Trials In Soft Tissue Sarcoma Research Articles

Serum protein acidic and rich in cysteine (SPARC) as a prognostic marker in soft tissue sarcomas.

BackgroundSerum protein acidic and rich in cysteine (SPARC) is a matricellular secreted glycoprotein that performs several cellular functions and has been implicated in tumorigenesis in a variety of tumor types. The chemotherapeutic agent nanoparticle albumin-encapsulated (NAB)-paclitaxel has been postulated to exploit SPARC expression to target neoplastic cells. SPARC’s role, and potentially the role of NAB-paclitaxel, in the highly heterogeneous class of soft-tissue sarcomas (STS) has not been investigated. Our objective was to explore the pattern of SPARC expression and its prognostic significance in STS.Methods27 tissue specimens representing various STS histologies were stained for SPARC expression by immunohistochemistry (IHC). Staining intensity was scored blindly. Survival was determined from patients’ medical records and analyzed using Kaplan-Meier and log-rank with respect to SPARC expression level.ResultsElevated SPARC expression was observed in 15/27 (56%) specimens. Overall patient survival segregated strongly based on levels of SPARC expression. Patients who expressed low-to-moderate levels of SPARC exhibited median survival of 22.1 months, while the median survival of patients with moderate-to-high expression levels was 4.4 months (log rank; p = 0.0016).ConclusionsSPARC expression is elevated in a significant proportion of STS specimens analyzed in this study, but it does not appear to correlate with specific STS histologies. Given our limited sample size, we cannot draw definitive conclusions regarding association of SPARC with STS subtype. Overall survival segregates strongly by degree of SPARC expression, with elevated expression being adverse. If validated in a larger study, our results suggest that trials in STS with agents potentially targeting SPARC, such as NAB-paclitaxel, should be stratified by SPARC expression level.

Key Advances in the Systemic Therapy for Soft Tissue Sarcomas: Current Status and Future Directions

Soft tissue sarcomas (STS) represent a heterogeneous group of diverse neoplasms of mesenchymal origin. Once relapsed from standard therapy, STS patients have limited treatment options especially those that present with advanced or metastatic disease. In this review article, we highlight recent clinical data that led to the US Food and Drug Administration (FDA) approval of pazopanib (Votrient®) for STS and regorafenib (Stivarga®, BAY 73-4506) in gastrointestinal stromal tumours. We also review ongoing safety/efficacy data for trabectedin (Yondelis®, ET-743), and data from clinical studies of ridaforolimus (AP23573; MK-8669) and palifosfamide (ZIO-201). We provide a list of some promising ongoing trials in soft tissue sarcomas including first line studies of TH-302 and trabectedin. Finally, our article delves into recent advances in our understanding of the molecular pathogenesis of STS and novel therapies that might be explored as treatment options for specific STS histologies.

Antiangiogenic approach in soft-tissue sarcomas

Soft-tissue sarcomas (STS) are a group of more than 50 malignancies characterized by their rarity. The most effective treatments available only achieve a response rate (RR) of around 20%. Therefore, new therapeutic strategies are needed. Neoangiogenesis is one of the most fundamental mechanisms in cancer and many studies suggest that it also plays a crucial role in STS. Positive results from two Phase III trials in STS with drugs that target angiogenesis have recently been reported, showing an increase in progression-free survival. These data, although promising, are still insufficient and further investigations are needed. STS are unusual among solid tumors, in which single agent angiogenesis inhibitors produce a significant benefit. Unfortunately, we are currently not able to reliably define according to the histological subtype who are the patients that may benefit from this strategy. Moreover, it is clear that single agent treatment is insufficient, hence the current focus is on combination studies.

94IN - Perspectives of Subtyping in Soft Tissue Sarcomas: The Relevance for Clinical Trial Design

ABSTRACT In the relatively recent past soft tissue sarcomas were lumped together for the purpose of studying treatment effects in clinical trials. This has clearly served a purpose in the development of non-specific cytotoxic agents. But even for cytotoxic agents more recently hints of selective sensitivity of sarcoma subtypes emerged. So one can state in general that using unselected populations in soft tissue sarcoma trials increases the ease of patient accrual, but at the same time diminishes the chance of achieving a statistically significant clinical benefit. The identification of KIT as a single tumor growth driver in Gastrointestinal stromal tumor (GIST), and its subsequent effective inhibition with imatinib, have further strengthened the realization that the various subtypes of soft tissue sarcomas should each be considered as unique diseases. Because of the rarity of soft tissue sarcomas in general and the linked limited number of patients for each individual sarcoma subtype, the now required further subsetting creates a challenge for current and future trial design. Evidence from recent trials suggests that, if they are based on well-characterized preclinical data and/or clinical observations, performance of trials in select histologic subtypes should be pursued and is feasible; at least for tumor cell related targeted therapeutic approaches. For targets in the tumor environment there are also signals that subsets may be more sensitive, although this does not ensure that the other subsets are totally insensitive. There seems to be a gradual differentiation of sensitivity. For several agents the sensitivity of subsets could be predicted with predictive biomarkers, but biomarkers were of more limited value of biomarkers in assessing individual clinical benefit. This yields yet another challenge, certainly for agents where growth inhibition rather than tumor regression is expected. All of these aspects are guiding us towards new trial approaches that will shortly be discussed. Disclosure The author has declared no conflicts of interest.

