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Research Corner Abstracts by Tom Swartz and Bruce Shriver
In this issue: Short Telomeres: A Novel Potential Predictor of Relapse in Ewing Sarcoma Despite advances in therapy more than 50% of patients with Ewing’s sarcoma will relapse. The current prognostic factors are not optimal for risk prediction. Studies have shown that telomere length could predict outcome in different malignancies. The aim of this study was to evaluate whether telomere length could be a better prognostic factor in Ewing’s sarcoma and correlate the results with clinical variables, outcome, and chromosomal instability. Telomere length was determined in the primary tumor and peripheral blood of 32 patients with Ewing’s sarcoma. Chromosomal instability was evaluated by combining classical cytogenetics, comparative genomic hybridization and random aneuploidy. Telomere length was correlated to clinical variables, chromosomal instability, and outcome. The results were as follows: In 75% of the tumors, changes in telomere length, when compared with the corresponding peripheral blood lymphocytes, were noted. The majority of changes consisted of a reduction in telomere length. Patients harboring shorter telomeres had a significantly adverse outcome (P = 0.015). Chromosomal instability was identified in 65% of tumors, significantly correlating with short telomeres (P = 0.0094). Using multivariate analysis, telomere length remained the only significant prognostic variable (P = 0.034). Patients with short telomeres had a 5.3-fold risk of relapse as compared to those with unchanged or longer telomeres. Thus the authors conclude: that they have shown that tumors with telomere length reduction result in genomic instability. In addition, telomere length reduction was the only significant predictor of outcome. They suggest that reduction of telomere length in tumor cells at diagnosis could serve as a prognostic marker in Ewing’s sarcoma.
Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future In the era of oral molecular kinase inhibitors, cytotoxic chemotherapy agents are somewhat overlooked, but remain the backbone of treatment for most cancers. Patients with non–gastrointestinal stromal tumor sarcomas, such as leiomyosarcoma, liposarcoma, and undifferentiated high-grade pleomorphic sarcoma (formerly called malignant fibrous histiocytoma), have received doxorubicin and ifosfamide as the backbone of their treatment for over 15 years or more. The goal of this article is to review the data that have led to the use of gemcitabine and docetaxel as a useful combination for patients with metastatic sarcomas, and to comment on possible synergy of the combination. The literature regarding the use of gemcitabine, docetaxel, or both, is reviewed, with emphasis on patients with metastatic sarcoma. The author states that activity of gemcitabine and docetaxel is observed in leiomyosarcoma and undifferentiated high-grade pleomorphic sarcoma. There is apparent schedule dependence of the combination in other cancers; it is unclear if schedule matters in patients with sarcomas. The dose and schedule of gemcitabine and docetaxel examined in phase II studies are probably too high for routine practice. The author concludes that the combination of gemcitabine and docetaxel is an effective option for patients with metastatic sarcoma, increasing the armamentarium for the practicing oncologist in treating this heterogeneous group of diseases. Given the low response rate to docetaxel as a single agent, it is likely that there is true clinical synergy of the combination.
This phase II study was performed to determine the efficacy of irinotecan (IRN) in children with refractory solid tumors. Secondary objectives were to evaluate toxicity, pharmacokinetics, pharmacodynamics, and UGT1A1 genotype. A total of 181 patients were enrolled, of whom 171 were eligible. Patients received IRN 50 mg/m2/d for 5 days repeated every 3 weeks. Pharmacokinetic studies and UGT1A1 genotyping were performed. The results were as follows: Of 161 patients assessable for response, one patient with hepatoblastoma had a complete response, with partial responses observed in patients with medulloblastoma (n = 4), rhabdomyosarcoma (n = 1), neuroblastoma (n = 1), and germinoma (n = 1), for an overall response rate of 5%. Grade 4 neutropenia and grade 3 to 4 diarrhea occurred in less than 7% of the courses administered. Pharmacokinetic studies were available for 79 patients. The mean ± standard deviation IRN plasma clearance was 374 ± 148 mL/min/m2, with median relative extent of conversion and relative extent of glucuronidation of 0.05 (range, 0.01 to 0.25) and 2.24 (range, 0.39 to 9.6), respectively. No association between UGT1A1 genotype (n = 61) and toxicity or pharmacokinetic parameters was observed. The investigators conclude: IRN 50 mg/m2/d for 5 days every 21 days is well tolerated, but was not effective as a single agent in a spectrum of solid tumors, with the possible exception of patients with medulloblastoma (16% response rate). There was no association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.
