Advertisement

Sarcoma

  • Sezin Yuce Sari
  • Gozde Yazici
  • Melis Gultekin
  • Pervin Hurmuz
  • Murat Gurkaynak
  • Gokhan Ozyigit
Chapter
  • 604 Downloads

Abstract

This chapter on sarcomas is aiming to summarize the evidence-based current management for soft tissue sarcoma, retroperitoneal sarcoma, Ewing sarcoma, and rhabdomyosarcoma. We hope to ease the understanding in the appropriate delineation of tumor volumes/fields along with related case presentations covering diagnostic images, contouring, slice by slice final plan examples; accompanied by up-to-date key literature review.

8.1 Soft Tissue Sarcoma

Overview

Epidemiology: Soft tissue sarcomas (STS) are rare tumors and comprise <1% of all new cancer diagnoses in adults (www.seer.cancer.gov). The etiology is unknown for most STS; however, environmental factors such as radiation and chemical exposures, immunosuppression, lymphedema, viruses, and genetic syndromes (e.g. Li-Fraumeni syndrome, Werner syndrome, neurofibromatosis type 1, Gardner syndrome) can be responsible for some of them [1, 2].

Pathology: Soft tissue sarcomas can arise from any anatomic location and have various histological subtypes. The most common anatomic site is an extremity (60%) (mostly lower), then comes the trunk (15–20%), retroperitoneum (10–15%), and head and neck region (8%) [3]. STS tend to invade longitudinally along musculoaponeurotic planes, and generally do not invade fascial boundaries or bones [4, 5]. As they grow, the surrounding normal tissue is compressed and a pseudocapsule is formed. Microscopic tumor cells can perforate this pesudocapsule and extend beyond it. At the time of diagnosis, involvement of regional lymph nodes (LN) is very rare. However, certain subtypes such as clear cell sarcoma, angiosarcoma, and epithelioid sarcoma have a higher probability of invading LNs [6]. Distant metastasis (DM) at the time of diagnosis can be detected in nearly 25% of patients [3], the lung being the first and the most common site. According to the World Health Organization, STS are divided into four categories as benign, intermediate-locally aggressive, intermediate-rarely metastasizing, and malignant [1]. There are more than 50 histologic subtypes of STS, the most common being liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and pleomorphic sarcoma [1]. The most widely used grading systems are the United States National Cancer Institute (NCI) and the French Federation Nationale des Centres de Lutte Contre le Cancer grading systems which grade these tumors as low, intermediate, and high grade according to their scores of tumor differentiation, mitotic count and necrosis between 2 and 8 [7].

Diagnosis: The majority of patients present with a painless mass. Imaging should be performed for both the primary and potential sites of metastasis. The best imaging modality for STS is a magnetic resonance imaging (MRI) scan as it can show the relation between the tumor and adjacent structures as well as the associated edema. For ruling out metastasis, computed tomography (CT) of the chest and/or positron emission tomography (PET)/CT scan is recommended. For the exact diagnosis, an incisional biopsy or CT-guided core biopsy should be performed.

Treatment: The main treatment for STS is surgery. Based on prognostic factors, adjuvant or neoadjuvant radiotherapy (RT) is generally added to surgery with or without chemotherapy. The most important prognostic factor is shown to be the TNM stage. This staging is made based on the tumor size and grade, which are also independent risk factors for tumor recurrence [8, 9, 10]. Other prognostic factors include the depth, location and histopathology of the tumor, age, gender, surgical margin status, bone or neurovascular invasion, recurrent disease, and although rare, LN involvement [7, 8, 9, 11, 12].

Key Words: Soft tissue sarcoma; Radiotherapy

8.1.1 Case Presentation

A 21-year old woman applied to the hospital with a growing mass in the right lower leg in July 2013. A 5 × 5 cm mass lesion was palpated in the medial side of the right tibia without any sign of inflammation or pathologic LNs. The lab findings and chest x-ray were normal. Superficial ultrasonography revealed a 41 × 32 mm, hypoechoic, clearly-defined solid mass in the right tibia. On MRI, a 31 × 22 × 39 mm, lobulated, clearly-defined mass was identified in the middle 1/3 of the right tibia in the posterior compartment between the superficial and deep muscle layers which was hyperintense on T2- and isointense with the muscle tissue on T1-weighted images, respectively (Fig. 8.1). Tru-cut biopsy revealed a low-grade fibromyxoid sarcoma. In August 2013, marginal resection from the right tibia was performed. The final pathology revealed a 45 × 35 × 30 mm, low-grade fibromyxoid sarcoma with positive surgical margins on several sides. Re-excision was not planned due to the close proximity to local veins and nerves. According to the 8th edition AJCC/UICC staging system, the patient had stage IA (pT1N0M0) STS (Tables 8.1 and 8.2) (https://www.cancer.org/cancer/soft-tissue-sarcoma/detection-diagnosis-staging/staging.html). Because of the surgical margin positivity, adjuvant RT was indicated.
Fig. 8.1

The diagnostic MRI of the case ((a) T2-weighted transverse image, (b) T2-weighted sagittal image, (c) T1-weighted transverse image, (d) T1-weighted sagittal image)

Table 8.1

Soft tissue sarcomas—TNM staging AJCC UICC, 2017

Primary tumor (T), trunk and extremity sarcomas

T category

T criteria

TX

Main tumor cannot be assessed

T0

No evidence of a primary tumor

T1

Tumor size is ≤5 cm

T2

Tumor size is 5–10 cm

T3

Tumor size is 10–15 cm

T4

Tumor size is >15 cm

Regional lymph nodes (N), trunk and extremity sarcomas

N category

N criteria

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in regional lymph nodes

Distant metastasis (M), trunk and extremity sarcomas

M category

M criteria

M0

No distant metastasis

M1

Distant metastasis

Histologic grade (G), trunk and extremity sarcomas

G

G definition

GX

Grade cannot be assessed

G1

Total differentiation, mitotica count and necrosis score of 2–3

G2

Total differentiation, mitotica count and necrosis score of 4–5

G3

Total differentiation, mitotica count and necrosis score of 6–8

Used with permission of the American College of Surgeons, Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

Table 8.2

Pathologic stage groups for trunk and extremity sarcomas—AJCC UICC, 2017

Pathologic stage

T

N

M

Grade

IA

T1

N0

M0

G1, GX

IB

T2–T4

N0

M0

G1, GX

II

T1

N0

M0

G2–3

IIIA

T2

N0

M0

G2–3

IIIB

T3–4

N0

M0

G2–3

IV

Any T

N1

M0

Any G

Any T

Any N

M1

Any G

Used with permission of the American College of Surgeons, Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

8.1.2 Evidence Based Treatment Recommendations

The treatment of STS requires a multidisciplinary approach including an experienced radiologist, pathologist, orthopedic surgeon, reconstructive surgeon, medical oncologist, and radiation oncologist. The main goal is to eradicate the tumor with minimal toxicity. Surgical resection is essential for the curative treatment. Surgical procedures include a marginal resection or excisional biopsy, wide resection, and radical resection or amputation. A marginal resection is the removal of the tumor with its pseudocapsule which has up to 90% local recurrence (LR) rate, and is not an appropriate treatment for STS [5]. A wide resection is the en bloc removal of the tumor with some normal tissue which can spare the limb but LR rates can reach up to 25–60% [5]. A radical resection is the removal of all muscles and neurovascular structures within the compartment where the tumor resides with LR rates of 0–18% [5, 13]; however, the loss of limb is the disadvantage of this procedure. Taking all these data into account, wide resection with pre- or postoperative RT is the current standard of care in most patients.

Some single institution series have reported satisfactory results with surgery alone, the LR rate being 0–20% [14, 15, 16, 17]. However, these studies are mostly retrospective, and include highly selected patients with small and subcutaneous tumors with wide resection margins. The prospective trial from Pisters et al. [15] reported the results of patients with tumors <5 cm and negative surgical margins after surgery alone. The rate of LR was 8% in total and 5% in patients with subcutaneous tumors. Baldini et al. [14] also reported significantly reduced rates of LR with surgery alone in patients with resection margins ≥1 cm compared to patients with resection margins <1 cm (0% vs. 13% in 10 years). The LR rates after surgery alone are satisfactory in low-grade tumors with a range of 0–5% and the treatment of choice is surgery alone in these tumors [14, 15, 17]. However, if there is positive surgical margins or local recurrence, adjuvant RT is indicated for low-grade STS.

The main purpose of the surgeon should be to attain negative margins as the presence of positive margins increases LR rates even when RT is used [8, 9, 13]. If the first pathology reveals positive margins, re-excision should be performed as the probability of finding a residual disease is 24–63% [18, 19]. When performing re-resection; previous incisions, biopsy tracts, drain sites, and any tissues contaminated by the first surgery are also needed to be removed en bloc along with tumor-bed margins. However, if this wide of surgery would lead to loss of function or would require the removal of a body part such as a nerve or a bone, a planned positive margin is acceptable.

There are 3 randomized trials that show the role of RT combined with conservative surgery in the treatment of STS, and 1 randomized trial that compares adjuvant and neoadjuvant RT (Table 8.3).
Table 8.3

Randomized trials with combined surgery and radiotherapy

Trial

N of patients

Tumor location

Treatment arms

RT dose (Gy)

LC (%)

5y-OS (%)

5y-DFS (%)

Rosenberg et al. [13]

 43

Extremity

HG tumors:

Amputation +adj CHTa

CS + adj CHTa + EBRT

60–70

100

85

(p = 0.06)

88

83

(NS)

78

71

(NS)

Pisters et al. [20]

164

Extremity, trunk

HG tumors:

CS

CS + adj BRT

LG tumors:

CS

CS + adj BRT

42–45

42–45

70

91

(p = 0.0025)

74

64

(NS)

In all:

81

84

(NS)

In all:

76

83

(NS)

Yang et al. [21]

141

Extremity

HG tumors:

CS + adj CHTb

CS + adj CHTb + EBRT

LG tumors:

CS

CS + adj EBRT

63

63

100

80

(p = 0.003)

96

67

(p = 0.016)

74c

75c

(NS)

92c

92c

(NS)

O’ Sullivan et al. [22]

190

Extremity

Neoadj RT + CS

CS + adj RT

50

66

93

92

(NS)

73

67

(NS)

58

59

(NS)

Abbreviations: N number, EBRT external beam radiotherapy, LC local control, OS overall survival, DFS disease-free survival, adj adjuvant, CHT chemotherapy, CS conservative surgery, neoadj neoadjuvant, NS not significant, BRT brachytherapy, HG high-grade, LG low-grade

aDoxorubicin, cyclophosphamide, methotrexate

bDoxorubicin, cyclophosphamide

c10-year

As a result, adjuvant external beam RT (EBRT) decreases the rate of LR in high- and, particulary, low-grade tumors in patients that underwent conservative surgery. However, adjuvant brachytherapy (BRT) is not recommended for low-grade tumors as it has no impact on local control (LC) or survival. It is also known that in the presence of positive surgical margins, LR rates are higher in high-grade tumors treated with adjuvant BRT [23]. Therefore, adjuvant BRT can only be administered in patients with high-grade tumors with negative margins after conservative surgery [24]. In case of positive margins, EBRT should be performed either alone or in combination with BRT in high-grade tumors. The rate of LR after conservative surgery and adjuvant RT in high-grade tumors is <15% in more recent series [19, 22, 25, 26, 27]. In low-grade tumors, wide excision alone seems adequate, and the rate of LR is <20% if the surgical margins are negative [28]. In case of positive margins or locally recurrent disease in low-grade tumors, adjuvant EBRT is indicated after wide excision.

EBRT can be administered either before or after surgery, and the timing is still a controversial issue between radiation oncologists and surgeons. The LC rates are similar with each approach, and the randomized trial by O’Sullivan et al. [22] reported LC rates of 93% and 92% for the pre- and postoperative approach, respectively, without a significant difference in survival rates in the updated 7-year results. The main difference between these approaches is the toxicity profile. The authors reported the rate of wound complications 17% vs. 35% in post- and preoperative setting, respectively (p = 0.01). It has been shown that preoperative RT leads to an increased rate of acute wound complications with a range of 25–46% in other studies [29, 30]. However, it should not be forgotten that although wound complications increased in the early postoperative period with preoperative RT, the adverse effects were mostly reversible, and the statistically significant difference vanished 1 year after resection. On the contrary, postoperative RT resulted in increased rates of serious late and mostly irreversible toxicities such as subcutaneous fibrosis, joint stiffness, edema, and bone fractures [31, 32]. A systematic review and meta-analysis that compared the results of pre- and postoperative RT included 5 studies with 1098 patients [33]. They reported that the risk of LR was lower in patients that received preoperative RT with an odds ratio of 0.61 without statistical significance. The mean survival rate was 76% (62–88%) and 67% (41–83%) in the pre- and postoperative group, respectively.

There are certain advantages and disadvantages of each approach. In the preoperative RT setting, the RT field is smaller and the total dose is lower, both which reduce the rate of late toxicity. Owing to the lower dose of RT which is associated with good oxygenation of the tumor leading to increased efficacy of RT, the treatment time and cost are reduced, as well as the risk of second malignancies. Preoperative RT can also render unresectable tumors resectable, and tumor seeding of the operative bed or systemic circulation is prevented. On the other hand, the risk of wound complications is higher in the early period; however, they are generally treatable and reversible. Another disadvantage of preoperative RT is that the prior treatment leads to a potentially less informative pathology specimen. The advantages of postoperative RT are the complete pathological review, and lower risk of wound complications. However, the RT field is large due to uncertain tumor location and the need to include all drain and incision sites, the dose is higher due to hypoxic environment related to surgery, and these both lead to increased rates of long-term toxicity which are mostly irreversible. In conclusion, when these pros and cons of each approach are taken into account, preoperative RT seems the most appropriate treatment for STS.

Intensity modulated RT (IMRT) provides a more homogeneous dose distribution while better preserving the organs at risk. Alektiar et al. [34] reported 5-year LC rate of 94% with IMRT even in patients with positive or close (<1 mm) surgical margins. Folkert et al. [35] compared conventional EBRT and IMRT, and found the 5-year rate of LR 15% and 7.6%, respectively, although the number of patients with positive and close margins was higher in the IMRT group. When compared to BRT, significantly better LC rates were achieved with IMRT (5y-LC rate: 19% vs. 8%), and again more patients with positive and close margins and larger tumors were included in the IMRT group [36]. O’Sullivan et al. [37] reported the results of 59 patients with lower-extremity STS whom they treated with image-guided (IG)-IMRT, and the 5-year LC rate was found 88.2%. The results of Radiation therapy Oncology Group (RTOG)-0630 phase II trial using preoperative IGRT in extremity STS revealed the rate of LC 93% [38]. To sum up, although not being the standard treatment yet, modern RT techniques can provide satisfactory LC rate while decreasing the rate of RT-related morbidity and can be preferred in selected patients.

