Key points

Introduction

Sarcomas encompass a diverse array of malignancies that originate in the musculoskeletal system. The cell of origin is most often muscle, fat, or bone. Overall, there are approximately 10,000 of these malignancies diagnosed in the United States annually. Most occur in an extremity (50%). Other major sites are the retroperitoneum, trunk, and head and neck regions.

This article focuses on the use of radiation therapy for adult-type soft tissue sarcomas. Special mention is made of other sarcomas (eg, the management of retroperitoneal sarcoma) where appropriate. Although this article focuses on the use of radiotherapy, emphasis is placed on the multidisciplinary management of these malignancies.

Introduction

Sarcomas encompass a diverse array of malignancies that originate in the musculoskeletal system. The cell of origin is most often muscle, fat, or bone. Overall, there are approximately 10,000 of these malignancies diagnosed in the United States annually. Most occur in an extremity (50%). Other major sites are the retroperitoneum, trunk, and head and neck regions.

This article focuses on the use of radiation therapy for adult-type soft tissue sarcomas. Special mention is made of other sarcomas (eg, the management of retroperitoneal sarcoma) where appropriate. Although this article focuses on the use of radiotherapy, emphasis is placed on the multidisciplinary management of these malignancies.

Importance of multidisciplinary evaluation

Because of the rarity and marked heterogeneity of soft tissue sarcomas, it is crucial that patients be evaluated in centers with clinical expertise. The heterogeneity of histologic subtypes and varied clinical presentations observed require treatment plans that are ideally discussed and formulated in the context of a multidisciplinary setting. Pathologic expertise is essential in making an initial diagnosis. Radiologic evaluation is appropriate for adequate and complete staging. Discussion between the radiologist and surgeon additionally provides for a carefully planned surgical approach, allowing a determination of the proximity of disease to vital neurovascular and visceral structures. In addition, an open dialogue among the treating surgeons and medical and radiation oncologists allows timely consensus regarding the need, timing, and sequence of respective therapies in an effort to limit treatment-related morbidity while maintaining functional outcomes and performance status. Plastic and reconstructive and vascular surgical specialties may be used in specific scenarios. In addition, the evaluation and management of patients in a center with expertise may provide a sense of patient comfort and reduced anxiety in knowing that providers have experience and a working knowledge of an otherwise rare disease.

Staging work-up

The American Joint Committee on Cancer (AJCC) 7th Edition (2010) staging for sarcoma is now used. For soft tissue sarcoma, not only are tumor size, lymph node status, and distant metastatic status integral to staging but tumor grade is also incorporated in the system. All grade 1 tumors are considered stage I given their low risk of malignancy-related death. All metastatic tumors are stage IV. Stage III tumors are considered to be those greater than 5 cm and grade 3, or those with involved lymph nodes. The remainder are considered stage II.

The staging of individuals diagnosed with sarcoma requires adequate imaging not only of the primary site but also as an assessment for disseminated disease. A determination of tumor size, relationship to fascial planes, proximity to vital structures, and presence or absence of metastasis all aid in determining an optimal treatment plan for patients. Magnetic resonance imaging (MRI) is the preferred imaging for sarcomas of the extremity, whereas computed tomography (CT) may be appropriate for retroperitoneal and truncal sarcomas. Adequate imaging of the chest is essential because the lungs are the most common site for distant spread. Staging should be individualized based on histologic subtype because some histologic subtypes show varying patterns of metastasis. Cross-axial imaging of the abdomen and pelvis should additionally be considered for histologies prone to abdominal spread, including leiomyosarcoma, epithelioid sarcoma, angiosarcoma, and myxoid round cell liposarcoma. Myxoid round cell liposarcoma has additionally been associated with spinal metastasis, whereas alveolar soft part sarcoma has been associated with the development of brain metastasis. Positron emission tomography/CT may additionally be considered and has both prognostic and predictive abilities.

