Continuing Education Activity

Soft tissue sarcomas (STS) are a group of neoplasms that can affect individuals at the extremes of age and can originate from any location throughout the human body. These neoplasms can span a range of clinical presentations, from aggressive metastatic angiosarcomas to benign lipomas. These need to be evaluated using imaging studies and biopsy (core needle biopsy or incisional biopsy). The real challenge in diagnosing these conditions is that there are several non-neoplastic conditions that mimic STS. Soft tissue sarcomas are separated categorically as trunk and extremity from retroperitoneum. This activity illustrates the evaluation and management of sarcomas and explains the role of the interprofessional team in managing patients with this condition.

Objectives:

• Review the pathophysiology of sarcoma.
• Describe the evaluation of a patient with sarcoma.
• Summarize the treatment options for sarcoma.
• Outline the importance of improving care coordination among the interprofessional team to rule out cancer in all patients who present with painless masses, leading to earlier diagnosis and improving survival in those with sarcomas.

Introduction

Soft tissue sarcomas (STS) are a group of more than 60 different neoplasms that can originate from any location throughout the human body and affect individuals at the extremes of age. From skeletal muscle, adipose tissue, blood, and lymphatics to connective tissue and peripheral nerves, these neoplasms can span a range of clinical presentations from benign lipomas to aggressive metastatic angiosarcomas.[1][2][3] The real challenge in diagnosing these conditions is that several non-neoplastic conditions mimic STS. Soft tissue sarcomas are separated categorically as trunk and extremity from retroperitoneum. The majority of STS occurs spontaneously. However, germline mutations, radiation, and environmental exposure(s) have been causative.[4][5][6][7]

Etiology

While most of these cases occur sporadically, several causative factors have been identified. 

Germline Mutations

Neurofibromatosis Type 1 (NF1) Von Recklinghausen Disease

• Autosomal dominant (AD) condition caused by mutations in the NF1 gene, which codes for a protein called neurofibromin
• A tumor suppressor of the ras oncogene signaling pathway
• Mutations in the NF1 gene result in multiple cutaneous neurofibromas

Li-Fraumeni Syndrome

• Rare AD disorder caused by mutations in the TP53 gene (17p13.1), which codes for p53 (tumor suppressor gene)
• p53 functions to clear damaged cellular DNA
• This manifests in a wide array of phenotypes and clinical presentations; some patients will develop rhabdomyosarcoma by the age of 4

Familial Adenomatous Polyposis (FAP)

• AD disorder with a mutation in the APC gene (5q21-q22)
• Tumor suppressor gene, inhibiting localization of B-catenin to the nucleus
• Mutant protein fails to inhibit this localization which results in unchecked cell cycling and cellular proliferation
• Clinically this manifests in innumerable colonic polyps with extracolonic manifestations such as epidermoid cysts, osteomas, and desmoid tumors
• Desmoid tumors typically arise approximately five years post-prophylactic colectomy and represent a major source of morbidity and mortality; often arising in previous surgical sites

Radiation

• Significantly contributes to a patient's long-term risk for developing STS
• The effects are dose-dependent, and they typically occur at the periphery of the radiation field
• Shorter disease-specific survival as compared to the spontaneous counterparts
• Children who develop STS post-radiation do so at a median of 11.8 years later and in a dose-dependent fashion

Carcinogens 

• Thorotrast (thorium-based IV contrast 1930 to 1955): Patients diagnosed approximately 20 to 30 years post-exposure associated with hepatic angiosarcoma
• Polyvinyl chloride, a common form of plastic: Prolonged exposure
• Arsenic

Chronic Lymphedema

• A chronic lymphatic blockage is thought to stimulate the proliferation of lymphatics and vessels or lead to local immunodeficiency causing the development of malignancy.
• Most commonly seen in the post-radical mastectomy population, especially those who received radiotherapy
• Patients with parasitic roundworm infections such as filariasis can also develop these malignancies
• High risk of developing angiosarcoma
• Also known as Stewart-Treves syndrome

Epidemiology

Soft tissue sarcomas are rare, as there were 12,020 new cases and 4740 deaths reported in 2014 in the United States. They account for approximately 1% of all cancer incidence in the United States and represent approximately 2% of cancer-related deaths. As mentioned earlier, they are categorically separated regarding location within the body and extremity, and trunk STS is more common than intraperitoneal and retroperitoneal cases. In regards to the extremities, they occur more frequently on the proximal limb, with the thigh being the most common location in 44% of cases. The age at diagnosis and histological subtype is often linked with rhabdomyosarcoma, hemangioma, neurofibroma, and alveolar sarcoma affecting children and young adults more.[8]

Pathophysiology

Sarcomas are connective tissue tumors, and thus the tumors may occur in bone, cartilage, fat, muscle, or vascular or hematopoietic tissues. Sarcomas are much rarer compared to carcinomas. Most tend to grow locally and invade the adjacent tissues. Most patients present with complaints of a hard mass or pain, chiefly because of pressure on nearby nerves and soft tissues.

