Radiation therapy techniques for primary soft tissue sarcoma of the extremities and superficial trunk

INTRODUCTION — Sarcomas are malignant tumors that arise from skeletal and extraskeletal connective tissues, including the peripheral nervous system. They can arise from mesenchymal tissue at any site.

This topic will discuss radiation therapy (RT) techniques for the management of primary soft tissue sarcoma (STS) arising in the extremities and superficial trunk (chest wall, flank, abdominal wall, and paraspinal musculature). Other topics on the presentation and management of STS are discussed separately.

●(See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk".)

●(See "Surgical resection of primary soft tissue sarcoma of the extremities".)

●(See "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities".)

●(See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities".)

●(See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)

●(See "Radiation-associated sarcomas".)

●(See "Head and neck sarcomas".)

●(See "Breast sarcoma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging" and "Breast sarcoma: Treatment".)

●(See "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma" and "Surgical resection of retroperitoneal sarcoma" and "Management of locally recurrent retroperitoneal sarcoma".)

RADIATION THERAPY TECHNIQUES — The intent of radiation therapy (RT) is to achieve a maximal dose to the tumor while minimizing the exposure of RT-sensitive critical structures to high doses. RT techniques have evolved from the use of three-dimensional conformal radiation therapy (3D-CRT) to more advanced approaches, such as intensity-modulated radiation therapy (IMRT), which more optimally targets tumors that are composed of complex concavities or wrap-around critical structures [1]. (See "Radiation therapy techniques in cancer treatment".)

Intensity-modulated radiation therapy — For most patients with primary soft tissue sarcoma (STS) of the extremities and superficial trunk and an indication for RT, we suggest IMRT rather than other RT techniques (conventional external beam radiation therapy [EBRT] or brachytherapy) [2]. Studies demonstrate that the delivery of conformal RT using IMRT produces superior dose distributions compared with 3D-CRT for both dose conformity around the tumor and dose reduction to specified critical normal structures. IMRT is also associated with improved local control relative to EBRT [3] or brachytherapy [4]. However, IMRT may increase low-intermediate doses to some normal tissues that otherwise might not be irradiated [5,6].

Data supporting the efficacy and tolerability of IMRT in patients with extremity STS are as follows:

●In one observational series of 319 patients with extremity STS, IMRT was compared with conventional EBRT [3]. IMRT was associated with a higher five-year local control rate relative to conventional EBRT (92 versus 85 percent), despite the fact that patients treated with IMRT had higher-grade lesions and more close or positive margins [3]. IMRT also did not increase treatment-related morbidity rates relative to conventional EBRT and demonstrated lower rates of grade ≥2 radiation dermatitis (31 versus 49 percent). Although IMRT was associated with higher rates of grade ≥2 nerve damage, the risk was low overall (3.5 versus 1.6 percent).

●In a phase II study of 70 patients with lower extremity STS, the use of preoperative IMRT designed to spare the surgical flap reduced the risk of acute wound healing complications, especially when the radiation planning target volume did not extend into the planned surgical flap, and allowed more primary wound closures [7]. IMRT also reduced the need for reoperations for acute wound healing problems.

Other RT techniques

Brachytherapy — Brachytherapy is used less frequently at most centers, as observational data suggest lower rates of local disease control relative to IMRT [4]. Brachytherapy may be appropriate in select situations when a short radiation treatment time is preferred, and a technically acceptable brachytherapy catheter placement can be achieved intraoperatively. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Brachytherapy'.)

Brachytherapy minimizes the radiation dose to surrounding normal tissues, maximizes the dose delivered to the tumor, and shortens treatment times relative to preoperative or postoperative EBRT. In the usual schedule, treatment is completed within six days and requires one hospitalization. Afterloading catheters are placed in a target area of the tumor operative bed, defined by the surgeon, and spaced at 1 cm intervals to cover the entire area of risk. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Brachytherapy' and "Radiation therapy techniques in cancer treatment", section on 'Brachytherapy'.)

