A. Cioffi

Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas

Data regarding the role of anthracyclines and taxanes as first‐line treatments of metastatic angiosarcoma are limited.

Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNST) are uncommon, biologically aggressive soft tissue sarcomas of neural origin that pose tremendous challenges to effective therapy. In 50% of cases, they occur in the context of neurofibromatosis type I, characterized by loss of function mutations to the tumor suppressor neurofibromin; the remainder arise sporadically or following radiation therapy. Prognosis is generally poor, with high rates of relapse following multimodality therapy in early disease, low response rates to cytotoxic chemotherapy in advanced disease, and propensity for rapid disease progression and high mortality. The last few years have seen an explosion in data surrounding the potential molecular drivers and targets for therapy above and beyond neurofibromin loss. These data span multiple nodes at various levels of cellular control, including major signal transduction pathways, angiogenesis, apoptosis, mitosis, and epigenetics. These include classical cancer-driving genetic aberrations such as TP53 and phosphatase and tensin homolog (PTEN) loss of function, and upregulation of mitogen-activated protein kinase (MAPK) and (mechanistic) target of rapamycin (TOR) pathways, as well as less ubiquitous molecular abnormalities involving inhibitors of apoptosis proteins, aurora kinases, and the Wingless/int (Wnt) signaling pathway. We review the current understanding of MPNST biology, current best practices of management, and recent research developments in this disease, with a view to informing future advancements in patient care.

Advanced chondrosarcomas: role of chemotherapy and survival

BACKGROUND There are limited data about the role of chemotherapy in patients with advanced chondrosarcomas. METHODS The medical charts of 180 patients with advanced chondrosarcomas having received chemotherapy in 15 participating institutions between 1988 and 2011 were reviewed. RESULTS Median age was 52 years. Sixty-three percent of patients had conventional chondrosarcoma and 88% had metastatic disease. Combination chemotherapy was delivered in 98 cases (54.5%). One hundred and thirty-one patients (73%) received an anthracycline-containing regimen. Using RECIST, the objective response rate was significantly different according to histological subtype, being 31% for mesenchymal chondrosarcoma, 20.5% for dedifferentiated chondrosarcoma, 11.5% for conventional chondrosarcoma and 0% for clear-cell chondrosarcoma (P = 0.04). Median progression-free survival (PFS) was 4.7 months [95% confidence interval (CI) 3-6.5]. Performance status (PS) ≥2, number of metastatic sites ≥1 and single-agent regimen were independently associated with poor PFS. Median overall survival (OS) was 18 months (95% CI 14.5-21.6). PS, number of metastatic sites and palliative surgery were independently associated with OS. CONCLUSIONS Conventional chemotherapy have very limited efficacy in patients with advanced chondrosarcoma, the highest benefit being observed in mesenchymal and dedifferentiated chondrosarcoma. These data should be used as a reference for response and outcome in the assessment of investigational drugs in advanced chondrosarcoma.

Advanced well-differentiated/dedifferentiated liposarcomas: role of chemotherapy and survival

BACKGROUND Data regarding the role of systemic therapy in patients with advanced well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) are limited. METHODS From 2000 to 2010, 208 patients with advanced WDLPS/DDLPS received chemotherapy in 11 participating institutions. Clinical and pathological data were collected by reviewing medical records. RESULTS Median age was 63 years (range 32-84). Combination chemotherapy was delivered in 85 cases (41%) and single agent in 123 cases (59%), respectively. One hundred and seventy-one patients (82%) received an anthracycline-containing regimen. Using RECIST, objective response was observed in 21 patients (12%), all treated with anthracyclines. Median progression-free survival (PFS) was 4.6 months [95% confidence interval (CI) 3.3-5.9]. On multivariate analysis, age and performance status (PS) were the sole factors significantly associated with poor PFS. Median overall survival (OS) was 15.2 months (95% CI 11.8 -18.7). On multivariate analysis, grade and PS were the sole factors significantly associated with OS. CONCLUSIONS Chemotherapy was associated with clinical benefit in 46% of patients with advanced WDLPS/DDLPS. OS remains poor, even though visceral metastatic disease is less frequent than in other sarcomas.