History and Physical

Several different STS subtypes can affect the trunk and, or extremities. The most common presentation is a patient with a painless mass that requires a detailed history and physical examination upon initial evaluation. Of note, several conditions may mimic soft tissue sarcoma. These conditions include hypertrophic scars, hematoma, benign lipoma, cysts, abscesses, and melanoma. All of these can confuse the clinician when trying to work up an STS.

Neoplasms that are small, superficial, and mobile are highly suggestive of a soft tissue sarcoma. These are separate from skeletal or neurovascular structures and may be surgically resected with grossly wide margins. Tumors closer to vital organs or vascular structures are typically referred to a tertiary care center where surgeons trained explicitly in such resections can intervene. In such cases, preoperative biopsies are encouraged as there are several factors that may ultimately affect patient outcomes.

Evaluation

Indications for preoperative imaging and biopsy consider the extent of the mass on physical examination and the anticipated neurovascular involvement. The clinician also has to consider the likelihood of nodal involvement or distant metastases as well as the relative resectability and potential postoperative functional deficits as seen with STS of the extremities.

Regarding imaging, MRI is generally considered the most informative for trunk and extremity STS. Chest CT with contrast is considered in cases with high metastatic potential, as the lungs are often involved. The use of PET/CT in the workup of sarcomas has not yet become the standard of care. It has not shown value in distinguishing benign versus malignant disease. It has shown some promise in gauging response to neoadjuvant chemotherapy. However, further studies will be required to determine its role.[9][10][11]   

If a biopsy is recommended, then the choice is a core-needle biopsy, and if this is nondiagnostic, then an incisional biopsy may need to take place. The core-needle biopsy should be approached such that the entire needle trajectory can be incorporated into the forthcoming surgical resection volume to maximize diagnostic potential. It has been determined that approximately 74% of patients who undergo an unplanned trunk or extremity sarcoma resection have residual disease at the time of the following resection.

The high risk of recurrence warrants close postoperative surveillance with a physical exam every 3 to 6 months for 2 to 3 years and, after that, every six months for the next two years and finally annually. Radiographic surveillance of the chest, abdomen, and pelvis and indications for follow-up MRI is based on the individual patient and tumor characteristics.

Treatment / Management

Lipomatous Tumors

Benign adipocytic tumors can arise from any part of the body and cause symptoms primarily through mass effect. They are usually encapsulated, homogenous without evidence of nodularity or septations, and may contain calcifications or hemorrhage resulting from trauma. Treatment consists of excision beyond the capsule of the tumor. There is some degree of clinical overlap with the potentially malignant form and most common soft tissue sarcoma; liposarcoma. Liposarcomas are defined as tumors greater than 10 cm in size, with thick internal septations and lesions that are generally less than 75% adipose tissue. They represent 45% of retroperitoneal sarcomas. Treatment for liposarcoma is surgical resection with wide margins. Local recurrence is common. Malignant behavior attributed to the amplification of (12q13-15), which leads to the upregulation of MDM2 and CKD4. Tumor-promoting pathways MET, RET, and PI3K/Akt are thought to be activated. For Liposarcomas of the extremities, the goal of care is limb-sparing resection with a gross negative margin. For retroperitoneal liposarcomas, the goal is complete resection. Typically, well-differentiated liposarcomas have a low risk of distant metastases, whereas de-differentiated extremity liposarcoma generally benefits from neoadjuvant radiation therapy.[1]

Trunk and Extremity Sarcoma

There is a fine balance between preserving limb function and tumor control. Many types are chemoresistant, and several studies have reported conflicting results regarding the utility of neoadjuvant and adjuvant chemotherapy. Several studies have supported a surgical margin of 1 cm regarding adequate resection.[12]

Desmoid Tumors

These are rare forms of fibroblastic tumors. Approximately 80% are sporadic, whereas others are related to familial adenomatous polyposis (FAP). Sporadic cases are related to pregnancy and prior trauma. They are 2 to 3 times more common in women than men and are usually diagnosed between the ages of 30 to 40. They can originate in the extremities, intraperitoneal space, abdomen, and/or chest wall. They are usually slow growing but can be quite aggressive. They utilize the WNT signaling pathway. Clinically, they can range from an asymptomatic firm mass to a painful mass resulting in bowel obstructions or ischemia. Radiographically they are usually homogenous and solid in appearance with a distinct or infiltrating boundary. Despite resection, these tumors have a high incidence of recurrence.[13]

Angiosarcoma

A malignant tumor arises from the endothelial lining of blood vessels and can arise from essentially any region within the body. Two percent are considered soft tissue sarcomas, and 40% are radiation-induced. They usually occur in the scalp, head, neck (scalp), and viscera and generally occur during the seventh or eighth decade of life. There is usually regional lymphatic nodal involvement. Histologically they can range from well-differentiated to poorly differentiated. Again, therapy is aimed at surgical resection with negative margins. Tumors that are larger than 5 cm and with evidence of epitheliod are considered indicators of poor prognosis. These tumors are often locally advanced and beyond resection at presentation; however, there have been some noted benefits from chemoradiation.[14]

