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Background: Local recurrence of microinvasive sarcoma or benign aggressive pathologies can be limb- and life-threatening. Although frozen pathology is reliable, tumor microinvasion can be subtle or missed, having an impact on surgical margins and postoperative radiation planning. The authors' service has begun to temporize the tumor bed after primary tumor excision with a wound vacuum-assisted closure (VAC) pending formal margin analysis, with coverage performed in the setting of final negative margins., Methods: This retrospective analysis included all patients managed at a tertiary referral cancer center with VAC temporization after soft tissue sarcoma or benign aggressive tumor excision from 1 January 2000 to 1 January 2019 and at least 2 years of oncologic follow-up evaluation. The primary outcome was local recurrence. The secondary outcomes were distant recurrence, unplanned return to the operating room for wound/infectious indications, thromboembolic events, and tumor-related deaths., Results: For 62 patients, VAC temporization was performed. The mean age of the patients was 62.2 ± 22.3 years (median 66.5 years; 95% confidence interval [CI] 61.7-72.5 years), and the mean age-adjusted Charlson Comorbidity Index was 5.3 ± 1.9. The most common tumor histology was myxofibrosarcoma (51.6%, 32/62). The mean volume was 124.8 ± 324.1 cm 3 , and 35.5% (22/62) of the cases were subfascial. Local recurrences occurred for 8.1% (5/62) of the patients. Three of these five patients had planned positive margins, and 17.7% (11/62) of the patients had an unplanned return to the operating room. No demographic or tumor factors were associated with unplanned surgery., Conclusions: The findings showed that VAC-temporized management of microinvasive sarcoma and benign aggressive pathologies yields favorable local recurrence and unplanned operating room rates suggestive of oncologic and technical safety. These findings will need validation in a future randomized controlled trial., (© 2021. Society of Surgical Oncology.)

Background and Objectives: Radiotherapy (RT) enables conservative surgery for soft tissue sarcoma (STS). RT can be delivered either pre-operatively (PreRT) or postoperatively (PORT), yet in some patients, neither approach is fully satisfactory (e.g., urgent surgery or wound healing risk prevents PreRT, yet PORT alone cannot cover the entire surgical field). We hypothesized that, in such situations, low-dose PreRT (LD-PreRT) would decrease the risk of intraoperative tumor seeding and thus permit PORT to a reduced volume (covering the high-risk tumor bed but not all surgically manipulated tissues)., Methods: We identified a single-institution retrospective cohort of 78 patients treated with LD-PreRT (10-30 Gy), resection, and PORT between 1980 and 2018., Results: At a median follow-up of 8.2 years, 8-year overall survival (OS) was 65.9%, disease-free survival (DFS) 50.5%, and local control (LC) 76.7%; in 45 patients with extremity/superficial trunk (E/ST) STS, 8-year LC was 80.9%. Both before and after propensity score adjustment, there were no differences in OS, DFS, or LC between this cohort and a separate cohort of 394 STS (221 E/ST-STS) patients treated with surgery and PORT alone., Conclusions: In patients for whom neither PreRT nor PORT alone is optimal, LD-PreRT may prevent intraoperative tumor seeding and enable PORT to a reduced volume while preserving oncologic outcomes., (© 2021 Wiley Periodicals LLC.)

Purpose: This guideline provides evidence-based recommendations addressing the indications for radiation therapy (RT), sequencing of local therapies, and appropriate dose and planning techniques for management of primary, operable, localized, soft tissue sarcoma (STS) in adults., Methods: The American Society for Radiation Oncology convened a task force to address 5 key questions focused on the use of RT for management of STS. These questions included indications for RT for STS of the extremity and superficial trunk; considerations for sequencing of RT with respect to surgery, dose of RT, appropriate treatment volumes and techniques; and the role of RT in management of retroperitoneal sarcoma. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength., Results: Multidisciplinary evaluation and decision making are recommended for all cases of STS. RT is recommended for patients in whom there is increased risk of local recurrence of resected STS, particularly if close or microscopically positive margins are anticipated or have occurred. When RT is indicated, preoperative RT is strongly recommended over postoperative RT. Postoperative RT is conditionally recommended in specific clinical circumstances (eg, uncontrolled pain or bleeding) or when the risk of wound complications outweighs that of late toxicity from RT. Routine use of RT in addition to oncologic resection for retroperitoneal sarcoma is conditionally not recommended. When RT is used for retroperitoneal sarcoma, preoperative RT is recommended, whereas postoperative RT is not recommended., Conclusions: Based on currently published data, the American Society for Radiation Oncology task force has proposed evidence-based recommendations regarding the use of RT for STS in adults. Future studies will ascertain whether alterations in dosing and sequencing may optimize outcomes and quality of life., (Copyright © 2021 American Society for Radiation Oncology. All rights reserved.)

Opinion Statement: Soft tissue sarcomas (STS) are rare, aggressive, and heterogenous tumors, comprising approximately 1% of adult cancers with over 50 different subtypes. The mainstay of treatment for retroperitoneal sarcomas (RPS) includes surgical resection. The addition of radiation therapy (RT), either preoperatively or postoperatively, has been used to potentially decrease the risk of local recurrence. The recently published results from STRASS (EORTC-STBSG 62092-22092), which randomized patients to receive or not receive preoperative radiation, indicate no abdominal recurrence-free survival benefit (primary endpoint) nor overall survival benefit to date from the addition of preoperative RT prior to surgical resection in patients with RPS. Keeping in mind caveats of subgroup analyses, the data show a significant reduction in local recurrence with radiation therapy in resected patients and non-significant trends toward improved abdominal recurrence-free survival in all patients and improved local control and abdominal recurrence-free survival in patients with liposarcoma and low-grade sarcoma. Given the high rate of local failure with surgery alone, it is possible that higher RT dose and/or selective RT dose painting may improve outcomes. Prior to treatment, the authors encourage multidisciplinary review and discussion of management options at a sarcoma center for patients with RPS. Selective use of RT may be considered for patients at high risk of local recurrence.

Background/objectives: Oligometastatic sarcoma pulmonary metastases (PM's) are traditionally treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) is an effective, safe alternative to surgery that can achieve excellent local control (LC) with a favorable toxicity profile., Methods: Patients treated with SBRT for sarcoma PM's from 2011 to 2016 at Massachusetts General Hospital and the University of Pennsylvania were included. Median dose was 50 Gy. Patients underwent computed tomography (CT) or positron emission tomography/CT Q3 months post-SBRT., Results: 44 patients with 56 separate PM's were treated with SBRT. Median age was 59 (range 19-82). 82% received prior chemotherapy, 66% had prior pulmonary resections (range, 1-5 resections), and 32% received prior thoracic radiotherapy. Median lesion size was 2.0 cm (range, 0.5-8.1 cm). Median follow-up was 16 months and 25 months for patients alive at last follow-up. Overall survival at 12 and 24 months was 74% (95% confidence interval [CI], 67%-81%) and 46% (95% CI, 38%-55%). LC at 12 and 24 months was 96% (95% CI, 93%-98%) and 90% (95% CI, 84%-96%). LC and overall survival did not differ based on age, gender, histology, fractionation, lesion location, or size (P > .05). Three developed Common Terminology Criteria for Adverse Events version 4 grade-2 chest-wall toxicities; one had grade-2 pneumonitis., Conclusions: In the first multi-institutional series on SBRT for sarcoma PM's, SBRT has excellent LC and is well-tolerated. SBRT should be considered as an alternative/complement to resection., (© 2020 Wiley Periodicals LLC.)

Competing Interests: Disclosure The authors have nothing to disclose.

