Localized High-risk Soft Tissue Sarcoma Research Articles

CXCR4 Expression as a Prognostic Biomarker in Soft Tissue Sarcomas.

Poor long-term survival in localized high-risk soft tissue sarcomas (STSs) of the extremities and trunk highlights the need to identify new prognostic factors. CXCR4 is a chemokine receptor involved in tumor progression, angiogenesis, and metastasis. The aim of this study was to evaluate the association between CXCR4 expression in tumor tissue and survival in STSs patients treated with neoadjuvant therapy. CXCR4 expression was retrospectively determined by immunohistochemical analysis in serial specimens including initial biopsies, tumors post-neoadjuvant treatment, and tumors after relapse. We found that a positive cytoplasmatic expression of CXCR4 in tumors after neoadjuvant treatment was a predictor of poor recurrence-free survival (RFS) (p = 0.003) and overall survival (p = 0.019) in synovial sarcomas. We also found that positive nuclear CXCR4 expression in the initial biopsies was associated with poor RFS (p = 0.022) in undifferentiated pleomorphic sarcomas. In conclusion, our study adds to the evidence that CXCR4 expression in tumor tissue is a promising prognostic factor for STSs.

Molecular residual disease (MRD) detection using bespoke circulating tumor DNA (ctDNA) assays in localized soft tissue sarcoma (STS).

11509 Background: Surgery and (neo)adjuvant radiotherapy (RT) are the mainstay curative treatments for localized STS. Despite treatment, up to 50% of STS patients experience metastatic relapse, and routine use of adjuvant systemic therapy (AST) remains controversial. The presence of ctDNA following curative-intent treatment of STS is a potential biomarker for MRD and may identify patients who are likely to benefit from AST. Given the genomic heterogeneity of STS, a histology-agnostic approach to ctDNA detection in this population is desirable. Methods: Patients (pts) with localized, high risk (size ≥ 5cm, grade ≥ 2) STS were enrolled prior to (neo)adjuvant RT and surgery. Pts who received (neo)adjuvant systemic treatment were excluded. Blood samples for ctDNA analysis were collected at diagnosis, post-RT, post-surgery and every 3 months for up to 2 years. Whole exome sequencing (WES) of archival tumor and matched normal were carried out to identify patient-specific, somatic, single nucleotide variants. Personalized and tumor-informed, multiplex PCR next generation sequencing-based ctDNA (Signatera) assays were then developed to track ctDNA in serially collected plasma samples. ctDNA levels were expressed as mean tumor molecules per milliliter (MTM/ml) of plasma. Radiologic surveillance was performed every 3 months following surgery. The primary endpoint was a ctDNA detection rate of >70% at diagnosis. Secondary endpoints included MRD detection after local therapy and correlation of ctDNA levels with disease relapse. Results: A total of 140 plasma samples from 22 pts [18 male and 4 female; median age: 65 years, range: 30 – 84] were obtained. RT was preoperative in 19/22 pts. Of the 22 tumor samples, 20 had adequate tissue quality for WES to enable ctDNA assay design. Tumor histologic subtypes included undifferentiated pleomorphic sarcoma (n = 6), myxofibrosarcoma (n = 5), and liposarcoma (n = 9). A median of 7 plasma samples per patient (range: 2 – 10) were analyzed. ctDNA was detected in 80% of pts (16/20) at diagnosis, with median ctDNA level of 3.4 MTM/mL (range: 0.2 – 1393.9). Of these 16 pts, 15 (94%) became ctDNA negative at the immediate post-surgical timepoint. In addition, ctDNA was detected in 4 pts (80%) prior to or around radiologic relapse with a median lead time of 92 days. Conclusions: Personalized, tumor-informed ctDNA assays can detect MRD after definitive local therapy and/or prior to radiologic recurrence in patients with localized high-risk STS. As such, serial ctDNA monitoring provides prognostic value and may further identify patients that will benefit from AST treatment. Additional studies evaluating ctDNA as a predictive biomarker for AST benefit are ongoing.

