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Abstracts by Tom Swartz and Bruce Shriver
In this issue:
Heat Therapy Makes High-Risk Soft Tissue Sarcomas More Treatable Results released at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago on June 4, 2007 suggest that adding a little heat to chemotherapy may improve the treatment of soft tissue sarcomas. While not common in the United States, regional hyperthermia (RH) therapy, has been developed and tested in clinical trials, primarily in Europe. RH heat therapy exposes the body tissue in and around a tumor to high temperatures, as much as 113º Fahrenheit. Not only can such heat kill cancer cells directly, but phase II studies have shown that it appears to make some tumors more susceptible to the effects of chemotherapy, with minimal injury to normal tissue.
Beginning July 1997 researchers enrolled 341 soft tissue sarcoma patients in a phase III clinical trial from multiple centers in Europe. Eligible patients had one of three high-risk characteristics: their stage II or III primary tumors were larger than 2 inches; the patient’s previously treated disease had recurred; or the patient’s surgery did not remove all detectable disease. Patients were randomly assigned to one of two groups. In the first group, 172 patients were treated with a combination chemotherapy regimen consisting of etoposide (Lastet®), ifosfamide (Cyfos®), and doxorubicin (Adriamycin®). The second group of 169 patients received the same combination chemotherapy as well as periodic heat treatments to their tumors. After an initial 12-week round of such therapy, doctors treated some patients in both groups with surgery and/or radiation therapy, as appropriate to their condition. About 60 percent of patients in both groups had their tumors surgically removed, and about 60 percent received radiation treatment. Subsequently, those who could tolerate it received another 12-week round of their assigned experimental treatment: either chemotherapy alone or chemotherapy plus the heat treatment. The trial (known as the EORTC 6291/ESHO-RHT 95 Intergroup Study) was led by Rolf Issels, M.D., Ph.D., of the University of Munich in Germany, and supported by the European Organization for Research and Treatment of Cancer (EORTC) and the European Society for Hyperthermic Oncology (ESHO).
The results were as follows. After a median follow-up of nearly 25 months, patients receiving heat therapy did significantly better by nearly all measures. Their disease-free survival was 16 months, compared to 13 months for those on chemotherapy alone, a 35 percent reduction in risk. Partial and complete tumor responses were seen in 28.7 percent of heat therapy patients, compared to 12.6 percent for those receiving chemotherapy alone. Patients treated with heat therapy also went an average of 38 months before local progression of disease, compared to 26 months for chemotherapy alone, a 32 percent reduction in risk. Local progression was slower for patients whose tumors were in an arm or leg, but the advantage from heat therapy was about 18 percent, wherever the site of the cancer. The researchers provided no data at the ASCO meeting on any adverse effects from either the heat therapy or the chemotherapy.
The purpose of this phase II clinical trial was to study gemcitabine as a single agent as compared to the combination of gemcitabine and docetaxel in patients with metastatic soft tissue sarcoma. The investigators compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. The primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions.
The Results were as follows: One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999.
Thus, the investigators Conclude: Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.
Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin. Thus, the purpose of this randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity.
The Results were as follows: The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (i.e., no significant difference would be shown).
The investigators thus Conclude: Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma.
Docetaxel: A therapeutic option in the treatment of cutaneous angiosarcoma - Report of 9 Patients Effective treatment options are limited for patients with cutaneous angiosarcoma (AS). Docetaxel, a member of the taxane family of drugs, reportedly has been effective in the treatment of lung, head and neck, and breast cancers. Another taxane drug, paclitaxel, reportedly had unique activity in the treatment of AS of the scalp and neck and acquired immunodeficiency syndrome-related Kaposi sarcoma. Therefore, the authors of this study hypothesized that docetaxel may be of value in the treatment of cutaneous AS that is resistant to conventional therapy. However, there were only 3 case reports of the successful treatment of AS in elderly patients using docetaxel in combination with surgery and radiotherapy. This was a retrospective trial. After written informed consent was obtained, docetaxel was administered intravenously at a dose of 25 mg/m2 for 1 hour weekly over a period of 8 weeks on the basis of previous reports. This treatment regimen was received by 9 patients with cutaneous AS who were treated at Kobe University Hospital between January 2003 and October 2006.
