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Despite the risk of complications, high dose radiation therapy is increasingly utilized in the management of selected bone malignancies. In this study, we investigate the impact of moderate to high dose radiation (over 50 Gy) on bone metabolism and structure. Between 2015 and 2018, patients with a primary malignant bone tumor of the sacrum that were either treated with high dose definitive radiation only or a combination of moderate to high dose radiation and surgery were prospectively enrolled at a single institution. Quantitative CTs were performed before and after radiation to determine changes in volumetric bone mineral density (BMD) of the irradiated and non-irradiated spine. Bone histomorphometry was performed on biopsies of the irradiated sacrum and the non-irradiated iliac crest of surgical patients using a quadruple tetracycline labeling protocol. In total, 9 patients were enrolled. Two patients received radiation only (median dose 78.3 Gy) and 7 patients received a combination of preoperative radiation (median dose 50.4 Gy), followed by surgery. Volumetric BMD of the non-irradiated lumbar spine did not change significantly after radiation, while the BMD of the irradiated sacrum did (pre-radiation median: 108.0 mg/cm3 (IQR 91.8–167.1); post-radiation median: 75.3 mg/cm3 (IQR 57.1–110.2); p = 0.010). The cancellous bone of the non-irradiated iliac crest had a stable bone formation rate, while the irradiated sacrum showed a significant decrease in bone formation rate [pre-radiation median: 0.005 mm3/mm2/year (IQR 0.003–0.009), post-radiation median: 0.001 mm3/mm2/year (IQR 0.001–0.001); p = 0.043]. Similar effects were seen in the cancellous and endocortical envelopes. This pilot study shows a decrease of volumetric BMD and bone formation rate after high-dose radiation therapy. Further studies with larger cohorts and other endpoints are needed to get more insight into the effect of radiation on bone. Level of evidence: IV. [ABSTRACT FROM AUTHOR]

Background: Local recurrence of microinvasive sarcoma or benign aggressive pathologies can be limb- and life-threatening. Although frozen pathology is reliable, tumor microinvasion can be subtle or missed, having an impact on surgical margins and postoperative radiation planning. The authors' service has begun to temporize the tumor bed after primary tumor excision with a wound vacuum-assisted closure (VAC) pending formal margin analysis, with coverage performed in the setting of final negative margins. Methods: This retrospective analysis included all patients managed at a tertiary referral cancer center with VAC temporization after soft tissue sarcoma or benign aggressive tumor excision from 1 January 2000 to 1 January 2019 and at least 2 years of oncologic follow-up evaluation. The primary outcome was local recurrence. The secondary outcomes were distant recurrence, unplanned return to the operating room for wound/infectious indications, thromboembolic events, and tumor-related deaths. Results: For 62 patients, VAC temporization was performed. The mean age of the patients was 62.2 ± 22.3 years (median 66.5 years; 95% confidence interval [CI] 61.7–72.5 years), and the mean age-adjusted Charlson Comorbidity Index was 5.3 ± 1.9. The most common tumor histology was myxofibrosarcoma (51.6%, 32/62). The mean volume was 124.8 ± 324.1 cm3, and 35.5% (22/62) of the cases were subfascial. Local recurrences occurred for 8.1% (5/62) of the patients. Three of these five patients had planned positive margins, and 17.7% (11/62) of the patients had an unplanned return to the operating room. No demographic or tumor factors were associated with unplanned surgery. Conclusions: The findings showed that VAC-temporized management of microinvasive sarcoma and benign aggressive pathologies yields favorable local recurrence and unplanned operating room rates suggestive of oncologic and technical safety. These findings will need validation in a future randomized controlled trial. [ABSTRACT FROM AUTHOR]