Postoperative complications and oncologic outcomes after multimodal therapy of localized high risk soft tissue sarcoma

BackgroundStandard therapy for localized high-risk soft tissue sarcoma includes surgical resection and neoadjuvant or adjuvant radiation therapy (± chemotherapy and locoregional hyperthermia). No difference in oncologic outcomes for patients treated with neoadjuvant and adjuvant radiation therapy was reported, whereas side effect profiles differ. The aim of this analysis was to analyse oncologic outcomes and postoperative complications in patients treated with multimodal treatment.MethodsOncologic outcomes and major wound complications (MWC, subclassified as wound healing disorder, infection, abscess, fistula, seroma and hematoma) were evaluated in 74 patients with localized high-risk soft tissue sarcoma of extremities and trunk undergoing multimodal treatment, and also separately for the subgroup of lower extremity tumors. Clinical factors and treatment modalities (especially neoadjuvant vs. adjuvant radiotherapy) were evaluated regarding their prognostic value and impact on postoperative wound complications.ResultsOncologic outcomes were dependent on number of high risk features (tumor size, depth to superficial fascia and grading), but not on therapy sequencing (however with higher risk patients in the neoadjuvant group). Different risk factors influenced different subclasses of wound healing complications. Slightly higher MWC-rates were observed in patients treated with neoadjuvant therapy, compared to adjuvant radiotherapy, although only with a trend to statistical significance (31.8% vs. 13.3%, p = 0.059). However, except for wound infections, no significant difference for other subclasses of postoperative complications was observed between neoadjuvant and adjuvant therapy. Diabetes was confirmed as a major risk factor for immune-related wound complications.ConclusionRates of major wound complications in this cohort are comparable to published data, higher rates of wound infections were observed after neoadjuvant radiotherapy. Tumor localization, patient age and diabetes seem to be major risk factors. The number of risk factors for high risk soft tissue sarcoma seem to influence DMFS. Neoadjuvant treatment increases the risk only for wound infection treated with oral or intravenous antibiotic therapy and appears to be a safe option at an experienced tertiary center in absence of other risk factors.

Circulating tumor DNA (ctDNA) detection of molecular residual disease (MRD) as a potential biomarker in localized soft tissue sarcoma (STS).

11547 Background: Surgery and (neo)adjuvant radiotherapy are the mainstay curative treatments for localized STS. Despite treatment, approximately 50% of STS patients (pts) experience metastatic relapse and routine use of adjuvant systemic therapy (AST) remains controversial. The presence of ctDNA following curative treatment of STS is a potential biomarker for MRD and may identify patients who benefit from AST. Given the genomic heterogeneity of STS, a histology-agnostic approach to ctDNA detection in this population is desirable. Methods: Pts with localized, high risk (size ≥ 5cm, grade ≥ 2) disease were enrolled prior to (neo) adjuvant radiotherapy and surgery. Blood for ctDNA was collected at diagnosis; post-radiotherapy, post-surgery and every 3 months for up to 2 years. Whole exome sequencing (WES) of archival tumor- and matched buffy coat-DNA were carried out to identify somatic variants. Personalized and tumor-informed, multiplex PCR next generation sequencing-based ctDNA assay (Signatera™ assay) was performed on plasma obtained at the serial timepoints. A sample level positive call required ≥ 2 variants above a confidence calling threshold. Absolute ctDNA levels were expressed as mean tumor molecules per milliliter (MTM/ml) of plasma, based on variant allele frequencies and quantity of cell free DNA. Standard radiologic surveillance (every 3 months) was performed following surgery. The primary endpoint was a ctDNA detection rate of 70% at diagnosis. Secondary endpoints included MRD detection and correlation of ctDNA levels with disease relapse. Results: Seventy-six plasma samples from 10 pts [8 males and 2 females; median age 64 years (range 46–84)] were obtained prospectively. STS subtypes were undifferentiated pleomorphic sarcoma (n = 4), myxofibrosarcoma (n = 2), dedifferentiated liposarcoma (n = 2), myxoid liposarcoma (n = 1), and pleomorphic liposarcoma (n = 1). All tumors successfully underwent WES with adequate data quality for Signatera™ assay design. The personalized ctDNA assay was performed on a median of 7 plasma samples per patient (range: 5 – 10). ctDNA was detected in 7 pts (70%) at diagnosis, with median ctDNA level of 1.6 MTM/ml (range: 0.2 – 137.8), achieving the study primary endpoint. Immediate post-surgery samples were negative in all pts. However, ctDNA was detected in 2 out of 2 pts who developed metastatic disease during follow-up. Conclusions: Personalized tumor-informed ctDNA assays in localized high-risk STS at diagnosis are feasible. In this series, all patients had undetectable levels of ctDNA post-surgery and patients who experienced disease relapse demonstrated a detectable rise in ctDNA levels. Further interrogation of this approach for detection of post-treatment MRD as a possible biomarker of benefit from AST is ongoing.

