non-GIST Soft Tissue Sarcomas Research Articles

EE31 Costs of Gist and Non-GIST STSs in Turkiye: A Delphi Panel Study

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract. This study aims to calculate the annual treatment costs for GIST and non-GIST soft tissue sarcomas (STSs) in Turkiye.

Systemic Treatment for Soft Tissue Sarcoma: What is Standard, What is New

Abstract Soft tissue sarcoma (STS) is a biologically heterogeneous malignancy with over 50 subtypes. This solid tumor is one of the most challenging diseases to treat for the medical oncologist. STS often forms in the body’s muscles, joints, fat, nerves, deep skin tissues, and blood vessels. The natural history of high-grade STS is characterized by a strong tendency toward local recurrence and metastatic spreading, despite optimal initial strategies. The lung is the most common site of metastases, with poor prognosis. We present the current international guidelines for the adjuvant treatment and systemic treatment for advanced STS and the new discoveries. Many new molecular targeting drugs have been tried in the last ten years, and some were approved for soft tissue sarcoma. The first approved was Imatinib, as a treatment for gastrointestinal stromal tumors (GISTs). Following Imatinib, other tyrosine kinase inhibitors (TKIs) received the approval for GISTs such as Sunitinib and Regorafenib, and Pazopanib for non-GIST soft tissue sarcomas. In 2016, FDA approved the first monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR)-α, Olaratumab. The new treatment demonstrates an overall survival advantage. In this review, we aimed to summarize the results from the most recent studies on adjuvant treatment for high-grade STS and systemic strategies for advanced STS.

Current Molecular Targeted Therapies for Bone and Soft Tissue Sarcomas.

Systemic treatment options for bone and soft tissue sarcomas remained unchanged until the 2000s. These cancers presented challenges in new drug development partly because of their rarity and heterogeneity. Many new molecular targeting drugs have been tried in the 2010s, and some were approved for bone and soft tissue sarcoma. As one of the first molecular targeted drugs approved for solid malignant tumors, imatinib’s approval as a treatment for gastrointestinal stromal tumors (GISTs) has been a great achievement. Following imatinib, other tyrosine kinase inhibitors (TKIs) have been approved for GISTs such as sunitinib and regorafenib, and pazopanib was approved for non-GIST soft tissue sarcomas. Olaratumab, the monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR)-α, was shown to extend the overall survival of soft tissue sarcoma patients and was approved in 2016 in the U.S. as a breakthrough therapy. For bone tumors, new drugs are limited to denosumab, a receptor activator of nuclear factor κB ligand (RANKL) inhibitor, for treating giant cell tumors of bone. In this review, we explain and summarize the current molecular targeting therapies approved and in development for bone and soft tissue sarcomas.

Current Concepts in Non-Gastrointestinal Stromal Tumor Soft Tissue Sarcomas: A Primer for Radiologists.

Non-gastrointestinal stromal tumor (GIST) soft tissue sarcomas (STSs) are a heterogeneous group of neoplasms whose classification and management continues to evolve with better understanding of their biologic behavior. The 2013 World Health Organization (WHO) has revised their classification based on new immunohistochemical and cytogenetic data. In this article, we will provide a brief overview of the revised WHO classification of soft tissue tumors, discuss in detail the radiology and management of the two most common adult non-GIST STS, namely liposarcoma and leiomyosarcoma, and review some of the emerging histology-driven targeted therapies in non-GIST STS, focusing on the role of the radiologist.

First line palliative chemotherapy in elderly patients with advanced soft tissue sarcoma.

BackgroundThe efficacy and toxicity of first line palliative chemotherapy for soft tissue sarcomas (STS) in the elderly is poorly described.MethodsPatients over the age of 65 years receiving first line chemotherapy for advanced non-GIST STS January 1998 - January 2012 at the Royal Marsden Hospital were identified. Data regarding survival and predictive factors were collected retrospectively.Results120 patients (52 females) with a median age of 72 (range 65–83) were treated. The most common histological subtypes were undifferentiated sarcoma (30%), leiomyosarcoma (27%), angiosarcoma (14%). 42% of patients had high grade tumours. 70% of patients had metastatic disease at presentation; lung metastasis being the most common disease site (72%). 80% received single agent chemotherapy, mostly with doxorubicin (60%). The median number of cycles was 2 (IQR 3). A partial response was reported in 20% of patients with disease stabilisation in a further 20%. 38% of patients were hospitalised for chemotherapy related toxicity. The median overall survival (OS) was 6.5 months (95% CI 4.7-8.3). Anaemia, lymphopenia, hypoalbuminemia, sarcoma subtype and co-morbidities were predictive for overall survival.ConclusionThe overall survival for elderly patients with STS is poor but several predictive factors have been identified. Hospital admissions for chemotherapy related toxicity are common.

