Soft tissue sarcomas are rare mesenchymal cancers that pose a treatment challenge. Although small superficial soft tissue sarcomas can be managed by surgery alone, adjuvant radiotherapy in addition to limb-sparing surgery substantially increases local control of extremity sarcomas. Compared with postoperative radiotherapy, preoperative radiotherapy doubles the risk of a wound complication, but decreases the risk for late effects, which are generally irreversible. For retroperitoneal sarcomas, intraoperative radiotherapy can be used to safely escalate the radiation dose to the tumor bed. Patients with newly diagnosed sarcoma should be evaluated before surgery by a multidisciplinary team that includes a radiation oncologist.
Key points
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Radiotherapy is an effective treatment of soft tissue sarcomas.
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Randomized trials show that radiation therapy in combination with surgery increases local control compared with surgery alone; no statistically significant differences in survival were observed in these small studies.
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In large national cancer databases, treatment of high-grade soft tissue sarcomas with adjuvant radiation therapy is associated with a 10% improvement in survival.
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Preoperative radiotherapy doubles the risk of a wound complication, whereas postoperative radiotherapy increases the risk of late effects, such as fibrosis, edema, and joint stiffness.
Introduction
For more than 100 years, radiation therapy has been a mainstay of cancer therapy because of the exquisite ability of ionizing radiation to kill cancer cells. Historically, even though James Ewing used short-term tumor response to radiation therapy to help differentiate Ewing sarcoma from osteosarcoma, short-term changes in the size of a tumor following radiotherapy do not accurately quantify its efficacy. For some cancers (including soft tissue sarcoma), if they do not dramatically shrink following radiation therapy, clinicians may surmise that they are radiation resistant. However, this misconception is not consistent with clinical trials of radiation therapy in which the end point is local control. As discussed in this article, randomized clinical trials show that radiation therapy improves local control after surgery to a similar extent as surgery for breast cancer or rectal cancer. Therefore, radiation therapy is an effective modality for treating patients with soft tissue sarcoma.
Introduction
For more than 100 years, radiation therapy has been a mainstay of cancer therapy because of the exquisite ability of ionizing radiation to kill cancer cells. Historically, even though James Ewing used short-term tumor response to radiation therapy to help differentiate Ewing sarcoma from osteosarcoma, short-term changes in the size of a tumor following radiotherapy do not accurately quantify its efficacy. For some cancers (including soft tissue sarcoma), if they do not dramatically shrink following radiation therapy, clinicians may surmise that they are radiation resistant. However, this misconception is not consistent with clinical trials of radiation therapy in which the end point is local control. As discussed in this article, randomized clinical trials show that radiation therapy improves local control after surgery to a similar extent as surgery for breast cancer or rectal cancer. Therefore, radiation therapy is an effective modality for treating patients with soft tissue sarcoma.
Patient evaluation overview
Because radiation therapy is an effective therapy for soft tissue sarcoma and can be integrated with surgical resection before, during, or after surgery, it is critical that a radiation oncologist experienced in treating sarcomas evaluates patients at the time of initial diagnosis. The 2015 National Comprehensive Cancer Network (NCCN) guidelines for the management of soft tissue sarcomas state that, “prior to the initiation of therapy, all patients should be evaluated and managed by a multidisciplinary team with expertise and experience in sarcoma.” Except for the rare clinical scenario in which a soft tissue sarcoma is causing progressive neurologic deficits or life-threatening bleeding, there is almost always sufficient time for evaluation by a radiation oncologist, facilitating a multidisciplinary consensus treatment plan before definitive surgical resection.
The 2015 NCCN guidelines for soft tissue sarcoma state that, before the initiation of therapy, all patients should be evaluated and managed by a multidisciplinary team with expertise and experience in sarcoma.
Surgery alone
For extremity soft tissue sarcomas, the goals of local therapy include maximizing local control and function. Therefore, most patients with extremity soft tissue sarcomas undergo limb-sparing surgical resection. Limb-sparing surgery by surgeons experienced in soft tissue sarcoma resection achieves local control in approximately two-thirds of patients. In a setting in which limb-sparing surgery would not lead to a functional extremity, amputation without radiation therapy is an established treatment option. When limb-sparing surgery can lead to a functional extremity, surgery alone may still be the optimal local therapy, particularly in the clinical setting in which local recurrence is unlikely to lead to the development of metastases or loss of limb function. Soft tissue sarcomas in this category include small (<5 cm), low-grade tumors, particularly those superficial to the fascia. If a tumor with these clinical features recurs after surgery alone, salvage therapy including radiotherapy and surgery is likely to lead to a functional limb. Data supporting this approach come from a retrospective series from the Dana Farber Cancer Institute, concerning 74 patients with soft tissue sarcoma of the extremity or trunk with a median tumor size of 4 cm, of which 54% were low grade. These patients were treated with function-sparing surgery alone (ie, no radiotherapy) and the 10-year actuarial rate of local control was 93%. All of the sarcomas with a histologic resection margin of at least 1 cm achieved local control with surgery alone.