Individuals with localized or locally advanced disease (stage I–III) are often treated with multimodality therapies, primarily surgery with additional consideration for radiation and/or chemotherapy as part of a neoadjuvant or adjuvant approach. Individuals with disseminated disease (stage IV) are traditionally treated with palliative systemic therapies, although the degree of disease burden, particularly in the setting of oligometastatic disease, may warrant aggressive treatment approaches, including metastasectomy.

Surgical considerations

Evidence for the use of radiotherapy in sarcoma management

Classic studies from the 1970s and 1980s established the role of radiotherapy in the management of extremity sarcomas. A randomized trial at the National Cancer Institute comparing amputation versus limb-sparing surgery followed by radiotherapy showed similar overall survival rates with an acceptable local recurrence rate in the surgery and radiotherapy arm (15%). The benefit of radiation therapy in addition to limb-sparing surgery was evaluated in a second National Cancer Institute study that randomized patients with extremity sarcoma to a compartmental resection versus tumor resection followed by radiotherapy. The surgery alone arm had a lower local control rate (80% vs 100%) and again overall survival was not affected. Another prospective, randomized trial at Memorial Sloan Kettering Cancer Center compared limb-sparing surgery alone versus surgery plus brachytherapy. The addition of brachytherapy increased the rate of local control from 69% to 82%.

The seminal contemporary contribution to this area is the randomized study of preoperative versus postoperative radiotherapy conducted by the National Cancer Institute of Canada (NCIC). The radiotherapy techniques consisted of 50 Gy in the preoperative setting and 66 Gy given postoperatively. Longitudinal expansions around the tumor were 5 cm and radial expansions were 2 cm. The local control rate (90%) and overall survival were similar. There was a doubling (35% vs 17%) of the wound complications within 120 days after surgery in preoperative versus postoperative radiotherapy arms. However, these wound complications were predominantly in the lower extremity. Moreover, long-term complications such as fibrosis, edema, and joint stiffness seemed to be decreased in the preoperative radiotherapy arm.

Therefore, the body of randomized data suggests that radiotherapy in combination with tumor resection provides excellent local control at the primary site. The optimal timing of radiotherapy (preoperative or postoperative) can be influenced by individual factors such as overall life expectancy of the patient and therefore the concern regarding long-term complications, and the underlying risk and potential complications from a wound infection (eg, vascular disease or uncontrolled diabetes).

Radiation therapy for unresected sarcomas

As described in detail earlier, surgery is the foundation of local therapy for sarcomas. However, there are clinical scenarios in which surgery is not an option. In some cases, patient comorbidities may make certain surgeries too risky. In other cases, en bloc surgical resection may cause such significant morbidity that patients decline surgery. In these cases, the multidisciplinary team needs to consider creative options to try to achieve local control. In these situations, radiation therapy alone can be considered. In contrast with the radiation doses used in preoperative (50 Gy) or postoperative (60 Gy) radiation therapy, to achieve local control with radiation therapy alone, a higher dose of radiation is generally required for most soft tissue sarcomas.

The sarcoma group at the Massachusetts General Hospital reported the outcome of 112 patients whose unresected soft tissue sarcomas were treated with radiation therapy. At the time of the analysis, median follow-up was 139 months. Tumor size at the time of radiation therapy and radiation therapy dose influenced local control. Local control at 5 years for sarcomas less than 5 cm, 5 cm to 10 cm, and greater than 10 cm was 51%, 45%, and 9%, respectively. Five-year local control for tumors treated with less than 63 Gy was 22%, whereas 5-year local control was 60% for tumors treated to doses of 63 Gy or greater. Use of chemotherapy, histologic grade, and tumor location did not influence the results of this retrospective study. Fourteen percent of all patients had a major complication from radiation therapy. The complication rate from radiotherapy increased to 27% for patients treated with at least 68 Gy. Although these results of radiotherapy for the treatment of unresected soft tissue sarcomas are inferior to the combination of surgery and adjuvant radiation therapy, they show that radiation therapy alone with a dose of at least 63 Gy can achieve local control in approximately half of all soft tissue sarcomas up to 10 cm in size. Therefore, for select patients who are unable or unwilling to undergo surgery, radiation therapy alone or with concurrent ifosfamide chemotherapy should be considered.