Sarcoma Trials Research Articles

Bayesian decision theoretic two‐stage design in phase II clinical trials with survival endpoint

In this paper, we consider two-stage designs with failure-time endpoints in single-arm phase II trials. We propose designs in which stopping rules are constructed by comparing the Bayes risk of stopping at stage I with the expected Bayes risk of continuing to stage II using both the observed data in stage I and the predicted survival data in stage II. Terminal decision rules are constructed by comparing the posterior expected loss of a rejection decision versus an acceptance decision. Simple threshold loss functions are applied to time-to-event data modeled either parametrically or nonparametrically, and the cost parameters in the loss structure are calibrated to obtain desired type I error and power. We ran simulation studies to evaluate design properties including types I and II errors, probability of early stopping, expected sample size, and expected trial duration and compared them with the Simon two-stage designs and a design, which is an extension of the Simon's designs with time-to-event endpoints. An example based on a recently conducted phase II sarcoma trial illustrates the method.

Abstract C153: Quantitative analysis of IGF-1R expression in FFPE human rhabdomyosarcoma tumor tissue by mass spectrometry.

Abstract The IGF-1R pathway is activated in many cancer types which has led to clinical development of many IGF1R targeted therapeutics. Multiple clinical trials targeting IGF1R are currently underway, however after initial optimism in NSCLC and Ewing's sarcoma, several trials have failed to show efficacy or had severe toxicity. Pretreatment quantitation of tumor IGF1R protein expression remains a challenge due to high homology between IGF1R and the insulin receptor. Thus, there is a need for a specific and quantitative clinical assay for IGF1R protein expression. The ability to quantify IGF1R expression and determine signaling pathway activation status directly in formalin-fixed paraffin-embedded (FFPE) patient tissue biopsies should help identify patients most likely to benefit from anti-IGF1R therapies. We have developed a quantitative IGF1R assay which can be performed directly in FFPE patient tissue. This approach is based on the Liquid Tissue®-SRM technology platform which enables relative and absolute quantification of proteins and their phosphorylation status directly in formalin fixed tissue. The IGF1R-specific SRM assay was preclinically validated on cell lines expressing a range of IGF1R protein. The expression levels of IGF1R in seven formalin fixed rhabdomyosarcoma (RMS) cell lines were measured by SRM mass spectrometry. We detected a range of IGF1R expression from 68 to 333 amol/ug for these cell lines, values that showed extremely high correlation with antibody based techniques. Analysis of FFPE human rhabdomyosarcoma xenograft explants demonstrates that variable levels of IGF1R expression can be measured accurately. In xenografts where treatment with a therapeutic IGF1R antibody caused tumor regression there was a concomitant loss of IGF1R expression. We have extended these studies by characterizing the expression of IGF1R in a clinical cohort of 25 RMS tumors. IGF1R was detected in 13/14 embryonal RMS tumors and all 11 syncytial RMS tumors. The range of expression in these tissues was 50–250 amol/ug of protein tissue. However, there was one tumor which expressed ∼4500 amol/ug of IGF1R and may represent a stable amplification, or mutation resulting in this extremely high level of IGF1R expression. Additional studies are underway to continue characterization of this tumor. These novel techniques for quantifying IGF1R protein expression in FFPE RMS tumor tissue may enhance our ability to select patients for IGF1R targeted therapy. We are extending this work in two ways. First we are initiating retrospective analysis of IGF1R levels in a sarcoma trial of an IGFR targeted therapy, and second, we are also preparing to use this assay for prospective analysis of FFPE sarcoma tissue in a future IGF1R targeted therapy trial. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C153.

Workshop Report on the European Bone Sarcoma Networking Meeting: Integration of Clinical Trials with Tumor Biology