Modern Management of High-risk Soft Tissue Sarcoma With Neoadjuvant Chemoradiation: A Single-center Experience.

Neoadjuvant chemoradiation (NA-CRT), followed by resection of high-risk soft tissue sarcoma (STS), may offer good disease control and toxicity outcomes. We report on a single institution's modern NA-CRT experience. Delay to surgical resection, resection margin status, extent of necrosis, tumor cell viability, presence of hyalinization, positron emission tomography (PET)/computed tomography data, and treatment toxicities were collected. Using the Kaplan-Meier survival analysis, 5-year overall survival, disease-free survival, distant metastasis-free survival, and local control (LC) were estimated. Clinicopathologic features and PET/computed tomography avidity changes were assessed for their potential predictive impact using the log-rank test. From 2011 to 2018, 37 consecutive cases of localized high-risk STS were identified. Twenty-nine patients underwent ifosfamide-based NA-CRT to a median dose of 50 Gy before en bloc resection. At a median follow-up of 40.3 months, estimated 5-year overall survival was 86.1%, disease-free survival 70.2%, distant metastasis-free survival 75.2%, and LC 86.7%. Following NA-CRT, a median reduction of 54.7% was observed in tumor PET avidity; once resected, median tumor necrosis of 60.0% with no viable tumor cells was detected in 13.8% of the cases. Posttreatment resection margins were negative in all patients, with 27.6% having a margin of ≤1 mm. Delays of over 6 weeks following the end of radiation treatment to surgical resection occurred in 20.7% cases and was suggestive of inferior LC (92.8% vs. 68.6%, P=0.025). This single-institution series of NA-CRT demonstrates favorable disease control. Delay in surgical resection was associated with inferior LC, a finding that deserves further evaluation in a larger cohort. Level III-retrospective cohort study.

Prognostic role of % changes in longest tumor diameter (LTD) in localized high-risk soft tissue sarcoma (STS) treated with neoadjuvant chemotherapy in a randomized clinical trial.