The addition of adjuvant brachytherapy to surgery alone improved local control in a randomized phase III trial. However, observational data suggest that brachytherapy has lower rates of local disease control relative to IMRT. Data are as follows:

●In a phase III trial, 164 patients with a completely resected extremity or superficial trunk STS (45 low-grade, 119 high-grade) were randomly assigned to either postoperative low dose-rate brachytherapy (45 Gy) or no brachytherapy [8]. At a median follow-up of 76 months, the addition of adjuvant brachytherapy to surgery improved five-year local control rates (82 and 69 percent), but this advantage was seen only in patients with high-grade (five-year local control 89 versus 66 percent) and not the low-grade subtypes. There was no difference in distant metastasis or disease-specific survival for the two treatment arms, regardless of histology.

●In a subsequent retrospective study of 134 patients with localized soft tissue sarcoma of the extremities, IMRT was associated with improved five-year local control rate relative to brachytherapy (92 versus 82 percent), despite the fact that patients treated with IMRT had somewhat worse prognostic tumor features [4]. There have been no randomized trials comparing brachytherapy with EBRT.

Although it is unclear if brachytherapy is associated with a higher risk of wound complications [9], there may be a higher rate of wound reoperation with this technique [10].

Proton beam RT — Further data are needed prior to incorporating proton beam RT into the standard clinical treatment of patients with STS of the extremity and superficial trunk.

Proton beam RT has been used to deliver highly conformal RT doses to sarcomas of the base of the skull and spine, as well as pediatric rhabdomyosarcomas. Since experience is limited, it is not clear if there is an advantage for protons for all patients with extremity STS. Although proton beam RT may be effective in select patients (eg, those with large proximal thigh tumors and/or lesions closely approximated to joints [11]), clinical trials are necessary to formally test this approach. (See "Radiation therapy techniques in cancer treatment", section on 'Particle therapy'.)

RADIATION TREATMENT PLANNING — For primary soft tissue sarcoma (STS) of the extremities and superficial trunk, radiation therapy (RT) should be carefully planned so that the tissues being irradiated are only those judged to be at risk for malignancy. To use smaller planning target volumes, the part to be irradiated must be securely and reproducibly immobilized. We use custom immobilization devices prepared for each patient. This may require casting, especially for hand, foot, or elbow sites. For some sites, the part is placed in standard plastic supports, and the extremity fastened tightly in place using a hook and loop fastener (eg, Velcro). Others describe their experience with vacuum lock bags [12] or polyurethane foam systems [13].

Developing the treatment plan — Principal tasks for developing the RT treatment plan for primary STS of the extremities and superficial trunk should focus on achieving the most conformal dose distribution that covers the target volume while maximally sparing adjacent normal structures. These tasks include:

●Defining the target volume on each section of the computed tomography (CT)/magnetic resonance imaging (MRI) of the affected region.

●Defining nontarget critical structures in the treatment volume and specify dose constraints for each such structure.

●In the case of postoperative RT, defining a series of target volumes to realize the appropriate dose distribution using "shrinking treatment volume methods."

●Designing a reproducible immobilization device to ensure the target is reliably covered in the high dose region.

Preoperative radiation is delivered to a single clinical target volume. Although controversial, a reduced field is sometimes delivered postoperatively in the setting of a histologically positive margin. For postoperative radiation, we use a "shrinking treatment volume technique" with a series of progressively smaller target volumes, with the highest dose being administered to the tumor bed itself. (See 'Clinical target volume' below.)

CT-based treatment planning systems are part of standard practice; these systems allow smaller and more accurate treatment volumes in patients with extremity STS [14]. These systems also allow image fusion with the MRI scans to better define the target volumes [15]. MRI simulators, which allow MRI acquisition in the treatment position at the time of radiation simulation, are also available [16].

Clinical target volume — Data are evolving to determine the optimal clinical target volume (CTV). Prior to the routine use of MRI, radiation fields traditionally included a generous longitudinal margin of 5 to 10 cm beyond the gross tumor. However, CTVs have reduced over time, based on subsequent studies demonstrating good local control and toxicity profiles [17]. There are limited randomized trials that address the appropriate CTV for patients with extremity or superficial trunk STS, and further studies are ongoing. (See 'Can clinical target volume be further reduced?' below.)