Global differences in chemotherapeutic regimens of soft tissue sarcoma (STS): Results of PALETTE, an EORTC 62072/GSK VEG110727 global network phase III trial of pazopanib versus placebo.

10067 Background: The global PALETTE EORTC/GSK network study on advanced STS patients (pts) randomized 223 European (EU), 43 American (US), 81 Asian, and 22 Australasian (AUS) pts between pazopanib and placebo. Prior to study entry pts should have received at least one anthracycline containing regimen, and preferably, if pts’condition allowed, all available standard chemotherapy treatments for STS in their countries. We investigated the differences in chemotherapy pts received prior- and post-protocol at a global level. Methods: Pts were grouped by continent. Pre- and post-protocol chemotherapeutic treatments (txs) were analyzed. The number of prior lines of systemic tx for advanced STS was divided between 0-1 vs 2 or more. Chemotherapy was studied in detail between Asian and other countries. Fisher’s exact test was used for statistical analysis. Results: Data from all 369 pts were analyzed. (Neo-) adjuvant systemic tx was given in 21% of EU, 23% of US, 36 % of Asian and 41% of AUS pts. In advanced STS: 2 or more lines of prior systemic txs were administered in 60% of EU, 84% of US, 42% of Asian, 22% of AUS pts before study entry. Prior to study entry 68% of EU, 65% of US, 84% of Asian and 68% of AUS pts received ifosfamide(or analogs); after protocol 21 % of EU, 14% of US, 13% of Asian and 5% of AU pts. There were significant differences in chemotherapy between Asian (n=81) and other (n=288) pts: prior to protocol trabectedin was administered in 1 vs 21%; gemcitabine 19 vs 39 %; cisplatin: 36 vs 5%; etoposide 32 vs 4% (all p<0.001), and docetaxel: 17 vs 31 % (p=0.004) of pts. Post-protocol trabectedin was given to 4 vs 34% (p<0.001), gemcitabine both in 19%; cisplatin 10 vs 4% (p=0.01); etoposide 12 vs 6%, and docetaxel 20 vs 12 % (both, p=0.02) of pts. Conclusions: The PALETTE study showed considerable intercontinental differences in chemotherapeutic txs for advanced STS pre- and post study drug. These differences might be due to availability and reimbursement of drugs, clinical studies and the practice patterns of sarcoma specialists world-wide. This is of particular interest for the design of future randomised global clinical trials in advanced STS.

Systematic Therapy for Unresectable or Metastatic Soft-Tissue Sarcomas: Past, Present, and Future

Unresectable or metastatic disease occurs in 40% to 60% of soft-tissue sarcoma (STS) patients and portends a poor prognosis. For decades, doxorubicin has formed the backbone of systemic treatment, with response rates of approximately 26%. Patients progressing following first-line therapy were left with few proven options. No other cytotoxic chemotherapy agent or combination has demonstrated superiority to doxorubicin. Advances in targeted therapy of STS have been hindered by STS heterogeneity and poorly understood disease biology. Despite challenges, progress has been made in specific STS subtypes. Here, we highlight the challenges, progress, and lessons learned from STS trials published in the last 20 to 25 years.

Treatment efficiency, outcome and surgical treatment problems in patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma: A report from the cooperative soft tissue sarcoma trial CWS‐96

To analyze the clinical course, treatment modalities, complications and outcome of patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma (BPRMS) treated on the CWS-96 trial. There were 85 patients with BPRMS enrolled and 63 patients with embryonal non-metastatic BPRMS were analyzed. Fifty-six patients received neoadjuvant chemotherapy and response was assessed radiographically after 9 weeks. Local therapy with radiation and or surgery was performed based on age, tumor size, and response. Patients were treated with adjuvant chemotherapy following local control. Patient's age ranged from 0 to 16 years with a median follow up of 5.3 years. Eighty nine percent of the patients had IRS group III disease. The 5-year overall survival (OS) for the whole group was 76.3 ± 5.6% and the 5-year event-free survival (EFS) 69.8 ± 6.2%. Seventeen patients underwent preoperative radiochemotherapy followed by tumor resection (5-year-OS: 87.8 ± 8.1%). Eight patients were treated with solely radiochemotherapy (87.5 ± 11.7%). Twenty-five patients received chemotherapy and tumor resection (OS: 83.6 ± 7.5%). Thirteen patients underwent incomplete tumor resection and were treated with radiochemotherapy postoperatively (OS: 39.9 ± 14.8%, P < 0.05 vs. other groups). Local therapy is an important factor for prognosis of localized embryonal BPRMS. Inadequate primary or secondary surgery compromises the outcome and should be avoided. Radiotherapy alone, complete surgical tumor resection or combined preoperative radiotherapy with surgical resection lead to similar good local control rates and prognosis.