11558 Background: We investigated the prognostic relevance of % change in LTD in patients (pts) with localized high-risk STS treated with neoadjuvant chemotherapy in a phase 3 randomized trial (NCT01710176), aimed at comparing 3 cycles of a neoadjuvant histology-tailored (HT) over 3 cycles of standard anthracycline + ifosfamide chemotherapy (S). Methods: Pts with localized high-risk STS of extremities or trunk wall, and a diagnosis of myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors, undifferentiated pleomorphic sarcoma were randomly assigned to receive 3 cycles of S or HT. Pts affected by myxofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabomyosarcoma unclassified spindle cell sarcoma were prospectively registered and treated by S. Change of LTD was assessed comparing baseline dimension with that measured after 3 cycles of S or HT, before surgery. Only pts treated with neodjuvant chemotherapy alone were selected for the analysis. We first investigated Overall Survival (OS) from surgery of the groups identified by “any % reduction”, “no-change” or “increase” in LTD by Kaplan-Meier estimates and log-rank tests. Then we searched for cutoffs able to separate prognosis among pts with a LTD reduction applying the change-point method proposed by Contal - O’Quigley. Results: Of 325 pts who entered the study and evaluable for response, 181 received neoadjuvant chemotherapy alone (92 S and 89 HT group respectively) and were analyzed, while 144 received concurrent chemo-radiotherapy and were excluded. In the whole population, % changes in LTD were significantly associated (log rank p = 0.032) to OS. “Any % reduction in LTD (101/181pts) displayed a better prognosis compared to “no-change” (28/181 pts) or “any % increase” (52/181). The change-point analysis was applied to all, S and HT groups separately; a cutoff of = / > 18.75% decrease in LTD was the optimal predictor of outcome for the S group (p = 0.031), while no size cut-off could be identified for the HT group. Conclusions: In our study, % change in LTD of pts treated with neoadjuvant chemotherapy for localized high-risk STS correlated with OS. However, a % decrease in LTD cut-off able to predict the best outcome could be identified only for pts treated in the S group, while no differences in outcome were found by any % LTD change in the HT group. Interestingly, the LTD cut-off identified in the S group was lower than the one selected to define a response by RECIST ( = / > 18.75% decrease in LTD vs = / > 30%). Clinical trial information: NCT01710176 .

Prognostic role of MRP1 in localized high-risk soft tissue sarcoma (STS): Translational research associated to randomized phase III trial (ISG-STS 1001).

11543 Background: The ceiling-drug effect seen for most active drugs in STS could be related, partially, to multidrug resistance mechanisms (MDRM). We previously reported the independent prognostic role for RFS and OS of MRP1 in high-risk localized STS of limbs and trunk-wall treated with epirubicin and ifosfamide (Mol Cancer Ther.2014 13(1):249-59). A translational study was carried out within the randomized phase III trial of epirubicin plus ifosfamide vs histotype-tailored neoadjuvant chemotherapy (NCT01710176), to investigate MRP1 prognostic value using the trial population as validation set. Methods: Patients enrolled in the trial were invited to participate, through the informed consent, to this analysis. IHC used QCRL-1 (Santa Cruz biotechnology) MRP1 monoclonal antibody. TMAs were built on the highest-grade area of each tumor, being the procedure blinded for clinical data. MRP1 expression was grouped as low (≤ 25% positive cells) vs high ( > 25% positive cells) expression. For data analysis, patients were grouped as A) epirubicin plus ifosfamide control arm and B) histotype-tailored experimental arm. Drugs used in group B were: gemcitabine-docetaxel (UPS), gemcitabine-DTIC (LMS), trabectedin (High-grade (HG) myxoid LPS), ifosfamide-etoposide (MPNST) and high-dose ifosfamide (SS). Prognostic value of MRP1’s extension was analyzed using Cox’s proportional hazard regression. A p-value < 0.05 was considered statistically significant. Results: 175 patients were analyzed (median age 49; males 61%) with median follow-up of 4.66 y. Group A (n = 88) included HG-myxoid LPS (27%), SS (25%), UPS (24%), LMS (12%) MPNST (10%) and others (2%); group B (n = 87) included UPS (38%), SS (24%), HG-myxoid LPS (20%), LMS (10%) and MPNST (8%). MRP1 high extension was distributed as follows: 48% (A) and 57% (B). High MRP-1 expression showed significantly worse prognosis for disease-free survival (DFS) (HR 2.71 (1.31-5.62) p = 0.007) and a trend towards worse OS (HR = 2.75 (0.97-7.81) p = 0.058) in group A. No correlation was seen between MRP-1 expression and DFS (p = 0.384) or OS (p = 0.665), in group B. Conclusions: MRP1 overexpression was related to significant worse prognosis in 2 prospective randomized series of high-risk, localized, STS treated with neoadjuvant epirubicin and ifosfamide. These agents are both substrate of MRP1; this could add rationale for a possible predictive role, as MDRM, for the two most active drugs in STS. A trial combining epirubicin, ifosfamide and MRP1 inhibitor is currently under design.

