Natural history of undifferentiated pleomorphic sarcoma: Experience from the US Sarcoma Collaborative.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS. METHODS: From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at seven academic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR), time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed. RESULTS: Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLR recurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation. CONCLUSION: For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.

Outcomes of plastic surgical reconstruction in extremity and truncal soft tissue sarcoma: Results from the US Sarcoma Collaborative.

BACKGROUND: This study aimed to define how utilization of plastic surgical reconstruction (PSR) affects perioperative outcomes, locoregional recurrence-free survival (LRRFS), and overall survival (OS) after radical resection of extremity and truncal soft tissue sarcoma (ETSTS). The secondary aim was to determine factors associated with PSR. METHODS: Patients who underwent resection of ETSTS between 2000 and 2016 were identified from a multi-institutional database. PSR was defined as complex primary closure requiring a plastic surgeon, skin graft, or tissue-flap reconstruction. Outcomes included PSR utilization, postoperative complications, LRRFS, and OS. RESULTS: Of 2750 distinct operations, 1060 (38.55%) involved PSR. Tissue-flaps (854, 80.57%) were most commonly utilized. PSR was associated with a higher proportion of R0 resections (83.38% vs. 74.42%, p < 0.001). Tissue-flap PSR was associated with local wound complications (odds ratio: 1.81, confidence interval: 1.21-2.72, p = 0.004). Neither PSR nor postoperative complications were independently associated with LRRFS or OS. High-grade tumors (1.60, 1.13-2.26, p = 0.008) and neoadjuvant radiation (1.66, 1.20-2.30, p = 0.002) were associated with the need for PSR. CONCLUSION: Patients with ETSTS undergoing resection with PSR experienced acceptable rates of complications and a higher rate of negative margins, which were associated with improved LRRFS and OS. High tumor grade and neoadjuvant radiation were associated with requirement of PSR.

Extraskeletal myxoid chondrosarcoma: Clinicopathological features and outcomes from the United States sarcoma collaborative database.

BACKGROUNDS AND OBJECTIVES: This investigation described clinicopathological features and outcomes of extraskeletal myxoid chondrosarcoma (EMC) patients. METHODS: EMC patients were identified from the United States Sarcoma Collaborative database between 2000 and 2016. Overall survival (OS) and recurrence-free survival (RFS) were calculated, and prognostic factors were analyzed. RESULTS: Sixty individuals with a mean age of 55 years were included, and 65.0% (n = 39) were male. 73.3% (n = 44) had a primary tumor. A total of 41.6% (n = 25) developed tumor relapse following resection. The locoregional recurrence rate was 30.0% (n = 18/60), and mean follow-up was 42.7 months. The 5-year OS was 71.0%, while the 5-year RFS was 41.4%. On multivariate analysis for all EMC, chemotherapy (hazard ratio [HR], 6.054; 95% confidence interval [CI], 1.33-27.7; p = 0.020) and radiation (HR, 5.07, 95% CI, 1.3-20.1; p = 0.021) were independently predictive of a worse RFS. Among patients with primary EMC only, the 5-year OS was 85.3%, with a 30.0% (n = 12) locoregional recurrence rate, though no significant prognostic factors were identified. CONCLUSIONS: Long-term survival with EMC is probable, however there exists a high incidence of locoregional recurrence. While chemotherapy and radiation were associated with a worse RFS, these findings were likely confounded by recurrent disease as significance was lost in the primary EMC-only subset.

Extremity Soft Tissue Sarcoma: A Multi-Institutional Validation of Prognostic Nomograms.

