Radiation Therapy in Metastatic Soft Tissue Sarcoma: From Palliation to Ablation

The management of patients with metastatic cancer is rapidly changing. Historically, radiotherapy was utilized for the treatment of localized disease or for palliation. While systemic therapy remains the mainstay of management for patients with metastatic cancer, radiotherapy is becoming increasingly important not only to palliate symptoms, but also to ablate oligometastatic or oligoprogressive disease and improve local control in the primary site. There is emerging evidence in multiple solid malignancies that patients with low volume metastatic disease that undergo local ablative therapy to metastatic sites may have improved progression free survival and potentially overall survival. In addition, there is increasing evidence that select patients with metastatic disease may benefit from aggressive treatment of the primary site. Patients with metastatic soft tissue sarcoma have a poor overall prognosis. However, there may be opportunities in patients with low volume metastatic soft tissue sarcoma to improve outcomes with local therapy including surgery, ablation, embolization, and radiation therapy. Stereotactic body radiation therapy (SBRT) offers a safe, convenient, precise, and non-invasive option for ablation of sites of metastases. In this review article, we explore the limited yet evolving role of radiotherapy to metastatic and primary sites for local control and palliation, particularly in the oligometastatic setting

Evaluating Thresholds to Adopt Hypofractionated Preoperative Radiotherapy as Standard of Care in Sarcoma.

IntroductionData supporting hypofractionated preoperative radiation therapy (RT) for patients with extremity and trunk soft tissue sarcoma (STS) are currently limited to phase II single-institution studies. We sought to understand the type and thresholds of clinical evidence required for experts to adopt hypofractionated RT as a standard-of-care option for patients with STS.MethodsAn electronic survey was distributed to multidisciplinary sarcoma experts. The survey queried whether data from a theoretical, multi-institutional, phase II study of 5-fraction preoperative RT could change practice. Using endpoints from RTOG 0630 as a reference, the survey also queried thresholds for acceptable local control, wound complication, and late toxicity for the study protocol to be accepted as a standard-of-care option. Responses were logged from 8/27/2020 to 9/8/2020 and summarized graphically.ResultsThe survey response rate was 55.3% (47/85). Local control is the most important clinical outcome for sarcoma specialists when evaluating whether an RT regimen should be considered standard of care. 17% (8/47) of providers require randomized phase III evidence to consider hypofractionated preoperative RT as a standard-of-care option, whereas 10.6% (5/47) of providers already view this as a standard-of-care option. Of providers willing to change practice based on phase II data, most (78%, 29/37) would accept local control rates equivalent to or less than those in RTOG 0630, as long as the rate was higher than 85%. However, 51.3% (19/37) would require wound complication rates superior to those reported in RTOG 0630, and 46% (17/37) of respondents would accept late toxicity rates inferior to RTOG 0630.ConclusionConsensus building is needed among clinicians regarding the type and threshold of evidence needed to evaluate hypofractionated RT as a standard-of-care option. A collaborative consortium-based approach may be the most pragmatic means for developing consensus protocols and pooling data to gradually introduce hypofractionated preoperative RT into routine practice

Predictors of Wound Complications following Radiation and Surgical Resection of Soft Tissue Sarcomas

Wound complications represent a major source of morbidity in patients undergoing radiation therapy (RT) and surgical resection of soft tissue sarcomas (STS). We investigated whether factors related to RT, surgery, patient comorbidities, and tumor histopathology predict the development of wound complications. An observational study of patients who underwent STS resection and RT was performed. The primary outcome was the occurrence of any wound complication up to four months postoperatively. Significant predictors of wound complications were identified using multivariable logistic regression. Sixty-five patients representing 67 cases of STS were identified. Median age was 59 years (range 22–90) and 34 (52%) patients were female. The rates of major wound complications and any wound complications were 21% and 33%, respectively. After adjusting for radiation timing, diabetes (OR 9.6; 95% CI 1.4–64.8; P=0.02), grade ≥2 radiation dermatitis (OR 4.8; 95% CI 1.2–19.2; P=0.03), and the use of 3D conformal RT (OR 4.6; 95% CI 1.1–20.0; P=0.04) were associated with an increased risk of any wound complication on multivariable analysis. These data suggest that radiation dermatitis and radiation modality are predictors of wound complications in patients with STS

Disparities in Perioperative Radiation Therapy Use in Elderly Patients With Soft-Tissue Sarcoma

The benefit of perioperative radiation therapy in elderly patients with soft-tissue sarcoma (STS) is unclear due to the underrepresentation of elderly patients in clinical trials. We assessed patterns of care and overall survival (OS) associated with perioperative radiation therapy use in this population. Elderly patients (≥70 years) with high-grade STS who underwent surgery with or without perioperative radiation therapy from 2004 to 2013 were identified from the National Cancer Database. A nonelderly cohort (<70 years) was also identified for secondary comparative analyses. The association between perioperative radiation therapy use and OS was assessed using propensity score-weighted Cox proportional hazards analyses. Relative survival was calculated using national life tables to assess the impact of radiation therapy on estimated sarcoma-specific survival in elderly and nonelderly patients. Patterns of care were assessed using multivariable logistic regression analyses. Of 6978 elderly patients, 3549 (51%) underwent surgery alone, and 740 (11%) and 2,679 (38%) received pre- and postoperative radiation therapy, respectively. Elderly patients received radiation therapy less commonly than did nonelderly patients (49% vs 52%, P < .001) despite presenting with higher grade tumors (grade 3, 86% vs 80%, P < .001) and experiencing more frequent positive surgical margins (23% vs 16%, P < .001). On propensity score-weighted analyses, preoperative (hazard ratio = 0.64, 95% confidence interval: 0.54-0.77, P < .001) and postoperative (hazard ratio = 0.72, 95% confidence interval: 0.67-0.77, P < .001) radiation therapy use was associated with improved OS compared with surgery alone. These associations were robust to landmark analyses of patients surviving at least 12 months. Radiation therapy use resulted in a greater magnitude of 5-year relative survival improvement in elderly than nonelderly patients. There is an overall and an age-disparate underuse of perioperative radiation therapy in elderly patients with high-grade STS despite radiation therapy being associated with improved OS. Further research is warranted to minimize gaps in care for elderly patients

