Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. METHODS: This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. FINDINGS: 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. INTERPRETATION: Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. FUNDING: GlaxoSmithKline.

Phase III trial of standard versus dose-intensified doxorubicin, ifosfamide and dacarbazine (MAID) in the first-line treatment of metastatic and locally advanced soft tissue sarcoma.

Multidrug chemotherapy increases responses in advanced soft tissues sarcoma. Can a 20% increase of relative dose intensity of the MAID regimen, more improve responses? From 1994 to 1997, 162 patients were randomized in a phase III study to the conventional drug combination (6 cycles of MAID: 60, 7,500, 900 mg/m(2) for doxorubicin, ifosfamide and dacarbazine respectively), or at doses 20-33% higher per cycle (5 cycles of intensified MAID for similar cumulative doses) with systematic G-CSF. Primary endpoint was response rate; secondary were toxicity, event-free and overall survival. The objective response rate in assessable patients was 38% with intensified MAID and 35% with MAID (p = 0.72). Event-free and overall survivals were similar in both arms. Only grade 3-4 thrombocytopenia and anemia were significantly higher in intensified arm. Treatment with intensified MAID did not improve response rate neither survival and cannot be recommended for advanced or metastatic soft tissue sarcoma.

[Epithelioid sarcoma: a retrospective study of conservative treatment with initial surgery and radiotherapy]. / Sarcomes épithélioïdes: étude rétrospective après chirurgie conservatrice et radiothérapie.

INTRODUCTION: Epithelioid sarcoma is a rare type of soft tissue sarcomas with a high risk of recurrence both local and distant. The place of surgical conservative treatment and the role of radiation therapy remain controversial. PATIENTS AND METHODS: A serie of 9 consecutive patients treated with initial conservative surgery and postoperative radiotherapy (median dose of 52.8 Gy) from 1987 to 2006 in the same institution was analyzed. RESULTS: With a median follow-up of 40 months (range 15-153 months), the rate of local, nodal and distant relapse is respectively 56%, 11% and 33%. The rate of death is 44.5%. No imputation has been performed. CONCLUSION: Even with a high rate of local relapse observed, a conservative treatment doesn't seem to influence badly the overall survival (55.5% alive at 40 months). Indeed the rate of distant relapse and death are comparable with those found in the literature. Moreover relapse occurred almost within the irradiated volumes. An improvement of dose could be also discussed.

[Soft tissue sarcomas: update on molecular data]. / Sarcomes des tissus mous: données moléculaires actuelles.

Soft tissue sarcomas are rare and may be a source of problems for diagnosis and treatment. Four types of genetic disorders can be distinguished: translocations, gene amplifications, mutations and complex genetic imbalances. Detection of these disorders may help in diagnosis and in determining prognosis. Detection of specific translocation is recommended in synovial sarcoma, alveolar rhabdomyosarcoma or PNET diagnosis because of therapeutic consequences; in case of rarer histologic type (low grade fibromyxoid sarcoma, clear cell sarcoma, infantile fibrosarcoma...), it may confirm the diagnosis. In some cases, some translocations have a prognostic value (alveolar rhabdomyosarcoma) whereas it is discussed in others (synovial sarcoma). The techniques used to detect these translocations are very sensitive so it may be used to detect microscopical metastasis (bone marrow metastasis of alveolar rhabdomyosarcoma for example). Detection of MDM2 and CDK4 genes amplifications (FISH or quantitative PCR) may be sometimes useful in well differentiated and dedifferentiated liposarcomas diagnosis. Mutation detection of KIT or PDGFRA may help in GIST diagnosis and type of mutation is predictive of response to treatment. Study of complex genomic imbalances in sarcomas is not used in routine practice but remains useful in research.

[Soft tissue sarcomas: current data in the field of pathology]. / Sarcomes des tissus mous: données anatomopathologiques actuelles.