Tenosynovial giant cell tumour/pigmented villonodular synovitis: Outcome of 294 patients before the era of kinase inhibitors

BACKGROUND Tenosynovial giant cell tumour/pigmented villonodular synovitis (TGCT/PVNS) is a benign neoplasm of synovium and tendon sheath. We conducted a retrospective pooled analysis in three major referral centers. METHODS Patients treated between 1998 and 2008 were examined. Only patients presenting with primary disease or first relapse were included. 5-year local failure free survival (5-year-LFFS) was analysed. RESULTS 294 patients were included: 254 with new diagnosis and 40 in 1st local recurrence (171 F/123 M; median age: 36 years; tumour size ⩽2 cm in 27% of patients, >2 to ⩽5 cm in 41%, and >5 cm in 32%). A diffuse pattern was reported in 69%, localised in 31%. No metastases were documented. Local failure (LF) was reported in 28% of patients: 36% in diffuse pattern, 14% in localised (p = 0.002); median time to LF: 16 months. With a median follow-up of 4.4 years, 5-year-LFFS was 66%, with multiple (up to five) local recurrences in 40% of relapsed patients. Size <2 cm, macroscopically complete resection, female gender and new diagnosis were associated with a better local control. After multivariate analysis, a previous relapse was independently associated with local failure. CONCLUSIONS This study underlines the propensity of TGCT/PVNS to multiple local recurrences. In absence of clinical factors, biological studies are needed to identify prognostic factors of local failure. After a first local recurrence, surgery does not seem to have a curative potential. In these high risk patients, studies addressing the role of target therapies are needed.

Age-Stratified Risk of Unexpected Uterine Sarcoma Following Surgery for Presumed Benign Leiomyoma

BACKGROUND Estimates of unexpected uterine sarcoma following surgery for presumed benign leiomyoma that use age-stratification are lacking. PATIENTS AND METHODS A retrospective cohort of 2,075 patients that had undergone myomectomy was evaluated to determine the case incidence of unexpected uterine sarcoma. An aggregate risk estimate was generated using a meta-analysis of similar studies plus our data. Database-derived age distributions of the incidence rates of uterine sarcoma and uterine leiomyoma surgery were used to stratify risk by age. RESULTS Of 2,075 patients in our retrospective cohort, 6 were diagnosed with uterine sarcoma. Our meta-analysis revealed 8 studies from 1980 to 2014. Combined with our study, 18 cases of leiomyosarcoma are reported in 10,120 patients, for an aggregate risk of 1.78 per 1,000 (95% confidence interval [CI]: 1.1-2.8) or 1 in 562. Eight cases of other uterine sarcomas were reported in 6,889 patients, for an aggregate risk of 1.16 per 1,000 (95% CI: 0.5-4.9) or 1 in 861. The summation of these risks gives an overall risk of uterine sarcoma of 2.94 per 1,000 (95% CI: 1.8-4.1) or 1 in 340. After stratification by age, we predict the risk of uterine sarcoma to range from a peak of 10.1 cases per 1,000, or 1 in 98, for patients aged 75-79 years to <1 case per 500 for patients aged <30 years. CONCLUSION The risk of unexpected uterine sarcoma varies significantly across age groups. Our age-stratified predictive model should be incorporated to more accurately counsel patients and to assist in providing guidelines for the surgical technique for leiomyoma.

Angiosarcomas and Other Sarcomas of Endothelial Origin

Although benign hemangiomas are among the most common diagnoses among connective tissue tumors, angiosarcomas and other sarcomas arising from blood vessels are rare, even among sarcomas. Because endothelial tumors have unique embryonal derivation compared with other sarcomas, it is not surprising they have unique characteristics. Herein are reviewed some of these unique characteristics and therapeutic options for patients with some of these diagnoses, highlighting the potential of new agents for these tumors, which will in all likelihood also impact treatment on more common cancers.