Intermediate-grade and high-grade, large (>5 cm) sarcomas have a higher risk of developing metastases. Sarcomas deep to the fascia generally require a more extensive resection of normal muscle so surgery for a recurrence may substantially increase morbidity and decrease limb function. Because there are currently no reliable methods to detect residual microscopic sarcoma at the time of surgery, large sarcomas that are deep to the fascia are frequently treated with radiation therapy, particularly if they are intermediate or high grade. Several investigators are developing different approaches to imaging microscopic residual cancer during surgery. If these intraoperative imaging techniques can better identify patients at high risk of residual cancer, then this may enable more patients to be managed with surgery alone.
Limb-sparing surgery alone (without radiotherapy) may be adequate local therapy for extremity soft tissue sarcomas that are small (<5 cm), low grade, and superficial to the fascia.
Radiation therapy options
Definitive Radiation Therapy Without Surgery
Although surgery is usually the cornerstone of local therapy for soft tissue sarcomas, there are certain clinical settings in which surgical resection may not be possible. For example, a soft tissue sarcoma may be located in the head and neck in a location that cannot be removed without sacrificing major blood vessels and/or nerves. Similarly, patients may refuse an amputation that may be recommended to achieve an en bloc resection and optimize local control. In these settings, definitive radiation therapy, with or without concurrent chemotherapy, is an alternative treatment option. Kepka and colleagues reported the Massachusetts General Hospital institutional experience treating 112 patients with soft tissue sarcoma with definitive radiation therapy for gross disease. Locations included the extremities (43%), retroperitoneum (24%), head and neck (24%), and truncal wall (7%). The median size was 8 cm and 89% were intermediate or high grade. Median radiation dose was 64 Gy and 20% of patients received chemotherapy. With a median follow-up of 139 months, the 5-year actuarial local control, disease-free survival, and overall survival rates were 45%, 24%, and 35% respectively. Tumor size was a critical factor in 5-year local control: 51% for sarcomas less than 5 cm, 45% for sarcomas 5 to 10 cm, and 9% for sarcomas greater than 10 cm. Radiation dose also influenced outcome. Patients receiving less than 63 Gy achieved 5-year local control and overall survival rates of 22% and 14% respectively. Patients receiving 63 Gy or more achieved 5-year local control and overall survival rates of 60% and 52% respectively. Thus, for sarcomas less than 10 cm to which a radiation dose of 63 Gy or more can safely be delivered, definitive radiation therapy is a useful treatment option when surgery is not feasible or is declined by the patient.
For soft tissue sarcomas less than 10 cm, definitive radiation therapy (≥63 Gy) without surgery can achieve local control in approximately 50% of patients.
Radiation Therapy Plus Surgery
External beam radiotherapy as adjuvant therapy for extremity sarcomas
The use of adjuvant external beam radiotherapy (EBRT) with limb-sparing surgery for extremity sarcomas was initially implemented as an alternative approach to amputation in adult extremity soft tissue sarcomas. This approach was prospectively evaluated in 2 randomized studies conducted by the US National Cancer Institute (NCI) in the United States from the 1970s to 1990s. Rosenberg and colleagues compared amputation with a limb salvage approach in extremity sarcomas, consisting of resection of the involved limb compartment and adjuvant EBRT. All patients (n = 43) received chemotherapy (doxorubicin, cyclophosphamide, methotrexate). Postoperative radiotherapy was administered (60–70 Gy) to 27 patients. A local recurrence rate of 15% was seen in the limb salvage group versus 0% in the amputation group ( P = .06). However, overall survival was similar.