Background. External beam radiation therapy (RT) for retroperitoneal sarcoma often requires treatment of large target volumes close to critical normal tissues. Radiation may be limited by adjacent organs at risk (OAR). Intensity-modulated radiation therapy has been shown to improve target coverage and reduce doses to OAR. Objectives. To compare target coverage and dose to OAR with 3D conformal proton therapy (3D CPT), intensity-modulated proton therapy (IMPT), and intensity-modulated photon therapy (IMXT). Methods. We performed a comparative study of treatment plans with 3D CPT, IMPT, and IMXT for ten patients with retroperitoneal sarcomas. RT was delivered to 50.4 Gy to the clinical target volume (CTV), the structures considered at risk for microscopic disease. Results. CTVs ranged from 74 to 357 cc (mean 188 cc). Dose conformity was improved with IMPT, while 3D CPT provided better dose homogeneity. Mean dose to the liver, small bowel, and stomach was reduced with IMPT compared with 3D CPT or IMXT. Conclusions. IMPT, 3D CPT, and IMXT provide excellent target coverage for retroperitoneal sarcomas. OAR dose is lower with IMPT and 3D CPT, and IMPT achieves the closest conformity. These techniques offer the opportunity for further dose escalation to areas with positive margins. [ABSTRACT FROM AUTHOR]

Background: The microinvasive nature of suprafascial myxofibrosarcoma reduces the accuracy of intraoperative margin assessment, and tumor bed resections after soft-tissue reconstruction are unreliable. In 2017, we began temporizing the excised tumor bed with a wound VAC, delaying soft-tissue coverage until final negative margins were achieved. We compare the oncologic/surgical outcomes of suprafascial myxofibrosarcomas managed with VAC temporization (VT) with single-stage excision/reconstruction (SS). Methods: We retrospectively studied suprafascial myxofibrosarcomas managed from January 1, 2000 to January 1, 2019 for patients who received neoadjuvant or adjuvant radiation and had at least 2 years of oncologic follow-up at a tertiary referral cancer center. Our primary outcome was local recurrence. Comparisons were performed by using Fisher's exact test or Student's t test. A p value < 0.05 was considered significant. Results: Fifty-three patients (18 VAC temporized, 35 single stage) were included. While VT patients were older (74.9 ± 10.2 vs. 63.9 ± 13.6, p = 0.003), treatment groups did not significantly differ with respect to comorbidity, tumor volume, stage and grade. VT patients had significantly fewer local recurrences (5.6% vs. 28.6% after SS, p = 0.048) and R1 resections that required an unplanned readmission for tumor bed reexcision (0% vs. 37.1% after SS, p = 0.002). VT required more total surgeries (2.8 ± 0.9 vs. 1.8 ± 0.9 for SS, p = 0.0002). Postoperative infectious and wound complications were equivalent. Conclusions: Our VAC temporization strategy had a significantly lower LR than SS treatment. While high quality multi-institutional validation is required, VT may represent a paradigm shift in the management of myxofibrosarcoma. [ABSTRACT FROM AUTHOR]

Pseudoprogression, defined as the radiographic false appearance of disease progression, is not frequently observed in patients with malignant peripheral nerve sheath tumor (MPNST). We report on a case of a patient with neurofibromatosis type 1 (NF1) MPNST pseudoprogression that presented as suspected local recurrence 9.5 years after last treatment. The patient underwent surgical resection following growth of a mass on sequential MRI imaging; surgical pathology, however, showed skeletal muscle with atrophy, fibroadipose tissue, and fat necrosis, without any evidence of tumor. As MPNST survival rates increase, physicians should consider pseudoprogression as a potential presentation after prior treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. Dedifferentiated chondrosarcomas (DDCSs) are highly malignant tumors with a dismal prognosis and present a significant challenge in clinical management. Methods. In an IRB approved retrospective protocol, we identified 72 patients with DDCS treated at our institution between 1993 and 2017 and reviewed clinicopathological characteristics, treatment modalities, and outcomes to analyze prognostic factors. Results. Femur (44.4%), pelvis (22.2%), and humerus (12.5%) were most commonly involved sites. Twenty-three patients (31.9%) presented with distant metastasis, and 3 (4.2%) of them also had regional lymph node involvement. The median overall survival (OS) was 13.9 months. On multivariate analysis, pathological fracture, larger tumor size, lymph node involvement, metastasis at diagnosis, extraosseous extension, and undifferentiated pleomorphic sarcoma component correlated with worse OS, whereas surgical resection and chemotherapy were associated with improved OS. For progression-free survival (PFS), pathological fracture and metastasis at diagnosis showed increased risk, while chemotherapy was associated with decreased risk. Among patients who received chemotherapy, doxorubicin and cisplatin were significantly associated with improved PFS but not OS. Among patients without metastasis at diagnosis, 17 (34.7%) developed local recurrence. Thirty-one (63.3%) developed distant metastases at a median interval of 18.1 months. On multivariate analysis, R1/R2 resection was related with local recurrence, while macroscopic dedifferentiated component was associated with distant metastasis. Conclusions. The prognosis of DDCS is poor. Complete resection remains a significant prognostic factor for local control. Chemotherapy with doxorubicin and cisplatin seems to have better PFS. More prognostic, multicenter trials are warranted to further explore the effectiveness of chemotherapy in selected DDCS patients. [ABSTRACT FROM AUTHOR]