Soft-tissue sarcomas are cancerous growths of mesenchymal tissues, most commonly arising from fat, muscles, and other connective tissues. Sarcomas are rare, representing only a small fraction of solid malignant tumors. Because of their scarcity and a relative paucity of data, the management of sarcomas can be challenging, especially for those who infrequently encounter these tumors. Herein, the authors review the current literature regarding the diagnosis, workup, and treatment of adult soft-tissue sarcomas., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Solitary fibrous tumors (SFTs) are extremely rare mesenchymal malignancies. Given the lack of large prospective studies on radiation therapy (RT) with definitive and/or palliative intent in SFT patients, this retrospective study aimed to better define the benefit of RT in this disease., Methods and Materials: A retrospective observational study was performed across 7 sarcoma centers. Clinical information was retrieved from all patients receiving RT without surgery over the course of their locally advanced and/or metastatic disease. Differences in treatment characteristics between subgroups were tested using analysis-of-variance tests. Local control (LC) and overall survival (OS) rates were calculated as time from the start of RT until local progression and death from any cause, respectively., Results: Since 1990, a total of 40 patients were identified. RT was applied with definitive intent in 16 patients and with palliative intent in 24. The median follow-up period was 62 months. In patients treated with definitive RT (receiving approximately 60 Gy), the objective response rate was 67%. At 5 years, the LC rate was 81.3%, and the OS rate was 87.5%. In the case of palliative RT (typically 39 Gy), the objective response rate was 38%. The LC and OS rates at 5 years were 62.5% and 54.2%, respectively. In both subgroups, RT-associated toxicities were mild with predominantly grade 1 acute and late side effects., Conclusions: This retrospective study suggests a clinically meaningful benefit for RT given with either definitive or palliative intent without surgery in SFT management. Prospective registries potentially in collaboration with patient advocacy groups are warranted to further assess the role of RT in patients with this rare malignancy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To compare rates of secondary acute leukemia between sarcoma patients and the general population, using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry, and to examine whether various patient, tumor, and treatment factors were associated with development of a secondary acute leukemia., Methods and Materials: Patients with a primary diagnosis of connective tissue malignancy between 1973 and 2008 in the SEER database were included. Multivariable competing risk analysis was used to determine risk factors associated with subsequent development of acute leukemia. Using observed-to-expected ratios, we compared incidence rates of secondary acute leukemia between sarcoma patients and the general population., Results: A total of 72,945 patients were identified, with median follow-up of 131 months. On multivariable competing risk analysis, factors associated with increased risk of secondary acute leukemia included receipt of radiation therapy (hazard ratio [HR] 1.67, P=.02), distant disease (HR 2.67, P=.004), male gender (HR 1.53, P=.03), year of diagnosis (HR 0.98, P=.049), and Ewing sarcoma histology (HR 9.95, P < .0001) and osteosarcoma histology (HR 5.06, P=.0001). The observed-to-expected ratio for development of a secondary acute leukemia was 3.67 (95% confidence interval [CI] 1.95-6.28), 3.41 (95% CI 2.73-4.20), and 1.6 (95% CI 1.38-8.19) for acute lymphocytic leukemia, acute myeloid leukemia, and acute monocytic leukemia, respectively. The 10-year cumulative incidence of secondary acute leukemia for patients who did and did receive radiation therapy was 0.3% versus 0.1% (P=.02)., Conclusions: Patients treated for sarcoma, in particular those with Ewing sarcoma and osteosarcoma histology, seem to have a higher incidence of secondary acute leukemia as compared with the general population. Treatment factors including radiation therapy and chemotherapy seem to play a role in this increased risk, although the absolute incidence nevertheless remains very small., (Published by Elsevier Inc.)

Background: Nonretroperitoneal abdominal soft tissue sarcoma (NRA-STS) is a rare disease with limited data supporting its management. Our study aimed to reveal the utilization patterns of adjuvant therapy and its potential survival benefits using the National Cancer Data Base., Materials: The analysis included patients with resected high-grade NRA-STS. Chi-square analysis was used to evaluate distribution of patient and tumor-related factors within treatment groups. The Kaplan-Meier and Cox proportional hazards model were utilized to evaluate overall survival according to treatment approach. Multivariate analysis was used to determine the impact of these factors on patients' outcome. Matched propensity score analysis was implemented to control for imbalance of confounding variables., Results: At median follow-up of 49 months, 5-year overall survival improved from 46% without adjuvant radiation therapy to 52% (P = 0.009) with radiotherapy delivery with a 30% reduction in hazard of death (95% confidence interval = 0.58-0.84). On multivariate analysis, age <50, tumor <8 cm, negative margins and radiotherapy delivery were significant predictors of improved survival. Chemotherapy was not associated with significant survival improvement (Hazard Ratios [HR]: 0.89, P = 0.28)., Conclusion: Adjuvant radiotherapy was associated with improved survival in high-grade NRA-STS. Chemotherapy was not associated with a survival improvement; however, further studies are needed to refine treatment strategies., (© 2017 John Wiley & Sons Australia, Ltd.)

Surgery is potentially curative for primary non-metastatic retroperitoneal soft tissue sarcomas (RPS), although patients remain at risk for local recurrence. To reduce this risk, the addition of radiotherapy to radical surgery may be considered. Nevertheless, level I evidence to support radiotherapy is currently lacking. The results from the EORTC-STBSG 62092-22092 studying this question are awaited. This manuscript addresses issues to consider when radiation-oncologists engage in a multidisciplinary treatment approach for RPS patients, including radiotherapy., (© 2017 Wiley Periodicals, Inc.)

Purpose: Intergroup 9514 reported promising outcomes with neoadjuvant chemoradiotherapy for large extremity/trunk soft tissue sarcoma (ESTS). One decade later, optimum integration of chemotherapy and radiotherapy into the perioperative management of ESTS remains to be defined., Methods: The National Cancer Data Base was used to identify 3422 patients who underwent resection for large (>8cm) high-grade STS between 2004 and 2013. Chi-square analysis was used to evaluate distribution of patient and tumor related factors within treatment groups while multivariate analyses were used to determine the impact of these factors on patient outcome. The Kaplan Meier method and Cox proportional hazards model were utilized to evaluate overall survival according to treatment regimen, with a secondary analysis based on propensity score matching to control for prescription bias and potential confounders imbalance., Results: Hazard ratio for death was reduced by 35% with radiotherapy and 24% with chemotherapy, compared to surgery alone. Combination therapy incorporating both modalities improved 5-yr survival (62.1%) compared to either treatment alone (51.4%). The sequencing of chemotherapy and radiotherapy or whether they were delivered as adjuvant vs. as neoadjuvant therapy did not affect their efficacy. Age>50years, tumor size>11cm, and tumor location on the trunk/pelvis were poor prognostic factors., Conclusion: Our analysis suggests that adjunctive modalities are both critical in the treatment of large high-grade ESTS, improving survival when used individually and demonstrating synergy in combination, regardless of sequencing relative to each other or relative to surgery; thus providing a framework for future randomized trials., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Objectives: We sought to examine our outcomes with advanced preoperative and intraoperative radiation therapy (XRT) combined with aggressive en bloc surgical resection of retroperitoneal sarcoma (RPS) as a strategy to minimize the risk of local recurrence (LR)., Methods: From 2003 to 2013, 46 patients with RPS received preoperative XRT followed by radical en bloc surgical resection, with or without intraoperative electron radiation therapy (IOERT). Clinical and pathologic variables predictive of LR and distant recurrence (DR) were evaluated., Results: Thirty-seven patients had primary tumors and 80% were intermediate grade or higher. All patients received preoperative XRT to a median dose of 50.4 Gy and underwent complete (R0/R1) tumor resection, and 16 patients received IOERT. After a median follow-up of 53 months, 33 (72%) patients were disease-free, and there were 8 (17%) DRs, 2 (4%) abdominal recurrences outside of the XRT field, and 5 (10.9%) LRs. High tumor grade and recurrent disease at presentation were the only factors associated with higher rates of recurrence., Conclusions: Excellent local control can be achieved with a coordinated strategy of preoperative (±intraoperative) XRT combined with aggressive en bloc surgical resection of RPS, but systemic failure remains a problem for higher-grade tumors., (© 2017 Wiley Periodicals, Inc.)