Retroperitoneal and Visceral Sarcomas

Retroperitoneal sarcomas represent approximately 15% of all soft tissue sarcomas, with the average tumor size at presentation measuring 15 cm. Average age at presentation is 54 with the equal male-to-female distribution. There are a variety of clinical presentations depending on the size and location of the tumor. Many are asymptomatic and only incidentally discovered. Symptoms can range from abdominal pain, weight loss, early satiety, nausea, emesis, back or flank pain, paresthesias, and weaknesses. CT is the study of choice. Gross resection is the treatment of choice with or without neoadjuvant or adjuvant chemoradiation. The most frequent subtype is liposarcoma. The predominant intraperitoneal subtype is the Gastrointestinal stromal tumor. Despite optimal surgical resection, approximately 70% will relapse.[15] Newer trials have cast doubt on the utility of neoadjuvant radiotherapy in this patient population, given the lack of disease-free survival benefit, although some histologic subsets may benefit.[16]

Gastrointestinal Stromal Tumor (GIST)

GIST tumors are the most common visceral soft tissue sarcoma. The majority occur sporadically. They originate from the interstitial cells of Cajal within the gastrointestinal myenteric plexus and can occur at any location along the GI tract. The most prevalent location is the stomach, small bowel, and rectum. They function as the pacemaker cells of the bowel. GIST tumors have a marker for CD117 (also known as the KIT gene), which codes for a tyrosine kinase transmembrane receptor called c-kit. Classically a spindle cell neoplasm of smooth muscle origin. Clinically, they can range from asymptomatic to symptomatic with pain, nausea, hematemesis, and gastrointestinal (GI) blood loss. Endoscopically they appear as a smooth submucosal tumors that can impinge on the visceral lumen. Radiographically, it appears well encapsulated with heterogeneous areas of enhancement secondary to patchy necrosis within the tumor. Metastases are common, with common sites being the liver and peritoneal surface. Localized lesions are taken to the operating room for complete excision with negative margins with empiric lymphadenectomy. After resection and neoadjuvant therapy for unresectable or locally advanced disease, adjuvant therapy requires Imatinib (an oral tyrosine kinase inhibitor of c-kit).[17]

Leiomyosarcoma

This malignant smooth muscle tumor can originate from any part of the body. It is the second most common soft tissue sarcoma subtype. They occur during the sixth and seventh decades. The retroperitoneum and uterus are the most common locations in women, whereas, in males, they originate in other locations. On gross inspection, they are heterogeneous, well-circumscribed tumors with cystic or necrotic central areas. They stain positive for desmin and smooth muscle actin. First-line therapy is surgical resection with negative margins. Adjuvant radiotherapy is thought to improve local control.[18]

Differential Diagnosis

The differential diagnosis of a soft tissue mass is rather wide, ranging from benign conditions to metastatic disease. In general, benign lesions tend to be superficial in the dermal or subcutaneous soft tissue; however, this is not definitive. A partial list of potential diagnosis for a soft tissue mass are listed below. Ultimately, a high-quality biopsy and imaging will aid in establishing the diagnosis.

Benign  

• Acrochordons
• Lipoma
• Myositis ossificans (look for a history of physical trauma)
• Hemangioma 
• Keloids
• Dermoid cyst
• Ganglion cyst 
• Pilonidal cyst
• Angiofibroma
• Neurofibromas
• Rickets

Infectious 

• Abcess
• Cellulitis 

Malignant 

• Squamous cell carcinoma
• Melanoma 
• Basal cell carcinoma 
• Merkel cell carcinoma
• Skin metastasis 
• Keratoacanthoma
• Cutaneous lymphoma 
• Nonrhabdomyosarcoma soft tissues sarcoma
• Kaposi sarcoma 
• Pediatric neuroblastoma
• Pediatric non-Hodgkin lymphoma
• Pediatric osteomyelitis
• Pediatric osteosarcoma
• Pediatric rhabdomyosarcoma
• Ewings sarcoma
• Soft tissue sarcoma

Surgical Oncology

Surgical resection is a mainstay of sarcoma treatment. Patients that are operative candidates are encouraged to undergo resection. Prior to the 1980s, this consisted largely of limb amputations which, while having high rates of local control, led to increased morbidity and functional limitation. Currently, amputations make up <5% of all sarcoma surgeries.[19]