The Results were as follows: Six of the 9 patients who received treatment achieved major responses, including 2 complete responses and 4 partial responses. Neutropenia and peripheral neuropathy were not prominent, although severe radiation dermatitis enhanced by the docetaxel was observed in 3 patients. There were no deaths attributable to this therapy.
The authors conclude: The current study demonstrated that docetaxel was effective in patients with cutaneous angiosarcoma.
Tumor Angiogenesis: Cause or Consequence of Cancer? Both tumors and normal tissues need a blood supply for oxygen, nutrients, and waste removal. However, whereas normal vasculature is hierarchically assembled into efficient networks of arteries, capillaries, and veins, the blood vessels of tumors are a mess—chaotic, leaky, inefficient, and barely making do. Why the difference? Do tumor vessels lack the signals to mature or is their maturation actively suppressed? What triggers and maintains tumor vasculature?
In this study, the investigators used a switchable Myc-driven mouse tumor model to address these fundamental questions. They identified the inflammatory cytokine interleukin-1B as an essential initiating trigger of vascular endothelial growth factor–dependent angiogenesis. Their article also considers how kinetic studies using regulatable forms of Myc or other oncogenes can shed new light on the way tumors initiate and maintain their aberrant blood supplies.
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase overexpressed in a variety of human malignancies, against which targeted therapies have shown efficacy in lung and brain tumors. Clinical responses to EGFR inhibitors have been found to be highly dependent on the presence of activating mutations, whereas gene amplification, downstream activation of Akt, and abnormalities in PTEN are also reported predictive factors. The investigators of this study sought to evaluate these variables in pediatric renal tumors. They screened a series of 307 pediatric renal tumors for EGFR expression by immunohistochemistry and gene amplification by chromogenic in situ hybridization. In identifying a striking predilection for certain tumor types, they further analyzed the clear cell sarcomas of the kidney (CCSK) for mutations in EGFR and PTEN.
The Results were as follows: Although only 23 of 177 (13.0%) nonanaplastic Wilms' tumors were EGFR positive, 4 of 11 (36.4%) anaplastic tumors showed receptor overexpression. In addition, 5 of 9 (55.6%) mesoblastic nephromas and 12 of 12 (100%) CCSKs were strongly immunoreactive for EGFR. In studying the CCSKs in more detail, they identified gene amplification in 1 of 12 (8.3%) cases and a somatic T790M EGFR mutation in a further case. These two samples additionally harbored mutations in PTEN. Downstream pathway activation, as assayed by phosphorylated Akt expression, was observed in 8 of 12 (66.7%) cases.
The Investigators Conclude: Together, these data show dysregulation of the EGFR pathway at multiple levels in CCSKs. Identification of factors predictive of poor response to targeted therapy, including the drug resistance T790M mutation, may provide a rationale for upfront trials with irreversible inhibitors of EGFR in children with these tumors.
Previous studies have suggested that trabectedin (ecteinascidin-743) could have antitumor activity in soft-tissue sarcoma. The investigators of this study sought to study the usefulness of trabectedin in the treatment of patients with myxoid liposarcomas, a subtype of liposarcoma that is associated with specific chromosomal translocations t(12;16)(q13;p11) or t(12;22)(q13;q12) that result in the formation of DDIT3-FUS or DDIT3-EWSR1 fusion proteins.
51 patients with advanced pretreated myxoid liposarcoma who started treatment with trabectedin between April 4, 2001, and Sept 18, 2006 at five institutions in a compassionate-use program were analyzed retrospectively. Centralized radiological and pathological reviews were done for most patients. Trabectedin was given either as a 24-hr continuous infusion or as a 3-h infusion, every 21 days, at 1·1–1·5 mg/m². 558 courses of trabectedin were given in total, with a median of ten courses for each patient (range 1–23). The primary endpoints were response rate and progression-free survival, and the secondary endpoint was overall survival.
