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Merkel cell carcinoma (MCC) is a rare and aggressive epidermal cancer. We conducted a retrospective study and literature review to investigate the impact that radiation therapy has on local, regional, and distant control as part of the oncologic management of MCC of the head and neck and to further elucidate the role of radiation therapy with regard to regional control for the clinically uninvolved neck. We reviewed all registered cases of head and neck MCC that had occurred at four institutions from January 1988 through December 2005. Treatment and outcomes data were collected on patients with American Joint Committee on Cancer stage I, II, and III tumors. Local, regional, and distant control rates were calculated by comparing variables with the Fisher exact test; Kaplan-Meier analysis was used to report actuarial control data. Stage I to III head and neck MCC was identified in 36 patients--22 men and 14 women, aged 43 to 97 years (mean: 71.6) at diagnosis. Patients with stage I and II tumors were combined into one group, and their data were compared with those of patients with stage III tumors. Twenty-six patients (72%) had clinical stage I/II disease and 10 patients (28%) had clinical stage III disease. Median follow-up was 41 months for the stage I/II group and 19 months for the stage III group. Based on examination at final follow-up visits, local recurrence was seen in 7 of the 36 patients (19%), for a local control rate of 81%. The 2-year actuarial local control rate for all stages of MCC was 83%; by treatment subgroup, the rates were 95% for those who had undergone radiation therapy to the primary site and 69% for those who had not--a statistically significant difference (p = 0.020). Based on information obtained at final follow-ups, 10 of the 36 patients (28%) experienced a regional recurrence, for a regional control rate of 72%. The 2-year actuarial regional control rate among all patients was 70%; by subgroup, rates were 82% for patients who had undergone regional node radiation therapy and 60% for those who had not--not a statistically significant difference (p = 0.225). Nine patients (25%) overall developed a distant metastasis, for a distant control rate of 75%. Salvage therapies included chemotherapy and/or radiation therapy to the metastatic site, but neither had any significant effect on survival. Regardless of treatment, the Kaplan-Meier survival curves leveled off at 30 months with 82% survival for the stage I/II group and at 19 months with 60% survival for the stage III group. We conclude that radiation therapy to the primary tumor site (either following resection or definitively) results in a local control rate of more than 90% in patients with head and neck MCC. We also found a trend toward improved regional control of the clinically negative neck with the addition of radiation therapy. [ABSTRACT FROM AUTHOR]

Hypofractionated radiation therapy regimens should not be used as standard of care for localized soft tissue sarcoma.

Importance: Desmoid tumor (DT) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Previously, surgery was the standard primary treatment modality; however, within the past decade, a paradigm shift toward less-invasive management has been introduced and an effort to harmonize the strategy among clinicians has been made. To update the 2020 global evidence-based consensus guideline on the management of patients with DT, the Desmoid Tumor Working Group convened a 1-day consensus meeting in Milan, Italy, on June 30, 2023, under the auspices of the European Reference Network on Rare Adult Solid Cancers and Sarcoma Patient Advocacy Global Network, the Desmoid Foundation Italy, and the Desmoid Tumor Research Foundation. The meeting brought together over 90 adult and pediatric sarcoma experts from different disciplines as well as patients and patient advocates from around the world., Observations: The 2023 update of the global evidence-based consensus guideline focused on the positioning of local therapies alongside surgery and radiotherapy in the treatment algorithm as well as the positioning of the newest class of medical agents, such as γ-secretase inhibitors. Literature searches of MEDLINE and Embase databases were performed for English-language randomized clinical trials (RCTs) of systemic therapies to obtain data to support the consensus recommendations. Of the 18 full-text articles retrieved, only 4 articles met the inclusion criteria. The 2023 consensus guideline is informed by a number of new aspects, including data for local ablative therapies such as cryotherapy; other indications for surgery; and the γ-secretase inhibitor nirogacestat, the first representative of the newest class of medical agents and first approved drug for DT. Management of DT is complex and should be carried out exclusively in designated DT referral centers equipped with a multidisciplinary tumor board. Selection of the appropriate strategy should consider DT-related symptoms, associated risks, tumor location, disease morbidities, available treatment options, and preferences of individual patients., Conclusions and Relevance: The therapeutic armamentarium of DT therapy is continually expanding. It is imperative to carefully select the management strategy for each patient with DT to optimize tumor control and enhance quality of life.

This critical review aims to summarize the relevant published data regarding hypofractionation regimens for preoperative radiation therapy (RT) prior to surgery for soft tissue sarcoma (STS) of the extremity or superficial trunk. We identified peer-reviewed publications using a PubMed search on the MeSH headings of "soft tissue sarcoma" AND "hypofractionated radiation therapy." To obtain complication data on similar anatomical radiotherapeutic scenarios we also searched "hypofractionated radiation therapy" AND "melanoma" as well as "hypofractionated radiation therapy" AND "breast cancer." We then used reference lists from relevant articles to obtain additional pertinent publications. We also incorporated relevant abstracts presented at international sarcoma meetings and relevant clinical trials as listed on the ClinicalTrials.gov website. Detailed data are presented and contextualized for ultra-hypofractionated and moderately hypofractionated regimens with respect to local control, wound complications, and amputation rates. Comparative data are also presented for late toxicities including: fibrosis, joint limitation, edema, skin integrity, and bone fracture or necrosis. These data are compared to a standard regimen of 50 Gy in 25 daily fractions delivered over 5 weeks. This analysis supports the continued use of a standard regimen for preoperative RT for STS of 25 × 2 Gy over 5 weeks without concurrent chemotherapy. Use of concurrent chemotherapy with preoperative RT for STS should be reserved for well-designed clinical trials. A randomized trial of ultra-hypofractionated and moderately hypofractionated pre op RT for STS is warranted, but it is critical for the primary endpoint (or co-primary endpoint) to be late toxicity to: bone, soft tissue, joint, and skin., Competing Interests: Declaration of competing interest B. Ashleigh Guadagnolo has no conflicts of interest to disclose. Baldini: UpToDate-Royalties. EHB is an author for several sections of UpToDate, an evidence based online clinical resource. She receives financial payment/royalties for her services., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Myxoid liposarcoma (LPS) has a unique tendency to spread to extrapulmonary sites, including osseous sites such as the spine, and adjacent sites such as the paraspinous tissue. No clear consensus exists to guide the approach to imaging in these patients., Objective: The aim of this study was to investigate the rate and distribution of spine metastases in patients with myxoid LPS and detection modality., Methods: Records of all patients with myxoid LPS evaluated at our sarcoma center were retrospectively reviewed. Disease patterns and imaging modality utilization were analyzed., Results: Between 2000 and 2020, 164 patients with myxoid LPS were identified. The majority (n = 148, 90%) presented with localized disease, with half (n = 82, 50%) of all patients developing metastases or recurrence during their disease course. With a median follow-up of 69.2 months, spine/paraspinous metastases developed in 38 patients (23%), of whom 35 (92%) already had synchronous, non-spine metastases. Spine disease was only visible on magnetic resonance imaging (MRI), as opposed to other imaging modalities, for over one-quarter of patients with spine metastases (n = 10). For patients with metastatic disease, spine metastases were associated with worse median overall survival (2.1 vs. 8.7 years, p < 0.001)., Conclusion: Spine metastases occurred in nearly one-quarter of patients with myxoid LPS and represented an advanced disease state, as they primarily presented in the setting of synchronous, non-spine metastases, and were associated with worse overall survival. Routine surveillance with spine MRI in patients with localized disease likely provides no benefit but may be considered in those with known metastatic disease., (© 2023. Society of Surgical Oncology.)