Chemotherapy for Soft Tissue Sarcoma: Development of New Standard Treatments and Clinical Trials in Japan

Abstract Recently, pembrolizumab has been approved for microsatellite instability-high cancers, and genome profiling panel has also been approved for advanced refractory cancers including soft tissue sarcomas (STS) in Japan. However, efficacy and cost-benefit balance of these new strategies for STS should be confirmed by the future clinical trials. For localized STS, efficacy of perioperative chemotherapy has remained controversial. Meta-analysis of randomized controlled trials (RCT) comparing chemotherapy with surgery showed significant survival benefit of the chemotherapy for localized STS. Subsequently, recent RCT have compared chemotherapy regimens with each other especially in neoadjuvant setting, not with surgery. The Italian Sarcoma Group study ISG-STS1001 demonstrated significantly better survival by neoadjuvant epirubicin plus ifosfamide than histology-tailored regimens for high-risk STS. The 10-year follow-up of our trial, JCOG0304, also showed good stable results of neoadjuvant chemotherapy using adriamycin and ifosfamide (AI) for high-risk STS. These observations suggest that neoadjuvant AI could be recommended for localized high-risk STS. Besides high efficacy of AI, significant toxicities of the regimen should also be noted. We are now conducting a randomized phase II/III study, JCOG1306, to confirm the non-inferiority of neoadjuvant gemcitabine plus docetaxel (GD) to AI for high-risk STS. For advanced STS, adriamycin-based chemotherapy remains standard first-line treatment since phase III study of olaratumab resulted in negative. On the other hand, the standard second-line regimen for advanced STS has not been established yet. There are several options including GD, pazopanib, trabectedin and eribulin, however, no evidence has been shown which regimen is the best as second-line therapy. To establish the standard therapy of second-line treatment for advanced STS, we are currently conducting randomized phase II study comparing pazopanib, trabectedin and eribulin.

Multimodale Therapien bei Sarkomen: Standards und Neues in der medikamentösen und radioonkologischen Behandlung

Patients with localized high-risk soft tissue sarcoma are at high risk for both local recurrence and distant metastases despite optimal surgical treatment. Importance of preoperative or postoperative chemotherapy and hyperthermia. Evaluation and overview of published study results. Preoperative or postoperative radiotherapy is considered as standard for patients with localized high-risk soft tissue sarcoma. The results of two randomized studies on neoadjuvant chemotherapy showed asurvival benefit. As both studies did not have acontrol arm without chemotherapy but in one case the superiority of anthracycline/ifosfamide-based chemotherapy in combination with hyperthermia over chemotherapy alone and in the other case the superiority of anthracycline/ifosfamide-based chemotherapy over histology-specific chemotherapy were shown, the formal proof of the superiority of this treatment is still missing. Stratifying the patients treated in the so far largest randomized adjuvant chemotherapy trial according to current risk criteria ( http://www.sarculator.com ) revealed asignificant survival benefit for patients at high risk of recurrence. For high-risk soft tissue sarcomas, multimodal treatment strategies involving perioperative chemotherapy, radiotherapy and, if possible, hyperthermia should be considered in addition to tumor resection. Preoperative chemotherapy should be given preference over postoperative chemotherapy based on available data.

Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma

ImportancePatients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes.ObjectiveTo analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival.Design, Setting, and ParticipantsOpen-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014.InterventionsAfter stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia.Main Outcomes and MeasuresThe primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up.ResultsA total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98; P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%).Conclusions and RelevanceAmong patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted.Trial Registrationclinicaltrials.gov Identifier: NCT00003052

Tumor response assessment by Choi criteria in localized high-risk soft tissue sarcoma (STS) treated with chemotherapy (CT): Update at 10-year follow-up of an exploratory analysis on a phase III trial.

11044Background: We already reported (Cancer 2012;118:5857) on better correlation of Choi criteria (Choi) than RECIST with the outcome of pts affected by high-risk STS entering a multicentric Itali...