A key workshop was held in The Netherlands in June 2011, hosted by several European bone sarcoma networks and with a broad range of stakeholders from Europe and Australia. The purpose of the meeting was to identify the strengths and weaknesses in current clinical trials for bone sarcomas and to make recommendations as to how to accelerate progress in this field. Two areas of particular interest were discussed. First, all participants agreed upon the importance of tumor biology to understanding clinical responses for all types of bone sarcoma. Various barriers to biobanking tumor and germline specimens were canvassed and are outlined in this paper. Second, there was consideration of the particular challenges of dealing with adolescent and young adult cancers, exemplified by bone sarcomas. Participants recommended greater engagement of both pediatric and adult sarcoma trial organizations to address this issue. Specific opportunities were identified to develop biological sub-studies within osteosarcoma, focused on understanding germ line risk and pharmacogenomics defining toxicity and biological responses. In Ewing sarcoma, it was harder to define opportunities for biological insights. There was agreement that the results for insulin-like growth factor pathway inhibition in Ewing family tumors were disappointing, but represented a clear indication of the need for companion biologic studies to develop predictive biomarkers. The meeting ended with broad commitment to working together to make progress in this rare but important subgroup of cancers.

Phase 1 clinical trials for sarcomas: the cutting edge

Few standard second-line treatment options exist for advanced sarcoma patients. Some of these patients are offered early-phase clinical trials involving targeted or nontargeted agents. This review outlines recent phase 1 trials involving sarcoma patients, explores current challenges and highlights future opportunities in sarcoma developmental therapeutics. New molecularly targeted phase 1 studies have demonstrated efficacy in sarcomas. For instance, insulin-like growth factor-1 receptor (IGF1R) antibodies have produced single agent activity in Ewing's sarcoma. Other promising novel agents include an agonist for the apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) for chondrosarcoma, small molecule inhibitor crizotinib for anaplastic lymphoma kinase (ALK)-rearranged inflammatory myofibroblastic tumor, cedarinib for alveolar soft part sarcoma, and rexin-G, a tumor targeted retrovector for osteosarcoma. In addition, different combinations of chemotherapy in combination with newer agents such as trabectedin exhibited efficacy in advanced soft tissue sarcoma. Patients with refractory sarcoma demonstrate benefit from treatment with targeted drugs even in the setting of phase 1 trials. Sarcomas that have a defined translocation and those that express specific activated kinases are particularly promising tumors for targeted therapy. The primary challenge is identifying the biomarkers predictive of response or resistance, matching them with specific patient histology, resulting in successful translation of biology into clinical benefit.

Approaches to Increasing Clinical Trial Access and Enrollment for Adolescents and Young Adults with Cancer.

Approaches to Increasing Clinical Trial Access and Enrollment for Adolescents and Young Adults with Cancer.

Pilot immunotherapy trial in high-risk pediatric sarcomas.

9541 Background: The prognosis for children and young adults with metastatic pediatric sarcomas remains poor. While many of these patients can achieve a complete response with intensive therapy, gr...

Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy (CT).

10005 Background: The mTOR signaling pathway is activated in most sarcomas. R, an oral mTOR inhibitor, demonstrated activity in phase I-II trials in advanced sarcomas following failure of prior CT. Methods: This trial is an international, double-blind study randomized 1:1 between R (40 mg orally for 5 days/week) vs. placebo (P) as maintenance therapy in pts with metastatic sarcoma (stratified soft-tissue vs bone; 1st vs, 2nd/3rd line prior CT) following stable disease or better response to prior CT. Primary endpoint is progression-free survival (PFS) based on independent radiological review (IRR). Secondary endpoints include overall survival (OS), best target lesion response, cancer-related symptoms, and safety and tolerability. Results: 711 pts were randomized from Jun ’07 to Jan ’10 and analyzed for efficacy. At data cut-off, 53 pts remained on blinded drug. Baseline characteristics were well balanced between the study arms. Analysis of 552 PFS events per IRR showed that R met the prespecified study endpoint with a statistically significant improvement in PFS compared to P (Hazard Ratio HR=0.72, P=0.0001, stratified log-rank). Median PFS improved by 21% (17.7 wks R vs. 14.6 wks P). Based on local site assessment of PFS, R demonstrated an improvement with HR=0.69 (P<0.0001) and a 52% gain in median (22.4 wks R vs. 14.7 wks P). PFS benefit was noted across all prespecified strata. Follow-up for OS is ongoing; results at data cut-off (313 OS events) indicate a trend favoring R (median OS: 88.0 wks R vs. 78.7 wks P; HR=0.92, 95% CI (0.74, 1.15)). While incidence of stomatitis (52%) and other adverse events was higher in pts receiving R, the overall safety profile was consistent with other mTOR inhibitors. Conclusions: This randomized trial of ridaforolimus met the primary endpoint of improved PFS in pts with metastatic soft-tissue or bone sarcomas to maintain benefit from prior standard CT. The rapid progression of metastatic sarcomas demonstrates the aggressive nature of these malignancies, and maintenance therapy with R will provide a new option for pts with this life-threatening disease.