BACKGROUND: Prognostic nomograms for patients with resected extremity soft tissue sarcoma (STS) include the Sarculator and Memorial Sloan Kettering (MSKCC) nomograms. We sought to validate these two nomograms within a large, modern, multi-institutional cohort of resected primary extremity STS patients. METHODS: Resected primary extremity STS patients from 2000 to 2017 were identified across nine high-volume U.S. institutions. Predicted 5- and 10-year overall survival (OS) and distant metastases cumulative incidence (DMCI), and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated with Sarculator and MSKCC nomograms, respectively. Predicted survival probabilities stratified in quintiles were compared in calibration plots to observed survival assessed by Kaplan-Meier estimates. Cumulative incidence was estimated for DMCI. Harrell's concordance index (C-index) assessed discriminative ability of nomograms. RESULTS: A total of 1326 patients underwent resection of primary extremity STS. Common histologies included: undifferentiated pleomorphic sarcoma (35%), fibrosarcoma (13%), and leiomyosarcoma (9%). Median tumor size was 8.0 cm (IQR 4.5-13.0). Tumor grade distribution was: Grade 1 (13%), Grade 2 (9%), Grade 3 (78%). Median OS was 172 months, with estimated 5- and 10-year OS of 70% and 58%. C-indices for 5- and 10-year OS (Sarculator) were 0.72 (95% CI 0.70-0.75) and 0.73 (95% CI 0.70-0.75), and 0.72 (95% CI 0.69-0.75) for 5- and 10-year DMCI. C-indices for 4-, 8-, and 12-year DSS (MSKCC) were 0.71 (95% CI 0.68-0.75). Calibration plots showed good prognostication across all outcomes. CONCLUSIONS: Sarculator and MSKCC nomograms demonstrated good prognostic ability for survival and recurrence outcomes in a modern, multi-institutional validation cohort of resected primary extremity STS patients. External validation of these nomograms supports their ongoing incorporation into clinical practice.

Resection Status Does Not Impact Recurrence in Well-Differentiated Liposarcoma of the Extremity.

BACKGROUND: Well-differentiated liposarcoma (WDLPS) is a low-grade soft tissue sarcoma with a propensity for local recurrence. The necessity of obtaining microscopically free surgical margins (R0) to minimize local recurrence is not clear. This study evaluates recurrence-free survival (RFS) of extremity WDLPS in relation to resection margin status. METHODS: A retrospective review of adult patients with primary extremity WDLPS at seven US institutions from 2000 to 2016 was performed. Patients with recurrent tumors or incomplete resection (R2) were excluded. Clinicopathologic factors were analyzed to assess impact on local RFS. RESULTS: 97 patients with primary extremity WDLPS were identified. The majority of patients had deep, lower extremity tumors. Mean tumor size was 18.2±8.9cm. Patients were treated with either radical (76.3%) or excisional (23.7%) resections; 64% had R0 and 36% had microscopically positive (R1) resection margins. Ten patients received radiation therapy with no difference in receipt of radiation between R0 vs R1 groups. Thirteen patients (13%) developed a local recurrence with no difference in RFS between R0 vs R1 resection. Five-year RFS was 59.5% for R0 vs 85.2% for R1. Only one patient died of disease after developing dedifferentiation and distant metastasis despite originally having an R0 resection. DISCUSSION: In this large multi-institutional study of surgical resection of extremity WDLPS, microscopically positive margins were not associated with an increased risk of recurrence. Positive microscopic margin resection for extremity WDLPS may yield similar rates of local control while avoiding a radical approach to obtain microscopically negative margins.

A novel preoperative risk score to guide patient selection for resection of soft tissue sarcoma lung metastases: An analysis from the United States Sarcoma Collaborative.

BACKGROUND: Surgical resection for sarcoma lung metastases has been associated with improved overall survival (OS). METHODS: Patients who underwent curative-intent resection of sarcoma lung metastases (2000-2016) were identified from the US Sarcoma Collaborative. Patients with extrapulmonary metastatic disease or R2 resections of primary tumor or metastases were excluded. Primary endpoint was OS. RESULTS: Three hundred and fifty-two patients met inclusion criteria. Location of primary tumor was truncal/extremity in 85% (n = 270) and retroperitoneal in 15% (n = 49). Forty-nine percent (n = 171) of patients had solitary and 51% (n = 180) had multiple lung metastasis. Median OS was 49 months; 5-year OS 42%. Age ≥55 (HR 1.77), retroperitoneal primary (HR 1.67), R1 resection of primary (HR 1.72), and multiple (≥2) lung metastases (HR 1.77) were associated with decreased OS(all p < 0.05). Assigning one point for each factor, we developed a risk score from 0 to 4. Patients were then divided into two risk groups: low (0-1 factor) and high (2-4 factors). The low-risk group (n = 159) had significantly better 5-year OS compared to the high-risk group (n = 108) (51% vs. 16%, p < 0.001). CONCLUSION: We identified four characteristics that in aggregate portend a worse OS and created a novel prognostic risk score for patients with sarcoma lung metastases. Given that patients in the high-risk group have a projected OS of <20% at 5 years, this risk score, after external validation, will be an important tool to aid in preoperative counseling and consideration for multimodal therapy.