This result prompted the investigators at the NCI to ask whether radiotherapy was necessary in addition to limb-sparing surgery. This second NCI study compared limb salvage (surgery and postoperative EBRT) with surgery alone. Surgery consisted of resection of gross tumor with a 1-cm to 2-cm margin where feasible. After surgical healing, patients with high-grade tumors (n = 91) were randomized to chemotherapy alone (doxorubicin, cyclophosphamide) versus chemotherapy and radiotherapy (63 Gy). Patients with low-grade (n = 50) tumors did not receive chemotherapy, but were randomized to observation versus radiotherapy. With a median follow-up of 9.6 years, patients treated with limb-sparing surgery alone showed increased local recurrence (24.3% vs 1.4%). Of note, overall survival was not statistically different. This randomized clinical trial established that EBRT in addition to limb-sparing surgery increases local control.
Even in this early study, there was a prospective evaluation of quality of life. Patients receiving adjuvant radiotherapy experienced decreased limb strength, increased edema, and worse range of motion of joints. However, these late effects did not seem to affect global quality of life or activities of daily living. Remarkably, follow-up for this study was recently extended for a median of 17.9 years and 54 patients completed a telephone interview. During this extended follow-up, 1 of 24 patients in the surgery-alone group developed a local recurrence, but none of 30 patients in the radiotherapy group recurred locally. Twenty-year overall survival with surgery alone was 64% and 71% for patients who received EBRT. The 7% increase in overall survival for patients receiving adjuvant radiation therapy was not statistically significant, but the trial included low-grade and high-grade soft tissue sarcomas and was not powered to detect a 7% survival difference. The investigators appropriately concluded that EBRT following limb-sparing surgery provides excellent local control with acceptable toxicity with long-term follow-up, but no statistically significant improvement in overall survival.
A randomized clinical trial at the NCI showed that adjuvant radiation therapy after limb-sparing surgery significantly increases local control (24.3% vs 1.4%), with an improved overall survival of 7% (which was not statistically significant) in this small group of patients.
It is conceivable that, with a much larger sample size of patients with high-grade sarcoma, adjuvant radiation therapy would improve overall survival for some patients with soft tissue sarcoma. A retrospective study from the Surveillance, Epidemiology, and End Results (SEER) database with 6960 patients with soft tissue sarcoma of the extremities treated from 1998 through 2005 found that, for patients with high-grade sarcomas, 3-year overall survival was increased for patients receiving adjuvant radiation therapy: 73% versus 63% ( P <.001). No difference in 3-year overall survival was observed in patients with low-grade sarcomas. Similarly, a retrospective analysis of 10,290 patients from the National Cancer Database from 1998 through 2006 also found improved survival for patients with intermediate-grade and high-grade soft tissue sarcoma of the extremity treated with adjuvant radiation therapy. To create 2 similar groups of patients treated with or without adjuvant radiation therapy, propensity matching was performed to match age, sex, tumor size, tumor grade, histology, margin type, tumor location (upper vs lower extremity), and extent of resection. Overall survival was compared for 2584 patients treated with adjuvant radiation therapy and 2582 patients without radiation therapy. Overall survival was increased by approximately 10% for patients receiving adjuvant radiation therapy ( P <.001). In summary, retrospective studies from large databases show that adjuvant radiation therapy is associated with improved survival by up to 10% for patients with high-grade extremity sarcomas, although randomized trials of EBRT powered to detect a 10% survival difference have not been performed.
Retrospective studies from large databases (SEER, National Cancer Data Base) suggest that adjuvant radiation therapy may improve survival for patients with high-grade extremity sarcomas by as much as 10%.
Following the randomized trial of limb-sparing surgery with or without adjuvant radiotherapy at the NCI, limb salvage (surgery and EBRT) became the standard of care for eligible patients. Discussion then ensued regarding the timing of surgery and radiotherapy. Some clinicians proposed preoperative radiotherapy using a lower radiation dose and smaller treatment fields, as used in the treatment of other malignancies. One advantage of this approach is that the radiation oncologist can image and define the location of the tumor and more easily identify the adjacent area at risk of microscopic disease at the time of treatment planning. In contrast, if the radiation therapy is delivered after gross tumor resection, it is more challenging to define the treatment target. In addition, sarcoma cells can seed the surgical wound during surgery. Thus, the postoperative radiation field typically encompasses the entire operative bed, which can increase the size of the radiation field. Thus, a lower radiation dose delivered to a smaller treatment volume in a preoperative approach might decrease long-term complications. However, surgical oncologists expressed concern regarding the risk of wound complications associated with preoperative radiotherapy.