Over the last fifteen years, pathology underwent significant changes in the field of soft tissue tumours. They were related to considerable advances in molecular biology and genetics. New data led to the revision of the WHO classification. Malignant fibrous histiocytoma is no longer considered as an entity. It has split up into several subgroups belonging to liposarcomas, leiomyosarcomas or undifferentiated sarcomas. Haemangiopericytoma underwent reappraisal and was put in the same category as solitary fibrous tumour. Many tools have improved. Immunohistochemistry performed with new antibodies had its specificity increased, and became appropriate for the prediction of therapeutic response in some cases, e.g. CD117 detecting mutations of the c-kit proto-oncogen in gastro-intestinal stromal tumours. Refinement of the techniques allows accurate diagnoses from core needle biopsies. Surgical specimens are collegially examined by surgeons and pathologists with special attention paid to resection margins. Although bound by some limitations, the grading system of the French Federation of Cancer Centers has currently remained the best predictor of metastasis-free survival and overall survival of patients. It is based on an assessment of three parameters: differentiation, amount of necrosis, and mitotic count of tumours. The pathologist sets up a diagnosis, and actively takes part in the prediction of the prognosis and therapeutic response. He is one of the major participants in decision making for multimodal treatment of sarcomas.

Long-term outcome of molecular subgroups of GIST patients treated with standard-dose imatinib in the BFR14 trial of the French Sarcoma Group.

BACKGROUND: The added value of tumoural genomic profiles to conventional clinico-biological factors to predict progression-free survival (PFS) and overall survival (OS) was prospectively investigated in patients with advanced gastrointestinal stromal tumours (GIST) treated in the BFR14 study. METHODS: Of the 434 included patients, mutational analysis was performed in 322 patients. Survival analysis was performed in patients with validated mutational status. RESULTS: Mutational status was validated in 228 patients. We identified 196 patients with tumours harbouring 200 KIT alterations (exon 11: 173 patients, exon 9: 22 patients, exon 17: 3 patients, exon 13: 2 patients; 4 patients had double KIT mutations), 6 patients with PDGFRA mutations and 26 patients with wild-type (WT) GIST genotype. On a median follow-up of 73 months, median PFS/OS were 12.3/54.9 months for WT GIST, 12.6/55 months for KIT exon 9, and 39.4 months/not reached (69.1% at 5 years) for KIT exon 11. Tumour size, female gender, KIT exon 11 mutations and CD34 positivity were independent prognostic factors for a higher PFS. A higher OS was predicted by performance status (PS) <2, low neutrophil and normal lymphocyte counts, KIT exon 11 mutations, non-advanced tumour and female gender. KIT exon 11 mutations at codons 557-558 showed better tumour response (p=0.028) but shorter PFS (p=0.0176). CONCLUSIONS: In GIST patients, presence of a KIT exon 11 mutation is an independent prognostic factor for PFS and OS, along with gender, PS, tumour size, lymphocyte and neutrophil counts. Subsets of exon 11 mutations are associated with significantly different response patterns and PFS.

Trabectedin in patients with advanced soft tissue sarcoma: a retrospective national analysis of the French Sarcoma Group.

AIM: The French Sarcoma Group performed this retrospective analysis of the 'RetrospectYon' database with data of patients with recurrent advanced soft tissue sarcoma (STS) treated with trabectedin 1.5 mg/m(2) as a 24-h infusion every three weeks. METHODS: Patients who achieved non-progressive disease after six initial cycles could receive long-term trabectedin treatment until disease progression. RESULTS: Overall, 885 patients from 25 French centres were included. Patients received a median of four trabectedin cycles (range: 1-28). The objective response rate was 17% (six complete/127 partial responses) and 50% (n = 403) of patients had stable disease for a disease control rate of 67%. After a median follow-up of 22.0 months, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 12.2 months, respectively. After six cycles, 227/304 patients with non-progressive disease received trabectedin until disease progression and obtained a significantly superior median PFS (11.7 versus 7.6 months, P<0.003) and OS (24.9 versus 16.9 months, P < 0.001) compared with those who stopped trabectedin treatment. Deaths and unscheduled hospitalisation attributed to drug-related events occurred in 0.5% and 9.4% of patients, respectively. CONCLUSION: The results of this real-life study demonstrate that treatment with trabectedin of patients with STS yielded comparable or improved efficacy outcomes versus those observed in clinical trials. A long-term treatment with trabectedin given until disease progression is associated with significantly improved PFS and OS.

Phase II trial of paclitaxel-epirubicin in patients with recurrent soft-tissue sarcoma.