9PD - Impact of tumor infiltrating lymphocytes (TILs) on local progression-free (LPFS) and disease-free (DFS) survival in localized high-risk soft tissue sarcoma (HR-STS) after neo-adjuvant chemotherapy (NAC) with regional hyperthermia (RHT)

9PD - Impact of tumor infiltrating lymphocytes (TILs) on local progression-free (LPFS) and disease-free (DFS) survival in localized high-risk soft tissue sarcoma (HR-STS) after neo-adjuvant chemotherapy (NAC) with regional hyperthermia (RHT)

13LBA Improved overall survival by adding regional hyperthermia to neo-adjuvant chemotherapy in patients with localized high-risk soft tissue sarcoma (HR-STS): Long-term outcomes of the EORTC 62961/ESHO randomized phase III study

R.D. Issels, L.H. Lindner, P. Ghadjar, P. Reichardt, P. Hohenberger, J. Verweij, S. Abdel-Rahman, S. Daugaard, C. Salat, Z. Vujaskovic, R. Wessalowski, H.R. Duerr, F. Ploner, O. Mella, M. Schmidt, U. Mansmann, K.W. Jauch, C. Belka, W. Hiddemann, A. Gronchi. Klinikum der Univers. Munchen-Groshadern Klinikum Grosshadern, Medical Clinic III, Munchen, Germany; Klinikum der Universitat Munchen, Medizinische Klinik III, Munich, Germany; Charite Universitatsmedizin Berlin, Klinik fur Radio-Onkologie und Strahlentherapie, Berlin, Germany; Helios Klinikum Berlin-Buch, Interdisziplinare Onkologie, Berlin, Germany; Universitatsklinikum Mannheim, Spezielle chirurgische Onkologie, Mannheim, Germany; Erasmus Medical Center, Medical Oncology, Rotterdam, Netherlands; Rigshospitalet, Pathology, Copenhague, Denmark; University of Maryland, Translational Radiation Sciences, Baltimore, USA; Universitatsklinikum Duesseldorf, Klinik fur Kinder-Onkologie − Hamatologie und Immunologie, Duesseldorf, Germany; Klinikum der Universitat Munchen, Tumororthopadie, Munich, Germany; Universitatsklinikum Graz, Klinische Onkologie, Graz, Austria; Haukeland University Hospital, Medical Oncology, Bergen, Norway; Ludwig Maximilians Universitat Munchen, Institut fur Medizinische Informatik − Biostatistik und Epidemiologie, Munich, Germany; Klinikum der Universitat Munchen, Klinik fur Chirurgie, Munich, Germany; Klinikum der Universitat Munchen, Klinik fur Strahlentherapie, Munich, Germany; 16 Istituto Nazionale dei Tumori, Chirurgia dei Sarcoma, Milano, Italy

Neoadjuvant administration of radiation therapy and intratumoral autologous dendritic cells in patients with localized high-risk soft tissue sarcomas.

10519 Background: Patients with high grade, large (<5 cm) soft tissue sarcomas (STS) can develop metastases after surgical therapy with no proven benefit to adjuvant chemotherapy. Our in vivo murin...

MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study

Patients with localized high-risk soft tissue sarcomas (STS) of the limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drug-ceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by multidrug resistance (MDR) mechanisms. The aim of this study was to ascertain whether mRNA and protein expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and GSTA1 (glutathione S-transferase pi) was prognostic in localized high-risk STS. Immunohistochemistry and reverse transcriptase-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial that compared three versus five cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with relapse-free survival (RFS) were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, P = 0.029), histology (5-year RFS rate of 74% in undifferentiated pleomorphic sarcoma and 43% in synovial sarcoma, P = 0.028), and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, P = 0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR = 2.704, P = 0.005) and overall survival (HR = 2.208, P = 0.029). ABCC1/MRP1 expression shows robust prognostic relevance in patients with localized high-risk STS treated with anthracycline-based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS.