A multi-institutional validation study of prognostic nomograms for retroperitoneal sarcoma.

BACKGROUND AND OBJECTIVES: Prognostic nomograms for patients undergoing resection of retroperitoneal sarcoma (RPS) include the Sarculator and Memorial Sloan Kettering (MSK) sarcoma nomograms. We sought to validate the Sarculator and MSK nomograms within a large, modern multi-institutional cohort of patients with primary RPS undergoing resection. METHODS: Patients who underwent resection of primary RPS between 2000 and 2017 across nine high-volume US institutions were identified. Predicted 7-year disease-free (DFS) and overall survival (OS) and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated from the Sarculator and MSK nomograms, respectively. Nomogram-predicted survival probabilities were stratified in quintiles and compared in calibration plots to observed survival outcomes assessed by Kaplan-Meier estimates. Discriminative ability of nomograms was quantified by Harrell's concordance index (C-index). RESULTS: Five hundred and two patients underwent resection of primary RPS. Histologies included leiomyosarcoma (30%), dedifferentiated liposarcoma (23%), and well-differentiated liposarcoma (15%). Median tumor size was 14.0 cm (interquartile range [IQR], 8.5-21.0 cm). Tumor grade distribution was: Grade 1 (27%), Grade 2 (17%), and Grade 3 (56%). Median DFS was 31.5 months; 7-year DFS was 29%. Median OS was 93.8 months; 7-year OS was 51%. C-indices for 7-year DFS, and OS by the Sarculator nomogram were 0.65 (95% confidence interval [CI]: 0.62-0.69) and 0.69 (95%CI: 0.65-0.73); plots demonstrated good calibration for predicting 7-year outcomes. The C-index for 4-, 8-, and 12-year DSS by the MSK nomogram was 0.71 (95%CI: 0.67-0.75); plots demonstrated similarly good calibration ability. CONCLUSIONS: In a diverse, modern validation cohort of patients with resected primary RPS, both Sarculator and MSK nomograms demonstrated good prognostic ability, supporting their ongoing adoption into clinical practice.

Defining the Risk of Early Recurrence Following Curative-Intent Resection for Distal Cholangiocarcinoma.

BACKGROUND: Although multidisciplinary treatments including the use of adjuvant therapy (AT) have been adopted for biliary tract cancers, patients with distal cholangiocarcinoma (DCC) can still experience recurrence. We sought to characterize the incidence and predictors of early recurrence (ER) that occurred within 12 months following surgery for DCC. PATIENTS AND METHODS: Patients who underwent resection for DCC between 2000 and 2015 were identified from the US multi-institutional database. Cox regression analysis was used to identify clinicopathological factors to develop an ER risk score, and the predictive model was validated in an external dataset. RESULTS: Among 245 patients included in the analysis, 67 patients (27.3%) developed ER. No difference was noted in ER rates between patients who did and did not receive AT (28.7% vs. 25.0%, p = 0.55). Multivariable analysis revealed that neutrophil-to-lymphocyte ratio (NLR), peak total bilirubin (T-Bil), major vascular resection (MVR), lymphovascular invasion, and R1 surgical margin status were associated with a higher ER risk. A DIstal Cholangiocarcinoma Early Recurrence Score was developed according to each factor available prior to surgery [NLR > 9.0 (2 points); peak T-bil > 1.5 mg/dL (1 points); MVR (2 points)]. Cumulative ER rates incrementally increased among patients who were low (0 points; 10.6%), intermediate (1-2 points; 26.8%), or high (3-5 points; 57.6%) risk (p < 0.001) in the training dataset, as well as in the validation dataset [low (0 points); 3.4%, intermediate (1-2 points); 32.7%, or high risk (3-5 points); 55.6% (p < 0.001)]. CONCLUSIONS: Among patients undergoing resection for DCC, 1 in 4 patients experienced an ER. Alternative treatment strategies such as neoadjuvant chemotherapy may be considered especially among individuals deemed to be at high risk for ER.