Twenty-seven patients with recurrent soft-tissue sarcoma (STS) entered a multicenter study to determine the efficacy of the combination paclitaxel 200 mg/m and epirubicin 75 mg/m administered every 21 days. Patient characteristics included the following: 14 women and 13 men, median age of 52 years, 12 patients had local recurrence and 20 had metastasis. Eighteen patients had previously received chemotherapy for recurrent disease. The main grade III to IV hematologic toxicities were neutropenia (70%), anemia (3.7%), and thrombocytopenia (7.4%). Febrile neutropenia occurred in 5 patients (18.5%). Severe nonhematologic toxicities were rare. Two patients had a partial response (7.4%; 95% CI: 2.6-12.2%), with a median response duration of 3 and 5 months. Six patients had stable disease (22.2%), and 19 had progressive disease (70.5%). The median overall survival from study inclusion was 8 months. This study suggests the association paclitaxel-epirubicin does not increase the known activity of anthracycline in recurrent STS.

Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy.

PURPOSE: Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. PATIENTS AND METHODS: Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. RESULTS: A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). CONCLUSION: Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

Retroperitoneal liposarcomas: follow-up analysis of dedifferentiation after clinicopathologic reexamination of 86 liposarcomas and malignant fibrous histiocytomas.

BACKGROUND: Dedifferentiated liposarcoma (DDL) juxtapose components of well-differentiated liposarcoma (WDL) and nonlipogenic sarcoma. Malignant fibrous histiocytoma (MFH) is no longer considered a homogeneous entity, but rather as the common morphologic appearance of various subtypes of sarcomas. The objectives of the current retrospective study were: 1( to analyze the relation between DDLs and tumors previously diagnosed as MFHs; 2) to trace the evolution of liposarcomas, and 3) to assess the consequences of dedifferentiation. METHODS: Between 1974 and 2001, 86 patients with retroperitoneal liposarcoma (61 patients) or MFH (25 patients) underwent surgery at Institut Bergonie in Bordeaux, France. Histologic review was performed and tumors reclassified as WDL or DDL were retained for further clinicohistologic study. Subsequently, initial presentation and all recurrences were analyzed. RESULTS: The 61 liposarcomas consisted of 21 WDLs and 35 DDLs; 17 MFHs were reclassified as DDL. In all, approximately half of the retroperitoneal liposarcomas and MFHs were found to be DDLs. The DDLs presented with a smaller size (20 cm vs.30 cm; P = .05) but a lower rate of complete resection (72% vs.90%; P = .015) and remission (72% vs. 100%; P = .0015). Dedifferentiated recurrence was evidenced in 7 WDLs. Ten DDLs presented with metastatic evolution. DDLs demonstrated a tendency toward lower rates of 5-year overall survival (55% vs. 82%; P = .075). CONCLUSIONS: Most occurrences of retroperitoneal liposarcomas and MFHs are in fact DDLs and dedifferentiated recurrence of WDLs is frequent. Retroperitoneal DDLs present a lower rate of complete remission than WDLs and a risk of metastatic recurrence. Therefore, extensive histologic analysis of WDLs is required to identify an undifferentiated component and avoid misdiagnosis of DDL.

[Recommendations for the management of GIST patients]. / Recommandations pour la prise en charge des tumeurs stromales gastro-intestinales (GIST).

BACKGROUND: The management of gastrointestinal stromal tumors (GIST) has evolved very rapidly in the last years. A national consensus meeting was therefore organized in order to identify the optimal management procedures for patients with GIST in localized and advanced stages. METHODS: A panel of different specialties, including pathology, molecular biology, imaging, surgery, gastroenterology, medical oncology reviewed the current literature, in particular the recent Lugano conference, to identify consensus points and topics for future research in four different working groups: pathology and molecular biology, early management of small tumors and imaging, surgery, and medical treatment. Consensus points were categorized according to the Standard Options Recommendations (SOR) of the French Federation of Cancer Centers. RESULTS: The standard histological examination with immunohistochemical analysis using CD117, CD34, PS100, desmin and smooth muscle actin is considered standard. Molecular biology for the identification of KIT and PDGFRA mutation is advisable for GIST with negative CD117 staining, and otherwise is considered a research procedure. Complete tumor resection with negative tumor margins is the standard surgical treatment. Adjuvant imatinib after optimal tumor resection as well as neo-adjuvant imatinib remain experimental approaches to be performed within prospective clinical studies. Imatinib should be started at the date of diagnosis of metastatic relapse and given until development of intolerance or progressive disease. Resection of metastases is also considered as an experimental procedure which can not be recommended routinely. The criteria for tumor response to imatinib should include not only tumor size reduction or disease stabilization, but also reduction of tumor density (Hounsfield units) on computed tomography, metabolic activity (i.e. reduction of FDG uptake on positron emission tomography), and reduction of vascularisation of the tumors using contrast enhanced ultrasound evaluation. An increase in tumor size may be associated with pathologic response to imatinib therapy, and available survival data indicate that the survival of these patients is similar to that of patients with conventional tumor response. CONCLUSIONS: Consensus points in clinical management of GIST in this national conference adopted the majority of consensus points published in the Lugano conference. This multidisciplinary work will be published in the reference oncology, gastroenterology, and pathology journals in French languages.