Trends in survival for patients with metastatic soft‐tissue sarcoma

The objective of this study was to determine whether the overall survival of patients with metastatic soft tissue sarcoma (STS) has improved over the last 20 years. In total, 1024 patients who had synchronous metastatic (SM) STS or metachronous metastatic (MM) STS diagnosed between 1987 and 2006 were included prospectively in the French Sarcoma Group database after central histologic review. Four periods of diagnosis of metastatic disease were defined: P1, from 1987 to 1991 (n = 208); P2, from 1992 to 1996 (n = 287); P3, from 1997 to 2001 (n = 285); and P4, from 2002 to 2006 (n = 244). Patient characteristics were analyzed as prognostic factors by using a Cox model. The proportion of patients with SM, the interval between diagnosis and MM, and the clinical characteristics of the patients were similar across the 4 periods. Although there was no significant difference in the median overall survival (OS) from P1 through P2 (P1, 12.3 months; 95% confidence interval [CI], 9.9-14.7 months; P2, 11.4 months; 95% CI, 9-13.9 months), significant improvements were observed in the later periods (P3, 15 months; 95% CI, 11.8-18.2 months; P4, 18 months; 95% CI, 15.3-20.7 months; P = .029; log-rank test). The 2-year OS rate also increased throughout the study period from 28.1% during P1 to 38.7% during P4. On multivariate analysis, period of diagnosis, age, histologic subtype, time to metastatic recurrence, French Federation of Cancer Centers Sarcoma Group grade, and the number of metastatic sites were independent prognostic factors for OS. The current analysis revealed that the median OS of patients with metastatic STS had improved by 50% during the last 20 years. These data should be considered in the interpretation of results from ongoing and future STS trials.

Trends in survival for metastatic soft-tissue sarcoma: A French Sarcoma Group (GSF) database analysis.

10045 Background: Treatment of metastatic soft-tissue sarcoma (STS) has evolved over the last two decades with the improvement of supportive care,theincreased use of loco-regional treatments, the widespread use of additional lines of chemotherapy and the increasing participation of STS patients (pts) in investigational agents trials. The aim of this study is to evaluate the changes in overall survival (OS) of pts with metastatic STS. Methods: 1,024 consecutive pts with synchronous (SM) or metachronous metastatic (MM) STS diagnosed between 1987 and 2006 were included prospectively in the GSF database after central histological review. Four period of diagnosis of metastatic disease were defined: P1=1987-91: n=208, P2=1992-96: n= 287, P3=1997-2001: n=285, and P4 = 2002-2006: n=244). OS was estimated by the Kaplan-Meier method. Results: The proportion of pts with SM, the time to diagnosisof MM and theclinical characteristics (age, sex, histological subtype, grade, site of metastasis) were similar across the four periods. There was no significant difference in the median OS times from P1 through P2 (P1 = 12.3 months (m) 95% CI [9.9-14.7]; P2 = 11.4 m 95% CI [9-13.9]). However, significant improvements were seen in the later periods: P3 = 15 m 95% CI [11.8-18.2]; P4 = 18 m 95% CI [15.3-20.7] (log-rank test: P = 0.029). The 2-year OS rate has also increased all along the study period: P1= 28.1% 95% CI [22-34.5], P2 = 32% 95% CI [26.6-37.5], P3= 33.3% 95% CI [27.8-39], P4= 38.7%, 95% CI [32.3-45]. On multivariate analysis, period of diagnosis, age, histological subtype, time to metastatic relapse, FNCLCC grade and number of metastatic sites were independent prognostic factors for OS. Conclusions: Median OS of pts with metastatic STS has improved by 50% during the last 20 years. These data should be considered for the interpretation of the results of ongoing and future STS trials. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Pfizer, PharmaMar

Soft Tissue Sarcoma Trials: One Size No Longer Fits All

Soft Tissue Sarcoma Trials: One Size No Longer Fits All

Trabectedin

Trabectedin

An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated adult type soft tissue sarcoma