Two-Stage Hepatectomy for Bilateral Colorectal Liver Metastases: A Multi-institutional Analysis.

BACKGROUND: Two-stage hepatectomy (TSH) is an important tool in the management of bilateral colorectal liver metastases (CRLM). This study sought to examine the presentation, management, and outcomes of patients completing TSH in major hepatobiliary centers in the United States (US). METHODS: A retrospective review from five liver centers in the US identified patients who completed a TSH procedure for bilateral CRLM. RESULTS: From December 2000 to March 2016, a total of 196 patients were identified. The majority of procedures were performed using an open technique (n = 194, 99.5%). The median number of tumors was 7 (range 2-33). One-hundred and twenty-eight (65.3%) patients underwent portal vein embolization. More patients received chemotherapy prior to the first stage than chemotherapy administration preceding the second stage (92% vs. 60%, p = 0.308). Median overall survival (OS) was 50 months, with a median follow-up of 28 months (range 2-143). Hepatic artery infusion chemotherapy was administered to 64 (32.7%) patients with similar OS as those managed without an infusion pump (p = 0.848). Postoperative morbidity following the second-stage resection was 47.4%. Chemotherapy prior to the second stage did not demonstrate an increased complication rate (p = 0.202). Readmission following the second stage was 10.3% and was associated with a decrease in disease-free survival (p = 0.003). OS was significantly decreased by positive resection margins and increased estimated blood loss (EBL; p = 0.036 and p = 0.05, respectively). CONCLUSION: This is the largest TSH series in the US and demonstrates evidence of safety and feasibility in the management of bilateral CRLM. Outcomes are influenced by margin status and operative EBL.

Outcomes in Patients with Renal Cell Carcinoma Undergoing Inferior Vena Cava Ligation without Reconstruction versus Thrombectomy: A Retrospective, Case Controlled Study.

PURPOSE: Radical nephrectomy with tumor thrombectomy is considered standard of care in patients with renal cell carcinoma. However, surgical ligation and interruption of the inferior vena cava is sometimes necessary when the tumor thrombus invades the inferior vena cava wall. This study assesses the outcomes in patients with renal cell carcinoma undergoing inferior vena cava ligation compared to inferior vena cava thrombectomy. MATERIALS AND METHODS: We conducted a case controlled, retrospective study at a high volume single-center institution. All patients with renal cell carcinoma who underwent ligation without reconstruction were matched with patients undergoing thrombectomy in a 1:2 ratio based on preoperative renal function, renal cell carcinoma stage and intraoperative thrombus level. Endpoints were complications, change in renal function and mortality. RESULTS: A total of 26 patients with renal cell carcinoma who underwent inferior vena cava ligation between 2005 and 2019 were matched with 52 patients who underwent inferior vena cava thrombectomy in the same time period. When compared to thrombectomy, patients undergoing ligation had higher 90-day readmission rate (19% vs 4%, p=0.025). The ligation group also had a higher postoperative complication rate (73% vs 39%, p=0.004) and higher rates of lymphedema (23% vs 8%, p=0.055). However, by 1-month followup the rate of persistent overall and major complications for both ligation and thrombectomy groups were comparable at 49% vs 31% (p=0.497) ad 8% vs 8% (p=1.000), respectively. Importantly, at 18-month followup, mean estimated glomerular filtration rate declines were similar between ligation group (8.5 ml/min/1.73 m2) and thrombectomy group (9.9 ml/min/1.73 m2; p=0.834). Differences in cancer-specific mortality (p=0.993) and all-cause mortality (p=0.756) were also not statistically significant. CONCLUSIONS: The outcomes of inferior vena cava ligation compared to inferior vena cava thrombectomy for renal cell carcinoma are similar. Patients with inferior vena cava ligation initially face a more complicated postoperative course but in the longer term have similar renal function recovery, complication rates and survival.