The role of adjuvant chemotherapy in the treatment of STS is unclear, and studies have reported conflicting results. In a meta-analysis, adjuvant chemotherapy resulted in a longer LR-free interval and distant recurrence-free interval with better overall survival (OS) rates, although not statistically significant [39]. An updated second meta-analysis found a limited benefit of adjuvant chemotherapy with optimal doses of doxorubicin and ifosfamide [40]. The largest randomized trial, on the other hand, reported no benefit of adjuvant chemotherapy, leading to the thought that improvements in surgery and modern RT techniques may have dimmed the role of adjuvant chemotherapy [41].

The role of neoadjuvant chemotherapy has been studied in several trials. A randomized controlled trial showed no benefit of neoadjuvant chemotherapy over surgery alone in patients with resectable high-risk primary and recurrent STS [42]. The phase II study of RTOG 9514 reported 3-year OS, disease-free survival (DFS) and DM-free survival (DMFS) rates of 75%, 57%, and 65%, respectively; however, 83% of the patients suffered grade 4 toxicity [43]. In the updated phase II study of Delaney et al. [44], neoadjuvant chemotherapy resulted in a significant survival benefit without severe complications.

In summary, the role of either adjuvant or neoadjuvant chemotherapy is not clear in the treatment of STS. It may be administered in the context of patient-based data.

8.1.3 Treatment Recommendations

Treatment recommendations for STS according to the National Comprehensive Cancer Network (NCCN) guidelines are summarized in Table 8.4 (https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf).
Table 8.4

NCCN guideline version 2.2018 (extremity/superficial trunk)

Stage

Recommended treatment

IA, IB

Surgery

Negative margins/intact fascial plane

– Observe

Positive margins/no intact fascial plane

– Re-resection OR

– Observe (stage IA) OR

– RT

II (resectable with functional outcomes)

Surgery

Negative margins/intact fascial plane

– Observe

Positive margins/no intact fascial plane

– RT

Preoperative RT

– Surgery

IIIA (resectable with functional outcomes)

Surgery

RT OR

RT + adjuvant CXT

Preoperative RT/CRT

Surgery

– Consider RT boost ± adjuvant CXT

Preoperative CXT

Surgery

– RT OR

– RT + adjuvant CXT

II, IIA (unresectable/resectable without functional outcomes)

RT OR

CRT OR

CXT OR

Regional limb therapy

Resectable with functional outcomes

Surgery

– RT OR

– CRT OR

– (if previous RT+) consider RT boost ± adjuvant CXT

Unresectable/resectable without functional outcomes

– Definitive RT OR

– CXT OR

– Palliative surgery OR

– Observe (if asymptomatic) OR

– Best supportive care OR

– Amputation

IV

Single organ metastasis and limited tumor bulk

– Treat like resectable stage II, III and consider these:

 – Metastasectomy ± CXT ± RT

 – Ablation procedures (i.e. RFA, cryotherapy)

 – Embolization procedures

 – SBRT

 – Observe

Isolated regional disease or LN

– Regional LN dissection ± RT ± CXT

– Metastasectomy ± CXT ± RT

– SBRT

– Isolated limb perfusion/infusion ± surgery

Disseminated disease

– CXT

– RT/SBRT

– Surgery

– Observe (if asymptomatic)

– Supportive care

– Ablation procedures (i.e. RFA, cryotherapy)

– Embolization procedures

Abbreviations: RT radiotherapy, CXT chemotherapy, CRT chemoradiotherapy, RFA radiofrequency ablation, SBRT stereotactic body radiotherapy, LN lymph node

8.1.4 Target Volume Determination and Delineation Guidelines

8.1.4.1 Simulation

Appropriate positioning of the patient is important in RT planning. The patient should be in a reproducible position, and the extremity be positioned as far away from the body and the opposite extremity as possible. For the upper extremity, the arm should be in the abduction position with the arm supinated or pronated based on the tumor location. If the patient would be more comfortable the arm can be extended above the head while the patient is in prone position, which is called the ‘swimmer position’. For the lower extremitv, the patient can be positioned either supinely or pronely based on the tumor location (i.e. on the anterior or the posterior of the leg). If the tumor is in the proximal thigh the ‘frog-leg position’ can be used to optimally spare the perineum and inguinal regions, as well as the contralateral leg. Another way to stabilize the patient is the decubitus position for lower extremity tumors in the true anterior or posterior compartments. The treated leg is placed directly on the table and the untreated leg is flexed at the knee and placed either posterior or anterior to the treated leg, and the legs are separated as much as possible.

8.1.4.2 Contouring

Radiotherapy for STS can be administered either pre- or postoperatively. In the preoperative setting, the gross target volume (GTV) is the tumor detected in physical examination and on imaging studies. The RTOG Sarcoma Working Group reported a consensus for appropriate target volumes for preoperative RT [45]. Fusion of a diagnostic MRI and planning CT is strongly recommended, and the optimal sequence for MRI is the T1 post-contrast series. For the clinical target volume (CTV) longitudinal margins of as large as 5 cm and 2-cm radial margins were used. However, in recent years, attempts to minimize the margins have been raised, and in the RTOG report, the CTV is formed by adding 3-cm margins longitudinally and 1.5-cm margins radially to the GTV, respectively. If these margins extend beyond the compartment or an intact fascia or bone which are natural barriers, these margins can be truncated. With these margins, the peritumoral edema on T2 MRI will often be included in the CTV. Whether to include the whole edema is at the discretion of the radiation oncologist. It has been shown that microscopic tumor cells can be located 1–4 cm beyond the tumor; however, this does not correlate with the location or extent of peritumoral edema on MRI [46]. Therefore, it is reasonable to try to include the edema in the CTV if this would not require a significant increase in the treatment field. The planning target volume (PTV) is not specified in the RTOG report, but it is traditionally formed by adding 5–10 mm to the CTV. By using these margins, excellent LC rates up to 93% were achieved in various studies [22, 26, 27].

In the postoperative setting, there is no gross tumor, and therefore there is no GTV. However, it can be helpful to draw a virtual GTV in the location where the gross tumor was preoperatively. The CTV should include the whole surgical bed together with the incision and drain sites and metallic clips, and an additional 2–4 cm longitudinal and 1.5–2 cm radial margins should be added to form the final CTV. The PTV is formed by adding 5–10 mm margins to the CTV. With these margins, the historical 2–5 cm margins to the surgical bed is achieved. Typically, these fields are reduced after a certain dose, with diminishing all margins to 2 cm. This is the current standard of care in the postoperative setting, and excellent LC rates are achieved by using these margins [22, 26, 34].

If BRT is to be applied as monotherapy, the CTV should include the operative bed; however, there is no consensus on the margins. In a randomized trial from the Memorial Sloan Kettering Cancer Center, margins of 1.5–2 cm were used beyond the tumor bed [20].

8.1.4.3 Case Contouring

In the case presented here, we administered 50 Gy to the postoperative bed with 3-cm margins longitudinally and 2-cm margins radially (Fig. 8.2). In the second phase, we administered a boost dose of 14 Gy to the tumor bed with 2-cm margins in all directions (Fig. 8.3).
Fig. 8.2

The first phase contouring of the case (pink = GTV, red = CTV1, orange = CTV2)

Fig. 8.3

The boost phase contouring of the case (pink = GTV, red = CTV1, orange = CTV2)

8.1.5 Treatment Planning

8.1.5.1 Prescription Dose

In the preoperative setting, the standard dose for EBRT is 50 Gy delivered in 2-Gy fractions [9, 29]. In case of positive surgical margins in a patient that was irradiated preoperatively, a boost dose of 16–20 Gy can be applied. However, the efficacy of a boost dose has not been studied, and there is a concern that increased doses can also increase the rate of toxicity [47, 48].

The best timing for postoperative RT is 4–6 weeks after surgery which is a time for allowing the wound to fully heal. In the postoperative setting, the total dose varies based on the surgical margin status. As the oxygenation of the tumor bed is negatively affected after surgery, a higher total dose is required to achieve a similar LC with preoperatively-irradiated tumors. As stated in the ‘Contouring’ section, 50 Gy is prescribed to the wide-margined CTV and then the margins are diminished. A total dose of 60–66 Gy is adequate if the surgical margins are negative or close. If there is a positive surgical margin, a total dose of 66–68 Gy is recommended [9, 25]. In our center, we administer 60 Gy in case of negative and 64–66 Gy in case of close (<5 mm) or microscopic surgical margins, whereas 70 Gy is applied in case of a gross residual tumor. The dose-volume histogram of the case is shown in Fig. 8.4.
Fig. 8.4

The first and boost phase plans of the case

When BRT is used as monotherapy, American Brachytherapy Society (ABS) recommends 4–50 Gy, 30–54 Gy, and 45–50 Gy for low dose rate (LDR), high dose rate (HDR), and pulse dose rate (PDR)-BRT, respectively [49]. When combined with EBRT, the recommended doses are 15–25 Gy, 15–20 Gy, and 15–25 Gy for respective dose rates.

8.1.6 Follow-Up (F/U) Recommendations

Patients with STS should be carefully followed up for both LR and DM. The MRI of the relevant extremity and a chest x-ray should be performed every 3–6 months in the first 2–3 years, and annually thereafter. Patients that underwent surgery should also be evaluated for rehabilitation and it should be continued until maximal function is achieved (https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf).

8.2 Retroperitoneal Sarcoma

Overview

Epidemiology: Primary retroperitoneal sarcomas (RPS) constitute approximately 15% of all soft tissue sarcomas [50]. The age at diagnosis of RPS makes a peak during the sixth decade of life. Risk factors for the development of RPS are not clearly understood yet.

Pathology: There are various histopathologic types of RPS. The most common subtype is liposarcoma, followed by leiomyosarcoma.

Diagnosis: Most patients with RPS are asymptomatic until the tumor grows into a giant mass. When symptomatic, these tumors cause nonspecific abdominal pain, anorexia, and weight loss. For initial diagnosis, a magnetic resonance imaging (MRI) scan of the abdomen and pelvis is required as well as a computed tomography (CT) scan of the chest to rule out lung and liver lesions which are the most common sites of metastasis. Core biopsy with image guidance is the preferred diagnostic procedure.

Treatment: The treatment of choice is surgery for RPS, and although not adequate alone, it has been shown to improve the outcomes. The most important prognostic factors for RPS are the extent of resection, tumor volume, grade, and histopathology. Based on these prognostic factors, most RPS require radiotherapy (RT) that can be administered in the pre- or postoperative setting which have their own advantages and disadvantages.

Key Words: Retroperitoneal sarcoma; Radiotherapy

8.2.1 Case Presentation

A 68-year old woman applied to the hospital with pain in the left flank region in February 2018. Abdominal CT revealed a neoplastic mass of 90 × 80 mm in the left flank, infiltrating the abdominal wall muscles. The fat plan between the mass lesion and anterior pararenal fascia could not be visualized (Fig. 8.5). Because of a metallic implant, an MRI could not be performed on the patient. On thorax CT, no lung metastasis was detected. A tru-cut biopsy was performed and a malignant mesenchymal tumor was diagnosed. The Ki-67 proliferation index was 10%, and dedifferentiated liposarcoma was the most probable diagnose owing to morphologic findings and tumor location. According to 8th edition AJCC/UICC staging system, the patient was diagnosed as stage IIIA (cT2N0M0, grade 3) RPS (Tables 8.5 and 8.6) (https://www.cancer.org/cancer/soft-tissue-sarcoma/detection-diagnosis-staging/staging.html). Neoadjuvant RT followed by surgical resection was planned.
Fig. 8.5

The diagnostic CT images of the case

Table 8.5

Retroperitoneal sarcomas—TNM staging AJCC UICC, 2017

Primary tumor (T), retroperitoneal sarcomas

T category

T criteria

TX

Main tumor cannot be assessed

T0

No evidence of a primary tumor

T1

Tumor size is ≤5 cm

T2

Tumor size is 5–10 cm

T3

Tumor size is 10–15 cm

T4

Tumor size is >15 cm

Regional lymph nodes (N), retroperitoneal sarcomas

N category

N criteria

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in regional lymph nodes

Distant metastasis (M), retroperitoneal sarcomas

M category

M criteria

M0

No distant metastasis

M1

Distant metastasis

Histologic grade (G), retroperitoneal sarcomas

G

G definition

GX

Grade cannot be assessed

G1

Total differentiation, mitotica count and necrosis score of 2–3

G2

Total differentiation, mitotica count and necrosis score of 4–5

G3

Total differentiation, mitotica count and necrosis score of 6–8

Used with permission of the American College of Surgeons, Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

Table 8.6

Pathologic stage groups for retroperitoneal sarcomas—AJCC UICC, 2017

Pathologic stage

T

N

M

Grade

IA

T1

N0

M0

G1, GX

IB

T2–T4

N0

M0

G1, GX

II

T1

N0

M0

G2–3

IIIA

T2

N0

M0

G2–3

IIIB

T3–4

N0

M0

G2–3

 

Any T

N1

M0

Any G

IV

Any T

Any N

M1

Any G

Used with permission of the American College of Surgeons, Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

8.2.2 Evidence Based Treatment Recommendations

One of the most challenging issues in the management of RPS is that the patients often present with a large mass owing to delayed symptoms due to the anatomic location. The primary treatment for RPS is surgery, and gross total resection is the treatment of choice. It has been shown that an aggressive surgery increases the survival of patients with RPS [28, 51, 52]. However, it is not always possible due to tumor location and its close proximity with vital organs [53]. The total resectability rate of RPS was reported 65–85% [54, 55, 56].

The resection margin status defines the extent of surgical resection; R0 resection means the total resection of the tumor with microscopically negative margins, whereas R1 resection leaves microscopically positive margins, and R2 resection leaves a gross tumor residual behind. The rates of local control (LC) and survival increase with at least an Rl resection [55]. However, even an R0 resection alone do not lead to satisfactory results; the local recurrence (LR) and 5-year overall survival (OS) rate ranges between 33 and 77% and 35–63%, respectively [54, 55, 57]. It has clearly been shown that the primary cause of death in patients with RPS is LR which is responsible for the death of 75% of these patients [54, 55, 58]. Although LC rates are not satisfactory with surgery alone, the only curative treatment modality for RPS is complete surgical resection [59]. Five-year OS rates in patients with non-metastatic and completely resected RPS range between 49% and 70%, whereas LR rates can reach up to 82% in 10 years [54, 55, 57]. Hassan et al. [56] reported a median survival of 103 months for completely resected RPS compared to 18 months in patients that underwent an incomplete resection. Besides, in another study the 5-year OS was 62% and 26% in patients with and without complete resection, respectively [55]. Therefore, it is crucial the control the local disease with an additional treatment method.