Background: We developed a machine learning algorithm to predict the survival of patients with chondrosarcoma. The algorithm demonstrated excellent discrimination and calibration on internal validation in a derivation cohort based on data from the Surveillance, Epidemiology, and End Results (SEER) registry. However, the algorithm has not been validated in an independent external dataset.Questions/purposes: Does the Skeletal Oncology Research Group (SORG) algorithm accurately predict 5-year survival in an independent patient population surgically treated for chondrosarcoma?Methods: The SORG algorithm was developed using the SEER registry, which contains demographic data, tumor characteristics, treatment, and outcome values; and includes approximately 30% of the cancer patients in the United States. The SEER registry was ideal for creating the derivation cohort, and consequently the SORG algorithm, because of the high number of eligible patients and the availability of most (explanatory) variables of interest. Between 1992 to 2013, 326 patients were treated surgically for extracranial chondrosarcoma of the bone at two tertiary care referral centers. Of those, 179 were accounted for at a minimum of 5 years after diagnosis in a clinical note at one of the two institutions, unless they died earlier, and were included in the validation cohort. In all, 147 (45%) did not meet the minimum 5 years of followup at the institution and were not included in the validation of the SORG algorithm. The outcome (survival at 5 years) was checked for all 326 patients in the Social Security death index and were included in the supplemental validation cohort, to also ascertain validity for patients with less than 5 years of institutional followup. Variables used in the SORG algorithm to predict 5-year survival including sex, age, histologic subtype, tumor grade, tumor size, tumor extension, and tumor location were collected manually from medical records. The tumor characteristics were collected from the postoperative musculoskeletal pathology report. Predicted probabilities of 5-year survival were calculated for each patient in the validation cohort using the SORG algorithm, followed by an assessment of performance using the same metrics as used for internal validation, namely: discrimination, calibration, and overall performance. Discrimination was calculated using the concordance statistic (or the area under the Receiver Operating Characteristic (ROC) curve) to determine how well the algorithm discriminates between the outcome, which ranges from 0.5 (no better than a coin-toss) to 1.0 (perfect discrimination). Calibration was assessed using the calibration slope and intercept from a calibration plot to measure the agreement between predicted and observed outcomes. A perfect calibration plot should show a 45° upwards line. Overall performance was determined using the Brier score, ranging from 0 (excellent prediction) to 1 (worst prediction). The Brier score was compared with the null-model Brier score, which showed the performance of a model that ignored all the covariates. A Brier score lower than the null model Brier score indicated greater performance of the algorithm. For the external validation an F1-score was added to measure the overall accuracy of the algorithm, which ranges between 0 (total failure of an algorithm) and 1 (perfect algorithm).The 5-year survival was lower in the validation cohort than it was in the derivation cohort from SEER (61.5% [110 of 179] versus 76% [1131 of 1544] ; p < 0.001). This difference was driven by higher proportion of dedifferentiated chondrosarcoma in the institutional population than in the derivation cohort (27% [49 of 179] versus 9% [131 of 1544]; p < 0.001). Patients in the validation cohort also had larger tumor sizes, higher grades, and nonextremity tumor locations than did those in the derivation cohort. These differences between the study groups emphasize that the external validation is performed not only in a different patient cohort, but also in terms of disease characteristics. Five-year survival was not different for both patient groups between subpopulations of patients with conventional chondrosarcomas and those with dedifferentiated chondrosarcomas.Results: The concordance statistic for the validation cohort was 0.87 (95% CI, 0.80-0.91). Evaluation of the algorithm's calibration in the institutional population resulted in a calibration slope of 0.97 (95% CI, 0.68-1.3) and calibration intercept of -0.58 (95% CI, -0.20 to -0.97). Finally, on overall performance, the algorithm had a Brier score of 0.152 compared with a null-model Brier score of 0.237 for a high level of overall performance. The F1-score was 0.836. For the supplementary validation in the total of 326 patients, the SORG algorithm had a validation of 0.89 (95% CI, 0.85-0.93). The calibration slope was 1.13 (95% CI, 0.87-1.39) and the calibration intercept was -0.26 (95% CI, -0.57 to 0.06). The Brier score was 0.11, with a null-model Brier score of 0.19. The F1-score was 0.901.Conclusions: On external validation, the SORG algorithm retained good discriminative ability and overall performance but overestimated 5-year survival in patients surgically treated for chondrosarcoma. This internet-based tool can help guide patient counseling and shared decision making.Level Of Evidence: Level III, prognostic study. [ABSTRACT FROM AUTHOR]