1418PDLONG-TERM OUTCOME OF DASATINIB FIRST-LINE TREATMENT IN GASTROINTESTINAL STROMAL TUMORS: A MULTICENTER TWO STAGE PHASE II TRIAL SAKK 56/07

Background: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients (pts) with gastrointestinal stromal tumor (GIST), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of bcr-abl, kit and src-family kinases, and imatinib resistant cells, providing the rationale of this trial. Evaluation of GIST treated with TKIs is routinely done by computed tomography (CT). 18F-fluorodeoxyglucose positron-emission-tomography (FDG-PET) measures tumor metabolic activity for early response assessment and outcome prediction.

Abstract 5589: Age-stratified risk of unexpected uterine sarcoma following surgery for presumed benign leiomyoma

Background: Estimates of unexpected uterine sarcoma following surgery for presumed benign leiomyoma that utilize age-stratification are lacking. Patients and Methods: A retrospective cohort of 2075 patients that had undergone myomectomy was evaluated to determine the case incidence of unexpected uterine sarcoma. An aggregate risk estimate was generated using a meta-analysis of similar studies plus our cohort. Database-derived age distributions of the incidence rates of uterine sarcoma and uterine leiomyoma surgery were used to stratify risk by age. Results: Of 2075 patients in our cohort, six were diagnosed with uterine sarcoma. Our meta-analysis revealed 8 studies from 1980-2014. Combined with our cohort, there are 18 cases of leiomyosarcoma reported in 10120 patients, for an aggregate risk of 1.78 per 1000 [95% CI: 1.1-2.8], or 1 in 562. There are 8 cases of other uterine sarcomas reported in 6889 patients, for an aggregate risk of 1.16 per 1000 [95% CI: 0.5-4.9], or 1 in 861. The summation of these risks gives an overall risk of uterine sarcoma of 2.94 per 1000 [95% CI: 1.8-4.1], or 1 in 340. After stratification by age, we predict the risk of uterine sarcoma to range from a peak of 10.1 cases per 1000, or 1 in 98, for age 75-79 to less than 1 case per 500 for age Conclusion: The risk of unexpected uterine sarcoma varies significantly across age groups. Our age-stratified predictive model should be incorporated to more accurately counsel patients and to assist in providing guidelines for surgical technique for leiomyoma. Citation Format: Andrew S. Brohl, Li Li, Vaagn Andikyan, Angela Cioffi, Joel T. Dudley, Andrew Kasarskis, Robert G. Maki. Age-stratified risk of unexpected uterine sarcoma following surgery for presumed benign leiomyoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5589. doi:10.1158/1538-7445.AM2015-5589

The mechanistic target of rapamycin pathway in sarcomas: from biology to therapy

Introduction: The mechanistic target of rapamycin (mTOR) is a critical node at the junction of multiple intracellular signaling pathways. Amongst its many functions, mTOR instrumentally coordinates protein synthesis and cell growth in response to varying nutrient levels. The mTOR pathway has been implicated and targeted in several malignancies with modest success. Sarcomas are uncommon but diverse mesenchymal tumors for which systemic therapy is often suboptimal. Unsurprisingly, evidence is accumulating for the relevance of mTOR pathway activation across multiple sarcomas. Several clinical trials testing mTOR targeted therapy in sarcomas recently have yielded mixed results. Areas covered: The biology of the mTOR pathway and its relevance to the maintenance of the cancer phenotype shall be reviewed. The preclinical evidence for mTOR pathway activation in a range of sarcoma subtypes, the pharmacology of current and developing agents targeting mTOR, and results of completed clinical trials in sarcomas will also be discussed. In addition, potential reasons for suboptimal activity and avenues for maximizing therapeutic efficacy of targeting mTOR in sarcomas shall be evaluated. Expert opinion: While little doubt exists that mTOR activation has a role in sarcomagenesis, targeting this pathway with rapalogs has thus far yielded suboptimal results. Beyond the use of next-generation mTOR inhibitors to improve target inhibition, future efforts must focus on rational combinations and establishment of robust biomarkers to enhance therapeutic efficacy.