There are no randomized controlled studies comparing surgery alone to surgery with neoadjuvant or adjuvant RT in the treatment of RPS. The American College of Surgeons Oncology Group (ACOSOG) Z9031 trial was opened in 2004 to compare neoadjuvant RT and surgery to surgery alone in patients with RP sarcoma; however, was closed prematurely due to poor accrual. The European Organization for the Treatment of Cancer (EORTC) 62092-22092, a phase III trial is now closed to patient entry that aims to compare surgery alone to neoadjuvant RT and surgery, and the results are pending. However, some retrospective studies have reported increased rates of LC with adjuvant RT without a significant effect on OS [54, 57, 60] (Table 8.7).
Table 8.7

Retrospective studies comparing surgery with and without adjuvant radiotherapy

Study

N of patients

Follow-up

RT dose (Gy)

LC rate (with vs. without RT)

p value

Stoeckle et al. [54]

165

47 months

Median 50

5-y: 55% vs 23%

0.002

Catton et al. [57]

104

6.3 years

Median 40

LRF interval: 103 months vs. 30 months

0.06

Ferrario and Karakousis [60]

130

41 months

NS

62% vs. 47%

0.16

Abbreviations: N number, RT radiotherapy, LC local control, LRF local recurrence-free, NS not specified

Radiotherapy can be applied either in the adjuvant or neoadjuvant setting, and these two approaches have both their advantages and disadvantages [61]. In adjuvant RT, the field is larger because the whole surgical bed together with the incision and drain sites and surgical clips should be included. Besides, as the oxygenation of the tissues in the field is impaired due to surgery, a higher dose has to be applied for biological efficacy. In neoadjuvant RT, the field is smaller and a lower dose can be applied. Only the tumor is included in the RT field and the organs at risk (e.g. the bowels) can be spared easily, and the risk of intraoperative seeding is reduced. The main disadvantage of preoperative RT is that it increases the rate of wound complications after surgery; however, these complications are mostly curable and reversible. It also leads to a limited histologic sampling and delays definitive surgery. On the other hand, postoperative RT leads to more serious late complications that can be irreversible. Preoperative RT can also be preferred for unresectable tumors to make them amenable to surgery.

8.2.3 Treatment Recommendations

Treatment recommendations for RPS according to the National Comprehensive Cancer Network (NCCN) guidelines are summarized in Table 8.8.
Table 8.8

NCCN guidelines version 2.2018

Status

Treatment recommendations

Resectable disease

Biopsy performed

– Surgery ± IORT OR

– Preoperative RT/CHT followed by surgery ± IORT

Adjuvant treatment:

– R0 resection: Observe

– R1 resection: Consider boost dose (10–16 Gy) if previous RT+

– R2 resection: Consider re-resection

Biopsy not performed/ non-diagnostic

– Surgery ± IORT

Unresectable disease/stage IV

Biopsy

Attempt down-staging

– CXT OR

– CRT OR

– RT

If resectable, follow recommendations for resectable disease

If unresectable or progressive, follow no down-staging recommendations

No down-staging

Palliative care:

– CXT

– RT

– Surgery for symptom control

– Supportive care

– Observe if asymptomatic

Abbreviations: IORT intraoperative radiotherapy, RT radiotherapy, CHT chemotherapy, CRT chemoradiotherapy

Baldini et al. [61] published the treatment guidelines for RPS in 2015. In this report, they recommend preoperative RT over postoperative RT based on the advantages and disadvantages of both modalities. For a patient to be a candidate for preoperative RT followed by surgery, the following should be present: there should be no symptoms that necessitate urgent surgery, the tumor should be resectable with negative margins, the tumor should be localized and unifocal for the administration of RT (or at most 2 tumors close to each other), and the prescription dose of 50.4 Gy could be administered without unacceptable toxicity. The authors also recommend the radiation oncologist and surgeon argue about the treatment before it is initiated. In cases where the RPS invades or abuts one kidney which would result in radical nephrectomy, the function of the contralateral kidney must be measured prior to RT and it should be maximally spared during RT. Similarly, if the RPS invades or abuts the liver, the need for partial liver resection should be kept in mind. Liver functions should be evaluated prior to RT, and the sections of the liver to be resected should be spared from high dose.

8.2.4 Target Volume Determination and Delineation Guidelines

8.2.4.1 Simulation

For the CT planning, the patient should be in a reproducible supine position. As the abdomen is the target region, the arms should be over the head either by the patient holding arms up or by using a t-bar or a wing board. Using an intravenous contrast can identify the target volume more clearly. Oral contrast can also help the visualization of the gastrointestinal tract better [61]. The slice thickness of the planning CT is recommended to be ≤3-mm. As the tumor and organs at risk in the upper abdomen can move up to 9 mm with respiration, 4-dimensional (4D) CT scan is strongly recommended for tumors above the level of the iliac crest, if possible [61, 62, 63]. In case tumor motion of >1 cm is detected, a form of respiratory control (gating, abdominal compression, breath-hold) is recommended to be used.

8.2.4.2 Contouring

A fusion with a diagnostic MRI and/or positron emission tomography (PET)/CT is recommended while contouring. The ACOSOG Z9031 trial defined the preoperative gross tumor volume (GTV) as the gross tumor that can be visualized in the imaging studies, clinical target volume (CTV) as the tissues adjacent to the GTV that are not visualized by imaging studies but have a potential for microscopic disease and should be given a margin of at least 1.5 cm, and the planning target volume (PTV) with an additional margin to the CTV for setup errors and patient/organ movements. The PTV margin should be at least 0.5 cm to the CTV. However, Langen and Jones [64] showed that the intrafraction motion of the kidneys can be 11–19 mm and the pancreas 18–22 mm, respectively, during normal breathing. Therefore, using cone-beam CT imaging, active breathing control, or respiratory gating can help to decrease the margin for the PTV.

The panel for the treatment guidelines for RPS recommends to delineate an iGTV for tumors above the iliac crest by using 4D motion [61]. The authors choose to add an internal target volume (ITV) which the iGTV accounts for the internal margin, and they recommend adding a 1.5-cm margin for the CTV. The ITV should not include the anatomical barriers such as uninvolved bone, kidney, or liver, but may expand into bowel and air cavity 5 mm, and should be cropped 3–5 mm from the involved skin surface. If the ipsilateral kidney is to be resected after RT, there is no need to exclude it from the ITV. In case the tumor lies within the inguinal canal, the inferior margin is recommended to be 3 cm. The ITV does not need to cover the prior biopsy tract. For tumors below the iliac crest GTV and CTV are the terms to be used rather than iGTV and ITV when 4D motion assessment is not used [61]. The CTV is again formed by adding 1.5-cm margins to the GTV. However, if 4D motion is not used for upper abdominal tumors, the panel recommends adding 2–2.5 cm margins longitudinally and 1.5–2 cm margins radially to the GTV to form the CTV. The PTV is created by adding a 5-mm margin to the ITV or CTV if 4D motion assessment is or is not used, respectively. However, the panel recommends adding 9–12 mm margins for the PTV if image-guided RT (IGRT) is not to be administered due to tumor and organ motions.

For postoperative RT, there may be no GTV after complete resection but it may be helpful to delineate a virtual GTV using preoperative imaging studies in order to define the CTV better. The CTV should include this virtual GTV (and the residual disease if present) and the whole surgical bed with incision and drain sites and surgical clips. Then a longitudinal margin of 3–4 cm and radial margins of 2 cm should be added, limited by the anatomical boundaries. After a dose of 45–50 Gy to this CTV, a boost dose of 5.4–9 Gy should be added based on resection margins with a smaller margin of 2 cm at all directions.

8.2.4.3 Case Contouring

The tumor was contoured on the planning CT with a fusion of the diagnostic CT. As preoperative RT was planned, the CTV was formed by adding 4 cm longitudinally and 2 cm radially. However, due to the anatomical barriers at the superior and inferior, the longitudinal margins were also decreased to 2 cm (Fig. 8.6). 50 Gy was prescribed to this volume.
Fig. 8.6

Contouring of the case (pink = GTV, red = CTV, magenta = PTV)

8.2.4.4 Prescription Dose and Dose Constraints for Critical Structures

Dose Recommendations: There is not an optimal dose for adjuvant RT in the treatment of RPS. In the study of Fein et al. [65], adjuvant RT doses of >55 Gy significantly decreased the rate of LR when compared to doses of <55 Gy (25% vs. 38%, respectively). Sindelar et al. [66] reported a locoregional control rate of 60% after 20 Gy intraoperative RT (IORT) and adjuvant 35–40 Gy external beam RT (EBRT) compared to 20% after adjuvant 50–55 Gy EBRT alone. Similarly, the rate of LC rate in Alektiar et al.’s study [67] was 66% in patients that underwent 12–15 Gy IORT and adjuvant 45–50.4 Gy EBRT, whereas it was 50% in patients that underwent IORT alone. Based on these results, an EBRT dose of ≥55 to 60 Gy seems adequate for the adjuvant treatment of RPS.

For neoadjuvant RT, Jones et al. [68] reported 19.6% LR and 88% 2-year OS rates in patients that underwent a median 45 Gy EBRT prior to resection and adjuvant brachytherapy (BRT). Gieschen et al. [69] treated patients with neoadjuvant 45–50 Gy EBRT followed by surgery and IORT (10 Gy after complete resection, 12.5–15 Gy after microscopic residue and 15–20 Gy after macroscopic residue). In patients with a complete resection, the LC rate increased from 61% to 83% without statistical significance. Petersen et al. [70] reported the results of patients with primary and recurrent RPS or pelvic sarcomas that underwent neoadjuvant EBRT, adjuvant EBRT, or both with a median dose of 47.6 Gy together with IORT with a median dose of 15 Gy. The 5-year rate of LC was found 100%, 60%, and 41% in patients with complete resection, microscopic residue, and gross residue, respectively. The 5-year OS rate was 37% in patients with gross residual disease and 52% in others. The recommended doses for preoperative RT is 50–50.4 Gy in 1.8–2-Gy fraction doses [61]. Surgery can be performed 4–6 weeks following the completion of RT [61].

In our center, preoperative RT dose is 50 Gy in 2-Gy fractions. In the postoperative setting, first we administer 50 Gy to the first CTV with larger margins, then the margins are decreased and a boost dose 10 Gy, 14–16 Gy and 20 Gy is applied in patients with complete resection, microscopic residual disease and gross tumor, respectively. 95% of the PTV should receive >95%, of the prescription dose, and 99–100% of the CTV should receive >95% of the prescription dose. Intensity modulated RT (IMRT) should be preferred as the treatment technique for RPS [61]. The RT plan of the case is shown in Fig. 8.7.
Fig. 8.7

Treatment plan of the case

Dose Constraints for Critical Structures: The organs at risk at the retroperitoneal area include the kidneys, liver, bowel, rectum, stomach, duodenum, spinal cord, testicles, ovaries, perineum, urinary bladder, and the femoral head. These structures are needed to be delineated if they are within 2 cm of the PTV. As the spinal cord and bowel are serial organs, the whole organ is not necessarily contoured, but the area including 2 cm superior and inferior to the PTV. It is not recommended to subtract the organs at risk from the PTV in order to calculate the doses accurately. The recommended dose constraints for critical structures are shown in Table 8.9.
Table 8.9

Dose constraints for critical structures [61]

Critical structure

Dose constraints

Kidneys

Mean dose <15 Gy and V18 < 50%

If one kidney to be resected; V18 of the remaining kidney <15%

Liver

Mean dose <26 Gy

Bowel

If contoured together as ‘bowel bag’; V15 < 830 cm3 and V45 < 195 cm3

If contoured individually;

– Small bowel V15 < 120 cc and V55 < 20 cm3

– Large bowel V60 < 20 cm3

Rectum

V50 < 50%

Stomach and duodenum

V45 ≤ 100%, V50 < 50%, and maximum dose 56 Gy

Spinal cord

Maximum dose 50 Gy

Testicles

As low as possible;

V3 < 50% for fertility and maximum dose <18 Gy

Consider cryopreservation in young men

Ovaries

Maximum dose <3 Gy for fertility

Consider cryopreservation in young women

Perineum

If possible; V30 < 50%

Urinary bladder

If necessary; V50 ≤ 100%

Femoral head

If possible; maximum dose <50 Gy, V40 < 64%, and mean dose <37 Gy

8.2.5 Follow-Up (F/U) Recommendations

Patients with RPS should be followed up with an abdominopelvic MRI and chest x-ray every 3–6 months in the first 2–3 years, every 6 months in year 4, and annually thereafter (https://www.cancer.org/cancer/soft-tissue-sarcoma/detection-diagnosis-staging/staging.html).

8.3 Ewing’s Sarcoma

Overview

Epidemiology: Ewing’s sarcoma (ES), atypical ES, and primitive neuroectodermal tumor (PNET) of the bone constitute Ewing’s sarcoma family of tumors (ESFT). Ewing’s sarcoma is the second most common primary tumor of bone in childhood, and seen in 2.8 cases per million children per year. Median age is 14 years. Most lesions occur in the pelvis, followed by the lower extremity, the trunk, and upper extremity. The etiology of ESFT is unknown.

Pathology: ESFT are composed of small, round blue cells. They are characterized by a reciprocal translocation involving breakpoints on the EWSR1 gene on chromosome 22q12A. The majority of ESFT has the translocations tl1:22(q24:q12) or t21;22(q22;q12). Besides, there is expression of the c-myc proto-oncogene, without expression of n-myc. Approximately ¾ of patients with ES present with localized disease at the time of diagnosis. However, the majority of the patients have not-yet-identifiable micrometastases at that time, the most common sites being the lung and bones.

Diagnosis: Patients commonly present with localized pain, swelling, and a palpable mass. Systemic symptoms such as fever, malaise, and weakness may also be present. On plain x-rays, bone tumors are observed as a moth-eaten lesion with osteolytic and osteoblastic areas. An ‘onion skin’ appearance can be seen due to the subperiosteal reactive new bone. On the computed tomography (CT) scan, bone destruction can be seen better, whereas a magnetic resonance imaging (MRI) scan can show the presence of invasion to the adjacent soft tissues or bone marrow. Besides, for accurate staging of the disease, a chest x-ray or CT scan, a bone scan, and a bone marrow biopsy should also be performed. A positron emission tomography (PET)/CT can detect bone and lymph node metastases more sensitively. Biopsy is recommended to be performed at the same institution where the surgery will be performed. The biopsy specimen should be taken from the soft-tissue component. As the cytogenetics is important, a large sample should be achieved. The contamination of uninvolved areas and vital structures, and hematoma development should be avoided. No staging system is present for Ewing’s sarcoma; patients are classified as having either localized or metastatic disease.

Treatment: The treatment consists of both local and systemic therapy. It starts with chemotherapy (CHT) of multiple agents, and followed by a definitive therapy; surgery ± radiotherapy (RT), and of adjuvant CHT. Treatment of metastatic sites should also be considered as it increases survival rates. With this multimodality approach, the 5-year survival rate is 70%.

