Efficacy of first-line doxorubicin and ifosfamide in myxoid liposarcoma

<p>Abstract</p> <p>Background</p> <p>Myxoid liposarcoma (MLS) is a soft tissue sarcoma with adipocytic differentiation characterized by a unique chromosome rearrangement, t(12;16)(q13;p11). The exact efficacy of chemotherapy in MLS has not been clearly established.</p> <p>Patients and methods</p> <p>We retrospectively analyzed the records of 37 histologically confirmed MLS patients who were treated at the University of Texas MD Anderson Cancer Center from January 2000 to December 2009 with doxorubicin 75-90 mg/m²over 72 hours combined with ifosfamide 10 gm/m²in the first-line setting. Response was assessed using RECIST and Choi criteria. The Kaplan-Meier method and log-rank test was used to estimate clinical outcomes.</p> <p>Results</p> <p>The median follow-up period was 50.1 months. The overall response rates were 43.2% using RECIST and 86.5% using the Choi criteria. The 5-year disease-free survival rate was 90% for patients with resectable tumors. Median time to progression and overall survival time for the advanced-disease group were 23 and 31.1 months, respectively.</p> <p>Conclusion</p> <p>Our study demonstrates that doxorubicin-ifosfamide combination therapy has a role in the treatment of MLS. The Choi criteria may be more sensitive in evaluating response to chemotherapy in MLS.</p

Clinical outcomes of patients with advanced synovial sarcoma or myxoid/round cell liposarcoma treated at major cancer centers in the United States

BACKGROUND: Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials. METHODS: In this multi-center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first-line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox regression. RESULTS: At start of first-line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first-line therapy for SS was 24.7 months (95% CI, 20.9-29.4) and 7.5 months, respectively (95% CI, 6.4-8.4). Median OS and median PFS from start of first-line therapy for MRCL was 29.9 months (95% CI, 27-44.6) and 8.9 months (95% CI 4.5-12.0). CONCLUSIONS: To the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real-world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature

Retrospective Evaluation of the Role of Gemcitabine-Docetaxel in Well-Differentiated and Dedifferentiated Liposarcoma

OBJECTIVE: Well-differentiated (WDLPS) and dedifferentiated liposarcoma (DDLPS) account for the majority of liposarcomas. Although gemcitabine-docetaxel is used as second-line treatment in soft tissue sarcomas, its efficacy in WDLPS/DDLPS is not established. This study retrospectively analyzed the efficacy of gemcitabine regimens in WDLPS/DDLPS. METHODS: All patients with WDLPS or DDLPS who received gemcitabine-based chemotherapy at our institution between September 2002 and January 2021 were included. Response was evaluated by an independent radiologist using RECIST 1.1. The Kaplan-Meier method was used to estimate distributions of survival outcomes and log-rank tests were used to compare survival outcomes between subgroups. RESULTS: Sixty-five WDLPS/DDLPS patients were included. Seven patients (10.8%) received a gemcitabine-based regimen more than once, totaling 72 treatments. The median age at the start of treatment was 66 years (range 32-80 years). Sixty-five (90.3%) regimens were gemcitabine-docetaxel, and 7 (9.7%) were gemcitabine alone. Majorities of treatments were for disease that was recurrent/metastatic (86.1%), was abdominal/retroperitoneal (83.3%), and had DDLPS components (88.9%), while 25.0% of treatments were for multifocal disease. The overall response rate was 9.7% (7/72). All responses were in patients with documented DDLPS. The median time to progression was 9.2 months (95% CI 5.3-12.3 months). The median overall survival from the start of therapy was 18.8 months (95% CI 13.1-32.4 months). CONCLUSION: Gemcitabine-docetaxel is an efficacious second-line treatment for DDLPS. Though cross study comparisons are not advisable, response to gemcitabine-docetaxel compares favorably to current standard options trabectedin and eribulin. This combination is a valid comparator arm for future second-line trials in DDLPS

High-Grade Pleomorphic Sarcomas Treated with Immune Checkpoint Blockade: The MD Anderson Cancer Center Experience

BACKGROUND: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available. PURPOSE: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution. METHODS: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded. RESULTS: Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS ( CONCLUSIONS: Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors

The Immune Landscape of Undifferentiated Pleomorphic Sarcoma

INTRODUCTION: Undifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes. MATERIAL AND METHODS: Surgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters. RESULTS: Samples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p\u3c0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p\u3c0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p\u3c0.0001) and DFS (p\u3c0.001). CONCLUSION: We identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS

Adult versus Pediatric Neuroblastoma: The M.D. Anderson Cancer Center Experience

Background. Staging and treatment of adult neuroblastoma has yet to be formalized. We sought to determine the utility of the pediatric classification system in adults and determine the efficacy of different treatment modalities. Methods. Medical records of 118 adults (patients >17 years old) and 112 pediatric patients (ages 2–17), who were treated for neuroblastoma at M.D. Anderson Cancer Center from January 1994 to September 2012, were reviewed. International neuroblastoma risk group (INRG) variables were abstracted. The primary outcome of interest was actuarial progression-free survival. Results. Median age of pediatric patients was 5 years (range 3–16) and 47 years (range 18–82) for adult patients. There were no differences in PFS or OS between stage-matched risk categories between pediatric and adult patients (L1-P=0.40, L2-P=0.54, and M-P=0.73). In the treatment of L1 disease, median PFS for adults treated with surgery and radiation was 11.1 months compared with single modality local treatment ± chemotherapy (6.4 and 5.1 months, resp.; P=0.07). Median PFS in L2 adult patients was 5.2 months with local therapy and 4 months with the addition of chemotherapy (P=0.23). Conclusions. Adult and pediatric patients with neuroblastoma achieve similar survival outcomes. INRG classification should be employed to stratify adult neuroblastoma patients and help select treatment

Ulcerative Keratitis in Gastrointestinal Stromal Tumor Patients Treated with Perifosine

Perifosine is a novel alkylphospholipid with antiproliferative properties attributed to protein kinase B inhibition. The authors describe a form of ulcerative keratitis in 5 patients with advanced gastrointestinal stromal tumor (GIST) enrolled in a phase I/II trial of perifosine in combination with imatinib. Interventional case series. Five patients (1 man, 4 women) with imatinib-resistant metastatic GIST who received a combination of imatinib and perifosine orally. The medical records were reviewed retrospectively. Ocular toxicity and ulcerative keratitis associated with perifosine. The ocular symptoms included redness, irritation, tearing, photophobia, and a gradual decrease in vision. Slit-lamp biomicroscopy in each case revealed a peripheral, paralimbal, ring-shaped, superficial corneal stromal infiltration and ulcerative keratitis, reminiscent of the autoimmune keratitis in conditions such as rheumatoid arthritis. The ulcerative keratitis was unilateral in 3 and bilateral in 2 patients; it was National Cancer Institute grade II (symptoms interfering with function but not interfering with activities of daily living) in all patients. All 5 patients had imatinib-resistant metastatic GIST and had continued on the highest dose of imatinib tolerated and initiated therapy with perifosine 100 mg daily or 900 mg weekly. A combination of topical steroids, topical antibiotics, and lubricating drops were used to manage ulcerative keratitis. In the first 3 patients, ulcerative keratitis initially was treated with topical antibiotics without improvement, but subsequently they improved significantly after topical steroids were added. A vision-threatening form of ulcerative keratitis may occur in patients taking perifosine. It is possible that imatinib in combination with perifosine contributes to this corneal toxicity; however, the authors are unaware of this ocular toxicity having been reported for imatinib when used without perifosine. The visual loss associated with perifosine may be reversible if detected and treated early and with judicious early use of topical steroids, topical antibiotic coverage, and lubrication

Diagnostic Value of TLE1 in Synovial Sarcoma: A Systematic Review and Meta-Analysis

Background. Synovial sarcoma can present morphologically in multiple forms, including biphasic and monophasic subtypes. As a result, the histological diagnosis can sometimes be challenging. Transducin-Like Enhancer 1 (TLE1) is a transcriptional corepressor that normally is involved in embryogenesis and hematopoiesis but is also expressed in certain tumors. This systematic review examines the potential role of TLE1 as a diagnostic biomarker for the synovial sarcoma. Materials and Methods. A literature review and meta-analysis were conducted using the electronic databases Pubmed, the Cochrane Library, and Google Scholar. Thirteen studies met our eligibility criteria and were selected for in-depth analysis. Results. The mean sensitivity and specificity of TLE1 in detecting synovial sarcoma were 94% (95% CI 91%–97%) and 81% (95% CI 72%–91%), respectively, when all studies were aggregated together. The mean positive predictive value (PPV) of TLE1 was 75% (95% CI 62%–87%), whereas the negative predictive value (NPV) was 96% (95% CI 93%–98%). Conclusion. TLE1 is a sensitive and specific marker for synovial sarcoma that can aid in its diagnosis. Due to its involvement in several relevant signaling pathways, TLE1 might have direct relevance to the pathophysiology of the disease