Objective: The aim of the present study was to compare the effect of radiotherapy (RT) on abdominal recurrence-free survival (ARFS) in patients with primary retroperitoneal sarcoma treated in the EORTC-STBSG-62092 (STRASS) phase 3 randomized controlled trial (STRASS cohort) and off-trial (STREXIT cohort) and to pool STRASS and STREXIT data to test the hypothesis that RT improves ARFS in patients with liposarcoma., Background: The STRASS trial did not show any difference in ARFS between patients treated with preoperative radiotherapy+surgery (RT+S) versus surgery alone (S)., Methods: All consecutive adult patients not enrolled in STRASS and underwent curative-intent surgery for a primary retroperitoneal sarcoma with or without preoperative RT between 2012 and 2017 (STRASS recruiting period) among ten STRASS-recruiting centres formed the STREXIT cohort. The effect of RT in STREXIT was explored with a propensity score (PS)-matching analysis. Primary endpoint was ARFS defined as macroscopically incomplete resection or abdominal recurrence or death of any cause, whichever occurred first., Results: STRASS included 266 patients, STREXIT included 831 patients (727 after excluding patients who received preoperative chemotherapy, 202 after 1:1 PS-matching). The effect of RT on ARFS in STRASS and 1:1 PS-matched STREXIT cohorts, overall and in patients with liposarcoma, was similar. In the pooled cohort analysis, RT administration was associated with better ARFS in patients with liposarcoma [N=321, hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.42-0.89]. In particular, patients with well-differentiated liposarcoma and G1-2 dedifferentiated liposarcoma (G1-2 DDLPS, n=266) treated with RT+S had better ARFS (HR, 0.63; 95% CI, 0.40-0.97) while patients with G3 DDLPS and leiomyosarcoma had not. At the current follow-up, there was no association between RT and overall survival or distant metastases-free survival., Conclusions: In this study, preoperative RT was associated with better ARFS in patients with primary well-differentiated liposarcoma and G1-2 DDLPS., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS., Methods: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021)., Results: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice., Conclusions: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Surgery is the mainstay of treatment for retroperitoneal sarcoma (RPS), but local recurrence is common. Biologic behavior and recurrence patterns differ significantly among histologic types of RPS, with implications for management. The Transatlantic Australasian RPS Working Group (TARPSWG) published a consensus approach to primary RPS, and to complement this, one for recurrent RPS in 2016. Since then, additional studies have been published, and collaborative discussion is ongoing to address the clinical challenges of local recurrence in RPS., Methods: An extensive literature search was performed, and the previous consensus statements for recurrent RPS were updated after review by TARPSWG members. The search included the most common RPS histologic types: liposarcoma, leiomyosarcoma, solitary fibrous tumor, undifferentiated pleomorphic sarcoma, and malignant peripheral nerve sheath tumor., Results: Recurrent RPS management was evaluated from diagnosis to follow-up evaluation. For appropriately selected patients, resection is safe. Nomograms currently are available to help predict outcome after resection. These and other new findings have been combined with expert recommendations to provide 36 statements, each of which is attributed a level of evidence and grade of recommendation. In this updated document, more emphasis is placed on histologic type and clarification of the intent for surgical treatment, either curative or palliative. Overall, the fundamental tenet of optimal care for patients with recurrent RPS remains individualized treatment after multidisciplinary discussion by an experienced team with expertise in RPS., Conclusions: Updated consensus recommendations are provided to help guide decision-making for treatment of locally recurrent RPS and better selection of patients who would potentially benefit from surgery., (© 2022. Society of Surgical Oncology.)

Retroperitoneal sarcoma comprises a small subset of all soft tissue sarcoma and includes various histopathologic subtypes, each with unique patterns of behavior and differential risks for local recurrence and hematogenous metastatic spread. The primary treatment modality is surgery, although even with complete macroscopic resection, recurrence is common. The rationale for the addition of radiotherapy to resection is to improve local control; however, the use of radiation therapy for retroperitoneal sarcoma is controversial, and existing data are suboptimal to guide management. Treatment decisions should be determined with multidisciplinary input and shared decision-making. When used in selected patients, radiation therapy should be delivered preoperatively; postoperative treatment is not recommended.

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.)

Purpose: Patients with locally advanced non-small cell lung cancer (LA-NSCLC) have a high prevalence of pre-existing coronary heart disease and face excess cardiac risk after thoracic radiation therapy. We sought to assess whether statin therapy is a predictor of overall survival (OS) after thoracic radiation therapy., Methods and Materials: We performed a retrospective analysis of 748 patients with LA-NSCLC treated with thoracic radiation therapy, using Kaplan-Meier OS estimates and Cox regression., Results: Statin use among high cardiac risk patients (Framingham risk ≥20% or pre-existing coronary heart disease; n = 496) was 51.2%. After adjustment for baseline cardiac risk and other prognostic factors, statin therapy was associated with a significantly increased risk of all-cause mortality (adjusted hazard ratio, 1.39; 95% confidence interval [CI], 1.00-1.91; P = .048) but not major adverse cardiac events (adjusted hazard ratio, 1.18; 95% CI, 0.52-2.68; P = .69). Among statin-naïve patients, mean heart dose ≥10 Gy versus <10 Gy was associated with a significantly increased risk of all-cause mortality (hazard ratio, 1.32; 95% CI, 1.04-1.68; P = .022), with 2-year OS estimates of 46.9% versus 60.0%, respectively. However, OS did not differ by heart dose among patients on statin therapy (hazard ratio, 1.00; 95% CI, 0.76-1.32; P = 1.00; P-interaction = .031), with 2-year OS estimates of 46.9% versus 50.3%, respectively., Conclusions: Among patients with LA-NSCLC, only half of statin-eligible high cardiac risk patients were on statin therapy, reflecting the highest cardiac risk level of our cohort. Statin use was an independent predictor of all-cause mortality but not major adverse cardiac events. Elevated mean heart dose (≥10 Gy) was associated with increased risk of all-cause mortality in statin-naïve patients but not among those on statin therapy, identifying a group of patients in which early intervention with statins may mitigate the deleterious effects of high heart radiation therapy dose. This warrants evaluation in prospective trials., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies., Methods: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan., Results: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types., Conclusions: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients., (© 2021 American Cancer Society.)

Purpose: Mean heart dose (MHD) over 10 Gy and left anterior descending (LAD) coronary artery volume (V) receiving 15 Gy (V15Gy) greater than 10% can significantly increase the risk of major adverse cardiac events (MACE) in patients with non-small cell lung cancer (NSCLC). We sought to characterize the discordance between MHD and LAD dose and the association of this classification on the risk of MACE after radiation therapy., Methods and Materials: The coefficient of determination for MHD and LAD V15Gy was calculated in this retrospective analysis of 701 patients with locally advanced NSCLC treated with radiation therapy. Four groups were defined on the basis of high or low MHD (≥10 Gy vs <10 Gy) and LAD V15Gy (≥10% vs <10%). MACE (unstable angina, heart failure, myocardial infarction, coronary revascularization, and cardiac death) cumulative incidence was estimated, and Fine and Gray regressions were performed., Results: The proportion of variance in LAD V15Gy predictable from MHD was only 54.5% (R 2  = 0.545). There was discordance (where MHD was high [≥10 Gy] and LAD low [V15Gy < 10%], or vice versa) in 23.1% of patients (n = 162). Two-year MACE estimates were 4.2% (MHD high /LAD low ), 7.6% (MHD high /LAD high ), 1.8% (MHD low /LAD low ), and 13.0% (MHD low /LAD high ). Adjusting for pre-existing coronary heart disease and other prognostic factors, MHD high /LAD low (subdistribution hazard ratio [SHR], 0.34; 95% CI, 0.13-0.93; P = .036) and MHD low /LAD low (SHR, 0.24; 95% CI, 0.10-0.53; P < .001) were associated with a significantly reduced risk of MACE., Conclusions: MHD is insufficient to predict LAD V15Gy with confidence. When MHD and LAD V15Gy dose exposure is discordant, isolated low LAD V15Gy significantly reduces the risk of MACE in patients with locally advanced NSCLC after radiation therapy, suggesting that the validity of whole heart metrics for optimally predicting cardiac events should be reassessed., (Copyright © 2021 The Authors. Published by Elsevier Inc. 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.