Treatment approach — Target volume recommendations for the treatment of extremity STS have been developed by an international group of expert sarcoma radiation oncologists, as follows [2,18]:

●For preoperative RT, the gross tumor volume (GTV) is defined using T1-weighted, gadolinium-enhanced MRI. An anatomically constrained (ie, does not need to extend into bone or beyond a fascial barrier) 1.5 cm radial and 3 to 4 cm craniocaudal expansion (along the long axis of muscle) are suggested for the CTV that, if feasible, should also include any tumor-associated edema seen on the T2-weighted MRI. If local control for the treatment approach used in Radiation Therapy Oncology Group (RTOG) 0630 remains high at further follow-up, smaller target volumes might be considered [19]. (See 'Preoperative treatment and doses' below.)

●For postoperative RT, a similar expansion on the "tumor bed" is recommended for the elective CTV, which should also include the surgically manipulated tissues, as well as the surgical scar and drain site, if feasible. (See 'Postoperative treatment and doses' below.)

A boost to the tumor bed with a 1.5 cm radial and 2 cm proximal/distal margin is recommended. Appropriate planning target volume (PTV) expansions are recommended based upon the kind of immobilization and image guidance used for treatment and are typically on the order of 0.5 to 1 cm.

Can clinical target volume be further reduced? — Studies are ongoing to evaluate the effect of reduced CTVs on efficacy and long-term toxicity. Data on carefully selected patients treated with surgery alone show excellent local control in tumors with the closest negative surgical margin of 1 cm or more [20,21]. This has prompted interest in tailoring the CTV more closely to the distribution of microscopic residual tumors beyond the grossly visible tumor.

MRI is commonly used to define the preoperative CTV. Data are as follows:

●The distribution of microscopic residual tumors was addressed in a study correlating MRI findings with histopathology of the resected specimen [20]. Sarcoma cells were identified histologically in the tissues beyond the tumor in 10 of 15 cases. In 9 of 10 cases, the tumor cells were in areas of edema as imaged on T2-weighted MRI scans. In six cases, tumor cells were located within 1 cm of the tumor margin, and in four cases, malignant cells were found at a distance greater than 1 cm and up to a maximum of 4 cm.

●Patterns of local failure were studied in 56 patients treated with MRI-guided three-dimensional conformal radiation therapy (3D-CRT) field planning for extremity STS [21]. The CTV included the T1 postgadolinium-defined GTV with 1 to 1.5 cm radial and 3.5 cm longitudinal margins. PTV expansion was 5 to 7 mm, and >95 percent of the dose was delivered to the PTV. The median preoperative RT dose was 50 Gy. Postoperative boost of 10 to 20 Gy was given to 12 patients (six with positive margins and six with close margins).

No local recurrences were observed in patients whose surgical margins were >1 mm. However, three patients (all with positive margins) experienced local failure as first relapse (two isolated, one with distant failure), and two additional patients (all with margin <1 mm) had late local failure after distant metastasis. The local failures were within the CTV in three patients and within and extending beyond the CTV in two.

Thus, these target volume definitions appear to be appropriate for most patients. However, some patients with particularly infiltrative histologies, such as some subcutaneous myxofibrosarcomas, might require more generous surgical margins prior to RT.

Several clinical trials have also evaluated reducing CTV. Data are as follows:

●A phase II trial (RTOG 0630) evaluated the use of even more constrained CTVs in the setting of preoperative image-guided radiation therapy (IGRT) and suggested that this approach leads to a significant reduction in late toxicities [19]. The CTV encompassed the gross tumor plus 2 cm margins (for low-grade tumors and for intermediate- and high-grade tumors <8 cm in size) or 3 cm margins (for tumors >8 cm) in the longitudinal (proximal and distal) directions, as well as any areas of suspicious edema (defined by MRI T2 images). If this caused the field to extend beyond the compartment, the field could be shortened to include the end of a compartment plus a margin of 1 cm. The radial margin from the lesion for low-grade tumors and for intermediate- and high-grade tumors <8 cm was 1 cm, and it was 1.5 cm for intermediate- and high-grade tumors >8 cm, including any portion of the tumor not confined by an intact fascial barrier, or uninvolved bone or skin surface.

Among 79 eligible patients treated with IGRT without concurrent chemotherapy, at a median follow-up of 3.6 years, there were only five local treatment failures, all of which were in the radiated field (ie, there were no marginal field recurrences). In extended follow-up (median of six years), there was only one new in-field recurrence [22].

Of the 57 patients assessed for late toxicity at two years, 10.5 percent experienced at least one grade ≥2 toxicity. These results compare favorably with the 37 percent rate of grade ≥2 late toxicity reported in the preoperative RT alone arm of a trial conducted by the NCI Canada [23]. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Choosing between preoperative and postoperative RT'.)