Background and Objectives: It is unclear whether the quantitative width of the surgical margin influences outcomes in patients with extremity and truncal soft tissue sarcoma (STS) treated with radiotherapy (RT)., Methods: We performed a retrospective review of 382 patients with localized extremity or truncal STS who underwent limb-sparing surgery and RT from 1983 to 2010, and we analyzed the significance of resection margin status and quantitative margin width on outcomes., Results: Surgical margins were positive in 68 (18%) patients and negative in 314 (82%) patients. For those patients with a reported quantitative margin width (n = 235), the width of the negative margin was ≤1 mm (n = 128), >1 mm and ≤5 mm (n = 79), and >5 mm (n = 28). At a median follow-up of 82 months, the local recurrence rates were 5.4% and 11.8% for margin-negative and margin-positive patients, respectively. There were no differences in the rates of local or distant recurrence nor of any survival outcome based on the quantitative width of the surgical margin, provided that it was negative., Conclusions: In patients undergoing RT and limb-sparing surgery for STS, achieving a negative margin is essential for optimizing both local control and survival. However, the absolute quantitative width of the negative margin does not significantly influence outcome, and so attempts at wide margins of resection appear to be unnecessary. Importantly, the conclusions drawn from this study must not be applied to those patients undergoing surgery alone as the local treatment of their STS, in which case wider margins of resection may be necessary., Implications for Practice: In patients undergoing radiation therapy and limb-sparing surgery for soft tissue sarcoma, the quantitative width of the negative margin does not influence outcome, and so attempts at wide margins of resection appear to be unnecessary, especially when such attempts compromise the functional outcome. Importantly, the conclusions drawn from this study must not be applied to those patients undergoing surgery alone as the local treatment of their soft tissue sarcoma, in which case wider margins of resection may be necessary., Competing Interests: of potential conflicts of interest may be found at the end of this article., (©AlphaMed Press.)

Purpose: Acute gastrointestinal (GI) toxicity has been studied in GI and gynecological (GYN) cancers, with volume receiving 15 Gy (V15) <830 mL, V25 <650 mL, and V45 <195 mL identified as dose constraints for the peritoneal space (bowel bag [BB]). There are no reported constraints derived from retroperitoneal sarcoma (RPS), and prospective trials for RPS have adopted some of the GI and GYN constraints. This study quantified GI toxicity during preoperative radiation therapy (RT) for RPS, assessed toxicity using published constraints, and evaluated predictors for toxicity., Methods and Materials: From 2003 to 2013, 56 patients with RPS underwent preoperative RT at 2 institutions. Toxicity was scored using Radiation Therapy Oncology Group criteria for upper and lower acute GI toxicity. BB was contoured on planning computed tomography scans per Radiation Therapy Oncology Group atlas guidelines with review by a radiologist. Relationships among toxicity, clinical factors, and BB dose were analyzed., Results: Three patients (5%) developed grade ≥3 acute GI toxicity: 2 grade 3 toxicities (anorexia and nausea) and 1 grade 5 toxicity (tumor-bowel fistula). Thirty-six patients (64%) had grade 2 toxicity (nausea, 55%; diarrhea, 23%; pain, 20%). Tumor size was the only significant clinical predictor of grade ≥2 acute GI toxicity. Larger mean BB volumes predicted for grade ≥2 toxicity (P = .001). On receiver operating characteristics analysis, V30 was the best discriminator for toxicity (P = .0001). Median BB V15 was 1375 mL; 75% of patients had V15 ≥830 mL. Median V25 was 1083 mL; 68% had V25 ≥650 mL. Median V45 was 575 mL; 82% had V45 ≥195 mL. V25 ≥650 mL was significantly associated with grade ≥2 toxicity (P = .01)., Conclusions: Among patients treated with preoperative RT for RPS, significant acute GI toxicity was very low despite BB dose exceeding established constraints for most cases. Acceptable dose constraints for RPS may be higher than those for GI or GYN cancers. Further assessment of dose-volume constraints for RPS is needed., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Six imaging modalities were used in Radiation Therapy Oncology Group (RTOG) 0630, a study of image guided radiation therapy (IGRT) for primary soft tissue sarcomas of the extremity. We analyzed all daily patient-repositioning data collected in this trial to determine the impact of daily IGRT on clinical target volume-to-planning target volume (CTV-to-PTV) margin., Methods and Materials: Daily repositioning data, including shifts in right-left (RL), superior-inferior (SI), and anterior-posterior (AP) directions and rotations for 98 patients enrolled in RTOG 0630 from 18 institutions were analyzed. Patients were repositioned daily on the basis of bone anatomy by using pretreatment images, including kilovoltage orthogonal images (KVorth), megavoltage orthogonal images (MVorth), KV fan-beam computed tomography (KVCT), KV cone beam CT (KVCB), MV fan-beam CT (MVCT), and MV cone beam CT (MVCB). Means and standard deviations (SDs) for each shift and rotation were calculated for each patient and for each IGRT modality. The Student's t tests and F-tests were performed to analyze the differences in the means and SDs. Necessary CTV-to-PTV margins were estimated., Results: The repositioning shifts and day-to-day variations were large and generally similar for the 6 imaging modalities. Of the 2 most commonly used modalities, MVCT and KVorth, there were no statistically significant differences in the shifts and rotations (P = .15 and .59 for the RL and SI shifts, respectively; and P = .22 for rotation), except for shifts in AP direction (P = .002). The estimated CTV-to-PTV margins in the RL, SI, and AP directions would be 13.0, 10.4, and 11.7 mm from MVCT data, respectively, and 13.1, 8.6, and 10.8 mm from KVorth data, respectively, indicating that margins substantially larger than 5 mm used with daily IGRT would be required in the absence of IGRT., Conclusions: The observed large daily repositioning errors and the large variations among institutions imply that daily IGRT is necessary for this tumor site, particularly in multi-institutional trials. Otherwise, a CTV-to-PTV margin of 1.5 cm is required to account for daily setup variations., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