Purpose: Angiosarcoma is a sub-type of soft tissue sarcoma, often presenting as a multifocal or diffuse disease process with poor prognosis. This study presents outcomes of a single institution cohort of patients with angiosarcoma of the scalp and face following treatment with multimodality therapy, including high-dose-rate surface applicator (HDR-SA) brachytherapy, and represents the largest cohort utilizing this therapeutic approach., Material and Methods: Twenty patients with primary or recurrent angiosarcoma of the face or scalp were treated with HDR-SA brachytherapy between 2003-2018, with clinical characteristics and outcomes collected from medical records and used to identify prognostic features., Results: Median follow-up was 45 months. Patients treated with HDR-SA brachytherapy had a 4-year local control rate of 63%, a 4-year progression-free survival (PFS) rate of 20%, and a 4-year overall survival rate of 54%. Disease features associated with worse loco-regional control (LRC) included location on the scalp (vs. face, p = 0.04) and tumor size ≥ 5 cm ( p = 0.0099). Outcomes after HDR-SA brachytherapy for salvage therapy vs. HDR-SA brachytherapy as a component of an initial treatment approach were also significantly different, with worse LRC ( p = 0.0084) and worse overall survival (OS) ( p = 0.0019) in a setting of salvage therapy., Conclusions: Local control rates following HDR-SA brachytherapy for scalp or face angiosarcoma are moderate and similar to what is described in the literature using a variety of local control treatment modalities. Smaller tumors and those involving the face rather than scalp had better outcomes. PFS rates were poor and there is a pressing need for treatment intensification and novel therapeutic options., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Termedia.)

Importance: Radiotherapy accelerates coronary heart disease (CHD), but the dose to critical cardiac substructures has not been systematically studied in lung cancer., Objective: To examine independent cardiac substructure radiotherapy factors for major adverse cardiac events (MACE) and all-cause mortality in patients with locally advanced non-small cell lung cancer (NSCLC)., Design, Setting, and Participants: A retrospective cohort analysis of 701 patients with locally advanced NSCLC treated with thoracic radiotherapy at Harvard University-affiliated hospitals between December 1, 2003, and January 27, 2014, was performed. Data analysis was conducted between January 12, 2019, and July 22, 2020. Cardiac substructures were manually delineated. Radiotherapy dose parameters (mean, maximum, and the volume [V, percentage] receiving a specific Gray [Gy] dose in 5-Gy increments) were calculated. Receiver operating curve and cut-point analyses estimating MACE (unstable angina, heart failure hospitalization or urgent visit, myocardial infarction, coronary revascularization, and cardiac death) were performed. Fine and Gray and Cox regressions were adjusted for preexisting CHD and other prognostic factors., Main Outcomes and Measures: MACE and all-cause mortality., Results: Of the 701 patients included in the analysis, 356 were men (50.8%). The median age was 65 years (interquartile range, 57-73 years). The optimal cut points for substructure and radiotherapy doses (highest C-index value) were left anterior descending (LAD) coronary artery V15 Gy greater than or equal to 10% (0.64), left circumflex coronary artery V15 Gy greater than or equal to 14% (0.64), left ventricle V15 Gy greater than or equal to 1% (0.64), and mean total coronary artery dose greater than or equal to 7 Gy (0.62). Adjusting for baseline CHD status and other prognostic factors, an LAD coronary artery V15 Gy greater than or equal to 10% was associated with increased risk of MACE (adjusted hazard ratio, 13.90; 95% CI, 1.23-157.21; P = .03) and all-cause mortality (adjusted hazard ratio, 1.58; 95% CI, 1.09-2.29; P = .02). Among patients without CHD, associations with increased 1-year MACE were noted for LAD coronary artery V15 Gy greater than or equal to 10% (4.9% vs 0%), left circumflex coronary artery V15 Gy greater than or equal to 14% (5.2% vs 0.7%), left ventricle V15 Gy greater than or equal to 1% (5.0% vs 0.4%), and mean total coronary artery dose greater than or equal to 7 Gy (4.8% vs 0%) (all P ≤ .001), but only a left ventricle V15 Gy greater than or equal to 1% increased the risk among patients with CHD (8.4% vs 4.1%; P = .046). Among patients without CHD, 2-year all-cause mortality was increased with an LAD coronary artery V15 Gy greater than or equal to 10% (51.2% vs 42.2%; P = .009) and mean total coronary artery dose greater than or equal to 7 Gy (53.2% vs 40.0%; P = .01)., Conclusions and Relevance: The findings of this cohort study suggest that optimal cardiac dose constraints may differ based on preexisting CHD. Although the LAD coronary artery V15 Gy greater than or equal to 10% appeared to be an independent estimator of the probability of MACE and all-cause mortality, particularly in patients without CHD, left ventricle V15 Gy greater than or equal to 1% appeared to confer an increased risk of MACE among patients with CHD. These constraints are worthy of further study because there is a need for improved cardiac risk stratification and aggressive risk mitigation strategies.

Introduction: A meningeal solitary fibrous tumor (SFT), also called hemangiopericytoma, is a rare mesenchymal malignancy. Due to anatomic constrains, even after macroscopic complete surgery with curative intent, the local relapse risk is still relatively high, thus increasing the risk of dedifferentiation and metastatic spread. This study aims to better define the role of postoperative radiotherapy (RT) in meningeal SFTs., Patients and Methods: A retrospective study was performed across seven sarcoma centers. Clinical information was retrieved from all adult patients with meningeal primary localized SFT treated between 1990 and 2018 with surgery alone (S) compared to those that also received postoperative RT (S + RT). Differences in treatment characteristics between subgroups were tested using independent samples t -test for continuous variables and chi-square tests for proportions. Local control (LC) and overall survival (OS) rates were calculated as time from start of treatment until progression or death from any cause. LC and OS in groups receiving S or S + RT were compared using Kaplan-Meier survival curves., Results: Among a total of 48 patients, 7 (15%) underwent S and 41 (85%) underwent S + RT. Median FU was 65 months. LC was significantly associated with treatment. LC after S at 60 months was 60% versus 90% after S + RT ( p  = 0.052). Furthermore, R1 resection status was significantly associated with worse LC (HR 4.08, p  = 0.038). OS was predominantly associated with the mitotic count (HR 3.10, p  = 0.011)., Conclusion: This retrospective study, investigating postoperative RT in primary localized meningeal SFT patients, suggests that combining RT to surgery in the management of this patient population may reduce the risk for local failures.

Importance: Currently, preoperative radiotherapy for all soft-tissue sarcomas is identical at a 50-Gy dose level, which can be associated with morbidity, particularly wound complications. The observed clinical radiosensitivity of the myxoid liposarcoma subtype might offer the possibility to reduce morbidity., Objective: To assess whether a dose reduction of preoperative radiotherapy for myxoid liposarcoma would result in comparable oncological outcome with less morbidity., Design, Setting, and Participants: The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas (DOREMY) trial is a prospective, single-group, phase 2 nonrandomized controlled trial being conducted in 9 tertiary sarcoma centers in Europe and the US. Participants include adults with nonmetastatic, biopsy-proven and translocation-confirmed myxoid liposarcoma of the extremity or trunk who were enrolled between November 24, 2010, and August 1, 2019. Data analyses, using both per-protocol and intention-to-treat approaches, were conducted from November 24, 2010, to January 31, 2020., Interventions: The experimental preoperative radiotherapy regimen consisted of 36 Gy in once-daily 2-Gy fractions, with subsequent definitive surgical resection after an interval of 4 or more weeks., Main Outcomes and Measures: As a short-term evaluable surrogate for local control, the primary end point was centrally reviewed pathologic treatment response. The experimental regimen was regarded as a success when 70% or more of the resection specimens showed extensive treatment response, defined as 50% or greater of the tumor volume containing treatment effects. Morbidity outcomes consisted of wound complications and late toxic effects., Results: Among the 79 eligible patients, 44 (56%) were men and the median (interquartile range) age was 45 (39-56) years. Two patients did not undergo surgical resection because of intercurrent metastatic disease. Extensive pathological treatment response was observed in 70 of 77 patients (91%; posterior mean, 90.4%; 95% highest probability density interval, 83.8%-96.4%). The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%., Conclusions and Relevance: The findings of the DOREMY nonrandomized clinical trial suggest that deintensification of preoperative radiotherapy dose is effective and oncologically safe and is associated with less morbidity than historical controls, although differences in radiotherapy techniques and follow-up should be considered. A 36-Gy dose delivered in once-daily 2-Gy fractions is proposed as a dose-fractionation approach for myxoid liposarcoma, given that phase 3 trials are logistically impossible to execute in rare cancers., Trial Registration: ClinicalTrials.gov Identifier: NCT02106312.