Key Words: Ewing’s sarcoma; Radiotherapy

8.3.1 Case Presentation

A 6-year-old boy was brought to the emergency room by his parents with left hip pain in May 2015. The x-ray of the pelvis revealed serious destruction in the medullary spongiosus structure of the left iliac wing, and irregular and ill-defined sclerosis and osteolytic areas in the vicinity of the left sacroiliac joint (Fig. 8.8). On bilateral sacroiliac joint MRI, a 60 × 58 × 78 mm soft tissue mass infiltrating the left iliac muscle, causing expansion and cortical irregularity in the iliac bone with a suspicion of invasion to the minimus and medius gluteus muscles was observed (Fig. 8.9 and Fig. 8.10). The tru-cut biopsy from the left iliac wing revealed a small round cell neoplasm, and the fluorescent in-situ hybridization (FISH) supporting the presence of EWSR gene, ES was diagnosed. Thorax CT revealed a parenchymal nodule in the left lung (Fig. 8.11). On PET/CT, a 62 × 47-mm mass lying from the left iliac bone to the left acetabulum with a soft tissue component which destructs the bones and includes necrotic areas was detected with a SUVmax value of 6.4 (Fig. 8.12). In addition, a 6 × 5-mm subpleural nodule in the left lung with a SUVmax value of 1.5 was also observed (Fig. 8.13).
Fig. 8.8

Plain radiograph of the case at presentation

Fig. 8.9

The diagnostic MRI scan of the case ((a) T1-weighted transverse images, (b) T2-spare transverse images)

Fig. 8.10

The diagnostic MRI scan of the case (T2-spare coronal image)

Fig. 8.11

Thorax CT at diagnosis

Fig. 8.12

PET/CT images of the primary tumor ((a) transverse images, (b) Coronal image)

Fig. 8.13

PET/CT image of the solitary pulmonary nodule

The patient then received the Euro-EWING 99 protocol, and partial response in both the primary tumor and pulmonary nodule was observed in August 2015. On sacroiliac joint MRI, the tumor was decreased to 2/3 of its initial volume (Fig. 8.14). On PET/CT, the SUVmax of the primary lesion decreased to 2.8 (Fig. 8.15), and no fluouro-deoxy-glucose (FDG) involvement was detected in the lung nodule. Chemotherapy was continued. In October 2015, although the primary lesion and the lung nodule decreased in size on sacroiliac joint MRI and thorax CT, sclerosis in the primary lesion was increased and the FDG-involved area was widened on PET/CT and progression was thought (Fig. 8.16). After the decision of the tumor board with specialists of Pediatric Oncology, Pediatric Surgery, Radiation Oncology, Radiology and Nuclear Medicine, surgery was decided. In November 2015, the patient underwent internal hemipelvectomy and pelvic fixation. The final pathology revealed ES with vascular invasion. The tumor had invaded the bony cortex and soft tissues. Resection margins were negative but the response to CHT was minimal. The CHT protocol was changed in the tumor board, and RT was planned to both the primary tumor bed and lungs.
Fig. 8.14

Transverse and coronal T2-weighted MR images of the case after initial chemotherapy

Fig. 8.15

Transverse and coronal images of the PET/CT scan after initial chemotherapy

Fig. 8.16

Transverse and coronal images of the PET/CT scan after the completion of induction chemotherapy

8.3.2 Evidence Based Treatment Recommendations

The treatment of ES starts with induction CHT of multiple agents. Induction CHT helps the clinician to evaluate the effectiveness of the regimen, leads to a degree of bone healing which diminishes the risk of pathologic fractures, shrinks the tumor so that the volume to be resected and irradiated gets smaller, and increases the probability of achieving negative surgical margins. Response rates up to 90% have been reported, and the rate is directly correlated with the survival of the patient [71, 72, 73]. Following induction CHT, local therapy is essential as cure cannot be achieved with systemic therapy alone. Local therapy can be surgery, RT, or both. Retrospective analyses of randomized studies reported better local control (LC) with surgery; however, there may be a selection bias of patients with favorable characteristics that underwent surgery [74, 75, 76]. The risk of secondary malignancy with RT results in surgery being the first local treatment of choice. However, RT is recommended for tumors that cannot be resected without significant morbidity, as ES is known to be radiosensitive and RT is a curative option in these patients. Table 8.10 shows the results of major randomized trials.
Table 8.10

The results of major randomized trials for the treatment of Ewing sarcoma

Study

N of patients

Treatment

5-year EFS (%)

IESS-I [77]

(1973–1978)

342

VAC

VACD

VAC + WLI

24

44

40

IESS-II [78]

(1978–1982)

214

VACD-HD

VACD-MD

68

48

CCG/POG I (INT-0091) [79]

(1988–1993)

200

198

120

VACD

VACD + IE

VACD ± IE (metastatic)

54

69

22

CCG/POG INTERGROUP II [80] (1995–1998)

247

231

VCD + IE-48 weeks

VCD + IE-30 weeks

70

72

COG-AEWS 0031 [81]

247

231

VCD + IE

VCD + IE

65

73

CESS 81 [82]

(1981–1985)

 93

VACD

80 (<100 mL) (3 years)

31 (≥100 mL) (3 years)

CESS 86 [83]

(1986–1991)

301

VACD (SR)

VAID (HR)

52 (10 years)

51 (10 years)

ICESS 92 [84]

(1992–1999)

155

492

VAID/VACD (SR)

VAID/EVAID (HR)

68/67

44/52

UKCCSG-ET1 [85]

(1978–1986)

120

VACD

41

UKCCSG-ET2 [86]

(1987–1993)

201

VAID

62

MSKCC-T2 [87]

(1970–1978)

 20

VACD (adjuvant)

75

MSKCC-P6 [88]

(1990–1995)

 36

HD-CVD + IE

77 (2 years)

MSKCC-P6 [89]

(1991–2001)

 68

HD-CVD + IE

81 (4 years) (localized)

12 (4 years) (metastatic)

St. Jude ES-79 [90]

(1978–1986)

 52

VACD

82 (<8 cm) (3 years)

64 (≥8 cm) (3 years)

St. Jude ES-87 [91]

(1987–1991)

 26

IE

Clinical response in 96%

St. Jude EW-92 [92]

(1992–1996)

 34

VCD-IE

78 (3 years)

REN-3 [93]

(1991–1997)

157

VDC + VIA + IE

71

SFOP EW-88 [94]

(1988–1991)

141

VD + VD/VA

58

SFOP EW-93 [95]

(1993–1999)

116

 46

 48

VD + VD/VA (SR)

VD + VD/VA + IE (IR)

VD + VD/VA + IE + HD (HR)

70

54

48

SSG IX [96]

(1990–1999)

 88

VID + PID

58 (DMFS)

Euro-EWING 99 [97]

(1999–2005)

281

VIDE + VAI + HD

27 (3 years)

Abbreviations: N number, EFS event-free survival, WLI whole lung irradiation, IESS Intergroup Ewing’s Sarcoma Study, CCG Children’s Cancer Group, POG Pediatric Oncology Group, INT intergroup, COG Children’s Oncology Group, CESS Cooperative Ewing’s Sarcoma Study, EICESS European Intergroup Cooperative Ewing Sarcoma Study, UKCCSG ET United Kingdom Children’s Cancer Study Group Ewing Tumor, MSKCC Memorial Sloan Kettering Cancer Center, SFOP French Society of Pediatric Oncology, SSG Scandinavian Sarcoma Group, V vincristine, A actinomycin-D, C cyclophosphamide, D doxorubicin, HD high-dose, MD moderate-dose, I ifosfamide, E etoposide, P cisplatin, SR standard-risk, HR high-risk, R intermediate-risk, DMFS distant metastasis-free survival

For patients that will undergo surgery, limb-sparing techniques are preferred over amputation. Tumors located in the scapula, clavicle, ribs, proximal fibula, and wing of the ilium can easily be resected. However, amputation may be an option for younger patients with lesions of the fibula, tibia, and foot. After surgery, RT is indicated in most patients. To start with, adjuvant RT should be applied following debulking procedures that are not oncologic resections as they do not provide adequate LC. After a complete oncologic resection, in which the whole compartment of the muscle tissue is resected, the rate of local failure (LF) was reported 4%, compared to 25% and 50% for wide resection (tumor is resected with the surrounding reactive zone) and marginal resection (tumor is resected without its surrounding reactive zone), respectively [98]. Children’s Oncology Group (COG) trials recommend adjuvant RT if the resection margins are close (<1 cm for bone, <5 mm for muscle, and <2 mm along a fascial plane). The rate of LC was excellent with surgery alone in the Cooperative Ewing’s Sarcoma Study (CESS) and European Intergroup Cooperative Ewing Sarcoma Study (EICESS) trials [99]. However, the rate of LF was reported 12% in patients with a poor histologic response (soft tissue component reduction of <50%) to induction CHT and underwent wide resection, and it was decreased to 6% with adjuvant RT [75]. On the other hand, Bacci et al. [100] did not show any benefit of adjuvant RT in patients that underwent wide or marginal resection with LF rates of 6% and 7% with and without adjuvant RT, respectively. With these data in hand, adjuvant RT is indicated in patients with a poor histologic response to induction CHT and positive/close resection margins following surgery.

Neoadjuvant RT following induction CHT is an option for patients with a poor response [101, 102]. This was studied in the EICESS-92 trial in patients who were thought to leave the operation room with positive/close resection margins, with an aim of sterilizing the compartment to be resected and reducing the risk of dissemination during surgery [75]. This effort resulted in a LC rate of 95% without any benefit on systemic disease control. However, it should be kept in mind that postoperative infection risk may increase with neoadjuvant RT.

Patients who are not candidates for surgery undergo definitive RT. These patients usually present with large tumors that are amenable to surgery without significant morbidity. In the EICESS trials, the LF rate was found 26% in patients that underwent RT only compared to 10% and 4% in patients that underwent surgery only and surgery + RT, respectively [75, 76]. Bacci et al. [100] also reported higher LF rates with RT alone compared to surgery alone and surgery + RT (19% vs. 9% vs. 11%). The important point in this trial is that RT did not decrease LC for tumors in central parts of the body where the surgery is also not successful to control the disease. The COG INT-0091 trial was retrospectively analyzed for the LC of pelvic tumors only, and the LF rate was 22% in both surgery and RT arms [103]. However, although not statistically significant, patients that received both local therapies had better outcomes. Therefore, definitive RT is indicated when a gross residual tumor is suspected to be left with surgery. If an oncologic resection will not be able to be performed, debulking surgery is an unnecessary procedure because it results in increased rate of morbidity without any benefit on LC [75, 76, 100].

Nearly 75% of patients with ES present with localized disease but the majority of them have unidentifiable micrometastases at the time of diagnosis. The prognosis of these patients is poor despite aggressive multiagent CHT. The Euro-EWING 99 protocol included 6 cycles of VIDE (vincristine, ifosfamide, doxorubicin, etoposide) CHT followed by one cycle of VID and local therapy prior to high-dose busulfan and melphalan followed by stem cell rescue, and resulted in 3-year overall survival (OS) and event-free survival (EFS) rates of 34% and 27%, respectively [97]. Patients with lung metastasis constitute a more favorable group. In the CESS and EICESS trials, patients that received whole-lung irradiation (WLI) had higher EFS rates compared to patients who did not (5-year EFS rate was 40% vs. 19%) [104]. As a result, definitive treatment of all metastatic sites improves the outcomes in patients with metastatic ES. If definitive RT does not seem feasible for some sites, palliative RT is recommended.

8.3.3 Treatment Recommendations

Treatment recommendations for ES according to National Comprehensive Cancer Network (NCCN) guidelines are summarized in Table 8.11.
Table 8.11

NCCN guidelines version 2.2018 (https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf)

Primary treatment

Re-staging

Response evaluation

Local therapy

In case of progression

Multiagent CHT (≥9 weeks)

X-rays, MRI ± CT of the primary, chest CT, ± PET/CT or bone scan

Improved/stable disease

Wide excision

SM+

CHT + RT

CHT ± RT

RT + CHT

SM−

CHT

Definitive RT + CHT

Amputation

CHT ± RT

Progressive disease

RT and/or surgery to the primary for local control or palliation

CHT or BSC

Abbreviations: CHT chemotherapy, MRI magnetic resonance imaging, CT computed tomography, PET/CT positron emission tomography/CT, SM surgical margin, RT radiotherapy, BSC best supportive care

8.3.4 Treatment Planning

8.3.4.1 Simulation

Ewing’s sarcoma can arise from any part of the body. Simulation for RT planning should be done with the affected part being stabilized properly. Intravenous contrast use is recommended.

8.3.4.2 Contouring

Historically, the entire bone was irradiated; however, the randomized trial of Pediatric Oncology Group (POG) 8346 reported no benefit of this approach showing the fact that LF usually occurs within the high-dose volume [105]. The RT fields are currently more limited. The still open COG trial recommendations for the target volumes are shown in Table 8.12.
Table 8.12

COG contouring recommendations for the primary tumor of Ewing’s sarcoma

Volume

Definition

GTV-1

pre-chemotherapy tumor volume including all T1-contrast enhancing tumor, all T2 signal abnormality, and all bone abnormalities

CTV-1a

GTV-1 + 1 cm

PTV-1b

CTV-1 + 0.5–1 cma

GTV-2

Residual soft-tissue mass after induction chemotherapy and all bone abnormalities that were present before chemotherapy

CTV-2a

GTV-2 + 1 cm

PTV-2b

CTV-2 + 0.5–1 cma

Abbreviations: GTV gross tumor volume, CTV clinical target volume, PTV planning target volume

aCTVs should be modified for anatomic pushing borders such as the abdominal cavity and lung or to be restricted to fascial planes if there is no evidence of infiltration. All surgically contaminated areas, scars, and drainage sites must be included

bDepending on tumor location and daily image guidance

In patients with lung metastasis, both lungs down to the diaphragmatic recess should be irradiated from the anterior and posterior with 15–20 Gy in 1.5-Gy fractions. If possible, breath-hold technique should be used to reduce the volume of irradiated liver, stomach, and upper kidneys. The best timing for WLI is after conventional CHT is completed. During WLI, doxorubicin and actinomycin-D must be avoided to decrease the risk of pneumonitis, actinomycin-D should also be avoided after WLI because of the risk of ‘recall’ phenomenon, and WLI should not be administered at all in patients using a busulfan-containing regimen because of the risk of significant lung toxicity.

For a limited number of bone metastasis, definitive RT is recommended to all initially involved sites. In patients with multiple bone metastases, RT can be administered at the end of whole therapy to all involved sites or bulky, slowly-responding, or residual sites can be selected to be irradiated in order to avoid myelosupression.