This review on proton beam radiotherapy (PBT) focusses on an historical overview, cost-effectiveness, techniques, acute and late toxicities and clinical results of PBT for sarcoma patients. PBT has gained its place among the armamentarium of modern radiotherapy techniques. For selected patients, it can be cost-effective., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate and understand the tolerance of the thoracolumbar spinal cord using equivalent uniform dose (EUD) and dose volume histogram (DVH) analysis after combined high dose photon-proton radiotherapy., Materials and Methods: A total of 68 patients were identified as having high dose radiotherapy, ⩾5900cGy (RBE) in the region of the thoracolumbar spinal cord, defined as extending inferiorly to L2. Pathological diagnosis for patients in this review included chordoma (50 patients, 53.1%), chondrosarcoma (28 patients, 29.8%), osteosarcoma (3 patients, 3.2%), other sarcoma (11 patients, 11.7%), and other (2 patients, 2.1%). Patient data were reviewed retrospectively, detailed dose volume histogram data (DVH) were available for 23 patients. Composite plans and DVH were constructed for both pre-operative and post-operative radiation therapy courses in MIM-Vista software, as available. Dose constraints to the center and surface of the cord were 5400cGy (RBE), and 6300cGy (RBE) respectively, and patients receiving concurrent chemotherapy received an eight percent dose reduction. Spinal cord toxicity was recorded using the RTOG/EORTC late effects scoring system., Results: Clinical and dosimetric data for each patient were analyzed. Median prescription dose was 7020cGy (RBE), range (5940-7820cGy (RBE)). Median follow-up was 12.9months. Five-year overall survival for all patients in this group was 88.7%, 95%CI (74.7-95.2). One patient suffered from transient paralysis following stem cell transplant for treatment of myelodysplastic syndrome. Other reasons for spinal cord injury following treatment included: local disease progression, noted in 7 patients (10.3%), and direct result of surgery, noted in 8 patients (11.8%). Freedom from neurological injury (RTOG Grade 2 or higher) at 5years was 92.9%(95%CI: 74.6-98.2), at 6years was 80.9%(95%CI: 55.3-92.7), and at 8years 80.9%(95%CI: 55.3-92.7)., Conclusion: Our clinical and dosimetric data suggest that the noted dose constraints are safe and acceptable with regard to spinal cord complications. Pre-existing disease characteristics, surgical complications, as well as tumor progression, appear to be more important factors when it comes to spinal cord toxicity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: This critical review aims to summarize published data on limb sparing surgery for extremity soft tissue sarcoma in combination with pre-operative radiotherapy (RT)., Methods: This review is based on peer-reviewed publications using a PubMed search on the MeSH headings "soft tissue sarcoma" AND "preoperative radiotherapy". Titles and abstracts screened for data including "fraction size AND/OR total dose AND/OR overall treatment time", "chemotherapy", "targeted agents AND/OR tyrosine kinase inhibitors", are collated. Reference lists from some articles have been studied to obtain other pertinent articles. Additional abstracts presented at international sarcoma meetings have been included as well as information on relevant clinical trials available at the ClinicalTrials.gov website., Results: Data are presented for the conventional regimen of 50-50.4Gy in 25-28 fractions in 5-6 of weeks preoperative external beam RT with respect to the regimen's local control probability compared to surgery alone, as well as acute and late toxicities. The rationale and outcome data for hypofractionated and/or reduced dose regimens are discussed. Finally, combination schedules with conventional chemotherapy and/or targeted agents are summarized., Conclusion: Outside the setting of well-designed prospective clinical trials, the conventional 50Gy in 5-6week schedule should be considered as standard. However, current and future studies addressing alternative fraction size, total dose, overall treatment time and/or combination with chemotherapy or targeted agents may reveal regimens of equal or increased efficacy with reduced late morbidities., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Curative intent management of retroperitoneal sarcoma (RPS) requires gross total resection. Preoperative radiotherapy (RT) often is used as an adjuvant to surgery, but recurrence rates remain high. To enhance RT efficacy with acceptable tolerance, there is interest in delivering "boost doses" of RT to high-risk areas of gross tumor volume (HR GTV) judged to be at risk for positive resection margins. We sought to evaluate variability in HR GTV boost target volume delineation among collaborating sarcoma radiation and surgical oncologist teams., Methods: Radiation planning CT scans for three cases of RPS were distributed to seven paired radiation and surgical oncologist teams at six institutions. Teams contoured HR GTV boost volumes for each case. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics., Results: HRGTV boost volume contour agreement between the seven teams was "substantial" or "moderate" for all cases. Agreement was best on the torso wall posteriorly (abutting posterior chest abdominal wall) and medially (abutting ipsilateral para-vertebral space and great vessels). Contours varied more significantly abutting visceral organs due to differing surgical opinions regarding planned partial organ resection., Conclusions: Agreement of RPS HRGTV boost volumes between sarcoma radiation and surgical oncologist teams was substantial to moderate. Differences were most striking in regions abutting visceral organs, highlighting the importance of collaboration between the radiation and surgical oncologist for "individualized" target delineation on the basis of areas deemed at risk and planned resection.

Purpose: We performed a multi-institutional prospective phase II trial to assess late toxicities in patients with extremity soft tissue sarcoma (STS) treated with preoperative image-guided radiation therapy (IGRT) to a reduced target volume., Patients and Methods: Patients with extremity STS received IGRT with (cohort A) or without (cohort B) chemotherapy followed by limb-sparing resection. Daily pretreatment images were coregistered with digitally reconstructed radiographs so that the patient position could be adjusted before each treatment. All patients received IGRT to reduced tumor volumes according to strict protocol guidelines. Late toxicities were assessed at 2 years., Results: In all, 98 patients were accrued (cohort A, 12; cohort B, 86). Cohort A was closed prematurely because of poor accrual and is not reported. Seventy-nine eligible patients from cohort B form the basis of this report. At a median follow-up of 3.6 years, five patients did not have surgery because of disease progression. There were five local treatment failures, all of which were in field. Of the 57 patients assessed for late toxicities at 2 years, 10.5% experienced at least one grade ≥ 2 toxicity as compared with 37% of patients in the National Cancer Institute of Canada SR2 (CAN-NCIC-SR2: Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma) trial receiving preoperative radiation therapy without IGRT (P < .001)., Conclusion: The significant reduction of late toxicities in patients with extremity STS who were treated with preoperative IGRT and absence of marginal-field recurrences suggest that the target volumes used in the Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity) study are appropriate for preoperative IGRT for extremity STS., (© 2015 by American Society of Clinical Oncology.)

Background and Objectives: Although resection of RPS with en bloc nephrectomy confers the potential benefit of improved locoregional tumor control, little has been published about the long-term post-operative renal function of these patients., Methods: Retrospective review of 54 patients undergoing nephrectomy for RPS was performed. Clinicopathologic and treatment characteristics, pre- and post-operative creatinine (Cr) values, and estimated glomerular filtration rates (eGFR) were recorded. The primary outcome measure was progression of chronic kidney disease (CKD) stage., Results: Median preoperative eGFR was 85 ml/min. Post-nephrectomy, median nadir eGFR was 44 ml/min, rebounding to 62 ml/min at median follow-up of 50 months. Of 49 patients with preoperative eGFR ≥60 ml/min (CKD stage 1,2), 51% preserved eGFR ≥60 postoperatively, whereas 49% progressed to CKD stage 3 (eGFR 30-59). Independent risk factors for progression of CKD stage were age and preoperative eGFR. Eleven patients died of recurrent disease, whereas no patient died of end stage renal disease (ESRD) or required dialysis., Conclusions: Although progression of CKD stage occurs in nearly one-half of patients followed for more than 4 years after nephrectomy for RPS, no patient progressed to ESRD or had a limitation in systemic therapy options, even with progression to CKD stage 3., (© 2015 Wiley Periodicals, Inc.)

Objective: To compare outcomes of patients with retroperitoneal or pelvic sarcoma treated with perioperative radiation therapy (RT) versus those treated without perioperative RT., Background: RT for retroperitoneal or pelvic sarcoma is controversial, and few studies have compared outcomes with and without RT., Methods: Prospectively maintained databases were reviewed to retrospectively compare patients with primary retroperitoneal or pelvic sarcoma treated during 2003-2011. Multivariate Cox regression models were used to assess associations with the primary endpoints: local recurrence-free survival (LRFS) and disease-specific survival., Results: At 1 institution, 172 patients were treated with surgery alone, whereas at another institution 32 patients were treated with surgery and perioperative proton beam RT or intensity-modulated RT with or without intraoperative RT. The groups were similar in age, tumor size, grade, and margin status (all P > 0.08). The RT group had a higher percentage of pelvic tumors (P = 0.03) and a different distribution of histologies (P = 0.04). Perioperative morbidity was higher in the RT group (44% vs 16% of patients; P = 0.004). After a median follow-up of 39 months, 5-year LRFS was 91% (95% confidence interval, 79%-100%) in the RT group and 65% (57%-74%) in the surgery-only group (P = 0.02). On multivariate analysis, RT was associated with better LRFS (hazard ratio, 0.26; P = 0.03). Five-year disease-specific survival was 93% (95% confidence interval, 82%-100%) in the RT group and 85% (78%-92%) in the surgery-only group (P = 0.3)., Conclusions: The addition of advanced-modality RT to surgery for primary retroperitoneal or pelvic sarcoma was associated with improved LRFS, although this did not translate into significantly better disease-specific survival. This treatment strategy warrants further investigation in a randomized trial.