Background: Patients undergoing surgery for soft tissue sarcoma have high morbidity rates, particularly after preoperative radiation therapy (RT). An enhanced recovery after surgery (ERAS) programme may improve perioperative outcomes in abdominal surgery. This study reported outcomes of an ERAS programme tailored to patients with soft tissue sarcoma., Methods: A prospective ERAS protocol was implemented in 2015 at a high-volume sarcoma centre. Patients treated within the ERAS programme from 2015 to 2018 were case-matched retrospectively with patients treated between 2012 and 2018 without use of the protocol, matched by surgical site, surgeon, sarcoma histology and preoperative RT treatment. Postoperative outcomes, specifically wound complications and duration of hospital stay, were reported., Results: In total, 234 patients treated within the ERAS programme were matched with 237 who were not. The ERAS group had lower wound dehiscence rates overall (2 of 234 (0·9 per cent) versus 31 of 237 (13·1 per cent); P < 0·001), after preoperative RT (0 of 41 versus 11 of 51; P = 0·004) and after extremity sarcoma surgery (0 of 54 versus 6 of 56; P = 0·040) compared with the non-ERAS group. Rates of postoperative ileus or obstruction were lower in the ERAS group (21 of 234 (9·9 per cent) versus 40 of 237 (16·9 per cent); P = 0·016) and in those with retroperitoneal sarcoma (4 of 36 versus 15 of 36; P = 0·007). Duration of hospital stay was shorter in the ERAS group (median 5 (range 0-36) versus 6 (0-67) days; P = 0·003)., Conclusion: Treatment within an ERAS protocol for patients with soft tissue sarcoma was associated with lower morbidity and shorter hospital stay., (© 2020 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival., Methods: EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018., Findings: Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8-59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71-1·44; log rank p=0·95). The most common grade 3-4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events., Interpretation: Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma., Funding: European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Angiosarcoma of the face and scalp is a rare disease with high rates of recurrence. The optimal treatment approach is not well defined. This study presents a dosimetric comparison of high-dose-rate surface applicator (HDR-SA) brachytherapy to volumetric-modulated arc therapy (VMAT)., Methods: Between 2011 and 2018, 12 patients with primary or recurrent angiosarcoma of the face or scalp were treated with HDR-SA brachytherapy using CT-based planning at our institution. For comparison, deliverable VMAT plans for each patient were generated, and dose distribution was compared to the delivered HDR-SA brachytherapy plans., Results: Both VMAT and HDR-SA brachytherapy plans delivered good coverage of the clinical target. However, the dose distribution of VMAT was significantly different from HDR-SA brachytherapy across a variety of parameters. Mean doses to the lacrimal gland, orbit, lens, and cochlea were significantly higher with HDR-SA brachytherapy vs. VMAT. Brain Dmax, V80%, and V50% were also significantly higher with HDR-SA brachytherapy., Conclusions: There may be dosimetric advantages to VMAT over HDR-SA brachytherapy for many patients. However, individual tumor location, patient anatomy, and treatment reproducibility may result in HDR-SA brachytherapy being the preferred technique in a subset of patients. Ultimately, a personalized approach is likely to be the optimal treatment plan., Competing Interests: The authors have no conflicts of interest., (Copyright © 2020 Devarati Mitra et al.)

Background: Solitary fibrous tumor (SFT) is a rare mesenchymal malignancy. Although surgery is potentially curative, the local relapse risk is high after marginal resections. Given the lack of prospective clinical trial data, the objective of the current study was to better define the role of perioperative radiotherapy (RT) in various SFT presentations by location., Methods: This was retrospective study performed across 7 sarcoma centers. Clinical information was retrieved from all adult patients with extrameningeal, primary, localized SFT who were treated between 1990 and 2018 with surgery alone (S) compared with those who also received perioperative RT (S+RT). Differences in treatment characteristics between subgroups were tested using analysis of variance statistics and propensity score matching. Local control and overall survival rates were calculated from the start of treatment until progression or death from any cause., Results: Of all 549 patients, 428 (78%) underwent S, and 121 (22%) underwent S+RT. The median follow-up was 52 months. After correction for mitotic count and surgical margins, S+RT was significantly associated with a lower risk of local progression (hazard ratio, 0.19: P = .029), an observation further confirmed by propensity score matching (P = .012); however, this association did not translate into an overall survival benefit., Conclusions: The results from this retrospective study investigating perioperative RT in patients with primary extrameningeal SFT suggest that combining RT with surgery in the management of this patient population is significantly associated with a reduced risk of local failures, especially in patients who have less favorable resection margins and in those who have tumors with a high mitotic count., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: In prior reports from population-based databases, black patients with extremity soft tissue sarcoma (ESTS) have lower reported rates of limb-sparing surgery and adjuvant treatment. The objective of this study was to compare the multimodality treatment of ESTS between black and white patients within a universally insured and equal-access health care system., Methods: Claims data from TRICARE, the US Department of Defense insurance plan that provides health care coverage for 9 million active-duty personnel, retirees, and dependents, were queried for patients younger than 65 y with ESTS who underwent limb-sparing surgery or amputation between 2006 and 2014 and identified as black or white race. Multivariable logistic regression analysis was used to evaluate the impact of race on the utilization of surgery, chemotherapy, and radiation., Results: Of the 719 patients included for analysis, 605 patients (84%) were white and 114 (16%) were black. Compared with whites, blacks had the same likelihood of receiving limb-sparing surgery (odds ratio [OR], 0.861; 95% confidence interval [95% CI], 0.284-2.611; P = 0.79), neoadjuvant radiation (OR, 1.177; 95% CI, 0.204-1.319; P = 0.34), and neoadjuvant (OR, 0.852; 95% CI, 0.554-1.311; P = 0.47) and adjuvant (OR, 1.211; 95% CI, 0.911-1.611; P = 0.19) chemotherapy; blacks more likely to receive adjuvant radiation (OR, 1.917; 95% CI, 1.162-3.162; P = 0.011)., Conclusions: In a universally insured population, racial differences in the rates of limb-sparing surgery for ESTS are significantly mitigated compared with prior reports. Biologic or disease factors that could not be accounted for in this study may contribute to the increased use of adjuvant radiation among black patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Limited stage small cell lung cancer (LS-SCLC) has a poor prognosis. Additional prognostic markers are needed for risk-stratification and treatment intensification. This study compares quantitative CT-based volumetric tumor measurements versus International Association for the Study of Lung Cancer (IASLC) TNM staging to predict outcomes., Materials & Methods: A cohort of 105 patients diagnosed with LS-SCLC and treated with chemoradiation (CRT) from 2000 to 2013 were analyzed retrospectively. Patients were staged by the Union for International Cancer Control (UICC) TNM Classification, 8th edition. Tumor volumes and diameters were extracted from radiation planning CT imaging. Univariable and multivariable models were used to analyze relationships between CT features and overall survival (OS), locoregional recurrence (LRR), in-field LRR, any progression, and distant metastasis (DM)., Results: Median follow-up was 21.3 months. Two-year outcomes were as follows: 38% LRR, 31% in-field LRR, 52% DM, 62% any progression, and 47% OS (median survival 16.5 months). On univariable analysis, UICC T-stage and N-stage were not associated with any clinical outcome. UICC overall stage was only statistically associated with in-field LRR. One imaging feature (3D maximum tumor diameter) was found to be significantly associated with LRR (HR 1.10, p = 0.003), in-field LRR (HR 1.10, p = 0.007), DM (HR 1.10, p = 0.02), any progression (HR 1.10, p = 0.008), and OS (HR 1.10, p = 0.03). On multivariable analysis, this feature remained significantly associated with all outcomes., Conclusion: For LS-SCLC, quantitative CT-based volumetric tumor measurements were significantly associated with outcomes after CRT and may be better predictors of outcome than TNM stage.