In this issue, Xiang and colleagues present data from the National Cancer Database comparing the number of second malignancies observed in adult and pediatric patients with 9 major cancer subtypes who received different radiation modalities. These are important findings because understanding the risk of late, radiation‐associated malignancies with different radiation modalities may help physicians reduce the risk of this devastating late treatment effect. [ABSTRACT FROM AUTHOR]

Introduction. Myxoid liposarcoma (MLS) is a subtype of liposarcoma characterized morphologically by lipomatous differentiation with a myxoid stroma. The purpose of this study was to review clinical and pathological information for patients treated for MLS at our institution to better understand neoadjuvant and adjuvant therapy. Materials and Methods. An institutional database of sarcomas was queried for patients who were treated for MLS at our institution between 1992 and 2013. Survival curves were constructed using Kaplan–Meier analysis, and univariate and multivariate statistics were performed using the Cox-proportional hazards model and using linear regression. Results. A total of 85 patients with myxoid liposarcoma were identified. The mean and median histologic response rate to treatment for patients who received preoperative radiation therapy was 77.6%. Five-year disease-free survival, distant metastasis-free survival, local recurrence-free survival, and overall survival were 78.6% (95% CI: 67.8–86.1), 84.7% (95% CI: 74.5–91.0), 95.6% (95% CI: 86.9–98.6), and 87.5% (95% CI: 77.2–93.3) respectively. On univariate analysis, there was a trend towards higher necrosis or treatment response rates in patients who received concurrent chemotherapy, 84.7% (95% CI: 75.9–93.4) and 69.5% (95% CI: 55.1–83.8), p=0.061. Tumor size was associated with inferior disease-free and overall survival. Hazard ratio for disease-free survival is 1.08 (per cm) (95% CI: 1.01–1.16), p=0.019. Conclusions. Myxoid liposarcoma exhibits histological response to chemotherapy and radiation therapy. Tumor size appears to be greatest predictor of long-term disease control and overall survival. We were not able to show that chemotherapy provides a clinical benefit with regard to local control, disease-free survival, or overall survival. However, it is important to note that the selected usage of chemotherapy in the highest risk patients confounds this analysis. Further investigation is needed to help better determine the optimal use of chemotherapy in this group of patients. [ABSTRACT FROM AUTHOR]