The Findings were as follows: According to Response Evaluation Criteria in Solid Tumors (RECIST), after a median follow-up of 14·0 months (IQR 8·7–20·0), two patients had complete responses (CR) and 24 patients had partial responses (PR); the overall response was 51% (95% CI 36–65). Five patients had early progressive disease. In 17 of the 23 patients who achieved PR or CR as defined by RECIST and who had centralized radiological review, tissue-density changes, consisting of a decrease in tumor density on CT scan or a decrease in contrast enhancement on MRI (or both), preceded tumor shrinkage. Median progression-free survival was 14·0 months (13·1–21·0), and progression-free survival at 6 months was 88% (79–95).
The Investigators Conclude: Trabectedin was associated with antitumor activity in this series of patients with myxoid liposarcoma. The noted patterns of tumor response were such that tissue density changes occurred before tumor shrinkage in several patients. In some patients, tissue-density changes only were seen. Long-lasting tumor control was noted in responsive patients. The compassionate-use program is still ongoing. This analysis has resulted in the initiation of two prospective studies to assess the role of trabectedin in the treatment of patients with myxoid liposarcoma in preoperative and metastatic settings. Furthermore, the selective mechanism of action for trabectedin in this translocation-related sarcoma is being studied.
Delays in Cancer Diagnosis in Underinsured Young Adults and Older Adolescents In the U.S., adolescents and young adults diagnosed with cancer have had less survival improvement than older or younger patients, a deficit that may be a result of delays in diagnosis in an age group with the lowest rates of health insurance. In this study, the relationship between health insurance status and the time from the onset of first cancer-specific symptom or sign to definitive diagnosis (lagtime) was retrospectively compared with other sociodemographic factors in newly diagnosed cancer patients aged 15–29 years who were evaluated between June 2001 and June 2003. Data on 270 patients with the six most common cancer types in this cohort (leukemia, Hodgkin's and non-Hodgkin's lymphoma, sarcoma, brain tumors, thyroid cancer) were retrospectively collected in 2004.
The Results were as follows: Lagtimes were evaluable in 235 (88%) patients. In multivariate analysis, the type of cancer and health insurance were significantly associated with lagtime, whereas race/ethnicity, age, gender, marital status, and surrogate measures of socioeconomic status were not. The mean lagtime in patients with public or no health insurance was 13.1 weeks longer than in patients with private health insurance, and longer in four of six evaluable histology-specific types of cancer. In cancers evaluable for stage at diagnosis, advanced stage was associated with longer lagtimes.
The authors conclude: In the U.S., older adolescents and young adults with cancer are likely to have a delay in diagnosis because of inadequate health insurance and consequently present with a more advanced stage of disease.
August Research Corner #9
Osteosarcoma, the most common malignant primary bone tumor, typically occurs during the adolescent growth spurt. Germ-line genetic variation in genes critical in growth regulation could confer altered risk of osteosarcoma. In this study, Fifty-two common single nucleotide polymorphisms (SNP) in 13 genes were genotyped in a prospective case-control study of osteosarcoma (104 osteosarcoma cases and 74 orthopedic controls). Genotype data analyzed with contingency tables suggested the strongest association with insulin-like growth factor 2 receptor (IGF2R) SNPs. Additional SNPs were genotyped to capture IGF2R common haplotypes and resequencing was done across the IGF2R block associated with osteosarcoma risk. Percentage methylation was determined by pyrosequencing of the IGF2R variant allele located in a CpG island.
The Results were as follows: IGF2R Ex16+88G>A (rs998075) and IVS16+15C>T (rs998074) SNPs were associated with increased risk for osteosarcoma compared with orthopedic controls (haplotype odds ratio, 2.04; 95% confidence interval, 1.29-3.24). Follow-up genotyping showed that IGF2R IVS15+213C>T was also associated with increased osteosarcoma risk. Resequence analysis identified two additional SNPs linked to the risk-associated SNPs; linkage disequilibrium was strongest in a 1-kb pair region around them. The Ex16+88G>A SNP is located within a CpG island and alters methylation at that site.