A diligent pre-operative work-up is necessary, consisting of an MRI to determine the tumor extent. The modern surgical approach to sarcoma resections consists of a wide en-bloc resection with the goal of at least a 1cm margin of uninvolved tissue in all directions. A 2cm margin may be considered for tumors with infiltrative borders.[1][20][21][22][23] However, this may not be possible due to the extent of the disease or proximity to neurovascular structures. However, if the tumor is close to or displacing neurovascular structures, they do not need to be resected if the adventitia and/or perineurium are removed. While bone is rarely involved, it may need to be resected if involved to obtain adequate margins. A planned positive margin followed by adjuvant therapy may be needed. Unplanned excisions of these tumors, commonly occurring in community settings, have demonstrated an increased risk of local recurrence and possibly distant metastasis (22% vs. 7%).[24]

Macroscopic residual disease portends a poor prognosis. Low-grade tumors may still have acceptable local control with < 1 cm margin. Margins are classified as intralesional, marginal, wide, or radical. Intralesional margins run through a tumor and leave residual tumor.[25] Marginal resections have a surgical plane running through the reactive zone and a high recurrence rate. Wide margins (preferred) have surrounding normal tissue but remain within the same compartment. Radical resections remove the tumor and the affected compartment [25]. Regional nodal evaluation can be considered in patients with certain histologies (i.e., epithelioid, angiosarcoma, clear cell, or rhabdomyosarcoma). The skin surrounding the biopsy site should also be entirely removed. If the tissue defect is expected to be large, a myocutaneuous flap may be necessary.

For locally recurrent tumors, surgery may still be an option with either a wide excision or amputation. For wide excision, local recurrence-free survival at 5 and 10 years was 66% and 50%, respectively.[26] For amputations, the recurrence rate is typically <10%.[26] The decision to operate and what type of operation is based on location, size, proximity to vital structures, and ability to preserve limb function.

Tumors that are large and unresectable or present in the patient not deemed a surgical candidate may be observed if there are no symptoms. However, in symptomatic individuals, palliative surgery may be used.[27][28][29]

Local control rates for low-grade sarcomas are approximately 5% and typically can be treated with surgery alone.[30] Surgery alone in the case of high-grade sarcomas has a recurrence rate of 33% at five years, and thus adjuvant radiotherapy is typically recommended [31]. In the recurrent setting, surgery alone had a local recurrence rate of 33% at five years.[26]

Given the rarity of these tumors and the need for a multidisciplinary approach to their treatment, it is recommended that patients be treated at high-volume centers that have the experience and expertise. Patients will require diligent follow-up, especially in the first few years posttreatment and continued physical therapy.

Radiation Oncology

Radiation

As limb-sparing resections of soft tissue sarcomas began to replace amputations in the 1970s, they were associated with high local recurrence rates. Radiotherapy was seen as a means of maintaining high rates of local control while preserving limb function. Several randomized studies from the 1980s to the early 2000s demonstrated that incorporating radiotherapy with limb-sparing surgery resulted in acceptable rates of local recurrence and equivalent disease-free and overall survival.[32][31][33][34] Consequently, amputations make up <5% of the treatment of sarcomas.[19]

Radiotherapy can be incorporated into any phase of treatment for STS of the trunk and extremities (i.e., pre-operatively, post-operatively, intraoperatively, and concurrently with chemotherapy).[35] Indications for radiotherapy include high-grade, Stage II+, inoperable disease, recurrent disease, or positive margins. The two most commonly used techniques are External Beam Radiotherapy and Brachytherapy. Randomized trials comparing pre-operative vs. postoperative have indicated equivalent local control (93% vs. 92%) and overall survival (73% vs. 67%) with superior functional outcomes and less wound fibrosis in pre-operative radiotherapy.[34] It also has the advantage of using lower doses, smaller field sizes, and easier target delineation. Pre-operative radiotherapy has become the preferred mode of treatment when possible. Postoperative radiotherapy may be needed in the setting of positive margins either as a boost after pre-op treatment or by itself. It will require a larger field size to incorporate the entire post-op bed, residual disease, as well as any scars and drains. In addition, higher doses are needed, and functional complications are common. 

External Beam Radiotherapy (EBRT)

External beam radiotherapy is the most common means of treating sarcomas. It can be delivered definitively, pre or post-operatively using a 3D conformal or intensity-modulated radiation therapy (IMRT). It can also be given concurrently with chemotherapy [35]. Pre-operative radiotherapy is the preferred method because of several advantages. It allows for lower doses of radiation, easier target delineation, ease of set-up, smaller radiation field size, and better functional outcomes with similar rates of local control. However, adjuvant therapy may be needed in the case of positive margins or a high-grade tumor where pre-operative treatment was not planned.