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

Purpose: This study is to present a large cohort of extraskeletal osteosarcoma (ESOS) and evaluate prognostic factors and treatment options. Methods: Medical records were reviewed retrospectively for 41 patients with extraskeletal osteosarcoma that was diagnosed by pathology, and treated at our institution between 1960 and 2016. Kaplan-Meier analysis and Cox proportional hazards regression were used to identify variables that affect survival outcomes. Results: 41 patients were identified from 952 osteosarcomas. 32 patients had non-metastatic disease. Prognostic factors were identified by univariate analysis and multi-variate analysis. Surgery (p<0.001), and surgery type (p<0.001) both were shown to significantly affect overall survival (OS). Chemotherapy and radiation therapy (RT) did not show any significant effect on OS, local recurrence, or progression free survival as a whole. However for patients who had incomplete resection with residual tumor RT improved OS (p=0.03). The survival curve for ESOS follows more closely that of nonrhabdomyosarcoma soft tissue sarcomas (NRSTS). Conclusions: ESOS is a very rare tumor. Attempt to achieve wide resection is the treatment of choice. However for patients who are not able to achieve complete resection, RT may improve OS. The behavior of ESOS more closely follows that of NRSTS than osteosarcoma of the bone. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

Background: En bloc resection for treatment of sacral tumors is the approach of choice for patients with resectable tumors who are well enough to undergo surgery, and studies describe patient survival, postoperative complications, and recurrence rates associated with this treatment. However, most of these studies do not provide patient-reported functional outcomes other than binary metrics for bowel and bladder function postresection.Questions/purposes: The purpose of this study was to use validated patient-reported outcomes tools to compare quality of life based on level of sacral resection in terms of (1) physical and mental health; (2) pain; (3) mobility; and (4) incontinence and sexual function.Methods: Our analysis included 33 patients (19 men, 14 women) who had a mean age of 53 years (range, 22-72 years) with a quality-of-life survey administered at a mean postoperative followup of 41 months (range, 6-123 months). The majority of patient-reported quality-of-life outcome surveys for this study were taken from the National Institute of Health's Patient Reported Outcome Measurement Information System (PROMIS) system. To assess physical and mental health, the PROMIS Global Items Survey with physical and mental subscores, Anxiety, and Depression scores were used. Pain outcomes were assessed using PROMIS Pain Intensity and Pain Interference surveys. Patient-reported lower extremity function was assessed using the PROMIS Mobility Survey. Patient-reported quality of life for sexual function was assessed using the PROMIS Sex Interest and Orgasm survey, whereas incontinence was measured using the International Continence Society Voiding and Incontinence scores and the Modified Obstruction and Defecation Score. Surveys were collected prospectively during clinic visits in the postoperative period. Patients were grouped by the level of osteotomy as determined by review of postoperative MRI or CT and half levels were grouped with the more cephalad level. This resulted in the inclusion of total sacrectomy (N = 6), S1 (N = 8), S2 (N = 10), S3 (N = 5), and S4 (N = 4). One-way analysis of variance tests on means or ranks were used to conduct statistical analysis between levels.Results: Patients with more caudal resections had higher physical health (95% confidence interval [CI] total sacrectomy 36-42 versus S4 50-64, p < 0.001), less intense pain (95% CI total sacrectomy 47-60 versus S4 28-37, p < 0.001), less interference resulting from pain (95% CI total sacrectomy 58-69 versus S4 36-51, p = 0.004), higher mobility (95% CI total sacrectomy 24-46 versus S4 59-59, p = 0.002), and were more functionally able to achieve orgasm (95% CI S1 1-1 versus S4 2.2-5.3, p = 0.043). No difference was found for PROMIS Global Item Mental Health Subscore, Sex Interest, Sex Satisfaction, modified obstruction and defecation score, and International Continence Society Voiding and Incontinence although this could be the result of an inadequate sample size.Conclusions: Our analysis on patient-reported quality of life based on the level of bony resection in patients who underwent resection for primary sacral tumor indicates that patients with higher resections have more pain and loss of physical function in comparison to patients with lower resections. Additionally, use of the PROMIS outcomes allows for comparisons to normative data.Level Of Evidence: Level III, therapeutic study. [ABSTRACT FROM AUTHOR]