Impact of 18F-FDG PET/CT Imaging in Therapeutic Decisions for Malignant Solitary Fibrous Tumor of the Pelvis

The decision to give neoadjuvant chemotherapy in patients with localized high-risk soft tissue sarcoma is often based on tumor grade evaluated from biopsies, but biopsies can have the inherent issue of sampling bias. Incorporation of SUVmax and heterogeneity assessed by F-FDG PET/CT could be other crucial components in the effort to tailor treatment to an individual patient, providing valuable parameters to guide the selection of the most appropriate management schedule for an individual. We present 1 representative case describing how FDG PET/CT can assist in clinical management decisions for treatment of malignant solitary fibrous tumor of the pelvis.

Phase II study of neoadjuvant high-dose ifosfamide with concurrent radiotherapy followed by surgical resection in high-risk soft tissue sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study.

10052 Background: High-dose ifosfamide (HDI) has shown promising activity as single agent in first-line chemotherapy for advanced soft tissue sarcoma (STS). The purpose of this study was to assess the activity and toxicity of a preoperative doxorubicin-free regimen of HDI given concurrently with radiotherapy (RT) and followed by surgery in patients (pts) with localized high-risk STS. Methods: Pts with localized &gt; 5 cm grade 2-3 and deep STS of the extremities and trunk wall, ≤65 years, no prior chemotherapy and ECOG PS 0-1 were enrolled in this multicenter phase II study. Pts received 3 cycles of preoperative HDI at a dose of 12 gr/m2 by continuous infusion over 5 days every 3 weeks, with mesna and prophylactic GCSF support, and concomitant external beam RT to a total dose of 50 Gy, followed by surgical resection. Postoperatively, pts with pathological response received 2 cycles of HDI and those with positive surgical margins 16 Gy of RT. The primary study endpoint was pathologic response (≥ 95% pathologic necrosis). A Simon 2-stage design (response rate P0=15%, P1=35%, α=0.10, β=0.10) required at least 2 responses in the first 17 pts to expand to a second cohort, and 7/32 responses to be considered of positive. Results: From March 08 to December 10, 34 pts were included. Two pts were ineligible. Median age was 54 (18-65). Tumor location was extremity (28 pts) and trunk wall (4). Preoperative planned treatment was completed in 87.5% pts. HDI was completed in 87.5% pts while RT in 94% pts. Grade 3-4 toxicities included neutropenic fever (3 pts), anemia (4), asthenia (2), infection (2) and radiation dermatitis (2). 31 pts underwent surgery: 27 were R0 resections, of which 2 were amputations, and 4 were R1 resections. Pathologic response was ≥ 95% necrosis in 9 pts (28%) and 50%-94% necrosis in 12 pts. After a median follow-up of 21 months, estimated 2-year rates for disease-free survival and overall survival were 58% (95%CI, 40%-77%) and 77% (95%CI, 61%-93%), respectively. Conclusions: Preoperative treatment with HDI given concurrently with RT in pts with high-risk STS is feasible and safe, yielding promising pathologic response rates.

Relationship of CUL4A gene underexpression and prognosis in localized high-risk soft tissue sarcoma (STS) patients of limbs or trunk wall.