The initial data supporting the use of radiotherapy for operable sarcoma is from the limb-sparing trials performed in the 1980s. While a limb-sparing approach offered a better chance at preserving function, it was at the expense of higher local recurrence rates ranging from 25% to 60%.[36][37][38] Radiotherapy was then introduced to reduce this risk of local recurrence to acceptable levels.[32] The patients with intermediate to high-grade sarcomas that underwent resection alone had recurrence rates of recurrence as high as 30%.[37] More recent data demonstrate the local recurrence rate with the addition of radiotherapy is approximately 7%.[34]

The dosing of radiotherapy depends on the margin status, resectability, and timing—patients with resectable high and intermediate-grade sarcomas where pre-operative radiotherapy is planned. A dose of 50Gy over 25 fractions is typically delivered. An adjuvant boost may still be needed if there is a positive margin (R1 or R2). For an R1 and R2 resection, the dose is 14 to 20Gy. Patients that receive adjuvant radiotherapy without pre-operative radiotherapy typically use doses of 60 to 70 Gy depending on margin status.[35] For patients with unresectable disease, the minimum dose is typically 63Gy, although 70 to 80 Gy are often delivered.[35] 

External beam radiotherapy requires the patient to undergo a CT simulation. Immobilization of the affected limb using custom casting is critical for targeting and day-to-day set-up accuracy and should also allow for as many potential beam angles as possible. This becomes important, especially if IMRT is used. For upper extremity tumors, abduction of the arm away from the body and either supinating or pronating the arm, depending on the location of the tumor, is appropriate. Alternatively, the patient is placed prone in a" swimmers position with the arm extended above the head. For lower extremity tumors, if the tumor is in the medial compartment of the thigh, then the patient can be placed supine in a "frog leg" position. This allows for a reduction in skin folds, places distance between the genitalia and the thigh, and separation with the contralateral leg. Tumors in the posterior or anterior compartment of the thigh will be more challenging to set up. One approach is to have the patient in the decubitus position with the legs separated. Of course, appropriate shielding of the genitals will be necessary, and the dose will be monitored. Fertility counseling should be offered to any patient with radiation fields in close proximity to the genitals. MRI fusion, specifically the T1 with contrast and T2 sequences, to the CT simulation is critical to ensure the volumes drawn are accurate.

For pre-operative radiotherapy, target delineation using the CT/MRI fusion is essential. The gross tumor volume (GTV) is drawn from the T1 contrast-enhanced weighted MRI. Traditionally, the clinical target volumes (CTV) are contoured, and the expansions placed on them are quite generous. The CTV includes the GTV plus a 4 cm longitudinal and 1.5 cm radial margins along with any peritumoral edema on T2 weighted MRI. The planning target volume (PTV) expansions are typically 0.5 to 1.0 cm. RTOG 0630 sought to reduce the late toxicities related to pre-operative radiotherapy using daily image guidance with cone beam CT and reduced margins based on size and grade.[39] Tumors ≥ 8 cm and/or high-intermediate grade were given a CTV expansion of 3cm longitudinally and 1.5cm radially, while all others were given a 2 cm longitudinal expansion and a 1 cm radial expansion.[39] They demonstrated reduced late toxicities at two years with a 10.5% grade 2+ compared to 37% reported in the literature.[39]

Postoperative radiotherapy is more technically challenging from a planning perspective due to the surgical manipulation of the tissue. Pre-operative and postoperative imaging is required and should be incorporated into treatment planning. The GTV should encompass the original site of the tumor, excluding air and uninvolved tissue. A low and high-dose CTV volume is created. The low dose CTV consists of the GTV plus a 4 cm longitudinal and 1.5 cm radial margins, edema, drains, scars, and any surgically disturbed tissues. The high-dose CTV volume consists of the post-op GTV with a 1 to 2 cm margin in the longitudinal plane and a 1.5 cm margin in the transverse plane. The PTV is typically a 0.5 to 1.0 cm expansion of the CTVs. The VORTEX trial is a randomized trial currently investigating the use of smaller volumes in the postoperative setting using a 2 cm all-around margin rather than the conventional 5 cm longitudinal and 1 to 2 cm radial margins (NCT00423618). Due to the small number of events, it was impossible to determine if the experimental arm had inferior local recurrence.

Treatment delivery can be accomplished with various techniques, including a simple anterior-posterior/posterior-anterior (AP/PA) to IMRT, depending on the tumor's location relative to other organs at risk. Significant dose constraints include weight-bearing bone V50 < 50%, joints V50Gy < 50%, femoral head/neck V60 < 5% and no more than 50% of a longitudinal stripe of skin should receive more than 20Gy.[39]

Brachytherapy

Brachytherapy (BRT) is typically utilized post-operatively as either monotherapy combined with external beam radiotherapy as a boost, as well as for recurrent disease. It offers the advantage of being highly conformal, thus limiting dose to adjacent structures through optimizing dwell-time positions. It may be delivered at a high dose rate (HDR - > 12 Gy/hr), low dose rate (LDR – 0.4 to 2 Gy/hr), or pulsed dose rate (PDR).[40] The most frequently used technique in the United States is HDR using a high-energy radionuclide Iridium-192 with a remote after loader. This treatment can be delivered as an outpatient, unlike previous brachytherapy techniques such as LDR implants that required an in-patient stay and, therefore, more costly and labor intensive. Despite its advantages, it remains an underutilized treatment technique compared to EBRT.[40]