Defining and Predicting Early Recurrence after Resection for Gallbladder Cancer.

BACKGROUND: The optimal time interval to define early recurrence (ER) among patients who underwent resection of gallbladder cancer (GBC) is not well defined. We sought to develop and validate a novel GBC recurrence risk (GBRR) score to predict ER among patients undergoing resection for GBC. PATIENTS AND METHODS: Patients who underwent curative-intent resection for GBC between 2000 and 2018 were identified from the US Extrahepatic Biliary Malignancy Consortium database. A minimum p value approach in the log-rank test was used to define the optimal cutoff for ER. A risk stratification model was developed to predict ER based on relevant clinicopathological factors and was externally validated. RESULTS: Among 309 patients, 103 patients (33.3%) had a recurrence at a median follow-up period of 15.1 months. The optimal cutoff for ER was defined at 12 months (p = 3.04 × 10-18). On multivariable analysis, T3/T4 disease (HR: 2.80; 95% CI 1.58-5.11) and poor tumor differentiation (HR: 1.91; 95% CI 1.11-3.25) were associated with greater hazards of ER. The GBRR score was developed using ß-coefficients of variables in the final model, and patients were classified into three distinct groups relative to the risk for ER (12-month RFS; low risk: 88.4%, intermediate risk: 77.9%, high risk: 37.0%, p < 0.001). The external validation demonstrated good model generalizability with good calibration (n = 102: 12-month RFS; low risk: 94.2%, intermediate risk: 59.8%, high risk: 42.0%, p < 0.001). The GBRR score is available online at https://ktsahara.shinyapps.io/GBC_earlyrec/ . CONCLUSIONS: A novel online calculator was developed to help clinicians predict the probability of ER after curative-intent resection for GBC. The proposed web-based tool may help in the optimization of surveillance intervals and the counselling of patients about their prognosis.

Renal Function After Retroperitoneal Sarcoma Resection with Nephrectomy: A Matched Analysis of the United States Sarcoma Collaborative Database.

BACKGROUND: Nephrectomy often is required during en bloc resection of a retroperitoneal sarcoma (RPS) to achieve an R0 or R1 resection. The impact of nephrectomy on postoperative renal function in this patient population, who also may benefit from subsequent nephrotoxic systemic therapy, is not well described. METHODS: The United States Sarcoma Collaborative (USSC) database was queried for patients undergoing RPS resection between 2000 and 2016. Patients with missing pre- or postoperative measures of renal function were excluded. A matched cohort was created using coarsened exact matching. Weighted logistic regression was used to control further for differences between the nephrectomy and non-nephrectomy cohorts. The primary outcomes were postoperative acute kidney injury (AKI), acute renal failure (ARF), and dialysis. RESULTS: The initial cohort consisted of 858 patients, 3 (0.3%) of whom required postoperative dialysis. The matched cohort consisted of 411 patients, 108 (26%) of whom underwent nephrectomy. The patients who underwent nephrectomy had higher rates of postoperative AKI (14.8% vs 4.3%; p < 0.01) and ARF (4.6% vs 1.3%; p = 0.04), but no patients required dialysis postoperatively. Logistic regression modeling showed that the risk of AKI (odds ratio [OR], 5.16; p < 0.01) and ARF (OR 5.04; p < 0.01) after nephrectomy persisted despite controlling for age and preoperative renal function. CONCLUSIONS: Nephrectomy is associated with an increased risk of postoperative AKI and ARF after RPS resection. This study was unable to statistically assess the impact of nephrectomy on postoperative dialysis, but the risk of postoperative dialysis is 0.5% or less regardless of nephrectomy status.

Impact of resection margin on outcomes in high-grade soft tissue sarcomas of the extremity-A USSC analysis.