Primary Malignant Sarcomas of the Heart and Great Vessels in Adult Patients — A Single-Center ExperienceSarcomas arising in the heart or the great vessels are rare entities. The prognosis of the patients is dismal. This retrospective study was conducted from the experience of the South West German Cancer Center. Between January 1993 and September 2006, of 1,429 patients registered to the Sarcoma Center, 14 had a primary sarcoma of the heart or large vessels. Tumors were located in the left ventricle (n = 3), left/right atrium (n = 2/3), pulmonary artery (n = 2), and ventricular septum, aorta, pericardium, and inferior vena cava (n = 1 each). The most frequently encountered histologic subtypes were leiomyosarcoma and angiosarcoma. Six patients presented with distant metastases to the lungs (n = 5), lymph nodes (n = 2), and liver (n = 1). Eight patients had localized disease. Six of them underwent resection with curative intent. Of those, two developed local recurrence within 2 and 10 months from surgery. Eleven patients received palliative chemotherapy, seven of those as initial treatment. Eight patients attained a response to treatment, two had disease stabilization for 6 and 12 months. After a median follow-up of 14.5 months (range, 2–156), three patients were alive with no evidence of disease 11, 52, and 156 months after diagnosis. Two patients were alive with disease and nine patients had died. The authors conclude: Patients with primary sarcomas of the heart and the large vessels were of a young age, and more than half of them presented with advanced disease. Given the promising response to chemotherapy, an optimized treatment approach including neoadjuvant chemo-/radiotherapy in patients with locally advanced disease should be pursued.
MRI and Biologic Behavior of Desmoid Tumors in Children
The outcome of desmoid
tumor in children cannot be reliably predicted on the basis of
histologic findings. The authors of this study sought to
determine whether the postoperative presence of residual or
recurrent tumor can be predicted on the basis of demographic
variables and baseline MRI features of the tumor. They also aimed
to determine how imaging features change during adjuvant treatment
and how the imaging features relate to the histologic features. Two
radiologists retrospectively reviewed images from 281 MRI
examinations performed at baseline and during postoperative
therapy for desmoid tumor. The examinations had been performed on
17 children treated between September 1991 and March 2003. Tumor
volume; distinctness of margins; involvement of bone and neurovascular
bundle; and T1-weighted, T2-weighted, and STIR signal intensity
and contrast enhancement pattern were recorded. Baseline imaging
and demographic features were correlated with the postoperative
presence of residual or recurrent tumor. Imaging changes during
follow-up were compared with treatment response and outcome.
The imaging features of eight tumors were compared with percentage
cellularity and collagen deposition in biopsy samples obtained
within 30 days of imaging. The results were as follows:
Baseline involvement of the neurovascular bundle approached significance
as a predictor of the presence of residual or recurrent tumor (p
= 0.08). Other baseline imaging and demographic features were
not predictive (p
Markers of angiogenesis and clinical features in patients with sarcoma The growth and dissemination of sarcomas depends on angiogenesis. A number of measurable markers related to tumor angiogenesis have been studied in patients with sarcoma. In this article, the available literature related to markers of angiogenesis and clinical features in patients with sarcoma was reviewed. Clinical features of interest included tumor size, tumor grade, tumor stage, presence of metastatic disease, and prognosis. In patients with soft-tissue sarcomas, tumor vascular endothelial growth factor (VEGF) expression correlates with stage, grade, and prognosis. Circulating VEGF levels also correlate with tumor grade. High circulating angiopoietin-2 levels are associated with increased tumor size in soft-tissue sarcoma. For patients with osteosarcoma, tumor VEGF expression correlates with outcome. Elevated tumor and circulating VEGF levels are associated with the development of lung metastases in osteosarcoma. Patients with Ewing sarcoma have increased circulating VEGF levels compared with controls. Angiogenesis markers correlate with important clinical features in patients with sarcomas ranging from soft-tissue sarcomas to bone sarcomas. Thus, the authors conclude that markers of angiogenesis may serve an important role in predicting a particular patient's clinical course and in identifying patients for possible antiangiogenic therapy.