Definitive Local Therapy Is Associated with Improved Survival in Metastatic Soft Tissue Sarcomas

Background: Definitive local therapy is often utilized in patients with metastatic soft tissue sarcomas (STS) to reduce morbidity associated with local tumor progression. We hypothesize that it is associated with improved overall survival (OS). Methods: Patients with newly diagnosed metastatic STS treated with chemotherapy were identified from the National Cancer Database and dichotomized into cohorts: 1. definitive local therapy (defined as either definitive dose radiotherapy, definitive surgery, or surgery with perioperative radiotherapy) or 2. conservative therapy (defined as systemic therapy with or without palliative therapy). The association between definitive local therapy and OS, and factors associated with the receipt of definitive local therapy were assessed. Results: Total of 4180 patients were identified. Compared with the conservative therapy, receipt of any definitive local therapy was associated with improved OS (median 17.9 vs. 10.1 months). The survival benefit remained on multivariate analyses and propensity-score matched analyses, with a stepwise improvement with surgery and combined modality local therapy, specifically radiotherapy (HR: 0.77; p &lt; 0.001), surgery (HR: 0.67; p &lt; 0.001), and combined surgery and radiotherapy (HR: 0.42; p &lt; 0.001). Conclusions: Analysis of a large national cancer registry of patients with metastatic STS suggests that chemotherapy plus definitive local therapy is associated with a significant survival benefit compared to the standard chemotherapy alone

Chemotherapy and Survival in Patients with Primary High-Grade Extremity and Trunk Soft Tissue Sarcoma.

The use of upfront chemotherapy for primary localized soft tissue sarcoma (STS) of the extremity and trunk is debated. It remains unclear if chemotherapy adds clinical benefit, which patients are likely to benefit, and whether the timing of therapy affects outcomes. We used the National Cancer Database (NCDB) to examine the association between overall survival (OS) and chemotherapy in 5436 patients with the five most common subtypes of STS with primary disease localized to the extremity or trunk, mirroring the patient population of a modern phase 3 clinical trial of neoadjuvant chemotherapy. We then examined associations between timing of multi-agent chemotherapy (neoadjuvant or adjuvant) and OS. We used a Cox proportional hazards model and propensity score matching (PSM) to account for covariates including demographic, patient, clinical, treatment, and facility factors. In the overall cohort, we observed no association between multi-agent chemotherapy or its timing and improved OS. Multi-agent chemotherapy was associated with improved OS in several subgroups, including patients with larger tumors (&gt;5 cm), those treated at high-volume centers, or those who received radiation. We also identified an OS benefit to multi-agent chemotherapy among the elderly (&gt;70 years) and African American patients. Multi-agent chemotherapy was associated with improved survival for patients with tumors &gt;5 cm, who receive radiation, or who receive care at high-volume centers. Neither younger age nor chemotherapy timing was associated with better outcomes. These 'real-world' findings align with recent randomized trial data supporting the use of multi-agent chemotherapy in high-risk patients with localized STS

Chemotherapy and Survival in Patients with Primary High-Grade Extremity and Trunk Soft Tissue Sarcoma.

The use of upfront chemotherapy for primary localized soft tissue sarcoma (STS) of the extremity and trunk is debated. It remains unclear if chemotherapy adds clinical benefit, which patients are likely to benefit, and whether the timing of therapy affects outcomes. We used the National Cancer Database (NCDB) to examine the association between overall survival (OS) and chemotherapy in 5436 patients with the five most common subtypes of STS with primary disease localized to the extremity or trunk, mirroring the patient population of a modern phase 3 clinical trial of neoadjuvant chemotherapy. We then examined associations between timing of multi-agent chemotherapy (neoadjuvant or adjuvant) and OS. We used a Cox proportional hazards model and propensity score matching (PSM) to account for covariates including demographic, patient, clinical, treatment, and facility factors. In the overall cohort, we observed no association between multi-agent chemotherapy or its timing and improved OS. Multi-agent chemotherapy was associated with improved OS in several subgroups, including patients with larger tumors (&gt;5 cm), those treated at high-volume centers, or those who received radiation. We also identified an OS benefit to multi-agent chemotherapy among the elderly (&gt;70 years) and African American patients. Multi-agent chemotherapy was associated with improved survival for patients with tumors &gt;5 cm, who receive radiation, or who receive care at high-volume centers. Neither younger age nor chemotherapy timing was associated with better outcomes. These 'real-world' findings align with recent randomized trial data supporting the use of multi-agent chemotherapy in high-risk patients with localized STS