Purpose: Evidence for external beam radiation therapy (RT) as part of treatment for retroperitoneal sarcoma (RPS) is limited. Preoperative RT is the subject of a current randomized trial, but the results will not be available for many years. In the meantime, many practitioners use preoperative RT for RPS, and although this approach is used in practice, there are no radiation treatment guidelines. An international expert panel was convened to develop consensus treatment guidelines for preoperative RT for RPS., Methods and Materials: An expert panel of 15 academic radiation oncologists who specialize in the treatment of sarcoma was assembled. A systematic review of reports related to RT for RPS, RT for extremity sarcoma, and RT-related toxicities for organs at risk was performed. Due to the paucity of high-quality published data on the subject of RT for RPS, consensus recommendations were based largely on expert opinion derived from clinical experience and extrapolation of relevant published reports. It is intended that these clinical practice guidelines be updated as pertinent data become available., Results: Treatment guidelines for preoperative RT for RPS are presented., Conclusions: An international panel of radiation oncologists who specialize in sarcoma reached consensus guidelines for preoperative RT for RPS. Many of the recommendations are based on expert opinion because of the absence of higher level evidence and, thus, are best regarded as preliminary. We emphasize that the role of preoperative RT for RPS has not been proven, and we await data from the European Organization for Research and Treatment of Cancer (EORTC) study of preoperative radiotherapy plus surgery versus surgery alone for patients with RPS. Further data are also anticipated pertaining to normal tissue dose constraints, particularly for bowel tolerance. Nonetheless, as we await these data, the guidelines herein can be used to establish treatment uniformity to aid future assessments of efficacy and toxicity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy. While hypoxia increases tumor cell survival after radiation exposure because there is less oxygen to oxidize damaged DNA, it remains unclear whether signaling pathways triggered by hypoxia contribute to radiation resistance. For example, intratumoral hypoxia can increase hypoxia inducible factor 1 alpha (HIF-1α), which may regulate pathways that contribute to radiation sensitization or radiation resistance. To clarify the role of HIF-1α in regulating tumor response to radiation, we generated a novel genetically engineered mouse model of soft tissue sarcoma with an intact or deleted HIF-1α. Deletion of HIF-1α sensitized primary sarcomas to radiation exposure in vivo. Moreover, cell lines derived from primary sarcomas lacking HIF-1α, or in which HIF-1α was knocked down, had decreased clonogenic survival in vitro, demonstrating that HIF-1α can promote radiation resistance in a cell autonomous manner. In HIF-1α-intact and -deleted sarcoma cells, radiation-induced reactive oxygen species, DNA damage repair and activation of autophagy were similar. However, sarcoma cells lacking HIF-1α had impaired mitochondrial biogenesis and metabolic response after irradiation, which might contribute to radiation resistance. These results show that HIF-1α promotes radiation resistance in a cell autonomous manner.

Background: Negative surgical margins are uncommon for non-extremity soft tissue sarcomas. Radiation therapy is usually recommended to improve local control; however, appropriate RT dosing is challenging due to nearby dose-limiting normal structures., Material and Methods: Comprehensive literature search using PubMed (March 2014)., Results: Data suggest radiation therapy is an important modality in maximizing local tumor control in non-extremity sarcomas., Conclusion: The literature supports the use of RT to improve local control for non-extremity soft tissue sarcomas., (© 2014 Wiley Periodicals, Inc.)

Objective: The purpose of this study was to evaluate the role of CT perfusion in monitoring response to neoadjuvant antiangiogenic and radiation therapy in resectable soft-tissue sarcomas and correlate the findings with tumor size, circulating and tumor biomarkers, and gene expression., Subjects and Methods: This phase II clinical trial included 20 patients (13 men and 7 women; mean age, 55 years) with soft-tissue sarcomas who were undergoing treatment with the antiangiogenic drug bevacizumab followed by bevacizumab, radiation, and surgical resection. The patients underwent CT perfusion and diagnostic contrast-enhanced CT at baseline, at 2 weeks after bevacizumab therapy, and after completion of bevacizumab and radiation therapy. Multiple CT perfusion parameters (blood flow, blood volume, mean transit time, and permeability) were correlated with tumor size, circulating and tumor biomarkers, and gene expression., Results: Two weeks after bevacizumab therapy, there was substantial fall in blood volume (31.9% reduction, p = 0.01) with more pronounced reduction in blood flow, blood volume, and permeability after treatment completion (53-64% reduction in blood flow, blood volume, and permeability; p = 0.001), whereas tumor size showed no significant change (p = 0.34). Tumors with higher baseline blood volume and lower baseline tumor size showed superior response to bevacizumab and radiation (p = 0.05). There was also an increase in median plasma vascular endothelial growth factor and placental-derived growth factor concentration after bevacizumab therapy paralleled by a decrease in tumor perfusion depicted by CT perfusion, although this was not statistically significant (p = 0.4). The baseline tumor microvessel density (MVD) correlated with blood flow (p = 0.04). At least 20 different genes were differentially expressed in tumors with higher and lower baseline perfusion., Conclusion: CT perfusion is more sensitive than tumor size for monitoring early and late response to bevacizumab and radiation therapy. CT perfusion parameters correlate with MVD, and the gene expression levels of baseline tumors could potentially predict treatment response.

Background: Histologic response to chemotherapy has been shown to be an independent prognostic factor in patients with osteosarcoma and Ewing sarcoma. However, in patients with soft tissue sarcoma (STS), the prognostic impact of histologic response to chemotherapy is less clear. In the current study, the authors sought to determine the prognostic significance of treatment-induced pathologic necrosis in patients receiving neoadjuvant chemoradiotherapy for STS., Methods: Between 1989 and 2011, a total of 113 patients with grade 2 or 3 (graded according to the National Cancer Institute grading system using 3 tiers) extremity or truncal STS were identified who received neoadjuvant interdigitated chemoradiotherapy according to protocol followed by surgery. The extent of tumor necrosis in the resected specimens was quantified and correlated with outcome., Results: The median tumor necrosis rate was 90%, and 103 patients (91%) received all 3 cycles of planned neoadjuvant chemotherapy. The likelihood of achieving ≥95% necrosis was not related to the number of preoperative cycles of chemotherapy received but was found to be related to tumor histology (62% for malignant fibrous histiocytoma vs 0% for synovial sarcoma [P<.001]; 56% for myxoid liposarcoma vs 0% for synovial sarcoma [P = .002]). At a median follow-up of 6 years, there were no statistically significant differences noted in the 5-year local control, disease-specific survival, and overall survival rates for patients with ≥95% necrosis (50 patients; 44%) and <95% necrosis (63 patients; 56%), even when stratifying by histology., Conclusions: In a homogeneous population of patients with high-grade extremity and truncal STS who were treated with neoadjuvant chemoradiotherapy, the extent of pathologic tumor necrosis did not correlate with outcome., (© 2014 American Cancer Society.)