The authors conclude: This pilot study of germ-line genetic variation in growth pathway genes and osteosarcoma identified a haplotype block in IGF2R associated with increased risk of osteosarcoma. The presence of a SNP in this block results in loss of methylation at a CpG island, providing corroborative evidence of a possible functional variant. Our analysis of the IGF2R haplotype structure will be applicable to future studies of IGF2R and disease risk.
Classification of liposarcoma into three biological types encompassing five subtypes, (a) well-differentiated/dedifferentiated, (b) myxoid/round cell, and (c) pleomorphic, based on morphologic features and cytogenetic aberrations, is widely accepted. However, diagnostic discordance remains even among expert sarcoma pathologists. The investigators of this study sought to develop a more systematic approach to liposarcoma classification based on gene expression analysis and to identify subtype-specific differentially expressed genes that may be involved in liposarcoma genesis/progression and serve as potential therapeutic targets. A classifier based on gene expression profiling was able to distinguish between liposarcoma subtypes, lipoma, and normal fat samples. A 142-gene predictor of tissue class was derived to automatically determine the class of an independent validation set of lipomatous samples and shows the feasibility of liposarcoma classification based entirely on gene expression monitoring. Differentially expressed genes for each liposarcoma subtype compared with normal fat were used to identify histology-specific candidate genes with an in-depth analysis of signaling pathways important to liposarcoma pathogenesis and progression in the well-differentiated/dedifferentiated subset. The activation of cell cycle and checkpoint pathways in well-differentiated/dedifferentiated liposarcoma provides several possible novel therapeutic strategies with MDM2 serving as a particularly promising target. The investigators show that Nutlin-3a, an antagonist of MDM2, preferentially induces apoptosis and growth arrest in dedifferentiated liposarcoma cells compared with normal adipocytes. They therefore conclude that these results support the development of a clinical trial with MDM2 antagonists for liposarcoma subtypes which overexpress MDM2 and show the promise of using this expression dataset for new drug discovery in liposarcoma.
EWS/FLI1 Regulates Tumor Angiogenesis in Ewing's Sarcoma via Suppression of Thrombospondins Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Thrombospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes. In this study, the authors investigated the role of thrombospondins in Ewing's sarcoma and their regulation by EWS/ETS fusion oncoproteins. They showed that the EWS/FLI1 fusion suppresses the expression of thrombospondins in both NIH3T3 fibroblasts and Ewing's sarcoma tumor–derived cell lines. This regulation depends on an intact EWS/FLI1 DNA-binding domain and may involve direct interactions between EWS/FLI1 and thrombospondin promoter regions. Forced expression of thrombospondins in Ewing's sarcoma cell lines inhibited the rate of tumor formation in vivo and markedly decreased the number of microvessels present in the tumors. The authors thus conclude that these findings suggest that thrombospondins play a biologically significant role in tumor vascularization in Ewing's sarcoma and suggest potential therapeutic strategies for future therapeutic intervention.
Trabectedin (ET-743): evaluation of its use in advanced soft-tissue sarcoma Trabectedin (ET-743; Yondelis®) is a novel DNA-binding agent, originally derived from the marine tunicate, Ecteinascidia turbinata, and now produced synthetically. The efficacy of trabectedin in patients with advanced soft-tissue sarcoma has been demonstrated in three Phase II studies involving 189 previously treated patients. This article is a pooled analysis of data from these studies. It shows that trabectedin induced tumor control (objective responses plus disease stabilization) in approximately 50% of patients; median overall survival was 10.3 months and progression-free survival at 6 months was 19.8%, with 29.3% of patients alive at 2 years. Responses were achieved in patients who were resistant to both doxorubicin and ifosfamide. The data also indicate that Trabectedin is generally well tolerated, with adverse events being noncumulative, reversible and manageable. Unlike other commonly used cytotoxic agents, trabectedin is not associated with cardiotoxicity or neurotoxicity and alopecia is rare. Trabectedin is an interesting new anticancer agent that offers much promise for the treatment of advanced soft-tissue sarcoma.
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