Soft tissue sarcomas (STS) are a rare and diverse group of tumors that affect both adult and pediatric populations. This review discusses current screening recommendations for populations at increased risk for STS, including those with genetic predispositions. We also review surveillance guidelines for those at risk for recurrence following curative-intent surgery., (© 2019 Wiley Periodicals, Inc.)

Background and Purpose: Small studies of primarily metastatic non-small cell lung cancer (NSCLC) have suggested an association between EGFR mutation (EGFR+) and likelihood of brain metastasis. However, these studies are confounded by follow-up time bias. We performed a competing risk analysis of brain metastasis in a more uniform locally advanced NSCLC (LA-NSCLC) cohort with known tumor genotype., Materials and Methods: Between 2002 and 2014, 255 patients with LA-NSCLC underwent tumor genotyping for EGFR, ALK and/or KRAS (180 patients had follow-up brain imaging). Cumulative incidence and Fine-Gray regression were performed on clinical variables including genotype and risk of brain metastasis, with death as a competing event., Results: The proportion of tumors with aberrations in EGFR, ALK and KRAS were 17%, 4% and 28%, respectively. The median follow-up was 68 months. On multivariate analysis, EGFR+ was significantly associated with risk of brain metastasis in the full patient cohort (HR 2.04, 95% CI 1.22-3.39, p = 0.006) as well as in the subset of patients with brain follow-up imaging (HR 1.91. 95% CI 1.17-3.13, p = 0.01). This translated to a higher cumulative incidence of brain metastasis in EGFR+ patients at 3 and 5 years (33.3% vs. 23.2 and 43.8% vs. 24.2%, p = 0.006)., Conclusion: Patients with EGFR+ LA-NSCLC have a significantly higher likelihood of developing brain metastasis after standard combined modality therapy, independent of their longer overall survival. This high-risk genotypic subgroup may benefit from routine surveillance with brain MRI to allow early salvage with targeted systemic- and/or radiation-therapies., Competing Interests: RM – Astra Zeneca – Scientific Advisory Board; Varian – Consulting. All other authors declare they have no conflicts of interest.

Background: Radiotherapy-associated cardiac toxicity studies in patients with locally advanced non-small cell lung cancer (NSCLC) have been limited by small sample size and nonvalidated cardiac endpoints., Objectives: The purpose of this analysis was to ascertain whether cardiac radiation dose is a predictor of major adverse cardiac events (MACE) and all-cause mortality (ACM)., Methods: This retrospective analysis included 748 consecutive locally advanced NSCLC patients treated with thoracic radiotherapy. Fine and Gray and Cox regressions were used to identify predictors for MACE and ACM, adjusting for lung cancer and cardiovascular prognostic factors, including pre-existing coronary heart disease (CHD)., Results: After a median follow-up of 20.4 months, 77 patients developed ≥1 MACE (2-year cumulative incidence, 5.8%; 95% confidence interval [CI]: 4.3% to 7.7%), and 533 died. Mean radiation dose delivered to the heart (mean heart dose) was associated with a significantly increased risk of MACE (adjusted hazard ratio [HR]: 1.05/Gy; 95% CI: 1.02 to 1.08/Gy; p < 0.001) and ACM (adjusted HR: 1.02/Gy; 95% CI: 1.00 to 1.03/Gy; p = 0.007). Mean heart dose (≥10 Gy vs. <10 Gy) was associated with a significantly increased risk of ACM in CHD-negative patients (178 vs. 118 deaths; HR: 1.34; 95% CI: 1.06 to 1.69; p = 0.014) with 2-year estimates of 52.2% (95% CI: 46.1% to 58.5%) versus 40.0% (95% CI: 33.5% to 47.4%); but not among CHD-positive patients (112 vs. 82 deaths; HR: 0.94; 95% CI: 0.70 to 1.25; p = 0.66) with 2-year estimates of 54.6% (95% CI: 46.8% to 62.7%) versus 50.8% (95% CI: 41.5% to 60.9%), respectively (p for interaction = 0.028)., Conclusions: Despite the competing risk of cancer-specific death in locally advanced NSCLC patients, cardiac radiation dose exposure is a modifiable cardiac risk factor for MACE and ACM, supporting the need for early recognition and treatment of cardiovascular events and more stringent avoidance of high cardiac radiotherapy dose., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Radiation-associated sarcomas (RAS) are considered to have a poor prognosis. Although the incidence is anticipated to rise, contemporary data regarding predictors of outcomes are few. We performed a retrospective analysis to identify RAS prognostic factors and subset analyses for radiation-associated angiosarcoma arising after treatment for breast cancer (RAAB) and other RAS subtypes (other-RAS)., Methods and Materials: Patients with localized RAS evaluated at an institutional multidisciplinary sarcoma clinic were identified. Clinical and histologic review was performed, and outcomes were assessed to identify prognostic features. A subset of cases underwent molecular analysis by next-generation sequencing., Results: Among 176 patients, histologic subtypes of RAS included angiosarcoma (41%), undifferentiated/unclassified sarcoma (40%), leiomyosarcoma (8%), malignant peripheral nerve sheath tumor (6%), and osteosarcoma (2%). Sixty-seven patients (38%) had RAAB, and 109 (62%) had other-RAS. RAAB had significantly shorter latency from time of initial radiation compared with other-RAS (8 vs. 15 years; P < .001). Treatment approaches included surgery (91%), chemotherapy (44%), and radiation therapy (27%). Median follow-up was 3.2 years; 3-year overall survival (OS) was 74%. On multivariate analysis, positive margins (P < .0001), deep tumor location (intrathoracic/intra-abdominal, P = .002), and high grade (P < .0001) were associated with worse OS. In particular, 3-year OS with negative versus positive margins was 90% versus 66%. Patients with RAAB versus other-RAS showed a trend for higher 3-year OS (84% vs 68%; P = .09), significantly higher 3-year metastasis-free survival (82% vs 67%; P = .001), but similar 3-year local recurrence-free survival (54% vs 61%; P = .28). Next-generation sequencing identified overall low tumor mutational burden, recurrent MYC amplification in RAAB, and few clinically actionable mutations., Conclusions: Margin negative excision, superficial tumor location, and low tumor grade are determinants of improved OS for RAS, suggesting that complete surgical excision, when possible, is an optimal component of treatment. RAAB is a clinicopathologically distinct type of RAS with shorter latency from initial RT, different recurrence patterns, and when aggressively managed has potentially better outcomes compared with other-RAS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: In 699 patients with locally advanced non-small-cell lung cancer (NSCLC) treated with radiation therapy as part of combined modality therapy, we compared outcomes among genotyped and ungenotyped patients and by tumor genotype status ( EGFR , KRAS , and ALK )., Patients and Methods: Genotyping was performed in 250 patients: EGFR+ (19%), KRAS+ (32%), ALK + (9%), and wild type (WT -/-/- ; 40%). Outcomes were analyzed using the Kaplan-Meier method and Cox regression., Results: With a median follow-up of 48.2 months among genotyped patients, median overall survival (OS) was significantly longer for EGFR+ and ALK+ compared with KRAS+ and WT -/-/- (55.8 months v not reached v 28.0 v 33.2 months; P = .02). There was no difference in progression-free survival (median, 15.3 v 13.7 v 13.0 v 14.5 months; P = .47) or in freedom from distant metastases by genotype (3-year estimates: 42% v 49% v 27% v 25%; P = .25). There was higher freedom from locoregional recurrence (LRR) for EGFR+ tumors and lower freedom from LRR in ALK + tumors, compared with KRAS+ and WT -/-/- tumors (3-year: 77% v 38% v 49% v 46%). In multivariable analysis, ALK+ remained associated with increased OS (HR, 0.32; 95% CI, 0.12 to 0.87; P = .03), and EGFR+ was associated with decreased LRR (HR, 0.47; 95% CI, 0.24 to 0.92; P = .03). Analysis of post-recurrence survival demonstrated that EGFR+ / ALK+ patients treated with appropriate tyrosine kinase inhibitors had higher OS compared with other groups., Conclusion: In this series of locally advanced NSCLC treated with combined modality therapy, EGFR+ and ALK+ were associated with higher OS, whereas LRR was lower in EGFR+ patients, and the risk of distant metastases was high in all subgroups. The outcomes and patterns of failure in genotypic subgroups of NSCLC from this study can inform the design of future trials integrating targeted therapies.