Patients with resected high and intermediate-grade sarcomas treated with adjuvant LDR BRT monotherapy have superior local control rates compared to resection alone (70% vs. 91%), but this was not seen with low-grade sarcomas.[31] More contemporary studies that overwhelmingly utilized HDR brachytherapy also demonstrated local control rates ranging from 78 to 90%.[41][42] They can be used in the adjuvant or salvage setting and should be strongly considered, especially if the patient received prior EBRT. Brachytherapy offers highly conformal radiation plans that can help minimize dose to many previously radiated tissues. The local control rate in the recurrent setting ranges from 58 to 65%.[43][44]

Brachytherapy dosing will depend on the technique (LDR or HDR), margin status, and the use of EBRT. When used as monotherapy for high/intermediate grade sarcomas with negative margins, the dose is 45 to 50 Gy for LDR and 30 to 54Gy in 2 to 4.5Gy/fraction delivered twice daily.[35][40] When delivered as a boost, the pre-operative EBRT dose is considered. The HDR dose ranges from 12 to 20 Gy over 2 or 3 days and is delivered twice daily, with LDR ranging from 15 to 25Gy. In the recurrent setting, doses ranged from 32 to 45 Gy, delivered in 10 fractions twice daily.[44]

High-quality imaging is essential to radiotherapy planning, especially in sarcoma patients. MRI is the preferred imaging modality as it allows for superior soft tissue resolution. Pre and postoperative imaging are needed to identify both tumor extent, involvement of neurovascular structures, and edema when done pre-operatively and to identify positive margins, close margins, and the extent of the surgical bed when done post-operatively.

If brachytherapy is planned, the patient will have the catheters implanted in the operating room along the surgical site, ideally with a spacing of 1 to 1.5cm, and should avoid drastic changes in curvature. The catheters should not be placed directed on top of critical structures, no crossing catheters, or displacement of tissue. The catheters are implanted in parallel to one another to form a single plane, but it is possible to have multiplane implants as well. The catheters will need to cover at least 2cm along the muscle and 1cm radially along the muscle and tumor bed. They should also be placed 5mm deep to muscles involved over the intact fascial plane and > 5 mm away from critical structures.[40] In addition, radiopaque markers should also be implanted to identify the surgical bed and any high-risk areas.

Treatment typically commences within 2 to 4 days post-op. The patient will undergo CT-based planning, and target delineation is guided by the operative report and MRI imaging. The clinical target volume (CTV) should encompass the entire tumor bed with a≥ 2 cm longitudinal margin and a ≥ 1cm radial margin.[40] The scar and drain sites are typically not treated. No planning target volume (PTV) expansions are required. At each treatment, the position and integrity of the catheters should be examined. On dose-volume histogram (DVH) analysis, critical parameters include V100 ≥ 90%, V150  ≤ 50%, and D90 ≥ 90% for coverage of the target. For organs at risk, several dose constraints can be used. AAPM Task Group 101 extrapolates dose constraints from the stereotactic body radiotherapy data.[45] Practically, bone, neurovascular structures, and wound edges should receive <100% of the prescription dose unless they are involved, and skin should receive <66% of the prescription dose. Sources should be >5mm from the skin surface.

Medical Oncology

The use of systemic chemotherapy in treating non-pediatric extremity and trunk sarcomas has been studied extensively but has suffered from low enrollment and inconsistent results, making it difficult to determine the overall benefit to patients. Most conventional chemotherapy regimens are anthracycline-based as they appear to be the most active agents in sarcoma patients. Systemic therapy can be utilized in neoadjuvant, adjuvant, metastatic, and recurrent settings.[35] The most common adjuvant/neoadjuvant regimens are AIM (Doxorubicin/Ifosphamide/Mesna) and gemcitabine/docetaxel. Unfortunately, randomized trials to date have failed to demonstrate a disease-free or overall survival with conventional anthracycline-based chemotherapy regimens in both the adjuvant and neoadjuvant settings.[46][47] However, a large meta-analysis of adjuvant chemotherapy did show improvement in local and distant recurrence and a nonsignificant improvement in overall survival.[48] It is thought that the overall benefit of chemotherapy is likely small.[48] For advanced and metastatic STS, anthracyclines are the first-line therapy.