8.3.4.3 Case Contouring

In the first phase, the left hemipelvis of the patient was irradiated with 45 Gy in 1.8-Gy fractions. Then, the residual soft tissue mass with a 1-cm margin was administered a boost dose of 5.4 Gy in 1.8 Gy fractions (Fig. 8.17). The total dose applied was 50.4 Gy (Fig. 8.18). After the completion of RT to the primary site, CHT was continued. The solitary lung lesion disappeared after CHT and 15 Gy WLI was administered in 1.5-Gy fractions (Fig. 8.19).
Fig. 8.17

The contouring of the case. (ae). The first phase, (f). The second phase (pink = GTV, red = CTV)

Fig. 8.18

Final plan of the case

Fig. 8.19

Whole lung irradiation contouring (a) and plan (b) of the case

8.3.4.4 Prescription Dose and Dose Constraints for Critical Structures

Dose Recommendations

The Intergroup Ewing Sarcoma Study (IESS-I) trial reported no benefit of 65 Gy over 30 Gy in terms of LC [77]. However, in St. Jude Hospital series, the LC rate was reported to be lower with doses <40 Gy [106]. The recommended dose for definitive RT is 55–60 Gy. For neoadjuvant or adjuvant RT, the doses range between 45 Gy and 55 Gy. In the adjuvant setting, the recommended dose in AEWS 1031 trial is 45 Gy to pre-CHT CTV, 50.4 Gy for microscopic positive margins, and 55.8 Gy to post-CHT residual disease in 1.8-Gy fractions [81]. Hyperfractionated RT regimens did not result in LC benefit [99].

Patients with chest wall tumors often present with pleural effusion, and even the tumor is resected, hemithorax irradiation is recommended with a total dose of 15 Gy for patients <14 years and 20 Gy for older patients. The 7-year EFS was reported 63% in patients that underwent hemithorax irradiation compared to 46% in patients that did not in the EICESS 92 trial [84].

For vertebral lesions, 45 Gy is the standard dose but it is not clear whether this dose is adequate for LC. The average dose used in the CESS 81, CESS 86, and EICESS 92 trials was 49.6 Gy [101]. Sacral lesions should be treated to the full dose.

Dose Constraints for Critical Structures

The actuarial complication rate related to the treatment of ES was reported 70% at 35 years [107]. The most common complications of RT are on the skeletal system. Abnormal growth and development of the skeletal system due to premature closure of active epiphyses may occur. The degree of growth discrepancy depends on the patient’s age, the location of the epiphysis irradiated, and RT dose. Another skeletal complication of RT is pathologic fractures which is observed in 10% of patients. It usually occurs within 24 h after RT, and the most affected site is the proximal femur. Doses of <40 Gy in conventional fractionation and hyperfractionated schemes carry a lower risk of bone fractures [108, 109]. Radiotherapy can also cause decreased range of motion, weakness and pain in the extremity, and discoloration of the skin.

As the risk of lymphedema is increased, particularly in tumors of the leg, circumferential irradiation of the extremities should be avoided by sparing at least a 1- to 2-cm strip of tissue. Besides, growth plates and vertebral bodies should be either fully irradiated or not be included at all in growing children in order to prevent asymmetric growth and functional deficits.

In patients that receive high doses of cyclophosphamide or ifosfamide, the risk of radiation cystitis increases, even at doses as low as 20 Gy. Pelvic tumors do not usually invade to the tissues in the vicinity of the urinary bladder, but push them aside; therefore, neoadjuvant CHT allows sparing the bladder better if good tumor shrinkage is obtained. A 1-cm medial margin on the residual disease at the time of treatment is adequate from the beginning of RT.

The most frightening complication of RT in children is the increased risk of' secondary malignancies. There is no threshold for the development of secondary malignancies, but the risk increases with increased RT doses. The most common secondary malignancy related to RT is sarcoma, and the risk of sarcoma development was reported 1–4% at 20 years [77, 110, 111].

8.3.5 Follow-Up (F/U) Recommendations

Patients should be followed up with physical exam, plain radiographs, MRI ± CT of the primary site, and chest x-ray or CT every 2–3 months in the first 2 years, every 6 months in years 3–4, and annually thereafter (https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf). Complete blood count and other laboratory studies should be performed as indicated. A PET/CT (head-to-toe) or bone scan can also be considered.

8.4 Rhabdomyosarcoma

Overview

Epidemiology: Soft-tissue sarcomas account for approximately 7% of all pediatric cancers, and rhabdomyosarcoma (RMS) comprises 40% of them. Median age is <5 years, but there is a second incidence peak in the mid-teens. The etiology is unknown but some genetic mutations have been defined.

Pathology: Rhabdomyosarcoma is one of the small, round, blue cell malignancies of childhood. The most common histological subtype is embryonal RMS with the best prognosis, and it has spindle cell and botryoid variants. Alveolar RMS comprises approximately 25% of all RMS, and the least favorable subtype is the undifferentiated sarcoma. Loss of heterozygosity in chromosome 11p and RAS/NF1 pathway mutations were identified in patients with embryonal RMS, whereas t(2;13) or t(1;13) translocations result in PAX-FKHR fusion protein in 80% of all patients with alveolar RMS. Besides, RMS can also occur in patients with neurofibromatosis type-1, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome.

Diagnosis: Patients present with symptoms related to tumor location and extent of disease. The head and neck (H&N) region is the most frequent site of involvement. In general, lymph node (LN) involvement is <5% in RMS; however, the rate can be up to 25% in paratesticular and extremity tumors. Distant metastasis (DM) is present in 20% of all patients at the time of diagnosis. For the exact diagnosis, a magnetic resonance imaging (MRI) of the primary tumor site, computed tomography (CT) of the chest and abdomen (for infradiaphragmatic tumors), and a bone scintigraphy should be performed. A biopsy of the primary tumor and/or metastasis is warranted. As the rate of LN metastasis is high, LN sampling is recommended for paratesticular and extremity lesions. For H&N lesions, cerebrospinal fluid cytology; and for genitourinary lesions, examination under anesthesia should also be performed.

Treatment: For all RMS, an upfront surgery is the first line of therapy. Adjuvant chemotherapy (CXT) and radiotherapy (RT) are indicated in most cases. The standard CXT regimen is vincristine, actinomycin-D, and cyclophosphamide (VAC)–based CXT, resulting in a 5-year event-free survival (EFS) rate of 90%, 70%, and <30% in patients with low-risk, intermediate risk, and high risk, respectively. The recommended doses for adjuvant RT are 36 Gy for microscopic disease, 41.4 Gy for microscopic residual disease, and 50.4 Gy for gross residual disease with local failure rates of approximately 10%.

Key Words: Rhabdomyosarcoma; Radiotherapy

8.4.1 Case Presentation

An 8-year old girl was brought to the emergency room by her parents with abdominal pain lasting for 10 days in November 2016. Abdominal ultrasonography (USG) revealed an 87 × 75 × 85-mm heterogeneous, solid mass with cystic areas and central vascularization in the left adnexal region. The uterus and ovaries could not be visualized separately from the mass. On abdominal MRI, the lesion was 92 × 77 × 89 mm, filling the whole bony pelvis. The uterus was not separately visualized, and there was suspicious invasion to the pelvic muscles at the posterior (Fig. 8.20). The rectum and sigmoid colon were pushed to the right and the urinary bladder to the anterior and superior because of the mass. Fine needle aspiration cytology included a small number of cells resembling mesenchymal tissue fragments and a small round cell malignant tumor. Tru-cut biopsy also revealed a round cell malignant tumor. After immunohistochemical examination, embryonal RMS was diagnosed. The Ki-67 proliferation index was 80%. Thorax CT showed no lung metastasis.
Fig. 8.20

The diagnostic T2-weighted MRI images of the case

VAC chemotherapy was initiated. After 3 cycles, the size of the tumor diminished to 60 × 55 × 80 mm, and after 6 cycles it was 42 × 36 × 55 mm on abdominal USG. The MRI in April 2017 revealed a significant reduction in size (49 × 27 × 51 mm), the uterus could be visualized separately but not the left ovary (Fig. 8.21). Besides, the left internal iliac artery was in close proximity to the lesion and some of its branches were within it. In May 2017, the patient underwent excisional biopsy. During the operation, the mass was seen to have a venous plexus inside and massive hemorrhage had occurred; therefore, total excision was not possible. The final pathology revealed RMS infiltration in the lesion resected from the posterior of the bladder and on the internal iliac artery. On postoperative abdominal CT, the mass was 43 × 32 × 60 mm, and there was invasion in the left internal iliac vessels (Fig. 8.22). In the tumor board, the patient was accepted as intermediate risk (favorable site, T2bN0M0, stage I, group IIIA, embryonal) (Tables 8.13, 8.14, 8.15, 8.16, and 8.17), and adjuvant RT was planned.
Fig. 8.21

T2-weighted MRI images of the case after the completion of chemotherapy

Fig. 8.22

Postoperative CT images of the case prior to radiotherapy

Table 8.13

Favorability of RMS according to tumor site

Characteristic

Site

Favorable

Orbit

Non-parameningeal H&N (scalp, parotid, oropharynx, oral cavity, larynx)

Nonbladder-prostate genitourinary (paratestes, vagina, vulva, uterus)

Biliary tract

Unfavorable

Parameningeal H&N (nasopharynx, nasal cavity, paranasal sinuses, middle ear, mastoid, pterygopalatine fossa, infratemporal fossa)

Urinary bladder and prostate

Extremity

Other (trunk, retroperitoneum)

Abbreviations: RMS rabdomyosarcoma, H&N head and neck

Table 8.14

TNM classification of rhabdomyosarcoma

Primary tumor (T)

T category

T criteria

T1

Tumor is confined to site/organ of origin

 T1a

≤5 cm

 T1b

>5 cm

T2

Tumor extends beyond site/organ of origin

 T2a

≤5 cm

 T2b

>5 cm

 

Regional lymph nodes (N)

N category

N criteria

N0

No regional lymph node involvement

N1

Regional lymph node involvement

Distant metastasis (M)

M category

M criteria

M0

No distant metastasis

M1

Distant metastasis

Table 8.15

Intergroup rhabdomyosarcoma study (IRS) preoperative staging system

Stage

Site

T stage

N stage

M stage

I

Favorable

Any T

N0–1

M0

II

Unfavorable

T1a/T2a

N0

M0

III

Unfavorable

Unfavorable

T1b/T2b

Any T

N0

N1

M0

M0

IV

Any site

Any T

N0–1

M0

Table 8.16

Intergroup rhabdomyosarcoma study (IRS) surgical-pathological grouping system

Group

Definition

I

Localized disease, completely resected

 Ia

Confined to organ or muscle of origin

 Ib

Involvement outside organ or muscle of origin (contiguously)

II

Gross total resection

 IIa

Microscopic residual disease, no regional lymph node involvement

 IIb

Regional nodal involvement without microscopic residual disease

 IIc

Regional nodal involvement with microscopic residual disease

III

Incomplete resection with gross residual disease

 IIIa

After biopsy

 IIIb

After gross major resection (>50% of disease)

IV

Distant metastasis at diagnosis

Table 8.17

Intergroup rhabdomyosarcoma study (IRS) risk groups

Risk group

Definition

Low-risk

– Localized embryonal/botyroid histology at favorable sites (stage I, groups I–III)

– Localized embryonal/botyroid histology at unfavorable sites with completely resected or microscopic residual disease (stages II–III, groups I–II)

Intermediate-risk

– Embryonal/botyroid histology at unfavorable sites with gross residual disease (stages II–III, group III)

– Patients 2–10 years with metastatic embryonal histology (stage IV)

– Nonmetastatic alveolar/undifferentiated histology (stages I–III)

High-risk

– Any stage IV/group IV (except for patients 2–10 years with embryonal histology)

8.4.2 Evidence Based Treatment Recommendations

8.4.2.1 Intergroup RMS Study (IRS) Group Trials

Multimodality approach is performed in patients with RMS. A number of IRS trials have been held since 1972, and each one answered several important questions.

In IRS-I (1972–1978), 40–45 Gy RT was given to all patients; at the beginning of treatment in groups I and II, but was delayed until the sixth week in groups III and IV [112]. All patients also underwent VAC chemotherapy for 2 years. The results were:
  1. 1.

    In group I, postoperative RT is unnecessary if the patient is given 2 years of VAC. The 5-year relapse-free survival (RFS) and overall survival (OS) rate was 80% and 81–93%, respectively, in these patients. However, postoperative RT can be beneficial in patients in this group with alveolar or undifferentiated histology [113].

     
  2. 2.

    In group II, VAC is not superior to intensive VA if the patient receives RT. The 5-year RFS and OS was 65–72% and 72% in these patients, respectively.

     
  3. 3.

    In groups III and IV, VACA (VAC + Adriamycin) is not superior to VAC if the patient receives RT. The complete remission rate was 69% and 50% in group III and IV, respectively. The chance of staying in remission after complete remission was 60% and 30%, and the 5-year OS rate was 52% and 20% in the respective groups.

     
  4. 4.

    The 5-year OS rate was 55% in all patients.

     
  5. 5.

    After relapse, the 1- and 2-year OS rate was 32% and 17%, respectively.

     
  6. 6.

    The risk of DM is higher than the risk of local recurrence (LR).

     
  7. 7.

    The sites with best prognosis are the orbit and genitourinary tract, and the worst is the retroperitoneum.

     
  8. 8.

    Patients with alveolar histology have a poor prognosis, especially if the lesion is in the extremities.

     
Based on the findings of IRS-I, IRS-II was held (1978–1984) [114]. The results were:
  1. 1.

    In group I (excluding alveolar histology in the extremity), VAC is superior to VA in terms of disease-free survival (DFS) (82% vs. 68%) with similar 5-year OS rates (82% vs. (8%). Therefore, VAC is standard if the patient does not receive RT.

     
  2. 2.

    In group II, intensive VA has similar results with VAC if the patient receives postoperative RT. The 5-year OS rate was 77% and 90%, and 5-year DFS rate was 68% and 75% in patients that received VA and VAC, respectively.

     
  3. 3.

    In group III, 2 years of repetitive pulse CXT (doxorubicin or dactinomycin) increased the survival rate, but not in group IV. Patients in group III and IV had a complete remission rate of 72%, and this remained in 70% at 5 years with a survival rate of 64%.

     
  4. 4.

    The 5-year OS was increased to 62% in the whole group (7% improvement over IRS-I).

     
  5. 5.

    The 5-year OS rate after relapse was 17%.

     
  6. 6.

    In IRS-I, patients with parameningeal tumors with high-risk factors such as cranial nerve palsy, erosion of the skull base, or intracranial extension had a high incidence of central nervous system (CNS) relapse. In IRS-II, whole brain RT +/- intrathecal CXT decreased the rate of meningeal recurrence and increased survival in these patients.

     
  7. 7.

    VAC did not reduce the frequency of total cystectomy or produce durable bladder salvage in genitourinary tumors, and the survival was not compromised.

     
The results of IRS-III (1984–1991) are below [115]:
  1. 1.

    In group I with favorable histology, the efficacy of 1-year of VA was similar to VAC with 5-year progression-free survival (PFS) rate of 83% and 76%, respectively.

     
  2. 2.

    In group II with favorable histology (excluding orbit, H&N, and paratesticular tumors), VAD (VA + doxorubicin) was not superior to 1-year of VA + RT.

     
  3. 3.

    In group III (excluding genitourinary, orbit, and non-parameningeal H&N tumors), better results were achieved with a more intensive treatment with CXT (VAC + D + P[cisplatin] + E[etoposide]) + RT and second-look surgery compared to IRS-II with 5-year PFS rates of 62% and 52%, respectively.