Objectives: Tumor control (TC), toxicity and survival, following stereotactic body radiation therapy (SBRT) were compared between patients with and without a prior lung resection (PLR)., Materials and Methods: The study is comprised of 130 patients with 141 peripheral tumors treated with SBRT at our institution from 2009 to 2013. Primary TC and lobar control (LC) were defined per RTOG 0236. Toxicity was scored using Common Terminology Criteria for Adverse Events version 4.0. Survival/TC and toxicity were compared between patients with and without PLR using the Kaplan-Meier method and cumulative incidence, respectively. Fine and Gray regression was used for univariable/multivariable analysis for radiation pneumonitis (RP)., Results: Of the 130 patients with median age 70 years (range, 42 to 93 y), 50 had undergone PLR (median time between PLR and SBRT: 33 mo; range, 1 to 206), including pneumonectomy (12%), lobectomy (46%), wedge resection (42%). With a median follow-up of 21 months in survivors, the PLR group had better TC (1-y 100% vs. 93%; P<0.01) and increased grade ≥2 (RP; 1-y 12% vs. 1%; P<0.01). OS was not significantly different between the 2 groups (1-y 91% vs. 85%; P=0.24). On univariable/multivariable analyses, biologically effective dose was associated with TC (hazard ratios, 0.97; 95% confidence interval, 0.94-0.999; P=0.04). Chemotherapy use was associated with grade ≥2 RP for all patients (hazard ratios, 14.92; 95% confidence interval, 5.68-39.21; P<0.0001) in multivariable analysis. PLR was not associated with increased RP in multivariable analysis., Conclusions: Patients with PLR who receive lung SBRT for lung tumors have high local control and relatively low toxicity. SBRT is an excellent option to treat second lung tumors or pulmonary metastases in patients with PLR.

Standard treatment of large intermediate- and high-grade extremity soft tissue sarcoma (ESTS) typically includes wide excision and radiation therapy. Many patients do well with this approach, but for those with unfavorable features, risk for distant recurrence and, ultimately, mortality can exceed 50%. Unfortunately, universally accepted data elucidating effective treatments to prevent recurrences and improve survival for such high-risk patients are lacking. Accordingly, opinions about the appropriate role of systemic therapy for patients with high-risk localized ESTS vary. This article reviews the current literature pertaining to neoadjuvant chemotherapy, concurrent chemoradiation, and adjuvant chemotherapy for high-risk ESTS. All of these approaches are feasible and reasonable to consider. Ultimately, the decision to incorporate chemotherapy into the treatment regimen is best reached by discussion among an experienced multidisciplinary sarcoma team and should be tailored to the individual patient risk profile.

Introduction: Amputation for localized extremity sarcoma (ES), once the primary therapy, is now rarely performed. We reviewed our experience to determine why patients with sarcoma still undergo immediate or delayed amputation, identify differences based on amputation timing, and evaluate outcomes., Methods: Records of patients with primary, nonmetastatic ES who underwent amputation at our institution from 2001 to 2011 were reviewed. Univariate analysis was performed, and survival outcomes were calculated., Results: We categorized 54 patients into three cohorts: primary amputation (A1, n = 18, 33%), secondary amputation after prior limb-sparing surgery (A2, n = 22, 41%), and hand and foot sarcomas (HF, n = 14, 26%). Median age at amputation was 54 years (range 18-88 years). Common indications for amputation (> 40%) were loss of function, bone involvement, multiple compartment involvement, and large tumor size (A1); proximal location, joint involvement, neurovascular compromise, multiple compartment involvement, multifocal or fungating tumor, loss of function, and large tumor size (A2); and joint involvement and prior unplanned surgery (HF). There was no difference in disease-specific survival (DSS) (p = 0.19) or metastasis-free survival (MFS) (p = 0.31) between early (A1) and delayed (A2) amputation. Compared with cohorts A1/A2, HF patients had longer overall survival (OS) (p = 0.04)., Conclusions: Indications for amputation for extremity sarcoma vary between those who undergo primary amputation, delayed amputation, and amputation for hand or foot sarcoma. Amputations chosen judiciously are associated with excellent disease control and survival. For patients who ultimately need amputation, timing (early vs. delayed) does not affect survival.

Surgery is potentially curative for primary nonmetastatic extremity soft tissue sarcomas. After surgery alone, patients may remain at risk for local recurrences and/or metastatic disease. To reduce the likelihood of a local relapse, the addition of radiotherapy (RT) to limb-sparing surgery may result in higher local control rates of at least 85%. Generally, it can be stated that local control after both preoperative and postoperative RT is comparable, but that preoperative RT comes with a more favorable toxicity profile after prolonged follow-up, albeit at the cost of a higher wound complication rate. Furthermore, recent data suggest that preoperative RT is more cost effective. To reduce the risk of subsequent metastatic disease, systemic chemotherapy can be introduced early during the primary management of these patients. These systemic chemotherapy regimens can also be applied both preoperatively and postoperatively. Finally, with the aim of increasing the antitumor response of perioperative RT, these agents may even be combined with RT, concurrently and sequentially. While designing new preoperative combination regimens, responses should be carefully monitored by both sophisticated radiologic and pathologic evaluations. This article reviews all these aspects, in addition to limb-sparing surgery.