●A randomized study (VORTEX) also suggested that reducing the CTV of tissue treated with postoperative RT results in similar clinical outcomes when compared with larger target volumes. In this study, 216 patients with extremity STS who were candidates for tumor resection and postoperative RT were randomly assigned to either an initial larger CTV extending 5 cm proximally and distally on the tumor bed or 1 cm beyond the scar (whichever is longer in the craniocaudal direction) and a minimum margin of 2 cm axially to 50 Gy, followed by a reduced field with a 2 cm craniocaudal margin on the tumor bed GTV and minimum margin of 2 cm axially for another 16 Gy; or to the single reduced field for the entire 66 Gy [24]. At a median follow-up of 4.8 years, preliminary results demonstrated similar rates of five-year local recurrence-free survival between the two treatment arms (86 versus 84 percent), as well as late radiation toxicity rates for the skin, subcutaneous tissues, bones, and joints.

PREOPERATIVE TREATMENT AND DOSES

Preoperative treatment doses — For patients treated with preoperative radiation therapy (RT), we suggest using the standard dose of 50 Gy administered in 25 daily fractions over five weeks, followed four to six weeks later by a conservative resection [2].

Investigational preoperative radiation schedules

Reduced dose conventional fractionation for myxoid liposarcoma — Deintensification of preoperative intensity-modulated radiation therapy (IMRT) may reduce postoperative complications and is an active area of investigation for specific radiation-sensitive subtypes. In a single-arm phase II trial (DOREMY) of 79 patients with localized myxoid liposarcoma treated with deintensified IMRT using 36 Gy in once-daily 2 Gy fractions, rates of extensive pathologic treatment response and local control were 91 and 100 percent, respectively [25]. The rates of wound complication requiring intervention and grade ≥2 toxicities were 17 and 14 percent, respectively, suggesting lower toxicity rates compared with other studies. However, longer follow-up is needed before incorporating this approach into standard practice. It is also important to note this approach only applies to myxoid liposarcoma.

Hypofractionation — Hypofractionated radiation therapy refers to the use of larger daily doses (>2 Gy) delivered over a shorter time (less than five weeks) than conventional fractionation (50 Gy, 2 Gy per fraction). Several hypofractionated regimens, such as ultrahypofractionation and moderate hypofractionation, are under investigation as preoperative radiation therapy regimens for non-metastatic soft tissue sarcoma (STS). Some regimens appear promising, but further studies and longer follow-up are necessary to confirm safety and efficacy. Of note, hypofractionated radiation therapy has been frequently used in strategies incorporating chemoradiation [26-33].

●Ultrahypofractionation – In one study of 272 patients with localized STS, ultrahypofractionation (25 Gy, 5 Gy per fraction) was administered over five consecutive days, followed by more immediate surgery [34]. The five-year local control rate was only 81 percent, which was on the lower end of what would be expected for adequate local control with the combination of surgery and radiation. This finding suggests that this ultrahypofractionated radiation regimen of 25 Gy in five fractions may not be sufficient for disease control.

Several other trials used higher doses of ultrahypofractionation in localized STS, as follows:

•A phase II trial in 52 patients evaluated a higher dose ultrahypofractionation regimen (30 Gy over five fractions) and showed a grade ≥2 long-term toxicity rate of 16 percent at a median follow-up of 29 months [35]. The major wound complication rate was 32 percent, which is comparable to studies employing conventional preoperative RT doses (35 percent for 50 Gy administered over five weeks [23]). There were two local recurrences among 35 evaluable patients.

•A separate phase II trial evaluated an even higher dose of ultrahypofractionation (35 Gy over five fractions delivered every other day) in 32 patients [36]. At a median follow-up of 36 months, no patients developed a local recurrence. Major wound complications were seen for 25 percent, and rates of grade 2 or 3 fibrosis were 22 and 13 percent, respectively.

●Moderate hypofractionation – A phase II trial of 120 patients treated with moderate hypofractionation (42.75 Gy over 15 fractions) reported a major wound complication rate of 31 percent and a grade ≥3 long-term toxicity rate of 3 percent [37]. At a median follow-up of 24 months, among 119 evaluable patients, the 30-month local recurrence-free survival was 93 percent. These results were comparable to those expected for conventional fractionation.