Background: Surgery with high-dose radiation and high-dose radiation alone for sacral chordomas have shown promising local control rates. However, we have noted frequent sacral insufficiency fractures and perceived this rate to be higher than previously reported.Questions/purposes: We wished (1) to characterize the incidence of sacral insufficiency fractures in patients with chordomas of the sacrum who received high-dose radiation, and (2) to determine whether patients treated with surgery plus high-dose radiation or high-dose radiation alone are more likely to experience a sacral fracture, and to compare time to fracture in these groups.Methods: Sixty-two patients who received high-dose radiation for sacral chordomas with (n = 44) or without surgical resection (n = 18) between 1992 and 2013 were included in this retrospective study. At our institution, sacral chordomas generally are treated by preoperative radiotherapy, followed by en bloc resection, and postoperative radiotherapy. Radiation alone, with an intent to cure, is offered to patients who otherwise are not good surgical candidates or patients who elect radiotherapy based on tumor location and the anticipated morbidity after surgery (such as sexual, bowel, or bladder dysfunction). MRI and CT scans were evaluated for evidence of sacral insufficiency fractures. Complete followup was available at a minimum of 2 years (or until fracture or death) for all 18 patients who underwent radiation alone, whereas 14% (six of 44 patients) in the surgery plus radiation group (9% [three of 33] after high sacrectomy and 27% [three of 11] after low sacrectomy) were lost to followup before 2 years.Results: Sacral insufficiency fractures occurred in 29 of the 62 patients (47%). A total of 25 of 33 patients (76%) with high sacrectomy had fractures develop compared with zero of 11 (0%) after low sacrectomy, and four of the 18 patients (22%) who had high-dose radiation alone (p < 0.001). The fracture rate was greater in the high sacrectomy group than in the low sacrectomy group (p < 0.001) and the radiation only group (p < 0.001). There was no difference with the numbers evaluated in fracture probability between patients in the low-sacrectomy group and those treated with radiation alone (p = 0.112). The fracture-free survival probability was 0.99 for the low sacrectomy group at all times as there were no insufficiency fractures in this group; the 1-year fracture-free survival probability was 0.53 (95% CI, 0.35-0.69) after high sacrectomy, 0.83 (95% CI, 0.57-0.94) after radiation alone; the 2-year fracture-free survival probability was 0.36 (95% CI, 0.19-0.52) after high sacrectomy and 0.77 (95% CI, 0.50-0.91) after radiation alone; and the 5-year fracture-free survival probability was 0.14 (95% CI, 0.04-0.30) after high sacrectomy and 0.77 (95% CI, 0.50-0.91) after radiation alone.Conclusions: Acknowledging the limitations of potential differences in baseline and followup among treatment groups in our study, we found that almost ½ of our patients experienced an insufficiency fracture. We found that the fracture rate was greater in the surgery group compared with the radiation alone group and that high sacrectomy accounted for all fractures in the surgery group. These findings can be used to inform patients and also support the need for further research to elucidate the influence of high-dose radiation on bone quality.Level Of Evidence: Level III, therapeutic study. [ABSTRACT FROM AUTHOR]

Chordoma is a rare, slow-growing malignant tumor arising from notochordal remnants. A retrospective review of patient records at two major referral centers was undertaken to assess the incidence, location, and prognostic factors of metastatic disease from chordoma. 219 patients with chordoma (1962–2009) were identified. 39 patients (17.8%) developed metastatic disease, most frequently to lung (>50%). Median survival from the time of initial diagnosis was 130.4 months for patients who developed metastatic disease and 159.3 months for those who did not (P=0.05). Metastatic disease was most common in the youngest patients (P=0.07), and it was 2.5 times more frequent among patients with local recurrence (26.3%) than in those without (10.8%) (P=0.003). Patient survival with metastatic disease was highly variable, and it was dependent on both the location of the tumor primary and the site of metastasis. Metastasis to distal bone was the most rapid to develop and had the worst prognosis. [ABSTRACT FROM AUTHOR]