Background: Recently, some have argued for routine resection of adjacent but uninvolved organs in patients with retroperitoneal sarcoma (RPS) without stipulating the rationale for such organ resection (beyond the need to achieve a macroscopically complete resection) or examining histopathologic organ invasion (HOI). This study reviewed the authors' experience with primary RPS to investigate the rate and rationale for individual organ resection and the rate of HOI., Methods: Operative and pathology reports for patients with primary RPS who underwent resection at our institution were retrospectively reviewed. Histopathologic organ invasion was confirmed by a dedicated sarcoma pathologist., Results: From 2002 through 2011, 118 patients underwent resection of a primary RPS, and 99 of these patients (84%) had at least one organ resected. Kidney (n = 57), colon (n = 51), and adrenal (n = 41) were the most commonly resected organs. For the 302 organs removed, the perioperative clinical rationale for the resection was suspected invasion or tumor origin (n = 52, 17%), involved end-organ vasculature (n = 39, 13%), organ encasement (n = 42, 14%), tumor adherence (n = 127, 42%), resection required for R0/R1 resection (n = 25, 8%), or other (n = 17, 6%). The presence of HOI was found in 77 (25%) of the 302 organs resected. In the reviewed studies, HOI was identified in 34 (65%) of 52 organs suspected of invasion or tumor origin, in 19% of organs resected due to tumor encasement, and in 26% of organs with adherent tumor, even when not suspected intraoperatively, but was never identified in organs resected purely as part of a liberal en bloc resection of adjacent organs. When invasion was suspected intraoperatively, HOI was confirmed in 50, 78, and 100% of resected organs respectively for well-dedifferentiated liposarcoma, dedifferentiated liposarcoma (DDLPS), and leiomyosarcoma (LMS)., Conclusions: Histologic organ invasion was observed more commonly in organs resected with suspicion of invasion than in organs resected simply to achieve a negative margin, although this reflects a degree of subjectivity and selection bias. In more than one-fourth of adherent organs, HOI was present even when not suspected intraoperatively. Histologic subtype may predict HOI because DDLPS and LMS are associated with high rates of HOI when invasion is suspected intraoperatively. Development of a data-driven, histology-specific rationale for adjacent organ resection is critical.

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.)

Background and Purpose: There is concern that patients with collagen vascular disease (CVD) are at higher risk of developing radiation toxicity. We analyzed radiation toxicities in patients with intrathoracic malignancy and CVD treated using modern radiotherapy., Materials and Methods: This single-institution retrospective study included 31 patients with CVD and 825 patients without CVD treated from 1998 to 2014. Radiation esophagitis (RE) and radiation pneumonitis (RP) were scored by RTOG scales. RE was analyzed with logistic regression and RP with Cox regression., Results: CVD patients experienced similar grade ≥3 RE compared to control patients (23% vs. 19%, p = 0.64) but more grade ≥3 RP (26% vs. 10%, p = 0.01). There was no significant association between CVD subtype and toxicities. In multivariate analysis, CVD and lung V20 >30% were associated with grade ≥3 RP. We identified V20 ≤30%, V5 ≤50%, and MLD ≤18 Gy as dose thresholds in patients with CVD. CVD patients with mild severity disease and only 1 organ system involved were at low risk for RP., Conclusions: Patients with CVD may be at higher risk of RP. However, CVD patients may be offered curative thoracic RT with particular attention to risk-reduction strategies and maintaining recommended dose constraints as described in this study., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In children with localized Ewing sarcoma (ES), addition of ifosfamide and etoposide to cyclophosphamide, doxorubicin, and vincristine (VDC/IE) improved 5-year overall survival (OS) to 70%-80%. Prior to delivery of VDC/IE in adults, 5-year OS was <50%. We reviewed our institutional outcomes for adults with ES who received VDC/IE-based treatment., Materials and Methods: Between 1997-2013, 67 adults with localized ES were treated with curative intent. Local recurrence-free survival (LRFS), progression-free survival (PFS), and OS were determined using Kaplan-Meier method; comparisons were assessed with log-rank. Proportional hazard models were used to determine predictive factors., Results: All patients received VDC/IE (median 14 cycles.) Local therapy was surgery for 33, radiation therapy for 17, or both for 17. Median follow-up for living patients was 5.2 years. Six patients had disease progression on therapy. Site of first failure was local for three, local and distant for two, and distant for ten. Five-year LRFS was 91%; 5-year LRFS was 96% for nonpelvic disease and 64% for pelvic disease ( p  = .003). Five-year PFS was 66%, and 5-year OS was 79%. On multivariate analysis, pelvic site had a 3.3 times increased risk of progression ( p  = .01)., Conclusion: Survival for adults with localized ES treated with VDC/IE-based multimodality therapy appears to be better than historical data and similar to excellent outcomes in children. Pelvic site of disease remains a predictor of worse outcome. Given the paucity of literature for adult ES, these data help validate VDC/IE-based therapy as an appropriate treatment approach for this rare disease in adults., Implications for Practice: Ewing sarcoma (ES) is rare in adults. Treatment approaches for adults have been extrapolated from the pediatric experience, and there is a sense that adults fare less well than children. We reviewed treatment outcomes in adults with localized ES treated with cyclophosphamide, doxorubicin, and vincristine in alternation with ifosfamide and etoposide (VDC/IE) as part of multimodality therapy. Survival outcomes appear to be better than historical data for adults and similar to the excellent outcomes for children. These data help validate VDC/IE-based therapy as an appropriate treatment approach for this rare disease in adults., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Background: Optimal distant recurrence (DR) surveillance strategies for extremity soft tissue sarcoma (STS) are unknown. We performed a cost-effectiveness analysis of different imaging modalities performed at guideline-specified intervals., Methods: We developed a Markov model simulating lifetime outcomes for 54-year-old patients after definitive treatment for American Joint Committee on Cancer stage II-III extremity STS using four surveillance strategies: watchful waiting (WW), chest X-ray (CXR), chest computed tomography (CCT), and positron emission tomography-computed tomography (PET/CT). Probabilities, utilities, and costs were extracted from the literature and Medicare claims to determine incremental cost-effectiveness ratios (ICER)., Results: CCT was the most effective and most costly strategy with CXR the most cost-effective strategy at a societal willing-to-pay (WTP) of $100,000/quality-adjusted life year (QALY). The ICER was $12,113/QALY for CXR versus $104,366/QALY for CCT while PET/CT was never cost-effective. Sensitivity analyses demonstrated CCT becomes the preferred imaging modality as the lifetime risk of DR increases beyond 33% or as the WTP increases beyond $120,000/QALY., Conclusions: Optimal DR surveillance imaging for stage II-III extremity STS should be individualized based on patients' risks for DR. These results suggest CXR, or CCT performed at more protracted intervals, may be preferred for lower-risk patients (i.e., DR risk <33%), whereas CCT may be preferred for higher-risk patients (i.e., DR risk >33%). Further study of optimal strategies is needed. In the interim, these findings may help to refine guidelines to reduce resource overutilization during routine surveillance of lower-risk sarcoma patients.

Purpose: To critically assess the prognostic value of the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) response score and define histologic appearance after preoperative radiation therapy (RT) for soft tissue sarcoma (STS)., Methods and Materials: For a cohort of 100 patients with STS of the extremity/trunk treated at our institution with preoperative RT followed by resection, 2 expert sarcoma pathologists evaluated the resected specimens for percent residual viable cells, necrosis, hyalinization/fibrosis, and infarction. The EORTC response score and other predictors of recurrence-free survival (RFS) and overall survival (OS) were assessed by Kaplan-Meier and proportional hazard models., Results: Median tumor size was 7.5 cm; 92% were intermediate or high grade. Most common histologies were unclassified sarcoma (34%) and myxofibrosarcoma (25%). Median follow-up was 60 months. The 5-year local recurrence rate was 5%, 5-year RFS was 68%, and 5-year OS was 75%. Distribution of cases according to EORTC response score tiers was as follows: no residual viable tumor for 9 cases (9% pathologic complete response); <1% viable tumor for 0, ≥1% to <10% for 9, ≥10% to <50% for 44, and ≥50% for 38. There was no association between EORTC-STBSG response score and RFS or OS. Conversely, hyalinization/fibrosis was a significant independent favorable predictor for RFS (hazard ratio 0.49, P=.007) and OS (hazard ratio 0.36, P=.02)., Conclusion: Histologic evaluation after preoperative RT for STS showed a 9% pathologic complete response rate. The EORTC-STBSG response score and percent viable cells were not prognostic. Hyalinization/fibrosis was associated with favorable outcome, and if validated, may become a valid endpoint for neoadjuvant trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Optimal surveillance imaging (SI) regimens following radiation therapy (RT) and radical resection for localized soft tissue sarcoma (STS) are unknown and practice patterns vary., Methods: Between 2006 and 2014, 94 patients with localized STS of the extremity/trunk treated with preoperative RT and radical resection were identified. Timing of local recurrence (LR), distant recurrence (DR), and SI were evaluated. The Kaplan-Meier method was used to determine recurrence-free and overall survival (OS), and the method of recurrence detection (SI or due to signs/symptoms) was determined., Results: Median tumor size was 7.5 cm, and 92% were intermediate/high grade. After a median follow-up of 60 months for surviving patients, 30 patients (32%) recurred, including 5 LRs and 26 DRs. The median time to LR and DR was 36.2 months (range 14.4-65.7) and 10.4 months (range 5.2-76.9), respectively, and the 5-year local recurrence-free survival (RFS), distant RFS, and OS was 95, 71, and 76%, respectively. Local SI was performed for 90% of patients, mostly by magnetic resonance imaging (MRI; 91%). Of the five LRs, two were detected by SI and three had signs/symptoms preceding imaging. All patients underwent distant SI. Of the 26 DRs, 23 (88%) were in the lung. SI detected 22 (85%) DRs, and only 4 of 26 had signs/symptoms prompting imaging., Conclusion: Given excellent local control with RT and radical resection for intermediate/high-grade STS of the extremity/trunk, SI of the primary site should be reserved for select patients at high risk of LR. Conversely, due to frequent occurrence of asymptomatic DR in the lungs, periodic lung SI is appropriate. Routine abdominopelvic SI may not be indicated for most histologies.