There are other systemic agents considered second-line agents after patients have failed anthracycline-based regimens. Temozolomide, an alkylating agent, has been utilized as a single agent in patients with advanced and pretreated STS.[49][50] Another alkylating agent, trabectedin, is also indicated in patients who progressed on anthracycline-based therapy and were superior to the best supportive care.[51] Eribulin, a microtubule inhibitor, is another recommended second-line therapy for patients with advanced or metastatic STS and is a category-one recommendation for liposarcoma.[35] It has been evaluated for single agent versus dacarbazine use in multiple STS histologies, demonstrating a median overall survival benefit.[52]

New trials utilizing targeted agents and immunotherapy have been initiated and have made their way into the guidelines in particular circumstances. Pazopanib, an oral multi-targeted tyrosine kinase inhibitor, has demonstrated single-agent activity in non-lipogenic STS. The PALETTE Trial was a randomized study for patients with advanced STS who had failed anthracycline-based chemotherapy.[53] It demonstrated improved median progression-free survival (4.6 months vs. 1.6 months) but without an overall survival benefit.[53] Other tyrosine kinase inhibitors, such as sunitinib and crizotinib, have shown efficacy in solitary fibrous tumors and ALK-rearranged inflammatory myofibroblastic tumors. Palbociclib, a CDK4 and CDK6 inhibitor, has shown a favorable improvement in progression-free survival in liposarcomas.[54] Pembrolizumab, an anti-PD-1 antibody, demonstrates encouraging activity in undifferentiated sarcomas and is currently an option for patients as a second-line therapy for advanced and metastatic disease.[55]

Isolated Limb Perfusion (ILP) is another technique that allows for the delivery of significantly higher doses of chemotherapy in patients with recurrent or primary STS that would otherwise require amputation. The technique involves isolating the patient’s arterial and venous system to allow exclusive delivery to the area of interest and prevent systemic exposure. Typically agents include melphalan, dacarbazine, doxorubicin, and tumor necrosis factor (TNF). The treatment response rate was 76%, and the 3-year limb preservation was 71%.[56]

Concurrent chemoradiotherapy has also been studied using three cycles of preoperative MAID (mesna, doxorubicin, dacarbazine, and ifosfamide) with 44Gy of split-course radiotherapy interdigitated with chemotherapy. The results were compared against historical controls and did demonstrate superior overall survival, distant metastasis, and disease-free survival but at the cost of significant hematologic toxicity, with three patients suffering fatal toxicities.[56] Ongoing trials are examining radiotherapy with the addition of doxorubicin/Ifosphamide with or without pazopanib.

Staging

Staging of soft tissue sarcomas utilizes the TNM system as well as tumor grading. The T-staging is based on size and location (i.e., trunk/extremity, retroperitoneal, head, neck, etc.). The size cutoffs for T-staging vary based on tumor location. Nodal staging (N0 or N1) is straightforward and merely indicates the involvement of regional lymph nodes. Certain sarcoma subtypes have a propensity for lymph node metastasis, such as epithelial sarcomas, clear cell sarcomas, angiosarcomas, and rhabdomyosarcomas. Metastasis (M0 or M1) could be fulfilled either through non-regional adenopathy or with spread to visceral organs.

Tumor grading is also essential for staging. Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading utilizes a point system based on necrosis (no necrosis – 0 pts, <50% necrosis – 1pt, or ≥50% necrosis – 2 pts), differentiation (resembling normal adult mesenchymal tissue – 1pt, Sarcomas with definite histologic typing – 2 pts, and undifferentiated – 3 pts), and mitotic count (0-9 mitosis/hpf – 1 pt, 10-19-mitosis/hpf – 2 pts, ≥20 mitosis/hpf – 3 pts).[35] The sum of these factors determines the tumor grade ranging from 1-3 (1- 2-3pts, 2- 4-5 pts, 3- 6-8 pts). Grading and nodal/metastatic status are what primarily drive staging, while tumor size plays a smaller role.

Prognosis

Despite the heterogeneity of sarcomas, the most important prognostic factors are histologic grade and tumor size. Histologic grade predicts distant metastasis and survival, while primary tumor size predicts local recurrence and distant metastasis. Several predictive nomograms exist for local recurrence, distant metastasis, and overall survival. Memorial Sloan Kettering Sarcoma nomogram derived from their experience treating non-metastatic sarcomas from 1982-2006 predicts the risk of local recurrence at 3 and 5 years using grade, depth, size, margin status, age, and histology.[57] These patients were treated with surgery alone. Two additional nomograms predicting overall survival and distant metastasis were constructed using patients treated for operable sarcomas from 1994 to 2013 at a single institution and then externally validated on three independent cohorts outside the institution.[58]

Age, tumor size, FNCLCC grade, and histologic subtype were found to have a significant effect on both overall survival and distant metastasis on multivariable analysis. In general, for localized and early-stage lesions, curative resection can be done with good long-term survival, but recurrences are common. For those with advanced disease, a cure is not possible, and the median survival is 12 to 18 months, depending on the subtype. The risk of recurrence even persists after 10 to 15 years, and patients need indefinite follow-up. The majority of recurrences occur within the first five years. Most sarcomas show a poor response to chemotherapy (10% to 50% response). The response also depends on histological subtype, grade, and patient.