     
  4. 4.

    In group IV, the aggressive therapy of IRS-III did not result in any benefit.

     
  5. 5.

    The 5-year OS for all patients was increased to 71% (9% improvement over IRS-II). The 5-year PFS rate was 65% (10% improvement over IRS-II).

     
  6. 6.

    In groups I and II with unfavorable histology, the combination of VADR-VAC + P and RT improved the outcome compared to IRS-II with VA or VAC + RT.

     
  7. 7.

    In group II with favorable-histology in the paratesticular regions and groups II and II with favorable-histology in the orbit and H&N, the addition of cyclophosphamide is unnecessary if the patient receives 1-year of VA + RT.

     
  8. 8.

    In group III with tumors of the bladder, vagina, and central pelvis, the outcomes were significantly improved compared to IRS-II. This was attributed to the early administration of RT, which increased the rate of bladder preservation to 60% from 25% of IRS-II.

     
  9. 9.

    In patients with parameningeal H&N tumors with cranial nerve palsy or skull base erosion, whole-brain RT was omitted, and the risk of CNS relapse and survival were not compromised. However, patients with intracranial extension still received whole-brain RT.

     
IRS-IV (1991–1997) introduced the presurgical staging [116]. The results were:
  1. 1.

    A prognostic classification was made based on histologic subtype, stage, and group: Low-risk disease included all groups of stage I embryonal histology and group I–II of stage II–III embryonal histology. All other patients with locoregional disease were accepted intermediate risk.

     
  2. 2.

    In group I–II orbit or eyelid tumors, VA led to excellent results, and so did RT in group II disease.

     
  3. 3.

    In group III, standard RT of 50.4 Gy in 1.8 Gy daily fractions were compared to hyperfractionated RT of 59.4 Gy in 1.1 Gy twice daily fractions, and no difference was observed between the two schemes in terms of failure-free survival (FFS) (73% vs. 73%) and local failure (LF) (15% vs. 12%) [117].

     
  4. 4.

    In patients with embryonal histology, the 3-year FFS was increased compared to IRS-III (83% vs. 74%); however, the rate did not differ for alveolar or undifferentiated histologies.

     
  5. 5.

    In non-metastatic disease survival rates were similar between patients that received VAC, VAI (VA + ifosfamide), and VIE.

     
  6. 6.

    In metastatic disease, IE resulted in increased OS rate compared to V + melphalan.

     
  7. 7.

    In this study, whole-brain RT was omitted in all patients with parameningeal H&N tumors but the ones with cytologic evidence of cerebrospinal fluid involvement. Survival was not compromised by this approach.

     
  8. 8.

    In group I paratesticular disease, the retrospective comparison to IRS-III revealed that patients <10 years of age could be evaluated by CT for retroperitoneal (RP) LN involvement without the need for RPLN dissection (RPLND) with a FFS rate of 90%. On the other hand, RPLND provided a FFS advantage over CT alone (100% vs. 63%) in patients ≥10 years of age benefited in terms of defining nodal involvement and the need for subsequent lymphatic RT [118].

     
IRSG V (1997–2005) is the last of the IRS trials. The results are below:
  1. 1.

    In group II, RT dose was reduced from 41.4 Gy–36 Gy in case of positive microscopic surgical margins. For orbital tumors the dose was reduced to 45 Gy. These doses were safe and effective in low-risk disease, especially if the patient received cyclophosphamide in the CXT regimen [119, 120].

     
  2. 2.

    In intermediate-risk disease, VAC and VAC alternated with VTC (topotecan instead of actinomycin-D) were compared, and the 4-year FFS was similar (73% vs. 68%, respectively) [121].

     
  3. 3.

    In intermediate- and high-risk disease, V + irinotecan demonstrated a 70% response rate with a low 2-year FFS rate (26%).

     

The ARST0331 trial reported the results of a tailored therapy for low-risk disease with embryonal histology groups I and II stages I–III, and group III stage I disease [122]. The RT dose was 36 Gy for microscopic disease and 41.4 Gy for nodal disease. In group III vaginal tumors, RT was delayed or completely omitted but the 2 year-FFS rate was 42% in these patients demonstrating that RT is necessary for improving local control (LC). The results of ARST0531 trial which compares VAC and VAC/V + irinotecan in intermediate-risk disease with embryonal histology group III stages II–III, and alveolar RMS group I–III stages I–III; ARST0431 trial on multiple-agent systemic therapy in high-risk disease; and ARST08P1 trial which incorporates an insulin-like growth factor-1 receptor inhibitor and temozolomide are awaited.

8.4.2.2 International Society of Pediatric Oncology (SIOP) Trials

The French SIOP began multi-institutional trials for RMS in 1975 and has reported results from three studies to date. These studies mainly focus on using risk-adapted intensification of CXT, minimizing local therapy at the first place and saving them for salvage. In the first SIOP study (RMS-75), VACD was used in group III patients and early local therapy was compared to delayed local therapy after maximal CXT response [123]. Surgery was preferred over RT as the local therapy. Although the OS rate was only 40%, two arms were similar in terms of survival. In the second SIOP study (MMT-84), RT was administered only in patients with residual tumor after CXT and surgery [124]. The 5-year OS and EFS was reported 68% and 53%, respectively, with an isolated LR rate of 29%. The third SIOP study (MMT-89), showed that alkylating agents can be omitted in patients with the most favorable prognosis [125]. Radiotherapy was used in a few patients, and the LF rate was 34%.

The difference of the aim of SIOP and IRS trials is that in IRS studies early introduction of RT is encouraged in patients with residual tumor after surgery, but in SIOP studies RT is avoided in most patients but the ones with residual tumor after CXT and surgery. The comparison of IRS and SIOP studies revealed that in some patients, cure can be achieved without the addition of RT; however, in the presence of residual tumor after initial surgery, RT yields higher survival rates in most subsets of patients [126].

8.4.2.3 Cooperative Weichteilsarkom Studiengruppe (CWS) Trials

Another group that studied on RMS is the German-based CWS. In the CWS-81 trial; no, 40 Gy or 50 Gy RT was applied based on the response to CXT and second-look surgery [127]. The authors reported that prognosis is similar in patients with a complete response to CXT and in patients with an initial complete tumor resection. On the other hand, patients without a complete response to CXT by week 9 should undergo early surgery or RT. In non-metastatic patients, the 5-year DFS rate was found 68%, and the most common cause of failure was LR. In the CWS-86 study, all patients received ifosfamide but in patients with favorable prognosis the CXT scheme was shortened [128]. Hyperfractionated accelerated RT was used in most patients; 32 Gy after a good response and 54.4 Gy after a poor response to CXT in 1.6 Gy twice daily fractions concurrently with ifosfamide and doxorubicin. In case of complete response to CXT, no RT was administered. The study concluded that in most favorable patients, the duration of CXT can be reduced to 16 weeks, response rates are improved with the use of ifosfamide compared to cyclophosphamide, and hyperfractionated accelerated RT concurrent with CXT can easily be tolerated providing satisfactory LC rates. Most failures were again local in this trial, especially in patients with group II and III disease that did not receive RT. In the CWS-91 study, induction CXT and second-look surgery was encouraged in all patients, and RT was not applied in case of a complete resection and no high-risk features [129]. Other patients received 32 or 48 Gy RT in 1.6 Gy twice daily fractions depending on the response to initial CXT and risk factors. When compared to historical controls from the CWS-86 study, the rates of LC and EFS were improved with RT, lower doses of 32 or 48 Gy resulted in similar outcomes with higher doses in the CWS-86 study, and in group I-II disease with favorable risk factors, less intensive CXT yielded similar results compared to the more intensive regimen in CWS-86.

8.4.3 Treatment Recommendations

Multimodality approach is applied in patients with RMS. A non-morbid surgical resection should be performed if applicable. Otherwise, RT should be chosen because it offers equivalent rates of LC with organ preservation. Radiotherapy can be administered after multiple weeks of CXT to allow reduction in tumor size and to give a chance to a second-look surgery. However, in patients with parameningeal disease and intracranial extension, RT should be initiated within the first few weeks of the start of CXT [130].

Radiotherapy is used to eradicate microscopic disease after resection, treat gross disease, and consolidate visible sites of metastatic involvement. In patients with group I disease, based on the IRS I-III trials, RT should be applied in case of alveolar histology as it increases the rates of FFS and OS, but unnecessary for patients with embryonal histology [113]. For all patients in groups II, III and IV, RT is indicated in different doses based on surgical margins and residual tumor bulk. Besides these general concepts, specific treatment approaches are present based on tumor location.
  1. 1.

    Orbital tumors are one of the favorable sites; the histology is embryonal in most tumors, and lymphatic involvement and DM are very rare. Surgery is not recommended in orbital tumors to preserve vision. Biopsy is adequate for diagnosis. Treatment starts with VAC or VA CXT, and local RT begins between the third and twelfth week of treatment. 45 Gy RT is sufficient when cyclophosphamide-containing regimens are used, otherwise 50 Gy RT can be more adequate [120]. Adding RT to CXT resulted in >90% cure rates [115]. The LC and EFS rates are lower with CXT alone, and although salvage RT can still be curative, vision is generally impaired in this setting [131].

     
  2. 2.

    In parameningeal tumors of the H&N, RT is essential for maximizing the chance of cure [114, 115]. The most important point for these tumors are that they have a propensity for invading the skull base, causing cranial nerve palsy, and directly extending into the CNS, which can be seen up to 41% of patients [130]. Complete resection is usually not possible, and can delay the initiation of CXT. Historically, whole-brain RT was applied to all patients with parameningeal tumors for CNS prophylaxis. However, based on the results of IRS trials, the current approach is to avoid whole-brain RT, even in patients with direct intracranial tumor extension because multi-agent CXT and adequate irradiation of the primary tumor and adjacent meninges is sufficient. On the other hand, in patients with known meningeal dissemination, craniospinal irradiation should be applied. Based on the IRS studies, RT should be started within 2 weeks of diagnosis in the presence of intracranial tumor extension to improve LC [130]. In non-parameningeal H&N tumors, the prognosis is better and they require a less-intensive CXT regimen [115, 116]. Complete surgical resection is more possible for these tumors, and RT is indicated based on surgical margins. The rate of regional LN metastasis is 15% in these tumors; however, prophylactic irradiation of lymphatic sites is not necessary.

     
  3. 3.

    In bladder and prostate tumors, anterior pelvic exenteration was performed together with CXT historically, and RT was indicated in case of microscopic or gross residual disease with a survival rate of approximately 70% [132]. However, recent approach is to preserve the bladder. In the IRS-II trial, more conservative surgical approaches resulted in inferior DFS; however, with an intensified CXT regimen and routine RT in the proceeding IRS trials, survival rates were similar to aggressive surgery [133].

     
  4. 4.

    Patients with paratesticular tumors generally present with early-stage disease that is amenable to complete resection with a cure rate of approximately 90%. Inguinal orchiectomy is recommended; however, RPLND is still controversial, and some authors prefer intensified CXT instead and salvage RT, if necessary. In the IRS trials, on the other hand, ipsilateral RPLND is recommended for children ≥10 years of age [118].

     
  5. 5.

    In gynecologic tumors, the most common site is the vagina. Vaginal RMS is often diagnosed before the age of 3, and botyroid histology is common. Initial treatment requires surgery but because of cosmetic and functional deformities, total resection is not always possible. These tumors are generally sensitive to CXT; however, CXT alone results in high rates of LF [120, 122]. The Children’s Oncology Group (COG) recommends adjuvant RT in case of microscopic or gross residual tumor. For uterine, cervical, and vulvar tumors, initial surgery continues with CXT and RT based on surgical margins. Brachytherapy (BRT) is a good alternative to external beam RT (EBRT) with fewer complications and excellent LC rates.

     
  6. 6.

    Extremity tumors have poor prognosis with alveolar or undifferentiated histology, large tumor bulk, deep invasive, and a high probability of LN involvement and DM. Complete surgical resection is difficult to achieve, and RT with multi-agent CXT provides excellent LC rates.

     

The timing of RT depends on the risk groups and presence of any urgent situation. In low- and intermediate-risk disease, RT is performed after 12 weeks of CXT. However, patients with parameningeal tumors and intracranial extension should receive RT within 2 weeks of the treatment scheme. In high-risk disease, aggressive CXT is required and local therapies can be considered at week 20. If symptomatic metastasis is present, urgent RT can be administered. In asymptomatic patients with metastatic disease, these sites are irradiated with similar doses at the end of systemic therapy. Vincristine, cyclophosphamide, and irinotecan can be administered concurrently with RT. However, actinomycin-D should not be applied concurrently with RT because of its potential for increased skin and mucosal toxicities.

8.4.4 Treatment Planning

8.4.4.1 Simulation

Simulation for RT planning should be done with the affected part being stabilized properly. Intravenous contrast use is recommended.

8.4.4.2 Contouring

Imaging studies at the time of diagnosis and after CXT should be used to define the extent of disease. An MRI is essential for better visualization of the soft tissue component. In the first phase of RT planning, the gross tumor volume (GTV)-1 is the tumor at the time of diagnosis. Clinical target volume (CTV)-1 is formed by adding 1 cm to the GTV1, and should not extend beyond anatomic barriers without tumor involvement. The planning target volume (PTV)-1 is generally formed by adding a 0.5-cm margin to CTV1. This volume is prescribed 36 Gy and if the surgical margins are negative, it is the only phase. If surgical margins are positive, in the second phase, GTV2 is the residual tumor after CXT and surgery including the whole surgical bed, clips and biopsy tracts; CTV2 is GTV2+1 cm; and PTV2 is CTV2+0.5 cm. Prophylactic LN irradiation is not necessary if the patient will be receiving combination CXT.

Although the bony orbit and the adjacent globe are very thin and fragile, they are not involved by orbital RMS and should not be included in the CTV. If the tumor extends through these structures, parameningeal involvement should be considered. In these patients, and also in patients with parameningeal H&N tumors, the adjacent meninges should be covered in the RT field. For orbital tumors, irradiation of the entire orbit is not necessary. For parameningeal H&N tumors, the skull base should also be included in the CTV to cover the possible intracranial extension.

For paratesticular tumors, irradiation of the periaortic and ipsilateral iliac LNs is recommended if there is LN involvement. In case the scrotum was surgically violated or invaded by the tumor, hemiscrotectomy or, less commonly, scrotal irradiation is indicated. If scrotal irradiation is to be performed, orchiopexy should be considered prior to treatment. Similarly, oophoropexy should be considered prior to RT for girls with pelvic tumors.