POSTOPERATIVE TREATMENT AND DOSES

Postoperative techniques and doses — For patients undergoing resection and postoperative radiation therapy (RT) only (ie, no preoperative RT), treatment usually begins approximately four to six weeks following surgery once the surgical wound has healed. The final total postoperative dose is [2,38]:

●60 Gy for tumors resected with negative surgical margins.

●66 Gy for tumors resected with positive surgical margins or locally recurrent disease [39].

●75 Gy for tumors resected with gross residual disease.

The initial volume (clinical target volume 1 [CTV1]) should include the tumor bed (as defined by the preoperative magnetic resonance imaging [MRI] and surgical clips) with 1.5 cm radial and 3 to 4 cm longitudinal expansions as well as the entire operative field, incision, and drain sites (if feasible). The reduced volume (clinical target volume 2 [CTV2]) should include the tumor bed plus 1.5 to 2 cm expansions [2]. Appropriate doses are 50 Gy to the initial volume (CTV1) and 10 to 16 Gy to the reduced volume (CTV2).

The initial volume (CTV1) should include all tissues handled during the surgical procedure, including the drain site. However, some experts may choose to avoid treating these tissues with RT, especially if this approach increases the risk of late treatment-related morbidity. One randomized trial (VORTEX) demonstrated similar local control rates regardless of whether treatment volume included the drain sites and the surgically manipulated tissues or not [24]. Further details of this trial are discussed separately. (See 'Can clinical target volume be further reduced?' above.)

What is the role of a postoperative RT boost after preoperative RT? — For patients treated with 50 Gy preoperative RT followed by resection with positive microscopic surgical margins alone, we do not offer a postoperative RT boost, as data are controversial for its utility in this setting. Studies have failed to demonstrate a benefit for this approach, and there are concerns about the long delay between the completion of preoperative RT and the start of postoperative RT [2,40,41].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Soft tissue sarcoma (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Indications for radiation therapy – For patients with primary soft tissue sarcoma (STS) of the extremities and superficial trunk, the indications for preoperative and postoperative radiation therapy (RT) are discussed separately. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Radiation therapy'.)

●Goals of radiation therapy planning – For patients with primary STS of the extremities and superficial trunk who receive RT, treatment should be carefully planned so that the tissues being irradiated are only those judged to be at risk for malignancy. Principal tasks for developing the RT treatment plan include achieving the most conformal dose distribution that covers the target volume while maximally sparing adjacent normal structures, among others. (See 'Radiation treatment planning' above.)

●Radiation therapy techniques – For most patients with STS of the extremities and superficial trunk who receive RT, we suggest intensity-modulated radiation therapy (IMRT) rather than other RT techniques (conventional external beam radiation therapy [EBRT] or brachytherapy) (Grade 2C). This approach offers superior dose distributions (for both dose conformity around the tumor and dose reduction to specified critical normal structures) and is associated with higher local control rates. (See 'Intensity-modulated radiation therapy' above.)

Brachytherapy may be appropriate in select situations when a short radiation treatment time is preferred, and a technically acceptable brachytherapy catheter placement can be achieved intraoperatively. (See 'Brachytherapy' above.)

●Preoperative radiation therapy – For patients treated with preoperative RT, we suggest using the standard dose of 50 Gy administered in 25 fractions over five weeks (Grade 2C), followed four to six weeks later by a conservative resection. (See 'Preoperative treatment and doses' above.)

●Postoperative radiation therapy

•No preoperative RT – For patients undergoing resection and postoperative RT only (ie, no preoperative RT), treatment usually begins approximately four to six weeks following surgery once the surgical wound has healed. The following final total postoperative doses are used (see 'Postoperative techniques and doses' above):

-For tumors resected with negative surgical margins: 60 Gy

-For tumors resected with positive surgical margins or locally recurrent disease: 66 Gy

-For tumors resected with gross residual disease: 75 Gy

•Preoperative RT with positive surgical margins – For patients treated with 50 Gy preoperative RT followed by resection with positive microscopic surgical margins alone, we do not offer a postoperative RT boost, as data are controversial for its utility in this setting.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Harmon, MD, and Thomas F DeLaney, MD, who contributed to earlier versions of this topic review.