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

BACKGROUND Histologic response to chemotherapy has been shown to be an independent prognostic factor in patients with osteosarcoma and Ewing sarcoma. However, in patients with soft tissue sarcoma (STS), the prognostic impact of histologic response to chemotherapy is less clear. In the current study, the authors sought to determine the prognostic significance of treatment-induced pathologic necrosis in patients receiving neoadjuvant chemoradiotherapy for STS. METHODS Between 1989 and 2011, a total of 113 patients with grade 2 or 3 (graded according to the National Cancer Institute grading system using 3 tiers) extremity or truncal STS were identified who received neoadjuvant interdigitated chemoradiotherapy according to protocol followed by surgery. The extent of tumor necrosis in the resected specimens was quantified and correlated with outcome. RESULTS The median tumor necrosis rate was 90%, and 103 patients (91%) received all 3 cycles of planned neoadjuvant chemotherapy. The likelihood of achieving ≥95% necrosis was not related to the number of preoperative cycles of chemotherapy received but was found to be related to tumor histology (62% for malignant fibrous histiocytoma vs 0% for synovial sarcoma [ P<.001]; 56% for myxoid liposarcoma vs 0% for synovial sarcoma [ P = .002]). At a median follow-up of 6 years, there were no statistically significant differences noted in the 5-year local control, disease-specific survival, and overall survival rates for patients with ≥95% necrosis (50 patients; 44%) and <95% necrosis (63 patients; 56%), even when stratifying by histology. CONCLUSIONS In a homogeneous population of patients with high-grade extremity and truncal STS who were treated with neoadjuvant chemoradiotherapy, the extent of pathologic tumor necrosis did not correlate with outcome. Cancer 2014;120:3676-3682. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: To evaluate feasibility and preliminary outcomes associated with sequential whole abdomen irradiation (WAI) as consolidative treatment following comprehensive surgery and systemic chemotherapy for advanced endometrial cancer.Methods: We conducted a retrospective analysis of patients treated at our institution from 2000 to 2011. Inclusion criteria were stage III-IV endometrial cancer patients with histological proof of one or more sites of extra-uterine abdomen-confined disease, treated with WAI as part of multimodal therapy. Endpoints were feasibility, acute toxicity, late effects, recurrence-free survival (RFS) and overall survival (OS). Twenty patients were identified. Chemotherapy consisted of 3 to 6 cycles of a platinum-paclitaxel regimen in 18 patients. WAI was delivered using conventional technique to a median total dose of 27.5 Gy.Results: No grade 4 toxicities occurred during chemotherapy or radiotherapy. No radiation dose reduction was necessary. Three patients developed small bowel obstruction, all in the context of recurrent intraperitoneal disease. Kaplan-Meier estimates and 95% confidence intervals for RFS and OS at one year were 63% (38-80%) and 83% (56-94%) and at 3 years 57% (33-76%) and 62% (34-81%), respectively. On univariate Cox analysis, stage IVB and serous papillary (SP) histology were found to be statistically significantly (at the p = 0.05 level) associated with worse RFS and OS. The peritoneal cavity was the most frequent site of initial failure.Conclusions: Consolidative WAI following chemotherapy is feasible and can be performed without interruption with manageable acute and late toxicity. Patients with endometrioid adenocarcinoma, especially stage FIGO III, had favorable outcomes possibly meriting prospective evaluation of the addition of WAI following chemotherapy in selected patients. Patients with SP do poorly and do not routinely benefit from this approach. [ABSTRACT FROM AUTHOR]

Background. Mutations in the gene-encoding β-catenin, CTNNB1, are highly prevalent in sporadic desmoid tumors and may predict the risk for recurrence. We sought to determine the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoids tumors and to determine whether CTNNB1 mutation status correlates with disease outcome. Methods. Single-base extension genotyping of the CTNNB1 gene was performed on 145 sporadic, paraffin-embedded desmoid tumor specimens. Correlation of mutation status with outcome was performed on a subset of 115 patients who underwent macroscopically complete surgical resection. Results. CTNNB1 mutations were detected in 106 of 145 (73%) tumor specimens and in 86 of 115 (75%) specimens from patients who underwent curative-intent surgical resection, including discrete mutations in the following codons of CTNNB1 exon 3: T41A (46%), S45F (25%), S45P (1.7%), and S45C (0.9%). Desmoid tumors of the superficial trunk were significantly less likely to harbor CTNNB1 mutations than tumors located elsewhere, but none of the other examined clinicopathologic factors were found to be associated with CTNNB1 mutation status. At a median follow-up of 31 months, 5-year recurrence-free survival was slightly, although not statistically significantly, worse for patients with β-catenin-mutated tumors than for those with wild-type tumors (58% vs. 74%, respectively). The specific CTNNB1 codon mutation did not correlate with the risk for recurrence. Conclusion. CTNNB1 mutations are indeed common in sporadic desmoid tumors. However, our study did not detect a statistically significant difference in recurrence risk according to either the CTNNB1 mutation status or the specific CTNNB1 mutation. [ABSTRACT FROM AUTHOR]