Complications

Chemotherapy

Early sarcoma regimens suffered from a high frequency of hematological toxicity and even patient deaths.[56] The newer regimens are better tolerated and do not have the same degree of myelosuppression. Toxicity associated with first-line anthracycline-based regimens, most commonly doxorubicin/ifosfamide, include myelosuppression, mucositis, alopecia, fatigue, nausea, vomiting, cardiotoxicity, hemorrhagic cystitis, salt wasting nephropathy, and CNS toxicity. The cardiac toxicity of anthracyclines can be devastating, and various methods have been employed to reduce the risk. These include lifetime dose limits of 450 to 550 mg/m, infusional rather than bolus administration, and ejection fraction cutoffs of LVEF ≤ 40%. Cardioprotective strategies such as beta-blockers, statins, and N-acetyl cysteine have all been explored but have not demonstrated a reduced risk of heart failure.[59] 

Dexrazoxane is the only FDA-approved drug for cardioprotection against anthracycline cardiotoxicity, but its use is restricted to patients with metastatic breast cancer who have received at least 300mg/m of doxorubicin and planned ongoing therapy. It was the only drug in a large meta-analysis to reduce the risk of heart failure in this patient population.[59] If anthracyclines are given after radiotherapy, then patients may experience radiation recall, resulting in blistering and peeling of the skin.

Mesna is typically delivered with ifosfamide to reduce the risk of hemorrhagic cystitis. With other first-line regimens such as gemcitabine/docetaxel, patients typically experience myelosuppression, fluid retention, acral erythema, nail bed separation, elevated liver enzymes, proteinuria, dyspnea, and neuropathy. Oral tyrosine kinase inhibitors such as pazopanib and sunitinib can cause diarrhea, dysgeusia, hand-foot syndrome, hypertension, elevation in liver enzymes, bone marrow suppression, and edema. The side effects are common in multi-targeted tyrosine kinase growth factor receptor inhibitors. 

Radiotherapy

External beam radiotherapy is generally well tolerated. The frequency of certain complications depends on the timing and also the dose of radiation delivered. Wound complications are more common with pre-operative radiotherapy (35% vs. 17%).[32] Post-operative radiotherapy was associated with an increased risk of bone fracture, fibrosis, joint stiffness, and edema. Secondary malignancies that emerge years after treatment are also a risk. Toxicity related to brachytherapy is generally low. Several factors may put patients at higher risk for experiencing complications, such as diabetes, smoking history, higher tumor volume, radiation dose, periosteal stripping, and type of closure. Wound healing delay is the most common complication and can occur in approximately 50% of patients (ABS guidelines). Other complications include subcutaneous fibrosis, impaired joint mobility, and lymphedema. Bone fractures can occur but are more frequently associated with EBRT than BRT (21% vs. 5%).[60] Periosteal stripping appears to be the only risk factor associated with this outcome.

Postoperative and Rehabilitation Care

All patients with sarcoma should enter a rehabilitation program after surgery. These patients often have marked functional deficits and can be confined to a bed or chair. Rehabilitation is crucial to regain some functionality.

Deterrence and Patient Education

Regardless of the specific sarcoma and therapy goals, the patient will need regular follow-up appointments, including physical exams and blood testing, to check for any signs of cancer recurrence. Radiological exams may also be part of the follow-up, depending on the type of sarcoma and location. Follow-ups will typically initially be every few months, then less frequently as the risk of recurrence diminishes over time. In general, high-risk sarcomas are expected to recur in the first two or three years following treatment, with sarcomas relapsing later but with lower odds. The exact follow-up routine will depend on tumor grade, size, and site.

Enhancing Healthcare Team Outcomes

Management of sarcomas involves an interprofessional team that includes clinicians, specialists, pharmacists, and nurses. The team should discuss each patient should before making any treatment decisions. In addition to the oncologist, a surgeon, an orthopedist, a neurologist, a pain consultation, an internist, and a plastic surgeon should be consulted before any major surgery. When a patient is suspected of having sarcoma, a referral to an oncologist should be the first step. Sarcomas are resistant to chemotherapy and radiation, and surgery is the definitive treatment. However, an oncology-specialized pharmacist can consult with the radiation therapy team for combination therapy when warranted. Nurses will play a crucial role in the follow-up and offer patient counseling, contacting the appropriate clinician when the situation warrants. It is important to remember these tumors are known to recur, and the prognosis for most patients is guarded.[61] 

It is, therefore, incumbent on all members of the interprofessional team to monitor the patient throughout their treatment and beyond and to immediately communicate with the other team members if there are any concerns; this includes accurate and updated patient records so all members of the care team can access the same information. This interprofessional approach will yield the best patient outcomes with the fewest adverse events. [Level 5]

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Disclosure: John Popovich declares no relevant financial relationships with ineligible companies.

Disclosure: Sarang Kashyap declares no relevant financial relationships with ineligible companies.

Disclosure: David Gasalberti declares no relevant financial relationships with ineligible companies.

Disclosure: Sebastiano Cassaro declares no relevant financial relationships with ineligible companies.