Background and Objectives: The role of a radiation therapy (RT) boost for positive margins following pre-operative RT and surgery in extremity soft tissue sarcomas (STS) is unclear. We assessed the contribution of a boost to local control (LC), disease-free survival (DFS), and overall survival (OS)., Methods: We identified 67 patients treated from 1987 to 2011 with pre-operative RT and surgery with positive margin(s). Select patients received a boost delivered as peri-operative Iridium-192 brachytherapy (BRT), intra-operative electrons (IORT), or post-operative external beam RT (EBRT)., Results: Ten patients received no RT boost, 10 received a BRT or IORT boost, and 47 received an EBRT boost. Five-year LC rates for no boost, BRT/IORT boost, and EBRT boost were 100%, 78%, and 71% (P = 0.5). On multivariate analysis, there were no significant predictors for LC. Variables associated with improved DFS rates were single positive margin (P = 0.007) and low tumor grade (P = 0.03). Tumor size <5 cm (P = 0.003), low grade (P = 0.001), and boost (P = 0.02) were associated with longer survival., Conclusions: We did not identify a LC advantage for an RT boost. Given the unidentified selection factors for delivery of boost and its potential toxicities, its role in this setting remains unproven., (© 2014 Wiley Periodicals, Inc.)

Background: Negative surgical margins are uncommon for spine sarcomas; hence, adjuvant radiotherapy (RT) may be recommended but tumor dose may be constrained by spinal cord, nerve, and viscera tolerance., Methods: Prospective Phase II clinical trial incorporating high dose RT. Eligible patients had primary or locally recurrent thoracic, lumbar, and/or sacral spine/paraspinal chordomas or sarcomas. Treatment included pre- and/or post-operative photon/proton RT ± radical resection., Results: Fifty patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). RT dose was ≤72.0 GyRBE in 25 patients and 76.6-77.4 GyRBE in 25 patients. With 7.3-year median follow-up, the 5 and 8-year actuarial local control (LC) rates were 94% and 85% for primary tumors and 81% and 74% for the entire group. Local recurrence was less common for primary tumors, 4/36 (11%) versus 7/14 (50%) for recurrent tumors, P = 0.002. The 8-year actuarial risk of grade 3-4 late RT morbidity was 13%. No myelopathies were seen. No late neurologic toxicities noted with radiation doses ≤72.0 GyRBE while three sacral neuropathies appeared after doses of 76.6-77.4 GyRBE., Conclusions: LC with this treatment is high in patients with primary tumors. Late morbidity appears to be acceptable., (© 2014 Wiley Periodicals, Inc.)

Purpose: Proper positioning of patients with extremity sarcoma tumors can be challenging. A surface imaging technique was utilized to quantify the setup uncertainties for sarcoma patients and to assess whether surface imaging could improve the accuracy of patient positioning., Methods and Materials: Pretreatment and posttreatment 3-dimensional (3D) surface images were obtained for 16 patients and 236 treatments. Offline surface registration was performed to quantify interfraction and intrafraction setup errors, and the required planning target volume (PTV) margins were calculated. Setup differences were also assessed using root mean square (RMS) error analysis., Results: For intrafraction variation, the mean 3D vector shift was 2.1 mm, and the systematic and random errors were 1.3 mm or less. When using a reference surface from the first fraction, the mean interfraction setup variation (3D vector shift) was 7.6 mm. Systematic and random errors were 3-4 mm in each direction. When using a computed tomographic based reference surface, the mean 3D vector shift was 9.5 mm. Systematic and random errors ranged from 3.1 to 7.9 mm. The required PTV margins were 1.0 cm, 1.2 cm, and 1.3 cm in the anterior-posterior, superior-inferior, and lateral directions, respectively. The mean (standard deviation) RMS errors for the uncorrected position were 4.7 mm (1.9 mm) and were reduced to 2.2 mm (0.8 mm) and 1.7 mm (0.8 mm), for 4 degree of freedom (DOF) and 6 DOF surface alignment, respectively., Conclusions: Intrafraction motion is small. Interfraction motion can exceed typical PTV margins and daily imaging should be utilized to reduce setup variations. Surface imaging may reduce setup errors and is a feasible technique for daily image guidance., (© 2014. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Local recurrence (LR) following limb-sparing surgery and radiation therapy (RT) for extremity soft tissue sarcoma (STS) is rare. The current study investigates the utility of surveillance nuclear magnetic resonance imaging (MRI) for detection of asymptomatic LRs., Methods: The study cohort consisted of 168 adult patients with extremity STS treated with limb-sparing surgery and RT with curative intent between October 2001 and January 2011. Follow-up surveillance MRIs and history and physical examinations were performed per the NCCN guidelines with additional MRIs as clinically indicated. The method of LR detection and MRI number and indication were determined., Results: After a median follow-up of 4.7 years (range: 0.6-10.5) 11 (6.5%; 11/168) patients developed LRs. Five hundred two MRIs were obtained, 429 (85.5%; 429/502) for surveillance and 73 (14.5%; 73/502) as clinically indicated. One hundred fourteen patients underwent ≥1 surveillance MRI. The median surveillance MRI interval was 6.4 months (range 1.4-68.9). Surveillance MRI detected an asymptomatic LR in 1 (0.9%; 1/114) patient with a complex reconstruction., Conclusions: Surveillance MRI infrequently detects asymptomatic LRs following limb-sparing surgery and RT for extremity STS and should be limited to patients whose primary tumor sites are not easily assessed by history and physical examination., (© 2013 Wiley Periodicals, Inc.)

These NCCN Guidelines Insights highlight the important updates to the NCCN Guidelines for Soft Tissue Sarcoma (STS) specific to the role of radiation therapy in the management of patients with retroperitoneal/intra-abdominal STS. The guidelines have also included recommendations for genetic testing and counseling for patients with a clinical and/or family history of genetic cancer syndromes associated with a predisposition for the development of STS.