Purpose: The delivery of post-mastectomy radiation therapy (PMRT) can be challenging for patients with left sided breast cancer that have undergone mastectomy. This study investigates the use of protons for PMRT in selected patients with unfavorable cardiac anatomy. We also report the first clinical application of protons for these patients. Methods and materials: Eleven patients were planned with protons, partially wide tangent photon fields (PWTF), and photon/electron (P/E) fields. Plans were generated with the goal of achieving 95% coverage of target volumes while maximally sparing cardiac and pulmonary structures. In addition, we report on two patients with unfavorable cardiac anatomy and IMN involvement that were treated with a mix of proton and standard radiation. Results: PWTF, P/E, and proton plans were generated and compared. Reasonable target volume coverage was achieved with PWTF and P/E fields, but proton therapy achieved superior coverage with a more homogeneous plan. Substantial cardiac and pulmonary sparing was achieved with proton therapy as compared to PWTF and P/E. In the two clinical cases, the delivery of proton radiation with a 7.2 to 9 Gy photon and electron component was feasible and well tolerated. Akimbo positioning was necessary for gantry clearance for one patient; the other was treated on a breast board with standard positioning (arms above her head). LAO field arrangement was used for both patients. Erythema and fatigue were the only noted side effects. Conclusions: Proton RT enables delivery of radiation to the chest wall and regional lymphatics, including the IMN, without compromise of coverage and with improved sparing of surrounding normal structures. This treatment is feasible, however, optimal patient set up may vary and field size is limited without multiple fields/matching. [ABSTRACT FROM AUTHOR]

Background and Objectives. Atypical lipomas are uncommon, slow-growing benign tumors. While surgery has been the primary treatment modality, we have managed some patients with radiation (RT) as a component of the treatment and have reported their outcomes in this study. Methods. A retrospective review of all cases of extremity and trunk atypical lipomas in The Sarcoma Database at the study institution was conducted. Results. Thirteen patients were identified. All patients underwent surgical resection at initial presentation and received pre- or postoperative radiation for subtotal resection (2 = 2), local recurrence (n = 8), or progressive disease (n = 3). The median total radiation dose was 50 Gy. Median followup was 65.1 months. All patients treated with RT remained free of disease at the last followup. No grade 3 or higher late toxicity from radiation was observed. No cases of tumor dedifferentiation occurred. Conclusion. For recurrent or residual atypical lipomas, a combination of reexcision and RT can provide long-term local control with acceptable morbidity. For recurrent tumors, pre-op RT of 50 Gy appears to be an effective and well-tolerated management approach. [ABSTRACT FROM AUTHOR]

Background and Objectives. Atypical lipomas are uncommon, slow-growing benign tumors. While surgery has been the primary treatment modality, we have managed some patients with radiation (RT) as a component of the treatment and have reported their outcomes in this study. Methods. A retrospective review of all cases of extremity and trunk atypical lipomas in The Sarcoma Database at the study institution was conducted. Results. Thirteen patients were identified. All patients underwent surgical resection at initial presentation and received pre- or postoperative radiation for subtotal resection (2 = 2), local recurrence (n = 8), or progressive disease (n = 3). The median total radiation dose was 50 Gy. Median followup was 65.1 months. All patients treated with RT remained free of disease at the last followup. No grade 3 or higher late toxicity from radiation was observed. No cases of tumor dedifferentiation occurred. Conclusion. For recurrent or residual atypical lipomas, a combination of reexcision and RT can provide long-term local control with acceptable morbidity. For recurrent tumors, pre-op RT of 50 Gy appears to be an effective and well-tolerated management approach. [ABSTRACT FROM AUTHOR]