Targeted therapy in sarcomas other than GIST tumors.

Non-GIST soft tissue sarcomas are a heterogeneous grouping of mesenchymal tumors that comprise less than 1% of adult malignancies. Treatment continues to be based on cytotoxic chemotherapy regimens. However, characterization of the molecular pathway deregulations that drive these tumors has led to the emergence of more customized treatment options. In this review, we focus on the multitude of molecular inhibitors targeting angiogenesis and cell cycle pathways being tested in clinical trials.

Molecular targeted therapies in non-GIST soft tissue sarcomas: what the radiologist needs to know.

Non-gastrointestinal stromal soft tissue sarcomas are uncommon neoplasms that have a dismal prognosis due to a high incidence of metastases and a poor response to conventional chemotherapy. The identification of characteristic genetic alterations in several of these tumors has opened the window for molecular targeted therapies in patients who have failed conventional chemotherapy. Imaging plays a critical role in assessing the response to these novel therapeutic agents. Just like the response of gastrointestinal stromal tumors to imatinib, the response of non-gastrointestinal stromal soft tissue sarcomas to molecular targeted drugs is better evaluated on imaging by alternate tumor response criteria such as the Choi criteria. In addition, these drugs are associated with distinct class-specific drug toxicities that can come to attention for the first time on imaging. The purpose of this article is to provide a primer for the radiologist on the various molecular targeted therapies in advanced/metastatic non-gastrointestinal stromal soft tissue sarcomas with emphasis on the role of imaging in assessing treatment response and complications.

Pazopanib for nonadipocytic, non-GIST soft tissue sarcomas

Pazopanib for nonadipocytic, non-GIST soft tissue sarcomas

Prognostic impact of CD57, CD68, M-CSF, CSF-1R, Ki67 and TGF-beta in soft tissue sarcomas

BackgroundPrognostic markers in curable STS may have the potential to guide therapy after surgical resection. The purpose of this study was to clarify the prognostic impact of the presence of cells and growth factors belonging to the innate immune system in soft tissue sarcomas (STS). The significance of macrophages (CD68), their growth factor macrophage colony-stimulating factor (M-CSF), its receptor colony-stimulating factor-1 receptor (CSF-1R), natural killer cells (CD57) and the general immunomodulating molecule (TGF-beta) are all controversial in STS. Herein, these markers are evaluated and compared to the cell proliferation marker Ki67.MethodsTissue microarrays from 249 patients with non-gastrointestinal (non-GIST) STS were constructed from duplicate cores of viable and representative neoplastic tumor areas and duplicate cores of peritumoral capsule. Immunohistochemistry was used to evaluate the expression of CD68, M-CSF, CSF-1R, CD57, TGF-beta and Ki67 in tumor and peritumoral capsule.ResultsIn univariate analyses increased expression of M-CSF (P = 0.034), Ki67 (P < 0.001) and TGF-beta (P = 0.003) in tumor correlated with shorter disease-specific survival (DSS). Increased expression of CD68 in tumor correlated significantly with malignancy grade (P = 0.016), but not DSS (P = 0.270). Increased expression of Ki67 in peritumoral capsule tended to correlate with a shorter DSS (P = 0.057). In multivariate analyses, co-expression of M-CSF and TGF-beta (P = 0.022) in tumor and high expression of Ki67 (P = 0.019) in peritumoral capsule were independent negative prognostic factors for DSS.ConclusionsIncreased co-expression of M-CSF and TGF-beta in tumor in patients with STS, and increased expression of Ki67 in peritumoral capsule were independent negative prognostic factors for DSS.

Platelet-Derived Growth Factors in Non-GIST Soft-Tissue Sarcomas Identify a Subgroup of Patients with Wide Resection Margins and Poor Disease-Specific Survival

Background. Optimal treatment of nongastrointestinal stromal tumor soft-tissue sarcomas (non-GIST STSs) is resection with wide margins. This study investigates the prognostic impact of the angiogenesis-associated platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) in non-GIST STS patients with wide and nonwide resection margins. Method. Tumor samples and clinical data from 249 patients with non-GIST STS were obtained, and tissue microarrays were constructed for each specimen. Immunohistochemistry was used to evaluate the expression of PDGF-A, -B, -C, and -D and PDGFR-α and -β. Results. In the multivariate analysis of patients with wide resection margins, high expression of PDGF-B (P = .013, HR = 2.954, and 95% CI = 1.255–6.956) and the coexpression of PDGF-B and PDGFR-α (overall; P = .016, high-low/low-high; P = .051, HR = 2.678, 95% CI = 0.996–7.200, high/high; P = .004, HR = 3.930, 95% CI = 1.542–10.015) were independent negative prognostic markers for disease-specific survival. Conclusion. PDGF-B and the coexpression of PDGF-B and PDGFR-α are strong and independent prognostic factors in non-GIST STSs with wide resection margins.