The number of effective cytotoxic agents for the treatment of patients with metastatic adult type soft tissue sarcoma (STS) is limited, when patients have failed anthracyline-based chemotherapy. The aim of this trial was to evaluate the efficacy of gemcitabine in this setting. Between August 2001 and March 2003 19 patients were eligible to enter. Gemcitabine was administered as a 30-minutes infusion at a dosage of 1 g/m2 on day 1, 8 and 15 every 4 weeks. All patients had progressive disease during (n = 12) or shortly after an anthracycline-based regimen (n = 3). Four of 19 patients did not start study treatment because of fulminant progression. Fifteen patients with a median age 47 years (32-72) were assessable. All patients had received at least one prior treatment regimen (range, 1-6) for metastatic disease containing anthracyclines (n = 15) and ifosfamide (n = 11). To date, a total of 72+ cycles have been applied (median; 3, 1-28+). Seven patients (47%) had progressive disease after completion of two cycles at the first response assessment. One patient (6%) attained a partial remission, and 7 patients (47%) achieved disease stabilisations. One patient is still on treatment after more than 2.5 years. The calculated progression-free rate at 3 and 6 months was 46.7% (CI(95%), 21.4-71.9) and 13.3% (CI(95%), (0-30.5). 95% of the cycles have been applied without any dose modification or treatment delay. Considering response and progression-free rate as the primary endpoints for phase II trials in pretreated STS, gemcitabine has moderate efficacy.

New therapeutic strategies for soft tissue sarcomas.

The treatment of patients with metastatic soft tissue sarcomas (STS) is complex. There are limited agents available and many are associated with significant toxicity. When evaluating a patient with metastatic disease, physicians should ask themselves whether there is a role for surgery to render the patient free of disease. Combination chemotherapy in patients who have not received chemotherapy in the adjuvant setting is one option, particularly in a young patient with a good performance status. Sequential single-agent therapy for patients who are more elderly or debilitated by their disease may be more appropriate. Gemcitabine appears to be an agent with activity, particularly in patients with leiomyosarcomas. The data regarding prolonged gemcitabine infusions suggest improved activity that was predicted based on prolonged intracellular gemcitabine levels. Because of these data, the prolonged infusion schedule should be used. In addition, because of the paucity of effective agents, consideration of clinical trial participation for patients with newly diagnosed metastatic disease is appropriate, particularly in chemotherapy-insensitive histologies. The role of the newer agents (eg, ecteinascidin-743, epothilones, and mammalian target of rapamycin) is undefined. Ecteinascidin-743 has been the most extensively tested agent, and its ability to slow growth kinetics of a tumor and stabilize it clinically is intriguing. Data regarding the response to BMS-247550 will be published shortly and will help define the further role of epothilones in this disease. There is a preclinical rationale that makes the mammalian target of rapamycin inhibitors attractive for the treatment of muscle-derived neoplasms. In addition, there are cell-line data suggesting activity in rhabdomyosarcoma. These agents are being tested in adult STS and will likely be tested in pediatric histologies when there are more safety data available in that population. SU11248 will continue to be tested in patients refractory to imatinib mesylate and may well prove to be another active agent for patients with gastrointestinal stromal tumors. As depicted by the analysis of gemcitabine efficacy, agents with activity in a subgroup of STS may be overlooked by the "come one come all" approach to clinical trials in STS. Identifying key targets in specific STS will be helpful in the testing of newer molecularly targeted agents. Biologic differences will support histology-specific trials to better understand the activity of an agent in a specific disease site or specifically target a biologic pathway with relevance to the malignant potential of the disease. For future clinical trials in STS to achieve the goal of histology-specific trials, cooperative group and multi-institutional trials will be required to obtain the appropriate patients with these rare histologies. It will also be increasingly important to be committed to obtaining tumor tissue in these patients to validate hypotheses regarding tumor biology and the effectiveness of therapeutic agents.

Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas

We have estimated progression-free rates (PFR) for various groups of soft-tissue sarcoma patients from our clinical trials database, to provide reference values for conducting phase II studies with PFR as the principal end-point. In 146 pretreated patients receiving an active agent, the PFR estimates were 39 and 14% at 3 and 6 months; with inactive regimens (234 patients), those estimates were 21 and 8% respectively. In 1154-non-pretreated patients, PFR estimates varied from 77% (synovial sarcoma) to 57% (malignant fibrous histiocytoma (MFH)) at 3 months, and from 56% (synovial sarcoma) to 38% (MFH) at 6 months. In 61 leiomyosarcomas from gastrointestinal origin, the corresponding figures were 44 and 30%, respectively. Consequently, for first-line therapy, a 6-month PFR of ⩾30–56% (depending on histology) can be considered as a reference value to suggest drug activity; for second-line therapy, a 3-month PFR of ⩾40% would suggest a drug activity, and ⩽20% would suggest inactivity.