BACKGROUND: The optimal margin of resection for high-grade extremity sarcomas and its impact on survival has long been questioned in the setting of adjuvant radiotherapy. The objective of this study was to investigate the impact of resection status on recurrence and survival. METHODS: All patients with primary, nonmetastatic, high-grade extremity sarcomas that underwent surgical resection from January 2000 to April 2016 in the U.S. Sarcoma Collaborative (USSC) were retrospectively reviewed. Recurrence patterns, recurrence-free survival (RFS), and overall survival (OS) were examined in multivariate analyses (MVA). RESULTS: A cohort of 959 patients was identified with a median follow-up of 34.7 months from diagnosis. R0 resection was achieved in 86.7% (831) while R1 resection in 13.3% (128). Locoregional recurrence for R0 and R1 groups occurred in 9.1% (76) versus 14.8% (19; p = .05) while distant recurrence occurred in 24.7% (205) versus 26.6% (34; p = .65), respectively. Median RFS was 171.2 versus 48.5 (p = .01) while median OS was 149.8 versus 71.5 months (p = .02) for the R0 versus R1 group, respectively. On MVA, female gender (hazard ratio [HR] = 0.69, p = .007) and adjuvant radiotherapy (0.7, p = .04) were associated with improved OS, whereas older age (HR = 1.03, p < .001) and tumor size (HR = 1.01, p < .001) were associated with worse OS. R0 resection status was associated with improved locoregional RFS (HR = 0.56, p = .03) but not with distant RFS (HR = 0.84, p = .4) or OS (HR = 0.7, p = .052). CONCLUSIONS: In high-grade extremity sarcomas, tumor size and gender are predictive of OS while R0 resection status is associated with improved locoregional recurrence rate without a significant impact on distant RFS or OS.

HSP90 expression and early recurrence in gastroenteropancreatic neuroendocrine tumors: Potential for a novel therapeutic target.

BACKGROUND: Heat shock protein (HSP)-90 promotes tumor growth and is overexpressed in many malignancies. HSP90 expression profile and its potential as a therapeutic target in primary and metastatic neuroendocrine tumors (NETs) are not known. METHODS: HSP90 cytoplasmic expression and Ki-67 index were re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables for patients who underwent resection of primary and metastatic gastroenteropancreatic (GEP) neuroendocrine tumors at a single institution (2000-2013). Primary outcome was recurrence-free survival (RFS). RESULTS: Of 263 tumors reviewed, 73% (n = 191) were primary GEP NETs, and 12% (n = 31) were NET liver metastases. Of the primary GEP-NETs, mean age was 56 years, 42% were male; 53% (n = 103) were pancreatic and 23% (n = 44) were small bowel. HSP90 expression was high in 34% (n = 64) and low in 66% (n = 127). Compared to low expression, high HSP90 was associated with advanced T-stage (T3/T4) (47 vs 27%; p = 0.02). Among patients who underwent curative-intent resections for primary, non-metastatic NETs (n = 145), high HSP90 was independently associated with worse RFS (HR 5.09, 95% CI 1.65-15.74; p = 0.005), after accounting for positive margin, LN involvement, increased tumor size, site of primary tumor, and Ki-67. When assessing NET liver metastases, 13% (n = 4) had high HSP90 expression and 87% (n = 26) had low expression. Patients with liver metastases with high HSP90 tended to have worse 1- and 3-year progression-free survival (25%, 25%) compared to those with low HSP90 (69%, 49%; p = 0.059). CONCLUSION: HSP90 exhibits differential expression in resected GEP-NETs and liver metastases. High cytoplasmic expression is associated with early disease recurrence, even after accounting for other adverse pathologic factors. HSP90 inhibition may be a potential therapeutic target for neuroendocrine tumors.

A closer look at the natural history and recurrence patterns of high-grade truncal/extremity leiomyosarcomas: A multi-institutional analysis from the US Sarcoma Collaborative.