Multicenter Phase II Trial of Sunitinib in the Treatment of Nongastrointestinal Stromal Tumor Sarcomas

PURPOSE To evaluate the potential benefit of continuous daily dosing sunitinib in patients with advanced nongastrointestinal stromal tumor (GIST) sarcomas. PATIENTS AND METHODS A total of 53 patients with advanced non-GIST soft tissue sarcomas received sunitinib 37.5 mg daily. Primary end point was Response Evaluation Criteria in Solid Tumors defined response. Secondary end points were stable disease at 16 and 24 weeks. [(18)F]-fluorodeoxyglucose positron emission tomography was performed on a subset of 24 patients at baseline and after 10 to 14 days of therapy. Results Forty-eight patients were eligible for response. One patient (desmoplastic round cell tumor [DSRCT]) achieved a confirmed partial response (PR) and remained on study for 56 weeks. Ten patients (20%) achieved stable disease for at least 16 weeks. Metabolic PR was seen in 10 (47%) of 21 of patients. Metabolic stable disease was seen in 11 (52%) of 21. There were no unexpected toxicities observed. CONCLUSION Sunitinib demonstrated notable evidence of metabolic response in several patients with non-GIST sarcoma. The relevance of disease control observed in subtypes with an indolent natural history is unknown, however, the durable disease control observed in DSRCT, solitary fibrous tumor, and giant cell tumor of bone suggests that future evaluation of sunitinib in these subtypes may be warranted.

Phase II study of sunitinib malate (SM) in subjects with metastatic and/or surgically unresectable non-GIST soft tissue sarcomas

10535 Background: Metastatic soft tissue sarcoma represents a diverse collection of disease types. Sunitinib malate is a multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor, with proven efficacy in imatinib mesylate-refractory or intolerant gastrointestinal stromal tumors (GIST). This study was designed to evaluate the efficacy and tolerability of sunitinib malate in four non-GIST sarcoma subytpes (liposarcoma, malignant fibrous histiocytoma, fibrosarcoma and leiomyosarcoma). Methods: Eligibility criteria included tissue documented metastatic soft tissue sarcomas, measurable disease (by RECIST criteria), and a maximum of three prior lines of therapy for metastatic disease. Treatment was with sunitinib malate 50 mg orally daily in 6 week cycles (4 weeks on/ 2 weeks off). Results: Thirty-six subjects have been accrued to date, 12 patients with leiomyosarcoma, 12 with liposarcoma, 11 with malignant fibrous histiocytoma (MFH) and one patient with fibrosarcoma. The median age was 64, range 42–86, male/female 18/18, ECOG performance status 0/1/2 24/11/1. The median number of cycles administered has been 3 (range 1 to 7). Tolerance of therapy has been acceptable with the only three serious drug-related adverse events being congestive heart failure and pulmonary emboli. One confirmed partial response was seen. 29 (80.6%) subjects have observed stable disease for at least 12 weeks. Conclusions: The data from the study to date demonstrate acceptable tolerability of sunitinib in metastatic soft tissue sarcomas of different histologies. A high percent of subjects with stable disease was observed. These finding support further evaluation of sunitinib malate in soft tissue sarcomas. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology

Change in quantitative FDG-PET was significantly more accurate than change in size at predicting histopathologic response to neoadjuvant therapy in high grade soft tissue sarcomas

10017 Background: Change in size by RECIST (Response Evaluation Criteria in Solid Tumors) has been the standard to assess response to therapy in non-GIST soft tissue sarcomas (STS). Although recent studies have demonstrated that Positron Emission Tomography with F18-fluorodeoxyglucose (FDG-PET) may be used to assess response, there has not been a direct comparison between these modalities. The aim of this study was to prospectively evaluate whether a change in quantitative FDG-PET or a change in size [computed tomography(CT)] was more accurate at predicting histopathologic response to neoadjuvant therapy in patients with high grade STS using a combined FDG-PET/CT scan. Methods: From 1/05 - 12/06 58 patients with resectable biopsy proven high grade STS scheduled to undergo neoadjuvant chemotherapy were prospectively enrolled in this study. Patients underwent FDG-PET/CT prior to and after neoadjuvant treatment (prior to surgery). Tumor FDG-uptake was quantified by standardized uptake values (SUV). Changes in tumor size were quantified according to RECIST. Following tumor resection, response was assessed histopathologically. Patients with = 10% viable tumor cells were classified as responders. To date, 36 patients have completed the study and are the subject of this analysis. Results: In histopathologic responders (n=10, 28%), reduction of tumor FDG-uptake was significantly greater (-64%) than in histopathologic non-responders (-37%), (p=0.005). Using a 50% decrease in tumor SUV as a threshold value resulted in a sensitivity of 90% and a specificity of 58% for assessment of histopathologic response (p=0.01). Response assessment per RECIST showed no significant correlation with histopathologic response (sensitivity 20%, specificity 89%, p=0.4). There was no correlation between changes in tumor size and histopathologic response (area under the ROC curve = 0.6, p=0.1). Conclusions: In patients with high grade STS, quantitative FDG-PET was significantly more accurate than size based criteria for assessment of histopathologic response to neoadjuvant therapy. FDG-PET should be considered as a modality to monitor treatment response is patients with high grade STS. No significant financial relationships to disclose.