8.4.4.3 Case Contouring

In our case, GTV1 was the pre-CXT tumor volume. By adding a 0.5 cm margin to GTV1, CTV1 was formed and 36 Gy was prescribed to this volume. The reason for the 0.5 cm margin was the anatomical borders that were not invaded by the tumor. The post-CXT and postsurgical volume with all surgical clips was contoured as GTV2. A 1-cm margin was added to GTV2 to form the CTV2, and a 14.4 Gy boost dose was prescribed to this volume (Figs. 8.23 and 8.24). 0.5-cm margin was added to both CTVs to form PTVs, and the total dose was 50.4 Gy (Fig. 8.25).
Fig. 8.23

The delineation of the case. Cyan = GTV1, red = CTV1, pink = GTV2, magenta = CTV2

Fig. 8.24

Transverse (a), coronal (c), and sagittal (d) views of contouring the case. (b) shows all target volumes and critical organs in coronal view

Fig. 8.25

Treatment plan of the case

8.4.4.4 Prescription Dose

Radiotherapy doses differ according to the surgical margin status and histological subtype. If the surgical margins are negative, RT is not indicated for embryonal histology, but 36 Gy RT is indicated for alveolar histology. If the surgical margins are microscopically positive, tumors of both histology should receive 36 Gy. If there is LN involvement, the involved regional LN area should receive 41.4 Gy in both histological subtypes. If there is gross residual disease, 50.4 Gy is prescribed for both histologies. Doses are delivered at 1.8 Gy per fraction daily.

For orbital tumors, a definitive RT dose of 45 Gy RT in 1.8 Gy daily fractions yields excellent local control. For parameningeal H&N tumors, 50.4 Gy in 28 fractions to the primary site is commonly used.

8.4.4.5 Dose Constraints for Critical Structures

Dose constraints for organs at risk of certain tumor locations can be found in related chapters.

8.4.5 Follow-Up (F/U) Recommendations

Patients are followed up with physical examination, laboratory studies, MRI of the primary area, CT of the chest and other metastatic imaging every 3 months in the first year; physical examination, laboratory studies, MRI of the primary area, CT of the chest and other metastatic imaging every 4 months in the second and third years; physical examination, MRI of the primary area and chest radiograph every 6 months in the fourth and fifth years, and annually thereafter.