BACKGROUND/OBJECTIVE: Natural history and outcomes for truncal/extremity (TE) soft tissue sarcoma (STS) is derived primarily from studies investigating all histiotypes as one homogenous cohort. We aimed to define the recurrence rate (RR), recurrence patterns, and response to radiation of TE leiomyosarcomas (LMS). METHODS: Patients from the US Sarcoma Collaborative database with primary, high-grade TE STS were identified. Patients were grouped into LMS or other histology (non-LMS). Primary endpoints were locoregional recurrence-free survival (LR-RFS), distant-RFS (D-RFS), and disease specific survival (DSS). RESULTS: Of 1215 patients, 93 had LMS and 1122 non-LMS. In LMS patients, median age was 63 and median tumor size was 6 cm. In non-LMS patients, median age was 58 and median tumor size was 8 cm. In LMS patients, overall RR was 42% with 15% LR-RR and 29% D-RR. The 3yr LR-RFS, D-RFS, and DSS were 84%, 65%, and 76%, respectively. When considering high-risk (>5 cm and high-grade, n = 49) LMS patients, the overall RR was 45% with 12% LR-RR and 35% D-RR. 61% received radiation. The 3yr LR-RFS (78vs93%, p = 0.39), D-RFS (53vs63%, p = 0.27), and DSS (67vs91%, p = 0.17) were similar in those who did and did not receive radiation. High-risk, non-LMS patients had a similar overall RR of 42% with 15% LR-RR and 30% D-RR. 60% of non-LMS patients received radiation. There was an improved 3yr LR-RFS (82vs75%, p = 0.030) and DSS (77vs65%,p = 0.007) in non-LMS patients who received radiation. CONCLUSIONS: In our cohort, patients with LMS have a low local recurrence rate (12-15%) and modest distant recurrence rate (29-35%). However, LMS patients had no improvement in local control or long-term outcomes with radiation. The value of radiation in these patients merits further investigation.

High neutrophil-lymphocyte ratio is not independently associated with worse survival or recurrence in patients with extremity soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas are a heterogenous group of neoplasms without well-validated biomarkers. Cancer-related inflammation is a known driver of tumor growth and progression. Recent studies have implicated a high circulating neutrophil-lymphocyte ratio as a surrogate marker for the inflammatory tumor microenvironment and a poor prognosticator in multiple solid tumors, including colorectal and pancreatic cancers. The impact of circulating neutrophil-lymphocyte ratio in soft tissue sarcomas has yet to be elucidated. METHODS: We performed a retrospective analysis of patients undergoing curative resection for primary or recurrent extremity soft tissue sarcomas at academic centers within the US Sarcoma Collaborative. Neutrophil-lymphocyte ratio was calculated retrospectively in treatment-naïve patients using blood counts at or near diagnosis. RESULTS: A high neutrophil-lymphocyte ratio (≥4.5) was associated with worse survival on univariable analysis in patients with extremity soft tissue sarcomas (hazard ratio 2.07; 95% confidence interval, 1.54-2.8; P < .001). On multivariable analysis, increasing age (hazard ratio 1.03; 95% confidence interval, 1.02-1.04; P < .001), American Joint Committee on Cancer T3 (hazard ratio 1.89; 95% confidence interval, 1.16-3.09; P = .011), American Joint Committee on Cancer T4 (hazard ratio 2.36; 95% confidence interval, 1.42-3.92; P = .001), high tumor grade (hazard ratio 4.56; 95% confidence interval, 2.2-9.45; P < .001), and radiotherapy (hazard ratio 0.58; 95% confidence interval, 0.41-0.82; P = .002) were independently predictive of overall survival, but a high neutrophil-lymphocyte ratio was not predictive of survival (hazard ratio 1.26; 95% confidence interval, 0.87-1.82; P = .22). CONCLUSION: Tumor inflammation as measured by high pretreatment neutrophil-lymphocyte ratio was not independently associated with overall survival in patients undergoing resection for extremity soft tissue sarcomas.

Analysis of textbook outcomes among patients undergoing resection of retroperitoneal sarcoma: A multi-institutional analysis of the US Sarcoma Collaborative.