10079 Background: Genes involved in cell cycle checkpoints and chromosome stability seem to be relevant in distant metastases appearance in STS. CUL4A is an E3 ubiquitin ligase that has been related to both p16 activation and maintenance of genomic stability. Expression of CUL4A has been scarcely described in some tumors with divergent outcome and there are no publications regarding its expression in STS patients. We previously showed that protein underexpression of CUL4A in metastatic STS was related to poor survival. Methods: The expression level of CUL4A was determined by quantitative qPCR and was retrospectively performed in a subset of 39 high-risk (grade 3, deep tumours and &gt; than 5 cm) localized STS of limbs or trunk wall patients for which histological material and clinical data were available. Patients of this series were enrolled prospectively into a randomized clinical trial conducted by the Italian and Spanish sarcoma groups (ISG-GEIS 0101) comparing 3 vs 5 cycles of epirrubicin and ifosfamide. Differences in PFS, RFS, and OS were calculated using log-rank test Results: The median age was 51 years with a median follow-up of 52 months. The pathologic subtypes were undifferentiated pleomorphic sarcoma (35.3%), synovial sarcoma (23.5%) and mixed subtypes (41.2%). Location was distributed as inferior limbs (66.6%), upper limbs (25.5%) and trunk wall (7.9%). No relationship was seen between CUL4A expression and clinical variables (histologic types, location, size or response to neoadjuvant treatment). The expression level of CUL4A was significantly associated with events of progression, 65% vs 32%, p =0.037, for expression values under and over the median respectively. Regarding 4 y actuarial survival, there was a significant worse PFS and RFS for patients underexpressing CUL4A (p=0.041 and 0.009 respectively) and a trend towards worse OS (p=0.056). Conclusions: Expression of CUL4A gene shows a prognostic role in sarcomas within this high risk localized subset of STS patients. The outcome of this exploratory analysis is aligned with our hypothesis that genes implicated in cell cycle regulation and chromosome stability could play a relevant prognostic role in STS.

Tumor response and outcome in localized high-risk soft tissue sarcomas (STS) treated with preoperative chemotherapy (CHT) with or without radiation therapy (RT) within a phase III trial from the Italian Sarcoma Group (ISG) and the Spanish Sarcoma Group (GEIS).

10019 Background: We showed that non-dimensional criteria (i.e. contrast enhancement and tumor density) correlate with pathologic responses better than RECIST in a group of 38 high-risk STS treated...

Histology and outcome in localized high-risk soft tissue sarcomas (STS) treated with preoperative chemotherapy (CHT) with or without radiation therapy (RT) within a phase III trial from the Italian Sarcoma Group (ISG) and the Spanish Sarcoma Group (GEIS).

10089 Background: We reported on a phase III trial comparing 3 versus 5 cycles of preoperative CHT in high-grade localized STS of the extremities and trunk wall. We explored to which extent histological subtype was prognostically relevant in such an adjuvant series. Methods: 311 pts were eligible. All received 3 cycles of preoperative Epirubicin + Ifosfamide, followed by surgery. Local RT was administered before or after surgery. 136 pts were randomized to receive 2 more cycles of adjuvant CHT. In 222 (71%) cases, centralized pathological review was performed. Histology was categorized into 4 groups: MFH/undifferentiated pleomorphic sarcoma and spindle cell sarcoma NOS (Group 1 = 125 pts), leiomyosarcoma (Group 2 = 41 pts), synovial sarcoma (Group 3 = 68 pts), other (Group 4 = 77 pts). The influence of histology OS and RFS was retrospectively assessed through a univariate Cox regression model. Besides, responses to the preoperative treatment according to RECIST (78% evaluated pts of those with measurable disease) and CHOI criteria (50% evaluated pts) were retrospectively recorded. Results: Group 1, Group 2 and Group 3 accounted for about 75% of cases. At a median follow-up of 60 months (range = 24-102), the OS probability was 0.76, 0.48, 0.64 and 0.73, and the RFS probability was 0.61, 0.48, 0.59 and 0.65, respectively, for Groups 1, 2, 3, 4. For both OS and RFS, a trend in favour of a better outcome was observed in Group 1. On the contrary, a diagnosis of leiomyosarcoma correlated with both a worse OS (Group 1 vs Group 2: HR 2.88, 95%CI 1.63 – 5.01) and a worse RFS (Group 2 vs Group 1: HR 1.72, 95%CI 1.03-2.88). Leiomyosarcoma was marked by the highest number of PD according to both RECIST and CHOI criteria, and Group 1 had the highest RR, when changes in tumor density were accounted for with CHOI criteria. Conclusions: In this series of localized high-risk limb and trunk wall STS, leiomyosarcoma performed worse than the other types. This may be the product of the combination of natural history and chemosensitivity. At least in part, the latter may correlate with the outcome.