutes of Health.1
Indications vary by lesion grade
In general, adjuvant RT is recommended for all intermediate- and high-grade soft-tissue sarcoma lesions. A potential exception is a superficial tumor smaller than 5 cm with widely negative margins after resection. For low-grade lesions, re-excision is favored over adjuvant RT for positive or close margins, and RT is avoided in the setting of negative margins.
Optimal timing of radiation remains unclear
The optimal timing of adjuvant RT—preoperative versus postoperative—remains unknown. The relative advantages of preoperative RT include smaller and well-defined treatment volume, ability to use a lower dose, lack of tissue hypoxia, increased tumor resectability (smaller surgery), and improved limb function with less late fibrosis and edema. The disadvantages include inability to precisely stage patients and higher risk of acute wound-healing complications.
The National Cancer Institute of Canada compared outcomes with preoperative versus postoperative RT among 190 patients with soft-tissue sarcoma in a prospective randomized trial.8 Patients were stratified by tumor size (≤ 10 cm or > 10cm) and then randomized to preoperative RT (50 Gy in 25 fractions) or postoperative RT (66 Gy in 33 fractions).8 There was no difference between the groups in local control, distant control, or survival rates, but a higher rate of late complications, including fibrosis and edema, was observed with postoperative RT.8,9 On the other hand, the incidence of wound complications was higher in the preoperative group (35%) than in the postoperative group (17%).8
Likewise, the optimal sequencing and benefits of systemic therapy (chemotherapy) with relation to local therapy (surgery with pre- or postoperative RT) remain unclear. More than a dozen individual randomized trials of adjuvant chemotherapy, as well as a meta-analysis of 14 trials of doxorubicin-based adjuvant chemotherapy, have failed to demonstrate significant improvement in overall survival in patients with soft-tissue sarcomas.10 With regard to neoadjuvant chemotherapy for soft-tissue sarcomas, there are studies suggesting improvement in local control but no consistent survival benefit.11 Chemotherapy may yield a benefit in select cases, as detailed elsewhere in this supplement.
MECHANISMS OF ACTION: DIRECT AND INDIRECT
In simplified terms, radiation kills cancer cells through two basic mechanisms: indirect and direct.
The indirect effect (the most common mechanism) results from the generation of free radicals in the intracellular medium via ionization by photons. Free radicals, in turn, deposit large amounts of energy that damage DNA or some other vital component of the cell, resulting in cell death.
The direct effect is a consequence of photons themselves interacting directly with the cell in a lethal manner.
The goal of RT is to kill tumor cells selectively, without irreversibly injuring adjacent normal tissue. This is done by exploiting two abnormal aspects of tumor behavior: decreased ability for repair and increased susceptibility to ionizing radiation damage. Tumors are generally less able than normal tissue to repair DNA damage, owing to defective repair mechanisms. Tumor cells are also comparatively more radiosensitive than normal tissues, as they are more frequently in radiosensitive cell-cycle phases. Thus, dividing the radiation dose into a number of treatment fractions provides two advantages that further exploit the biologic differences between tumor and normal tissue: it allows DNA repair to take place within the normal tissues, and it allows proliferating tumor cells to redistribute through the cell cycle and move into the more radiosensitive phases.