Rhabdomyosarcoma: value of myogenin expression analysis and molecular testing in diagnosing the alveolar subtype: an analysis of 109 paraffin-embedded specimens.

BACKGROUND: Identification of the alveolar subtype of rhabdomyosarcoma (ARMS) is important, because the poor prognosis associated with this subtype necessitates a modified therapeutic regimen. At present, ARMS diagnoses are made on the basis of histologic findings and the extent of myogenin immunopositivity. Nonetheless, the absence of an alveolar pattern in the solid variant, the low degree of differentiation in certain embryonal rhabdomyosarcomas (ERMS), and the increasing use of microbiopsy samples make the diagnosis of ARMS somewhat difficult. Two specific translocations have been found in ARMS, and fusion transcripts can be detected by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of paraffin-embedded tissue (PET). METHODS: To assess the value of myogenin staining and molecular testing in the diagnosis of rhabdomyosarcoma, the authors examined 109 rhabdomyosarcoma samples (45 ARMS samples and 64 ERMS samples). Real-time RT-PCR analysis of PET was performed in all 109 rhabdomyosarcomas, and RT-PCR analysis of frozen material was performed in 24 cases. RESULTS: PAX fusion transcripts were present in 44 cases (39 ARMS and 5 ERMS) and absent in 52 cases (2 ARMS and 50 ERMS). In 13 cases (4 ARMS and 9 ERMS), the results were not interpretable. Results were concordant between paired frozen and fixed tumor samples. All 35 interpretable ERMS samples that contained < 50% myogenin-positive cells failed to yield detectable PAX fusion transcripts. Of the 61 interpretable tumor samples (41 ARMS and 20 ERMS) that contained > 50% myogenin-positive cells, 44 (39 ARMS and 5 ERMS) yielded detectable PAX fusion transcripts. CONCLUSIONS: The current study demonstrates that molecular detection of PAX fusion transcripts via real-time RT-PCR analysis of PET is a sensitive and specific method for the diagnosis of ARMS and that immunohistochemical analysis of myogenin expression can be used to select cases for such molecular testing. Although RT-PCR analysis appears not to possess diagnostic value in tumors with < 50% tumor cell immunopositivity, it is strongly recommended for the diagnosis of tumors containing > 50% myogenin-positive cells.

Most malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas: a review of 25 cases initially diagnosed as malignant fibrous histiocytoma.

Forty-four samples from 25 cases of retroperitoneal sarcoma initially diagnosed as malignant fibrous histiocytoma were histologically reviewed. Immunohistochemistry for mdm2 and cdk4 was performed on 20 cases. Comparative genomic hybridization was performed on 18 samples from 13 patients. Seventeen cases were reclassified as dedifferentiated liposarcoma. Twenty-one of 32 samples from these patients showed areas of well-differentiated liposarcoma, allowing the diagnosis of dedifferentiated liposarcoma. Immunohistochemistry performed in 15 of these cases showed positivity for mdm2 and cdk4. Comparative genomic hybridization analysis performed on 15 samples from 11 of these patients showed an amplification of the 12q13-15 region. Eight cases were reclassified as poorly differentiated sarcoma. Twelve samples from these patients showed no area of well-differentiated liposarcoma. Immunohistochemistry showed positivity for mdm2 and cdk4 in one of six of these patients and showed positivity for CD34 in another one. Comparative genomic hybridization analysis performed on three samples from two of these patients showed no amplification of the 12q13-15 region but showed complex profiles. This study shows that most so-called malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcoma and that a poorly differentiated sarcoma in this area should prompt extensive sampling to demonstrate a well-differentiated liposarcoma component, immunohistochemistry for mdm2 and cdk4, and if possible, a cytogenetic or a molecular biology analysis.