Purpose: Peritumoral edema may harbor sarcoma cells. The extent of suspicious edema (SE) included in the treatment volume is subject to clinical judgment, balancing the risk of missing tumor cells with excess toxicity. Our goal was to determine variability in SE delineation by sarcoma radiation oncologists (RO)., Methods and Materials: Twelve expert ROs were provided with T1 gadolinium and T2-weighted MR images of 10 patients with high-grade extremity soft-tissue sarcoma. Gross tumor volume, clinical target volume (CTV)3cm (3 cm longitudinal and 1.5 cm radial margin), and CTV2cm (2 cm longitudinal and 1 cm radial margin) were contoured by a single observer. Suspicious peritumoral edema, defined as abnormal signal on T2 images, was independently delineated by all 12 ROs. Contouring agreement was analyzed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics., Results: The mean volumes of GTV, CTV2cm, and CTV3cm were, respectively, 130 cm(3) (7-413 cm(3)), 280 cm(3) and 360 cm(3). The mean consensus volume computed using the STAPLE algorithm at 95% confidence interval was 188 cm(3) (24-565 cm(3)) with a substantial overall agreement corrected for chance (mean kappa = 0.71; range: 0.32-0.87). The minimum, maximum, and mean volume of SE (excluding the GTV) were 4, 182, and 58 cm(3) (representing a median of 29% of the GTV volume). The median volume of SE not included in the CTV2cm and in the CTV3cm was 5 and 0.3 cm(3), respectively. There were 3 large tumors with >30 cm(3) of SE not included in the CTV3cm volume., Conclusion: Despite the fact that SE would empirically seem to be a more subjective volume, a substantial or near-perfect interobserver agreement was observed in SE delineation in most cases with high-grade soft-tissue sarcomas of the extremity. A median of 97% of the consensus SE is within the CTV2cm (99.8% within the CTV3cm). In a minority of cases, however, significant expansion of the CTVs is required to cover SE., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To present recommendations for the use of brachytherapy (BT) in patients with soft tissue sarcoma (STS)., Methods: A group of practitioners with expertise and experience in sarcoma BT formulated recommendations for BT in STS based on clinical experience and literature review., Results: The indications for adjuvant BT are discussed. There is no consensus on the use of BT alone or in combination with external beam radiation therapy (EBRT), but factors that influence the selection of this modality include tumor grade and size, prior surgeries, and tumor recurrence. Low-dose-rate, high-dose-rate, and pulsed-dose-rate radiation are all acceptable BT modalities to use for STS. Recommendations are made for patient selection, techniques, dose rates, and dosages. Outcome data and toxicity data are reviewed., Conclusions: BT is a useful component of the treatment of STS. The advantages of BT are the targeted dose distribution, low integral dose, and short treatment times. Ultimately the clinician should select the modality or combination of modalities that are most familiar to the treatment team and suitable to the patient., (Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: Patients with large, high-grade extremity and truncal soft tissue sarcomas (STS) are at considerable risk for recurrence. A regimen of pre-operative chemotherapy consisting of mesna, adriamycin, ifosfamide and dacarbazine (MAID), interdigitated with radiotherapy (RT), followed by resection and post-operative chemotherapy with or without RT, has demonstrated high rates of local and distant control. The goal of this study is to assess outcomes in a recent cohort of patients treated on this regimen., Methods: We retrospectively reviewed records of 66 consecutive patients with STS of the extremity or trunk who were treated with the aforementioned regimen from May 2000 to April 2011. Clinicopathologic characteristics and patient outcomes were analysed., Results: Sixty-six patients were analysed and were equally divided between grade 2 and 3 tumours. Margins were negative in 57 (89%) patients and positive in seven (11%) patients. At a median follow-up of 46 months, there were six (9%) locoregional and 20 (30%) distant recurrences. The locoregional and distant 5-year recurrence-free survival (RFS) rates were 91% and 64%, respectively. The 5-year overall (OS) and disease-specific survival rates were 86% and 89%, respectively. There were no treatment-related deaths or secondary myelodysplasias. Thirty-four (52%) patients had grade 3 or 4 acute haematologic chemotherapy-related toxicity. There were no statistically significant predictors of OS or RFS., Conclusions: For a contemporary cohort of patients with high-risk extremity and truncal STS, a regimen of neoadjuvant chemoradiotherapy and surgery continues to result in high rates of survival with tolerable short- and long-term toxicity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This critical review will focus on published data on the indications for radiotherapy in patients with extremity soft tissue sarcomas and its role in local control, survival, and treatment complications. The differences between pre- and postoperative radiotherapy will be discussed and consensus recommendations on target volume delineation proposed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Patients with large, high-grade, extremity soft tissue sarcomas (STS) are at significant risk for distant recurrence and death. A regimen of preoperative chemotherapy consisting of mesna, Adriamycin (doxorubicin), ifosfamide, and dacarbazine (MAID), interdigitated with radiotherapy (RT) and followed by resection and postoperative chemotherapy with or without RT, has demonstrated high rates of local and distant control. We report the long-term follow-up data on 48 patients treated with this regimen compared to an historical matched-control patient population., Methods: Adult patients with high-grade extremity STS ≥ 8 cm were treated with 3 cycles of preoperative chemotherapy combined with 44 Gy of RT followed by surgery. Three cycles of postoperative MAID were planned. For patients with positive surgical margins, 16 Gy of RT was delivered postoperatively., Results: Patients received the MAID/RT regimen from 1989 through 1999. After a median follow-up of 9.3 years in surviving patients in the MAID group and 13.2 years in surviving patients in the control group, the 7-year disease-specific and overall survival rates were 81% and 50% (P = .004) and 79% and 45% (P = .003) for the MAID and control patients, respectively. Five of 11 patients in the MAID group and 7 of 25 control patients died of sarcoma ≥5 years after treatment. One patient in the MAID group developed a fatal myelodysplasia at 53 months., Conclusions: For patients with high-risk, extremity STS, the significant survival benefits conferred by an intense regimen of neoadjuvant chemoradiotherapy and surgery are sustained even with long-term follow-up., (Copyright © 2011 American Cancer Society.)

The major changes to the 2012 and 2011 NCCN Guidelines for Soft Tissue Sarcoma pertain to the management of patients with gastrointestinal stromal tumors (GISTs) and desmoid tumors (aggressive fibromatosis). Postoperative imatinib following complete resection for primary GIST with no preoperative imatinib is now included as a category 1 recommendation for patients with intermediate or high risk of recurrence. The panel also reaffirmed the recommendation for preoperative use of imatinib in patients with GISTs that are resectable with negative margins but associated with significant surgical morbidity. Observation was included as an option for patients with resectable desmoid tumors that are small and asymptomatic, not causing morbidity, pain, or functional limitation. Sorafenib is included as an option for systemic therapy for patients with desmoid tumors.