A SARC multicenter phase III study of gemcitabine (G) vs. gemcitabine and docetaxel (G+D) in patients (pts) with metastatic soft tissue sarcomas (STS)

9514 Background: We sought to compare the response of metastatic STS to G vs. G+D in a phase III study using a novel Bayesian adaptive randomization strategy. Methods: Entry criteria included non-GIST STS diagnosis, age &gt; 10, measurable disease, ≤ 3 prior regimens, normal organ function, and Grade (Gr) ≤ 1 neuropathy. Pts were stratified by histology (leiomyosarcoma [LMS] vs. other), and history of prior pelvic radiation (PPR) or not, yielding 4 diagnostic subgroups. Therapy was G 1200 mg/m2 (over 120 min, d1+d8) or G 900 mg/m2 (over 90 min, d1+d8) and docetaxel (100 mg/m2 d8) q21d; all pts received (peg)-filgrastim starting d9. 25% dose reductions were employed for PPR or toxicity. The primary endpoint was tumor response (CR, PR, or 24+ weeks stable), using a double-blind Bayesian adaptive randomization procedure to incrementally assign more pts to the superior treatment arm, while accounting for possible treatment-subgroup interactions. Although this study is not based on a 1:1 randomized phase III design, enrolling ∼120 pts would show a difference between a response rate (RR) of 10% for G and 30% with G+D with a power of 0.8 and two-sided alpha of 0.05. Results: 122 pts were randomized; 119 pts had evaluable outcomes. Median number of prior regimens was 1; median number of cycles was 4 (range 1–26). 49 pts were adaptively randomized to G and 73 to G+D, indicating superiority of G+D. Of 119 evaluable pts, 27% (G) and 32% (G+D) showed response as defined. The odds of pts with LMS receiving G+D instead of G increased from 1:1 at the start of the study to ∼6:1 at its completion. RR was 10% (G) vs. 16% (G+D) (p=0.15, Fisher exact test). Consistent with the RR outcomes, progression free survival (PFS) was 6.2 m (G+D, K-M 95%CI 3.6–8.8) vs. 2.6 m (G, 95%CI 2.0–3.2). Overall survival (OS) was 18.0 m (G+D, K-M 95%CI 11.7–24.1) vs. 11.2 m (G, 95%CI 6.8–15.5). Pts receiving G+D had a higher rate of discontinuation due to toxicity than those receiving G (p&lt;0.01, log rank). Conclusions: We observed substantial clinical activity in this pre-treated STS population. G+D yields superior PFS and OS to G, but at the price of increased toxicity. Adaptive randomization is an effective method that substantively reduces the number of pts receiving inferior therapy. [Table: see text]

Protein kinase C theta is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias.

Gastrointestinal stromal tumors (GIST) are a distinctive group of mesenchymal neoplasms of the gastrointestinal tract. The oncogene KIT has a central role in the pathogenesis of GIST, with c-kit receptor tyrosine kinase (KIT) protein expression being the gold standard in its diagnosis. The identification of GIST patients has become crucial, because the tyrosine kinase inhibitor Imatinib is effective in the treatment of this malignancy. However, a small set of GISTs remain unrecognized, because KIT protein expression is not always evident. The aim of this study was the identification of new markers for the differential diagnosis of GIST. By analyzing publicly available data from transcriptional profiling of sarcomas, we found that protein kinase C theta (PKC-theta), a novel PKC isotype involved in T-cell activation, is highly and specifically expressed in GIST. PKC-theta expression in GIST was confirmed by reverse transcription-PCR and Western blot. PKC-theta was analyzed by immunohistochemistry in a panel of 26 GIST, 12 non-GIST soft-tissue sarcomas, and 35 tumors from other histologies. We found that all of the GISTs expressed PKC-theta, whereas this protein was undetectable in other mesenchymal or epithelial tumors, including non-GIST KIT-positive tumors. PKC-theta immunoreactivity was also observed in interstitial cells of Cajal. Our results show that PKC-theta is easily detected by immunohistochemistry in GIST specimens and that it could be a sensitive and specific marker for the diagnosis of this malignancy.