The objective of this study was to assess the therapeutic importance of surgical castration, adjuvant hormonal treatment and lymphadenectomy in endometrial stromal sarcoma (ESS). A retrospective and multicentric search was performed. Clinicopathologic data were retrieved from cases that were confirmed to be ESS after central pathology review. The protocol was approved by the Ethical Committee. ESS was confirmed histopathologically in 34 women, but follow-up data were available in only 31 women. Surgical treatment (n=31) included hysterectomy with or without bilateral salpingo-oophorectomy (BSO) in 23 out of 31 (74%) and 8 out of 31 (26%) cases, respectively. Debulking surgery was performed in 6 out of 31 cases (19%). Stage distribution was as follows: 22 stage I, 4 stage III and 5 stage IV. Women with stage I disease recurred in 4 out of 22 (18%) cases. Among stage I women undergoing hormonal treatment with or without BSO, 3 out of 15 (20%) and 1 out of 7 (14%) relapsed, respectively. Among stages III-IV women receiving adjuvant hormonal treatment or not, 1 out of 5 (20%) and 3 out of 4 (75%) relapsed, respectively (differences=55.0%, 95% CI=-6.8-81.2%). Kaplan-Meier curves show comparable recurrence rates for stage I disease without adjuvant hormonal treatment when compared to stages III-IV disease treated with surgery and adjuvant hormonal treatment. Furthermore, women taking hormones at diagnosis had a better outcome when compared to women not taking hormonal treatment. Three out of 31 (9%) patients had a systematic lymphadenectomy whereas 3 out of 31 (9%) had a lymph node sampling. In one case, obvious nodal disease was encountered at presentation. Isolated retroperitoneal recurrence occurred in 1 out of 31 (3%) of all cases and in 1 out of 8 (13%) recurrences. This single woman later also developed lung and abdominal metastases. Leaving lymph nodes in situ does not appear to alter the clinical outcome of ESS. Although numbers are low, the retrospective data suggest that the need for surgical castration (BSO) in premenopausal women with early-stage disease should be discussed with the patient on an individual basis. Thus, the authors conclude that the data support the current practice in some centers to administer adjuvant hormonal treatment.
The objective of this study was to evaluate the efficacy and adverse events (AEs) of thalidomide in previously treated, measurable, persistent or recurrent leiomyosarcoma (LMS) of the uterus, and to explore associations between angiogenic markers and treatment or clinical outcome. Eligible, consenting patients were treated until disease progression or toxicity intervened with daily starting dose of 200 mg thalidomide/day that was increased by 200 mg every 2 weeks to a target dose of 1000 mg/day. End-points included progression-free survival (PFS) ≥ 6 months, toxicity, response, PFS and survival. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble endothelial protein C receptor (sEPCR) were evaluated in pre- and post-treatment serum and plasma. The results were as follows: Of 30 enrolled patients, one was ineligible (wrong histology). Median age was 56 years. Among 29 eligible patients, seven reached the target dose and only two received more than 4 cycles. Two patients (7%) experienced PFS ≥ 6 months. There were no objective responses, seven (24%) had stable disease, 19 (66%) progressed and 3 (10%) were not evaluable for response. Median PFS was 1.9 months and median overall survival was 8.3 months. Grade 4 AEs were not observed. The most common grade 3 AEs were neurologic (6), pulmonary (4) and constitutional (3). Treatment with thalidomide was associated with a significant decrease in plasma bFGF (p = 0.008) and serum sEPCR (p = 0.006), but not in plasma VEGF. Plasma VEGF was associated with increased risk of progression (hazard ratio [HR] = 3.5; 95% confidence interval (CI) = 1.5–7.8; p = 0.003) and death (HR = 4.7; 95% CI = 1.6–13.8; p = 0.005) after adjusting for GOG performance status. The investigators conclude: Thalidomide was not active in patients with uterine LMS and did not alter VEGF concentration. The association between pretreatment VEGF and prognosis in this population supports further evaluation of anti-angiogenic therapies in uterine LMS.