Clinical trial data show that radiation enhances local tumor control of extremity sarcomas with acceptable morbidity when sophisticated radiation techniques are combined with limb-sparing resections performed by oncologic surgeons with sarcoma expertise. Similar controlled data is not available for retroperitoneal sarcomas but some studies suggest a benefit for radiotherapy. Radiation can be delivered by external beam or brachytherapy; it can be given pre-operatively, post-operatively, or intra-operatively. Indications for and advances in radiation therapy are discussed in this article., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate variability in the definition of preoperative radiotherapy gross tumor volume (GTV) and clinical target volume (CTV) delineated by sarcoma radiation oncologists., Methods and Materials: Extremity sarcoma planning CT images along with the corresponding diagnostic MRI from two patients were distributed to 10 Radiation Therapy Oncology Group sarcoma radiation oncologists with instructions to define GTV and CTV using standardized guidelines. The CT data with contours were then returned for central analysis. Contours representing statistically corrected 95% (V95) and 100% (V100) agreement were computed for each structure., Results: For the GTV, the minimum, maximum, mean (SD) volumes (mL) were 674, 798, 752±35 for the lower extremity case and 383, 543, 447±46 for the upper extremity case. The volume (cc) of the union, V95 and V100 were 882, 761, and 752 for the lower, and 587, 461, and 455 for the upper extremity, respectively. The overall GTV agreement was judged to be almost perfect in both lower and upper extremity cases (kappa=0.9 [p<0.0001] and kappa=0.86 [p<0.0001]). For the CTV, the minimum, maximum, mean (SD) volumes (mL) were 1145, 1911, 1605±211 for the lower extremity case and 637, 1246, 1006±180 for the upper extremity case. The volume (cc) of the union, V95, and V100 were 2094, 1609, and 1593 for the lower, and 1533, 1020, and 965 for the upper extremity cases, respectively. The overall CTV agreement was judged to be almost perfect in the lower extremity case (kappa=0.85 [p<0.0001]) but only substantial in the upper extremity case (kappa=0.77 [p<0.0001])., Conclusions: Almost perfect agreement existed in the GTV of these two representative cases. There was no significant disagreement in the CTV of the lower extremity, but variation in the CTV of upper extremity was seen, perhaps related to the positional differences between the planning CT and the diagnostic MRI., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Numerous preclinical studies have demonstrated that angiogenesis inhibitors can increase the efficacy of radiotherapy (RT). We sought to examine the safety and efficacy of bevacizumab (BV) and RT in soft tissue sarcomas and explore biomarkers to help determine the treatment response., Methods and Materials: Patients with ≥5 cm, intermediate- or high-grade soft tissue sarcomas at significant risk of local recurrence received neoadjuvant BV alone followed by BV plus RT before surgical resection. Correlative science studies included analysis of the serial blood and tumor samples and serial perfusion computed tomography scans., Results: The 20 patients had a median tumor size of 8.25 cm, with 13 extremity, 1 trunk, and 6 retroperitoneal/pelvis tumors. The neoadjuvant treatment was well tolerated, with only 4 patients having Grade 3 toxicities (hypertension, liver function test elevation). BV plus RT resulted in ≥80% pathologic necrosis in 9 (45%) of 20 tumors, more than double the historical rate seen with RT alone. Three patients had a complete pathologic response. The median microvessel density decreased 53% after BV alone (p <.05). After combination therapy, the median tumor cell proliferation decreased by 73%, apoptosis increased 10.4-fold, and the blood flow, blood volume, and permeability surface area decreased by 62-72% (p <.05). Analysis of gene expression microarrays of untreated tumors identified a 24-gene signature for treatment response. The microvessel density and circulating progenitor cells at baseline and the reduction in microvessel density and plasma soluble c-KIT with BV therapy also correlated with a good pathologic response (p <.05). After a median follow-up of 20 months, only 1 patient had developed local recurrence., Conclusions: The results from the present exploratory study indicated that BV increases the efficacy of RT against soft tissue sarcomas and might reduce the incidence of local recurrence. Thus, this regimen warrants additional investigation. Gene expression profiles and other tissue and circulating biomarkers showed promising correlations with treatment response., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To develop a Radiation Therapy Oncology Group (RTOG) atlas delineating gross tumor volume (GTV) and clinical target volume (CTV) to be used for preoperative radiotherapy of primary extremity soft tissue sarcoma (STS)., Methods and Materials: A consensus meeting was held during the RTOG meeting in January 2010 to reach agreement about GTV and CTV delineation on computed tomography (CT) images for preoperative radiotherapy of high-grade large extremity STS. Data were presented to address the local extension of STS. Extensive discussion ensued to develop optimal criteria for GTV and CTV delineation on CT images., Results: A consensus was reached on appropriate CT-based GTV and CTV. The GTV is gross tumor defined by T1 contrast-enhanced magnetic resonance images. Fusion of magnetic resonance and images is recommended to delineate the GTV. The CTV for high-grade large STS typically includes the GTV plus 3-cm margins in the longitudinal directions. If this causes the field to extend beyond the compartment, the field can be shortened to include the end of a compartment. The radial margin from the lesion should be 1.5 cm, including any portion of the tumor not confined by an intact fascial barrier, bone, or skin surface., Conclusion: The consensus on GTV and CTV for preoperative radiotherapy of high-grade large extremity STS is available as web-based images and in a descriptive format through the RTOG. This is expected to improve target volume consistency and allow for rigorous evaluation of the benefits and risks of such treatment., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: For soft tissue sarcoma, neoadjuvant external beam radiation therapy (EBRT) to 50 Gy has the same local control (LC) and overall survival as postoperative radiation therapy (PORT) to 60 Gy, but with increased wound complications. We examined whether low-dose neoadjuvant EBRT would decrease acute toxicity while maintaining LC., Methods and Materials: From 1971 to 2008, 1,765 patients with nonmetastatic soft tissue sarcoma were treated with radiation therapy at Massachusetts General Hospital. We identified 42 patients treated with low-dose neoadjuvant EBRT (median, 20 Gy; range, 16-26) followed by surgical resection and PORT. PORT included EBRT (25 patients; median, 40 Gy; range, 20-56.2), brachytherapy (13 patients; median, 42 Gy; range, 26-50), and intraoperative radiation therapy (IORT) (4 patients; median, 12.5 Gy; range, 8-20). The median total dose was 63.3 Gy (range, 28-78.4)., Results: Median follow-up was 36 months (range, 4-318). Severe acute wound complications were reported in 15 patients (36%) and correlated to PORT technique (16% EBRT, 69% brachytherapy, 50% IORT, p = 0.004). The 5-year LC was 73% and correlated to PORT technique (68% EBRT, 100% brachytherapy, 50% IORT, p = 0.03) and histology (p = 0.05), with a trend to improvement if >60 Gy (p = 0.10). The 5-year overall survival was 65% and correlated to extent of resection (p < 0.001) and margin status (p < 0.001)., Conclusions: Despite using low-dose neoadjuvant EBRT, we report a high rate of severe acute wound complications that was strongly associated with brachytherapy. Modification of the brachytherapy technique may decrease acute toxicity while maintaining excellent local control. Further study must be conducted before recommending broader application., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Acral myxoinflammatory fibroblastic sarcoma (AMFS) is a rare, low-grade sarcoma that commonly affects the distal extremities. From the published cases, therapy for AMFS to date has been comprised of excision or amputation, with limited use of radiotherapy (RT) or chemotherapy. In this report, the outcome of 17 patients with AMFS treated at the study institution was reported., Methods: A retrospective review of all cases of AMFS identified in the Sarcoma Database in the Department of Radiation Oncology at the study institution was conducted. Treatment records and data from follow-up visits of patients were reviewed., Results: Seventeen patients were identified. All the patients underwent surgical resection (15 excisions and 2 amputations). Positive surgical margins after excisions were noted in 5 patients and were widely positive in 1 patient. Of the 17 patients, 14 patients received some form of RT. The average total dose was 56.4 Gray (Gy). Eight patients received preoperative RT alone, 5 patients received preoperative RT and postoperative RT, and 1 patient received preoperative RT and intraoperative RT. Median follow-up was 24.5 months. One patient presented with recurrent disease and was treated with resection, and both pre- and postoperative RT. He was free of disease 23 months after his last treatment. No local recurrence was noted in the remaining patients. Of the 14 patients undergoing preoperative RT, complete pathologic necrosis or no tumor was noted in 1 of the patients. No metastatic disease was observed in any of the patients. There was no significant radiation toxicity observed in any of the patients., Conclusions: Data were consistent with local control of distal extremity sarcomas with resection and RT, suggesting that limb-sparing surgery with this treatment combination is an appropriate option in the limb-sparing control of patients with AMFS, even those with positive surgical margins., (Copyright © 2010 American Cancer Society.)

Purpose: There is little information on the appropriate three-dimensional (3D) preoperative radiotherapy (XRT) volume for extremity soft-tissue sarcomas (STS). We retrospectively analyzed the pattern of local failure (LF) to help elucidate optimal field design., Methods and Materials: We analyzed the 56 patients who underwent computed tomography-planned XRT for Stage I to III extremity STS between June 2000 and December 2006. Clinical target volume (CTV) included the T1 post-gadolinium-defined gross tumor volume with 1- to 1.5-cm radial and 3.5-cm longitudinal margins. Planning target volume expansion was 5 to 7 mm, and >or=95% of dose was delivered to the planning target volume. Preoperative XRT was 44 to 50.4 Gy (median, 50). Postoperative boost of 10 to 20 Gy was given to 12 patients (6 with positive and 6 with close margins)., Results: Follow-up ranged from 15 to 76 months (median, 41 months). The 5-year local control, freedom from distant metastasis, disease-free survival, and overall survival were 88.5%, 80.0%, 77.5% and 82.8%, respectively. Three patients (all with positive margin) experienced local failure (LF) as first relapse (2 isolated, 1 with distant failure), and 2 additional patients (all with margin<1 mm) had late LF after distant metastasis. The LFs were within the CTV in 3 patients and within and also extending beyond the CTV in 2 patients., Conclusions: These target volume definitions appear to be appropriate for most patients. No local recurrences were observed with surgical margins >or=1 mm, and it appears that these may be adequate for patients with extremity STS treated with preoperative radiotherapy., ((c) 2010 Elsevier Inc. All rights reserved.)