References

  1. 1.
    Fletcher CDM, Unni K, Mertens F. World Health Organization classification of tumours: pathology and genetics of tumours of soft tissue and bone. Lyon: IARC Press; 2002.Google Scholar
  2. 2.
    Burningham Z, Hashibe M, Spector L, Schiffman JD. The epidemiology of sarcoma. Clin Sarcoma Res. 2012;2(1):14.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Lawrence W Jr, Donegan WL, Natarajan N, Mettlin C, Beart R, Winchester D. Adult soft tissue sarcomas. A pattern of care survey of the American College of Surgeons. Ann Surg. 1987;205(4):349–59.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Simon MA, Enneking WF. The management of soft-tissue sarcomas of the extremities. J Bone Joint Surg Am. 1976;58(3):317–27.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Enneking WF, Spanier SS, Malawer MM. The effect of the Anatomic setting on the results of surgical procedures for soft parts sarcoma of the thigh. Cancer. 1981;47(5):1005–22.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Daigeler A, Klein-Hitpass L, Stricker I, Muller O, Kuhnen C, Chromik AM, et al. Malignant fibrous histiocytoma—pleomorphic sarcoma, NOS gene expression, histology, and clinical course. A pilot study. Langenbeck’s Arch Surg. 2010;395(3):261–75.CrossRefGoogle Scholar
  7. 7.
    Coindre JM, Terrier P, Guillou L, Le Doussal V, Collin F, Ranchere D, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91(10):1914–26.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF. Analysis of prognostic factors in 1041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996;14(5):1679–89.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS, et al. Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients. Cancer. 2003;97(10):2530–43.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Parsons HM, Habermann EB, Tuttle TM, Al-Refaie WB. Conditional survival of extremity soft-tissue sarcoma: results beyond the staging system. Cancer. 2011;117(5):1055–60.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Gutierrez JC, Perez EA, Franceschi D, Moffat FL Jr, Livingstone AS, Koniaris LG. Outcomes for soft-tissue sarcoma in 8249 cases from a large state cancer registry. J Surg Res. 2007;141(1):105–14.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Canter RJ, Beal S, Borys D, Martinez SR, Bold RJ, Robbins AS. Interaction of histologic subtype and histologic grade in predicting survival for soft-tissue sarcomas. J Am Coll Surg. 2010;210(2):191–8.e2.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennan M, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg. 1982;196(3):305–15.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Baldini EH, Goldberg J, Jenner C, Manola JB, Demetri GD, Fletcher CD, et al. Long-term outcomes after function-sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk. J Clin Oncol. 1999;17(10):3252–9.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Pisters PW, Pollock RE, Lewis VO, Yasko AW, Cormier JN, Respondek PM, et al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg. 2007;246(4):675–81; discussion 81-2.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Cahlon O, Spierer M, Brennan MF, Singer S, Alektiar KM. Long-term outcomes in extremity soft tissue sarcoma after a pathologically negative re-resection and without radiotherapy. Cancer. 2008;112(12):2774–9.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Fabrizio PL, Stafford SL, Pritchard DJ. Extremity soft-tissue sarcomas selectively treated with surgery alone. Int J Radiat Oncol Biol Phys. 2000;48(1):227–32.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS. Surgical margins and reresection in the management of patients with soft tissue sarcoma using conservative surgery and radiation therapy. Cancer. 2003;97(10):2544–53.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Lewis JJ, Leung D, Espat J, Woodruff JM, Brennan MF. Effect of reresection in extremity soft tissue sarcoma. Ann Surg. 2000;231(5):655–63.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol. 1996;14(3):859–68.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. 1998;16(1):197–203.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    O’Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359(9325):2235–41.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Alektiar KM, Leung D, Zelefsky MJ, Healey JH, Brennan MF. Adjuvant brachytherapy for primary high-grade soft tissue sarcoma of the extremity. Ann Surg Oncol. 2002;9(1):48–56.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Nag S, Shasha D, Janjan N, Petersen I, Zaider M, American Brachytherapy Society. The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 2001;49(4):1033–43.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Fein DA, Lee WR, Lanciano RM, Corn BW, Herbert SH, Hanlon AL, et al. Management of extremity soft tissue sarcomas with limb-sparing surgery and postoperative irradiation: do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control? Int J Radiat Oncol Biol Phys. 1995;32(4):969–76.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Dickie CI, Griffin AM, Parent AL, Chung PW, Catton CN, Svensson J, et al. The relationship between local recurrence and radiotherapy treatment volume for soft tissue sarcomas treated with external beam radiotherapy and function preservation surgery. Int J Radiat Oncol Biol Phys. 2012;82(4):1528–34.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Kim B, Chen YL, Kirsch DG, Goldberg SI, Kobayashi W, Kung JH, et al. An effective preoperative three-dimensional radiotherapy target volume for extremity soft tissue sarcoma and the effect of margin width on local control. Int J Radiat Oncol Biol Phys. 2010;77(3):843–50.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Mendenhall WM, Indelicato DJ, Scarborough MT, Zlotecki RA, Gibbs CP, Mendenhall NP, et al. The management of adult soft tissue sarcomas. Am J Clin Oncol. 2009;32(4):436–42.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Baldini EH, Lapidus MR, Wang Q, Manola J, Orgill DP, Pomahac B, et al. Predictors for major wound complications following preoperative radiotherapy and surgery for soft-tissue sarcoma of the extremities and trunk: importance of tumor proximity to skin surface. Ann Surg Oncol. 2013;20(5):1494–9.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Cheng EY, Dusenbery KE, Winters MR, Thompson RC. Soft tissue sarcomas: preoperative versus postoperative radiotherapy. J Surg Oncol. 1996;61(2):90–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Davis AM, O'Sullivan B, Turcotte R, Bell R, Catton C, Chabot P, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol. 2005;75(1):48–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Holt GE, Griffin AM, Pintilie M, Wunder JS, Catton C, O’Sullivan B, et al. Fractures following radiotherapy and limb-salvage surgery for lower extremity soft-tissue sarcomas. A comparison of high-dose and low-dose radiotherapy. J Bone Joint Surg Am. 2005;87(2):315–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Al-Absi E, Farrokhyar F, Sharma R, Whelan K, Corbett T, Patel M, et al. A systematic review and meta-analysis of oncologic outcomes of pre- versus postoperative radiation in localized resectable soft-tissue sarcoma. Ann Surg Oncol. 2010;17(5):1367–74.PubMedCrossRefGoogle Scholar
  34. 34.
    Alektiar KM, Brennan MF, Healey JH, Singer S. Impact of intensity-modulated radiation therapy on local control in primary soft-tissue sarcoma of the extremity. J Clin Oncol. 2008;26(20):3440–4.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Folkert MR, Singer S, Brennan MF, Kuk D, Qin LX, Kobayashi WK, et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol. 2014;32(29):3236–41.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Alektiar KM, Brennan MF, Singer S. Local control comparison of adjuvant brachytherapy to intensity-modulated radiotherapy in primary high-grade sarcoma of the extremity. Cancer. 2011;117(14):3229–34.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    O’Sullivan B, Griffin AM, Dickie CI, Sharpe MB, Chung PW, Catton CN, et al. Phase 2 study of preoperative image-guided intensity-modulated radiation therapy to reduce wound and combined modality morbidities in lower extremity soft tissue sarcoma. Cancer. 2013;119(10):1878–84.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Wang D, Zhang Q, Eisenberg BL, Kane JM, Li XA, Lucas D, et al. Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: results of radiation therapy oncology group RTOG-0630 trial. J Clin Oncol. 2015;33(20):2231–8.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet. 1997;350(9092):1647–54.CrossRefGoogle Scholar
  40. 40.
    Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113(3):573–81.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol. 2012;13(10):1045–54.PubMedCrossRefGoogle Scholar
  42. 42.
    Gortzak E, Azzarelli A, Buesa J, Bramwell VH, van Coevorden F, van Geel AN, et al. A randomised phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer. 2001;37(9):1096–103.PubMedCrossRefGoogle Scholar
  43. 43.
    Kraybill WG, Harris J, Spiro IJ, Ettinger DS, DeLaney TF, Blum RH, et al. Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. Cancer. 2010;116(19):4613–21.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    DeLaney TF, Spiro IJ, Suit HD, Gebhardt MC, Hornicek FJ, Mankin HJ, et al. Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys. 2003;56(4):1117–27.PubMedCrossRefGoogle Scholar
  45. 45.
    Wang D, Bosch W, Roberge D, Finkelstein SE, Petersen I, Haddock M, et al. RTOG sarcoma radiation oncologists reach consensus on gross tumor volume and clinical target volume on computed tomographic images for preoperative radiotherapy of primary soft tissue sarcoma of extremity in Radiation Therapy Oncology Group studies. Int J Radiat Oncol Biol Phys. 2011;81(4):e525–8.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    White LM, Wunder JS, Bell RS, O’Sullivan B, Catton C, Ferguson P, et al. Histologic assessment of peritumoral edema in soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2005;61(5):1439–45.PubMedCrossRefGoogle Scholar
  47. 47.
    Devisetty K, Kobayashi W, Suit HD, Goldberg SI, Niemierko A, Chen YL, et al. Low-dose neoadjuvant external beam radiation therapy for soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2011;80(3):779–86.PubMedCrossRefGoogle Scholar
  48. 48.
    Alektiar KM, Velasco J, Zelefsky MJ, Woodruff JM, Lewis JJ, Brennan MF. Adjuvant radiotherapy for margin-positive high-grade soft tissue sarcoma of the extremity. Int J Radiat Oncol Biol Phys. 2000;48(4):1051–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Holloway CL, Delaney TF, Alektiar KM, Devlin PM, O’Farrell DA, Demanes DJ. American Brachytherapy Society (ABS) consensus statement for sarcoma brachytherapy. Brachytherapy. 2013;12(3):179–90.PubMedCrossRefGoogle Scholar
  50. 50.
    Porter GA, Baxter NN, Pisters PW. Retroperitoneal sarcoma: a population-based analysis of epidemiology, surgery, and radiotherapy. Cancer. 2006;106(7):1610–6.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Anaya DA, Lahat G, Wang X, Xiao L, Pisters PW, Cormier JN, et al. Postoperative nomogram for survival of patients with retroperitoneal sarcoma treated with curative intent. Ann Oncol. 2010;21(2):397–402.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Pacelli F, Tortorelli AP, Rosa F, Papa V, Bossola M, Sanchez AM, et al. Retroperitoneal soft tissue sarcoma: prognostic factors and therapeutic approaches. Tumori. 2008;94(4):497–504.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Schwarzbach MH, Hohenberger P. Current concepts in the management of retroperitoneal soft tissue sarcoma. Recent Results Cancer Res. 2009;179:301–19.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Stoeckle E, Coindre JM, Bonvalot S, Kantor G, Terrier P, Bonichon F, et al. Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer. 2001;92(2):359–68.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Lewis JJ, Leung D, Woodruff JM, Brennan MF. Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg. 1998;228(3):355–65.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Hassan I, Park SZ, Donohue JH, Nagorney DM, Kay PA, Nasciemento AG, et al. Operative management of primary retroperitoneal sarcomas: a reappraisal of an institutional experience. Ann Surg. 2004;239(2):244–50.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Catton CN, O’Sullivan B, Kotwall C, Cummings B, Hao Y, Fornasier V. Outcome and prognosis in retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 1994;29(5):1005–10.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Gronchi A, Casali PG, Fiore M, Mariani L, Lo Vullo S, Bertulli R, et al. Retroperitoneal soft tissue sarcomas: patterns of recurrence in 167 patients treated at a single institution. Cancer. 2004;100(11):2448–55.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Singer S, Antonescu CR, Riedel E, Brennan MF. Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. Ann Surg. 2003;238(3):358–70; discussion 70-1.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Ferrario T, Karakousis CP. Retroperitoneal sarcomas: grade and survival. Arch Surg. 2003;138(3):248–51.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Baldini EH, Wang D, Haas RL, Catton CN, Indelicato DJ, Kirsch DG, et al. Treatment guidelines for preoperative radiation therapy for retroperitoneal sarcoma: preliminary consensus of an international expert panel. Int J Radiat Oncol Biol Phys. 2015;92(3):602–12.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Mori S, Hara R, Yanagi T, Sharp GC, Kumagai M, Asakura H, et al. Four-dimensional measurement of intrafractional respiratory motion of pancreatic tumors using a 256 multi-slice CT scanner. Radiother Oncol. 2009;92(2):231–7.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Wysocka B, Kassam Z, Lockwood G, Brierley J, Dawson LA, Buckley CA, et al. Interfraction and respiratory organ motion during conformal radiotherapy in gastric cancer. Int J Radiat Oncol Biol Phys. 2010;77(1):53–9.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Langen KM, Jones DT. Organ motion and its management. Int J Radiat Oncol Biol Phys. 2001;50(1):265–78.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Fein DA, Corn BW, Lanciano RM, Herbert SH, Hoffman JP, Coia LR. Management of retroperitoneal sarcomas: does dose escalation impact on locoregional control? Int J Radiat Oncol Biol Phys. 1995;31(1):129–34.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Sindelar WF, Kinsella TJ, Chen PW, DeLaney TF, Tepper JE, Rosenberg SA, et al. Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial. Arch Surg. 1993;128(4):402–10.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Alektiar KM, Hu K, Anderson L, Brennan MF, Harrison LB. High-dose-rate intraoperative radiation therapy (HDR-IORT) for retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys. 2000;47(1):157–63.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Jones JJ, Catton CN, O’Sullivan B, Couture J, Heisler RL, Kandel RA, et al. Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol. 2002;9(4):346–54.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Gieschen HL, Spiro IJ, Suit HD, Ott MJ, Rattner DW, Ancukiewicz M, et al. Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2001;50(1):127–31.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Petersen IA, Haddock MG, Donohue JH, Nagorney DM, Grill JP, Sargent DJ, et al. Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 2002;52(2):469–75.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Ahrens S, Hoffmann C, Jabar S, Braun-Munzinger G, Paulussen M, Dunst J, et al. Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study. Med Pediatr Oncol. 1999;32(3):186–95.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Marcus RB Jr, Berrey BH, Graham-Pole J, Mendenhall NP, Scarborough MT. The treatment of Ewing’s sarcoma of bone at the University of Florida: 1969 to 1998. Clin Orthop Relat Res. 2002;397:290–7.CrossRefGoogle Scholar
  73. 73.
    Oberlin O, Patte C, Demeocq F, Lacombe MJ, Brunat-Mentigny M, Demaille MC, et al. The response to initial chemotherapy as a prognostic factor in localized Ewing’s sarcoma. Eur J Cancer Clin Oncol. 1985;21(4):463–7.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Bacci G, Ferrari S, Longhi A, Donati D, Barbieri E, Forni C, et al. Role of surgery in local treatment of Ewing's sarcoma of the extremities in patients undergoing adjuvant and neoadjuvant chemotherapy. Oncol Rep. 2004;11(1):111–20.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Schuck A, Ahrens S, Paulussen M, Kuhlen M, Konemann S, Rube C, et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys. 2003;55(1):168–77.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Schuck A, Hofmann J, Rube C, Hillmann A, Ahrens S, Paulussen M, et al. Radiotherapy in Ewing’s sarcoma and PNET of the chest wall: results of the trials CESS 81, CESS 86 and EICESS 92. Int J Radiat Oncol Biol Phys. 1998;42(5):1001–6.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Nesbit ME Jr, Gehan EA, Burgert EO Jr, Vietti TJ, Cangir A, Tefft M, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing’s sarcoma of bone: a long-term follow-up of the First Intergroup study. J Clin Oncol. 1990;8(10):1664–74.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Burgert EO Jr, Nesbit ME, Garnsey LA, Gehan EA, Herrmann J, Vietti TJ, et al. Multimodal therapy for the management of nonpelvic, localized Ewing’s sarcoma of bone: intergroup study IESS-II. J Clin Oncol. 1990;8(9):1514–24.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348(8):694–701.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Granowetter L, Womer R, Devidas M, Krailo M, Wang C, Bernstein M, et al. Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children’s Oncology Group Study. J Clin Oncol. 2009;27(15):2536–41.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(33):4148–54.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Jurgens H, Exner U, Gadner H, Harms D, Michaelis J, Sauer R, et al. Multidisciplinary treatment of primary Ewing’s sarcoma of bone. A 6-year experience of a European Cooperative Trial. Cancer. 1988;61(1):23–32.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing’s Sarcoma Study CESS 86. J Clin Oncol. 2001;19(6):1818–29.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, et al. Results of the EICESS-92 Study: two randomized trials of Ewing’s sarcoma treatment—cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008;26(27):4385–93.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Craft AW, Cotterill SJ, Bullimore JA, Pearson D. Long-term results from the first UKCCSG Ewing’s Tumour Study (ET-1). United Kingdom Children’s Cancer Study Group (UKCCSG) and the Medical Research Council Bone Sarcoma Working Party. Eur J Cancer. 1997;33(7):1061–9.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Craft A, Cotterill S, Malcolm A, Spooner D, Grimer R, Souhami R, et al. Ifosfamide-containing chemotherapy in Ewing’s sarcoma: The Second United Kingdom Children’s Cancer Study Group and the Medical Research Council Ewing’s Tumor Study. J Clin Oncol. 1998;16(11):3628–33.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Rosen G, Caparros B, Mosende C, McCormick B, Huvos AG, Marcove RC. Curability of Ewing’s sarcoma and considerations for future therapeutic trials. Cancer. 1978;41(3):888–99.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Kushner BH, Meyers PA, Gerald WL, Healey JH, La Quaglia MP, Boland P, et al. Very-high-dose short-term chemotherapy for poor-risk peripheral primitive neuroectodermal tumors, including Ewing’s sarcoma, in children and young adults. J Clin Oncol. 1995;13(11):2796–804.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Kolb EA, Kushner BH, Gorlick R, Laverdiere C, Healey JH, LaQuaglia MP, et al. Long-term event-free survival after intensive chemotherapy for Ewing’s family of tumors in children and young adults. J Clin Oncol. 2003;21(18):3423–30.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Hayes FA, Thompson EI, Meyer WH, Kun L, Parham D, Rao B, et al. Therapy for localized Ewing’s sarcoma of bone. J Clin Oncol. 1989;7(2):208–13.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Meyer WH, Kun L, Marina N, Roberson P, Parham D, Rao B, et al. Ifosfamide plus etoposide in newly diagnosed Ewing’s sarcoma of bone. J Clin Oncol. 1992;10(11):1737–42.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Marina NM, Pappo AS, Parham DM, Cain AM, Rao BN, Poquette CA, et al. Chemotherapy dose-intensification for pediatric patients with Ewing’s family of tumors and desmoplastic small round-cell tumors: a feasibility study at St. Jude Children’s Research Hospital. J Clin Oncol. 1999;17(1):180–90.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Bacci G, Mercuri M, Longhi A, Bertoni F, Barbieri E, Donati D, et al. Neoadjuvant chemotherapy for Ewing’s tumour of bone: recent experience at the Rizzoli Orthopaedic Institute. Eur J Cancer. 2002;38(17):2243–51.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Oberlin O, Deley MC, Bui BN, Gentet JC, Philip T, Terrier P, et al. Prognostic factors in localized Ewing’s tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer. 2001;85(11):1646–54.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Gaspar N, Rey A, Berard PM, Michon J, Gentet JC, Tabone MD, et al. Risk adapted chemotherapy for localised Ewing’s sarcoma of bone: the French EW93 study. Eur J Cancer. 2012;48(9):1376–85.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Elomaa I, Blomqvist CP, Saeter G, Akerman M, Stenwig E, Wiebe T, et al. Five-year results in Ewing’s sarcoma. The Scandinavian Sarcoma Group experience with the SSG IX protocol. Eur J Cancer. 2000;36(7):875–80.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Ladenstein R, Potschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin O, et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol. 2010;28(20):3284–91.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Enneking WF. A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res. 1986;204:9–24.Google Scholar
  99. 99.
    Dunst J, Jurgens H, Sauer R, Pape H, Paulussen M, Winkelmann W, et al. Radiation therapy in Ewing’s sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys. 1995;32(4):919–30.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Bacci G, Longhi A, Briccoli A, Bertoni F, Versari M, Picci P. The role of surgical margins in treatment of Ewing’s sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65(3):766–72.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Schuck A, Ahrens S, von Schorlemer I, Kuhlen M, Paulussen M, Hunold A, et al. Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. Int J Radiat Oncol Biol Phys. 2005;63(5):1562–7.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Ozaki T, Hillmann A, Hoffmann C, Rube C, Blasius S, Dunst J, et al. Significance of surgical margin on the prognosis of patients with Ewing’s sarcoma. A report from the Cooperative Ewing’s Sarcoma Study. Cancer. 1996;78(4):892–900.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Donaldson S, Shuster J, Andreozzi C. The Pediatric Oncology Group (POG) experience in Ewing’s sarcoma of bone. Med Pediatr Oncol. 1989;17:283.Google Scholar
  104. 104.
    Paulussen M, Ahrens S, Burdach S, Craft A, Dockhorn-Dworniczak B, Dunst J, et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol. 1998;9(3):275–81.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Donaldson SS, Torrey M, Link MP, Glicksman A, Gilula L, Laurie F, et al. A multidisciplinary study investigating radiotherapy in Ewing’s sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys. 1998;42(1):125–35.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Krasin MJ, Rodriguez-Galindo C, Billups CA, Davidoff AM, Neel MD, Merchant TE, et al. Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. Int J Radiat Oncol Biol Phys. 2004;60(3):830–8.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Fuchs B, Valenzuela RG, Inwards C, Sim FH, Rock MG. Complications in long-term survivors of Ewing sarcoma. Cancer. 2003;98(12):2687–92.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Bolek TW, Marcus RB Jr, Mendenhall NP, Scarborough MT, Graham-Pole J. Local control and functional results after twice-daily radiotherapy for Ewing’s sarcoma of the extremities. Int J Radiat Oncol Biol Phys. 1996;35(4):687–92.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Wagner LM, Neel MD, Pappo AS, Merchant TE, Poquette CA, Rao BN, et al. Fractures in pediatric Ewing sarcoma. J Pediatr Hematol Oncol. 2001;23(9):568–71.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Kuttesch JF Jr, Wexler LH, Marcus RB, Fairclough D, Weaver-McClure L, White M, et al. Second malignancies after Ewing’s sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol. 1996;14(10):2818–25.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Tucker MA, D'Angio GJ, Boice JD Jr, Strong LC, Li FP, Stovall M, et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med. 1987;317(10):588–93.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Maurer HM, Beltangady M, Gehan EA, Crist W, Hammond D, Hays DM, et al. The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer. 1988;61(2):209–20.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Wolden SL, Anderson JR, Crist WM, Breneman JC, Wharam MD Jr, Wiener ES, et al. Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol. 1999;17(11):3468–75.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Maurer HM, Gehan EA, Beltangady M, Crist W, Dickman PS, Donaldson SS, et al. The Intergroup Rhabdomyosarcoma Study-II. Cancer. 1993;71(5):1904–22.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Crist W, Gehan EA, Ragab AH, Dickman PS, Donaldson SS, Fryer C, et al. The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol. 1995;13(3):610–30.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, et al. Intergroup Rhabdomyosarcoma Study-IV: results for patients with nonmetastatic disease. J Clin Oncol. 2001;19(12):3091–102.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Donaldson SS, Meza J, Breneman JC, Crist WM, Laurie F, Qualman SJ, et al. Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma—a report from the IRSG. Int J Radiat Oncol Biol Phys. 2001;51(3):718–28.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Wiener ES, Anderson JR, Ojimba JI, Lobe TE, Paidas C, Andrassy RJ, et al. Controversies in the management of paratesticular rhabdomyosarcoma: is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma? Semin Pediatr Surg. 2001;10(3):146–52.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Raney RB, Walterhouse DO, Meza JL, Andrassy RJ, Breneman JC, Crist WM, et al. Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol. 2011;29(10):1312–8.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Breneman J, Meza J, Donaldson SS, Raney RB, Wolden S, Michalski J, et al. Local control with reduced-dose radiotherapy for low-risk rhabdomyosarcoma: a report from the Children’s Oncology Group D9602 study. Int J Radiat Oncol Biol Phys. 2012;83(2):720–6.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Arndt CA, Stoner JA, Hawkins DS, Rodeberg DA, Hayes-Jordan AA, Paidas CN, et al. Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: Children’s Oncology Group study D9803. J Clin Oncol. 2009;27(31):5182–8.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Walterhouse DO, Meza JL, Breneman JC, Donaldson SS, Hayes-Jordan A, Pappo AS, et al. Local control and outcome in children with localized vaginal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma committee of the Children’s Oncology Group. Pediatr Blood Cancer. 2011;57(1):76–83.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Rodary C, Rey A, Olive D, Flamant F, Quintana E, Brunat-Mentigny M, et al. Prognostic factors in 281 children with nonmetastatic rhabdomyosarcoma (RMS) at diagnosis. Med Pediatr Oncol. 1988;16(2):71–7.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Flamant F, Rodary C, Rey A, Praquin MT, Sommelet D, Quintana E, et al. Treatment of non-metastatic rhabdomyosarcomas in childhood and adolescence. Results of the second study of the International Society of Paediatric Oncology: MMT84. Eur J Cancer. 1998;34(7):1050–62.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Stevens MC, Rey A, Bouvet N, Ellershaw C, Flamant F, Habrand JL, et al. Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology—SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol. 2005;23(12):2618–28.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Donaldson SS, Anderson JR. Rhabdomyosarcoma: many similarities, a few philosophical differences. J Clin Oncol. 2005;23(12):2586–7.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Koscielniak E, Jurgens H, Winkler K, Burger D, Herbst M, Keim M, et al. Treatment of soft tissue sarcoma in childhood and adolescence. A report of the German Cooperative Soft Tissue Sarcoma Study. Cancer. 1992;70(10):2557–67.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Koscielniak E, Harms D, Henze G, Jurgens H, Gadner H, Herbst M, et al. Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J Clin Oncol. 1999;17(12):3706–19.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Dantonello TM, Int-Veen C, Harms D, Leuschner I, Schmidt BF, Herbst M, et al. Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol. 2009;27(9):1446–55.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Michalski JM, Meza J, Breneman JC, Wolden SL, Laurie F, Jodoin M, et al. Influence of radiation therapy parameters on outcome in children treated with radiation therapy for localized parameningeal rhabdomyosarcoma in Intergroup Rhabdomyosarcoma Study Group trials II through IV. Int J Radiat Oncol Biol Phys. 2004;59(4):1027–38.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Rousseau P, Flamant F, Quintana E, Voute PA, Gentet JC. Primary chemotherapy in rhabdomyosarcomas and other malignant mesenchymal tumors of the orbit: results of the International Society of Pediatric Oncology MMT 84 Study. J Clin Oncol. 1994;12(3):516–21.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Rodary C, Gehan EA, Flamant F, Treuner J, Carli M, Auquier A, et al. Prognostic factors in 951 nonmetastatic rhabdomyosarcoma in children: a report from the International Rhabdomyosarcoma Workshop. Med Pediatr Oncol. 1991;19(2):89–95.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Raney RB Jr, Gehan EA, Hays DM, Tefft M, Newton WA Jr, Haeberlen V, et al. Primary chemotherapy with or without radiation therapy and/or surgery for children with localized sarcoma of the bladder, prostate, vagina, uterus, and cervix. A comparison of the results in Intergroup Rhabdomyosarcoma Studies I and II. Cancer. 1990;66(10):2072–81.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sezin Yuce Sari
    • 1
  • Gozde Yazici
    • 1
  • Melis Gultekin
    • 1
  • Pervin Hurmuz
    • 1
  • Murat Gurkaynak
    • 1
  • Gokhan Ozyigit
    • 1
  1. 1.Department of Radiation Oncology, Faculty of MedicineHacettepe UniversityAnkaraTurkey

Personalised recommendations