Background: The incidence of histopathologic organ invasion (HOI) in retroperitoneal sarcoma (RPS) is not well described. We reviewed our experience to investigate the rate and prognostic implications of HOI., Study Design: Patients with primary RPS who underwent surgery at our institution were reviewed. Histopathologic organ invasion was defined as microscopic organ invasion confirmed by re-review of pathology slides by an expert sarcoma pathologist. Impact of HOI on the crude cumulative incidence of locoregional recurrence, distant recurrence, and overall survival rates was analyzed., Results: Between 2002 and 2011, one hundred and eighteen patients underwent resection for primary RPS; 99 had at least 1 organ resected and, among those, HOI was present in 58% (57 of 99). Among the 77 patients with the 3 most common histologies, rates of HOI were 61% for dedifferentiated liposarcoma, 56% for leiomyosarcoma, and 40% for well-differentiated liposarcoma. In this subset, HOI was associated with no difference in 2-year crude cumulative incidence of locoregional recurrence (48% vs 47%; p = 0.55) or distant recurrence (46% vs 22%; p = 0.2). With a median follow-up of 33.6 months, HOI was an independent predictor of worse 5-year overall survival (34% vs 62%; p = 0.04; hazard ratio = 2.3; 95% CI 1.2 to 4.4; p = 0.02)., Conclusions: The likelihood of organ invasion can be predicted by histologic subtype of primary RPS. To the best of our knowledge, this is the first study to demonstrate that HOI is associated with worse overall survival. These data can help guide the minimal extent of surgical resection required for RPS., (Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Locally advanced non-small cell lung cancer (LA-NSCLC) patients have poorer survival and local control with mediastinal node (N2) tumor involvement at resection. Earlier assessment of nodal burden could inform clinical decision-making prior to surgery. This study evaluated the association between clinical outcomes and lymph node volume before and after neoadjuvant therapy., Materials and Methods: CT imaging of patients with operable LA-NSCLC treated with chemoradiation and surgical resection was assessed. Clinically involved lymph node stations were identified by FDG-PET or mediastinoscopy. Locoregional recurrence (LRR), distant metastasis (DM), progression free survival (PFS) and overall survival (OS) were analyzed by the Kaplan Meier method, concordance index and Cox regression., Results: 73 patients with Stage IIIA-IIIB NSCLC treated with neoadjuvant chemoradiation and surgical resection were identified. The median RT dose was 54 Gy and all patients received concurrent chemotherapy. Involved lymph node volume was significantly associated with LRR and OS but not DM on univariate analysis. Additionally, lymph node volume greater than 10.6 cm3 after the completion of preoperative chemoradiation was associated with increased LRR (p<0.001) and decreased OS (p = 0.04). There was no association between nodal volumes and nodal clearance., Conclusion: For patients with LA-NSCLC, large volume nodal disease post-chemoradiation is associated with increased risk of locoregional recurrence and decreased survival. Nodal volume can thus be used to further stratify patients within the heterogeneous Stage IIIA-IIIB population and potentially guide clinical decision-making.

Introduction: Quantification of volume changes on cone beam computed tomography (CBCT) during lung stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) may provide a useful radiological marker for radiation response and for adaptive treatment planning. This study quantifies inter-scan and inter-observer variability in tumour volume delineation on CBCT., Methods: Three clinicians independently contoured the primary gross tumour volume (GTV) manually on CBCTs taken immediately before SBRT treatment (pre) and after the same SBRT treatment (post) for 19 NSCLC patients. Relative volume differences (RVD) were calculated between the pre- and post-CBCTs for a given treatment and between any two of three observers for a given CBCT. Coefficient of variation (CV) was used to quantitatively measure and compare the extent of variability., Results: Inter-observer variability had a significantly higher CV of 0.15 ± 0.13 compared to inter-scan CV of 0.03 ± 0.04 with P < 0.0001. The greatest variability was observed with tumours (<2 cm in diameter) versus larger tumours with 95% limit of agreement (LOA) (Mean ± Standard Deviation) of 1.90% ± 19.55% vs. -0.97% ± 12.26% for inter-scan RVD and 29.99% ± 73.84% vs. 9.37% ± 29.95% for inter-observer RVD respectively., Conclusions: Inter-observer variability was greater than inter-scan variability for tumour volume delineation on CBCT with greatest variability for small tumours (<2 cm in diameter). LOA for inter-scan variability (~12%) helps defines a threshold for clinically meaningful tumour volume change during SBRT treatment for tumours with diameter greater than 2 cm, with larger thresholds needed for smaller tumours., (© 2016 The Royal Australian and New Zealand College of Radiologists.)

Purpose: To conduct phase 1 and 2 trials with photon intensity modulated radiation therapy and intensity modulated proton therapy (IMPT) arms to selectively escalate the retroperitoneal sarcoma preoperative radiation dose to tumor volume (clinical target volume [CTV] 2) that is judged to be at a high risk for positive margins and aim to reduce local recurrence. We report on the IMPT study arm in phase 1., Methods and Materials: Patients aged ≥18 years with primary or locally recurrent retroperitoneal sarcoma were treated with preoperative IMPT, 50.4 GyRBE in 28 fractions, to CTV1 (gross tumor volume and adjacent tissues at risk of subclinical disease) with a simultaneous integrated boost to CTV2 to doses of 60.2, 61.6, and 63.0 GyRBE in 28 fractions of 2.15, 2.20, and 2.25 GyRBE, respectively. The primary objective of the phase 1 study was to determine the maximum tolerated dose to CTV2, which will be further tested in the phase 2 study., Results: Eleven patients showed increasing IMPT dose levels without acute dose limiting toxicities that prevented dose escalation to maximum tolerated dose. Acute toxicity was generally mild with no radiation interruptions. No unexpected perioperative morbidity was noted. Eight months postoperatively, one patient developed hydronephrosis that was treated by stent with ureter dissected off tumor and received 57.5 GyRBE. Retained ureter(s) was (were) subsequently constrained to 50.4 GyRBE without further problem. With an 18-month median follow-up, there were no local recurrences., Conclusions: IMPT dose escalation to CTV2 to 63 GyRBE was achieved without acute dose limiting toxicities. The phase 2 study of IMPT will accrue patients to that dose. Parallel intensity modulated radiation therapy phase 1 arm is currently accruing at the initial dose level. Ureters that undergo a high dose radiation and/or surgery are at risk for late hydro-ureter. Future studies will constrain retained ureters to 50.4 GyRBE to avoid ureteral stricture.