The National Cancer Institute Canada (NCIC) SR2 study addressed the question of preoperative versus postoperative radiotherapy in a seminal randomized trial published in 2002. To date, this is the largest randomized study addressing the role of radiotherapy in extremity sarcoma. Nearly 200 patients were randomized to preoperative (50 Gy) versus postoperative (66 Gy) radiotherapy. The primary end point was wound complications at 120 days. Wound complications were defined as the need for a second surgery, or wound interventions requiring readmission, deep packing, or an invasive procedure. Secondary end points included local control and overall survival. At 120 days the wound complication rate was 17% in the postoperative radiotherapy group compared with 35% in the preoperative radiotherapy group. The rate of wound complication varied by anatomic site in multivariate analysis. In the upper extremity, in the absence of preoperative radiotherapy the rate of wound complications was 0% (0 of 19), which increased to 5.6% (1 of 18) after preoperative radiotherapy. In contrast, in the lower extremity the risk of a wound complication in the absence of preoperative radiotherapy was 21.3% (16 of 75), which increased to 42.9% (30 of 70) after preoperative radiotherapy. Therefore, a dose of radiation (50 Gy) does not seem to cause wound complications equally in all anatomic sites. Instead, it seems to double the risk of the baseline wound complication rate, which is much higher for lower extremity sarcomas. Local control (approximately 90%) and overall survival were similar between the groups.
Late effects on functional outcomes in the NCIC SR2 trial were also analyzed 2 years after therapy using the Musculoskeletal Tumor Rating Scale and the Toronto Extremity Salvage Score. There was a trend toward increased grade 2 or greater fibrosis in the postoperative radiotherapy group (48.2% vs 31.5%), which at that time point was not statistically significant ( P = .07). Although not statistically significant, extremity edema (23.2% vs 15.5%) and joint stiffness (23.2% vs 17.8%) were also more frequent in the postoperative arm. Radiation field size was predictive for greater fibrosis and joint stiffness, which correlated with lower functional scores. These data provide the basis for counseling patients with extremity sarcomas who are eligible for limb-sparing surgery about the risks and benefits of preoperative versus postoperative radiotherapy. Based on individual patient’s particular risk profiles for wound complications and goals regarding functionality after treatment of sarcoma, surgical or orthopedic oncologists and radiation oncologists can make recommendations regarding the timing of radiotherapy. In general, for younger patients, who may better tolerate a temporary wound complication, the authors usually offer preoperative radiation therapy to limit the risk of late effects, which might be permanent. For older patients with comorbidities, including diabetes and significant heart disease, in whom a wound complication could cause more serious morbidity and even increase the risk of mortality, the authors often recommend postoperative radiation therapy, particularly in patients in whom late effects from radiation may be less of a concern.
A randomized clinical trial from the NCIC showed that preoperative and postoperative radiotherapy achieved similar rates of local control and overall survival. Preoperative radiotherapy doubled the risk for a surgical wound complication, but used a lower radiation dose and a smaller treatment field, which resulted in fewer long-term side effects.
Practical aspects of EBRT treatment planning for extremity sarcomas include:
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Before any therapy, review all available data and consult with a multidisciplinary team. Specifically, the radiation oncologist should review the diagnostic MRI with a musculoskeletal radiologist and ensure that the pathology has been reviewed by a pathologist with experience interpreting soft tissue sarcomas.
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Discuss the planned (or completed) surgery with the surgeon. This discussion alerts the radiation oncologist to any special concerns regarding scars, ecchymoses, or drain sites to be treated, including a margin that may be particularly close at the time of surgery and may therefore benefit from higher doses of radiation therapy, and unusual patterns of spread related to specific histologic subtypes.