BACKGROUND: The novel composite metric textbook outcome (TO) has increasingly been used as a quality indicator but has not been reported among patients undergoing surgical resection for retroperitoneal sarcoma (RPS) using multi-institutional collaborative data. METHODS: All patients who underwent resection for RPS between 2000 to 2016 from eight academic institutions were included. TO was defined as a patient with R0/R1 resection that discharged to home and was without transfusion, reoperation, grade ≥2 complications, hospital-stay >50th percentile, or 90-day readmission or mortality. Univariate and multivariable analyses were performed. RESULTS: Among 627 patients, 56.1% were female and the median age was 59 years. A minority of patients achieved a TO (34.9%). Factors associated with achieving a TO were tumor size <20 cm and low tumor grade, while ASA class ≥3, history of a prior cardiac event, resection of left colon/rectum, distal pancreatic resection, major venous resection and drain placement were associated with not achieving a TO (all P < .05). Achievement of a TO was associated with improved survival (median:12.7 vs 5.9 years, P < .01). CONCLUSIONS: Among patients undergoing resection for RPS, failure to achieve TO is common and associated with significantly worse survival. The use of TO may inform patient expectations and serve as a measure for patient-level hospital performance.

Neoadjuvant radiation improves margin-negative resection rates in extremity sarcoma but not survival.

BACKGROUND AND OBJECTIVES: Radiation improves limb salvage in extremity sarcomas. Timing of radiation therapy remains under investigation. We sought to evaluate the effects of neoadjuvant radiation (NAR) on surgery and survival of patients with extremity sarcomas. MATERIALS AND METHODS: A multi-institutional database was used to identify patients with extremity sarcomas undergoing surgical resection from 2000-2016. Patients were categorized by treatment strategy: surgery alone, adjuvant radiation (AR), or NAR. Survival, recurrence, limb salvage, and surgical margin status was analyzed. RESULTS: A total of 1483 patients were identified. Most patients receiving radiotherapy had high-grade tumors (82% NAR vs 81% AR vs 60% surgery; P < .001). The radiotherapy groups had more limb-sparing operations (98% AR vs 94% NAR vs 87% surgery; P < .001). NAR resulted in negative margin resections (90% NAR vs 79% surgery vs 75% AR; P < .0001). There were fewer local recurrences in the radiation groups (14% NAR vs 17% AR vs 27% surgery; P = .001). There was no difference in overall or recurrence-free survival between the three groups (OS, P = .132; RFS, P = .227). CONCLUSION: In this large study, radiotherapy improved limb salvage rates and decreased local recurrences. Receipt of NAR achieves more margin-negative resections however this did not improve local recurrence or survival rates over.

Outcomes of palliative-intent surgery in retroperitoneal sarcoma-Results from the US Sarcoma Collaborative.

BACKGROUND AND OBJECTIVES: Outcomes of palliative-intent surgery in retroperitoneal sarcomas (RPS) are not well understood. This study aims to define indications for and outcomes after palliative-intent RPS resection. METHODS: Using a retrospective 8-institution database, patients undergoing resection of primary/recurrent RPS with palliative intent were identified. Logistic regression and Cox-proportional hazards models were constructed to analyze factors associated with postoperative complications and overall survival (OS). RESULTS: Of 3088 patients, 70 underwent 87 palliative-intent procedures. Most common indications were pain (26%) and bowel obstruction (21%). Dedifferentiated liposarcoma (n = 17, 24%), leiomyosarcoma (n = 13, 19%) were predominant subtypes. Median OS was 10.69 months (IQR, 3.91-23.23). R2 resection (OR, 8.60; CI, 1.42-52.15; P = .019), larger tumors (OR, 10.87; CI, 1.44-82.11; P = .021) and low preoperative albumin (OR, 0.14; CI, 0.04-0.57; P = .006) were associated with postoperative complications. Postoperative complications (HR, 1.95; CI, 1.02-3.71; P = .043) and high-grade histology (HR, 6.56; CI, 1.72-25.05; P = .006) rather than resection status were associated with reduced OS. However, in R2-resected patients, development of postoperative complications significantly reduced survival (P = .042). CONCLUSIONS: Postoperative complications and high-grade histology rather than resection status impacts survival in palliative-intent RPS resections. Given the higher incidence of postoperative complications which may diminish survival, palliative-intent R2 resection should be offered only after cautious consideration.