Ewing’s Sarcoma Family Tumors: Differences in Clinicopathological Characteristics At Presentation Between Localized And Metastatic TumorsDespite local treatment with systemic chemotherapy in Ewing’s sarcoma family tumors (ESFT), patients with detectable metastases at presentation have a markedly worse prognosis than those with apparently localized disease. The authors of this study investigated the clinical, pathological and laboratory differences in 888 patients with ESFT, 702 with localized disease and 186 with overt metastases at presentation, seen at their institution (Istituti Ortopedici Rizzoli, Italy) between 1983 and 2006. Multivariate analyses showed that location in the pelvis, a high level of serum lactic dehydrogenase, the presence of fever and a short interval between the onset of symptoms and diagnosis were indicative of metastatic disease. The rate of overt metastases at presentation was 10% without these four risk factors, 22.7% with one, 31.4% with two, and 50% for those with three or four factors. They authors conclude that in ESFT the site, the serum level of lactic dehydrogenase, fever, and the interval between the onset of symptoms and diagnosis are indicators of tumors having a particularly aggressive metastatic behavior.
Dolastatins are a group of structurally unique peptides originally isolated from a sea hare, Dolabella auricularia, which seem to inhibit tubulin polymerization and mitosis. In this study Tasidotin hydrochloride (tasidotin), a novel synthetic analogue of dolastatin 15, was evaluated in preclinical models of pediatric tumors. The cytotoxicity of tasidotin was evaluated in a panel of pediatric sarcoma cell lines in vitro and in vivo. Results: The IC50 in Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, and synovial sarcoma lines ranged from 0.002 µ to 0.32 µmol/L. In the SK-ES1 and RH30 cell lines, tasidotin induced a G2-M arrest that persisted for 48 h after the drug was washed from the cells. In vitro, more than half the cells were in the early or late phase of apoptosis 48 h after treatment with tasidotin. In vivo, a significant increase in apoptotic nuclei was apparent in xenograft tumors harvested within 24 h after a 5-day course of tasidotin. In vivo response was determined in severe combined immunodeficient xenograft models of pediatric sarcomas implanted heterotopically. Significant antitumor activity was observed in all tumor lines tested. A complete response was observed in 2 synovial sarcoma lines, 1 osteosarcoma line, 1 rhabdomyosarcoma line, and 1 Ewing's sarcoma line. A partial response was observed in 1 rhabdomyosarcoma and 1 Ewing's sarcoma. Conclusions: Tasidotin induces a G2-M block in treated cells ultimately resulting in apoptosis. Antitumor activity is confirmed in vivo in preclinical xenograft models of pediatric sarcomas.
Taurolidine: a novel anti-neoplastic agent induces apoptosis of osteosarcoma cell lines Taurolidine, the active agent of Taurolin®, is a broad spectrum anti-biotic that has been used for over 15 years for the treatment of severe surgical infections. Recently, taurolidine has been shown to possess anti-neoplastic properties in vitro and in vivo against a variety of cancers including ovarian, colon and prostate. In this study the investigators assessed the cytotoxic activity of taurolidine against human osteosarcoma (OS) cell lines and normal human bone cells. Treatment with taurolidine inhibited the growth of all ten osteosarcoma cell lines tested and taurolidine was equally potent against cell lines with and without distinct genetic defects (i.e. p53, Rb). Moreover, taurolidine-induced growth inhibition was found to be associated with a dose dependent increase in the number of apoptotic cells and apoptosis was shown to be caspase-dependent. Taurolidine treatment was also found to inhibit adhesion of OS cell lines. Compared to OS cell lines, normal bone cells in primary culture were found to be less sensitive to the cytotoxic and anti-adhesive effects of taurolidine. These data indicate that taurolidine possesses potent anti-neoplastic activity against osteosarcoma cell lines and may have potential as a novel OS chemotherapeutic agent.
V4N5 ESUN Copyright © 2007 Liddy Shriver Sarcoma Initiative.
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0.4).
Changes in imaging features were variable during follow-up.
T2-weighted and STIR signal intensity may be correlated with
percentage cellularity and collagen deposition. The authors conclude:
MRI has limited value in prediction of the postoperative presence
of residual or recurrent desmoid tumor in children. It is useful, however,
for detecting disease and monitoring postoperative adjuvant therapy.