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After signing informed consent for radiotherapy, the patient undergoes a computed tomography (CT) simulation in the treatment position. Reproducibility is key to ensuring that treatment is delivered precisely to the target on a daily basis. Positioning of the involved extremity should take into consideration potential radiation beam arrangements. The position of the contralateral extremity and other critical structures such as the genitalia needs to be considered. Therefore, at the time of simulation a patient-specific immobilization device is used to ensure patient comfort and maximize reproducibility of the position of the extremity. Once the patient is in a satisfactory position and the immobilization is built, then a CT scan is acquired. Intravenous contrast can be used to show the tumor more clearly. This CT scan is used by the radiation oncologist to contour the tumor target and the normal tissue avoidance structures. If possible, MRI can be obtained in the treatment position, but the narrow bore of many MRI scanners may preclude imaging the extremity after it has been immobilized. The diagnostic MRI may be merged with the treatment planning CT. The contrasted T1 and T2 series are often the most useful. The tumor is outlined on the CT and MRI as the gross tumor volume (GTV), which is shown in red in Fig. 1 . This volume is expanded to include regions at risk for microscopic spread. The MRI T2 peritumoral edema is usually included because of the risk of harboring microscopic extension of tumor. Typically, this clinical target volume (CTV) is an expansion of the GTV by 3 cm in the longitudinal direction and 1.5 cm radially. The CTV, which is outlined in green in Fig. 1 , is routinely customized to exclude regions that would not be characteristic of tumor spread, such as entering another compartment or invasion into the bone. The final expansion to the planning target volume (PTV), which is outlined in pink in Fig. 1 , accounts for setup error and is usually 0.5 cm when daily image-guided radiation therapy (IGRT) is used. Normal tissues are also contoured. These tissues include bone, genitalia, joints, and a normal strip of tissue on the opposite side of the extremity, which can be used as an avoidance structure.
Fig. 1
( A ) Contours of radiation target volumes on a CT simulation for radiation therapy planning. The gross tumor volume (GTV) is contoured in red. The clinical target volume (CTV) provides an additional margin for microscopic spread of the tumor and is contoured in green. A planning target volume (PTV) includes additional margin for setup error and is contoured in pink. The radiation dose is routinely prescribed to the PTV. The genitalia are contoured in yellow as a radiation avoidance structure. ( B ) The treatment plan shows the radiation dose distribution compared with the contoured volumes in ( A ). Each color within the dose distribution represents a relative percentage of the prescription dose with the key in the upper left.
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Volumetric-based treatment planning is then performed using three-dimensional planning or inverse planning for intensity-modulated radiation therapy (IMRT). Care is taken to avoid treating the entire circumference of the extremity by limiting radiation dose to a normal strip of tissue (to decrease risk of edema), to avoid treating an entire joint (to decrease risk of joint stiffness), and to minimize dose to weight-bearing bones (to minimize risk of fracture). For example, the risk of fracture after treatment in one series was decreased if the mean radiation dose to the bone was less than 37 Gy and the volume of the bone receiving 40 Gy was less than 64%.
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At the time of treatment, the patient is repositioned within the immobilization device in the identical position as at the time of CT simulation. Verification images with kilovoltage radiographs are taken at the center of the radiation plan as well as the treatment fields for quality assurance. Some treatment machines have the capability of performing a cone beam CT scan to aid in verification of soft tissues to further confirm an accurate setup. These types of images may be taken daily before treatment if IGRT is needed to minimize the daily setup error.
The clinical trials described earlier used conventional radiotherapy approaches. More recently, advances in physics, imaging, and computing have enabled more sophisticated methods of radiation delivery, such as IMRT and IGRT. IGRT was recently studied prospectively in extremity sarcoma in a multi-institutional setting in radiation therapy oncology group (RTOG) 0630. The rationale for IGRT is that the setup of the patient on the treatment table can vary from day to day and introduce error into treatment delivery. To minimize the risk of missing the target, the radiation field size can be increased, but this results in additional normal tissue irradiation, which may further increase side effects. To limit the expansion of the radiation field because of setup uncertainty, patient positioning can be verified by imaging the treatment area just before delivering radiotherapy. IGRT uses pretreatment imaging so that shifts (often measured in millimeters) can be made before delivering the daily treatment. Pretreatment imaging may consist of kilovoltage orthogonal radiographs or cone beam CT. By aligning the patient’s position with the treatment plan before delivery ( Fig. 2 ), the daily setup error can be decreased, which may allow the radiation field size to be safely reduced. In RTOG 0630, 86 patients were treated preoperatively to 50 Gy with daily IGRT using tailored radiotherapy fields with a PTV margin of 0.5 cm. Late toxicities at 2 years were compared with those in the preoperative arm of the NCIC SR2 cohort. In the IGRT group, 10% of patients had late toxicity compared with 37% in the NCIC group ( P <.001). Note that the wound complication rate and local control were similar in both studies. In a secondary analysis of the daily shifts made from the pretreatment imaging with IGRT in RTOG 0630, a PTV expansion of 1.5 cm in all directions would have been required to cover the CTV and account for the setup variations in the absence of daily pretreatment imaging. Patients with optimal immobilization may not need daily IGRT if the shifts following initial pretreatment images require shifts to correct patient position that are less than the PTV expansion.
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