What Should the Age Range Be for AYA Oncology?

What Should the Age Range Be for AYA Oncology?

Quality of Randomized Controlled Trials Reporting in the Treatment of Sarcomas

Randomized controlled trials (RCTs) represent the best evidence in oncology practice. The aim of this study was to assess the reporting quality of sarcoma RCTs and to identify significant predictors of quality. Two investigators searched MEDLINE for pediatric and adult bone and soft tissue sarcoma RCTs published between January 1988 and December 2008. The quality of each report was assessed by using a 15-point overall reporting quality score based on 15 items from the revised Consolidated Standards of Reporting Trials (CONSORT) statement (overall quality score [OQS] range, 0 to 15 points). Concealment of allocation, appropriate blinding, and analysis according to intention-to-treat principle were assessed separately because of their crucial methodologic importance by using a 3-point key methodologic index score (MIS; range, 0 to 3). We retrieved 72 relevant RCTs that included 16,029 patients. The median OQS was 9.5. Allocation concealment, blinding, and analysis by intent to treat were reported only in 21 (29%), nine (12.5%), and 23 (32%) of the 72 RCTs, respectively. The median MIS was 1 with a minimum of 0 and a maximum of 2. On multivariate analysis, publication after 1996 and high impact factor remained independent and significant predictors of improved OQS. The sole variable associated with improved MIS was the publication of chemotherapy-only trials. Although the overall quality of sarcoma RCTs reporting has improved over time, reporting of key methodologic issues remains poor. This may lead to biased interpretation of sarcoma trial results.

Treatment efficiency, outcome and surgical treatment problems in patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma: A report from the cooperative soft tissue sarcoma trial CWS‐96

To analyze the clinical course, treatment modalities, complications and outcome of patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma (BPRMS) treated on the CWS-96 trial. There were 85 patients with BPRMS enrolled and 63 patients with embryonal non-metastatic BPRMS were analyzed. Fifty-six patients received neoadjuvant chemotherapy and response was assessed radiographically after 9 weeks. Local therapy with radiation and or surgery was performed based on age, tumor size, and response. Patients were treated with adjuvant chemotherapy following local control. Patient's age ranged from 0 to 16 years with a median follow up of 5.3 years. Eighty nine percent of the patients had IRS group III disease. The 5-year overall survival (OS) for the whole group was 76.3 ± 5.6% and the 5-year event-free survival (EFS) 69.8 ± 6.2%. Seventeen patients underwent preoperative radiochemotherapy followed by tumor resection (5-year-OS: 87.8 ± 8.1%). Eight patients were treated with solely radiochemotherapy (87.5 ± 11.7%). Twenty-five patients received chemotherapy and tumor resection (OS: 83.6 ± 7.5%). Thirteen patients underwent incomplete tumor resection and were treated with radiochemotherapy postoperatively (OS: 39.9 ± 14.8%, P < 0.05 vs. other groups). Local therapy is an important factor for prognosis of localized embryonal BPRMS. Inadequate primary or secondary surgery compromises the outcome and should be avoided. Radiotherapy alone, complete surgical tumor resection or combined preoperative radiotherapy with surgical resection lead to similar good local control rates and prognosis.

Experimental Therapies and Clinical Trials in Bone Sarcoma

Sarcomas originating in the bone represent a challenge for physicians and patients. Because they constitute only 0.2% of all adult malignancies and 6% of pediatric malignancies, resources for studying this disease are often limited. Nonetheless, significant advancements have been made in the treatment of this disease, and there are ongoing efforts toward improvement. This article discusses recently completed and currently enrolling clinical trials for the 3 most common bone sarcomas: osteosarcoma, Ewing's sarcoma family tumors, and chondrosarcoma.

Effect of bortezomib on ER stress and killing of cisplatin-resistant U2OS osteosarcoma cell line.

9566 Background: Proteasome inhibitor bortezomib is a new class of antineoplastic agents. We believe that the conclusion from previous sarcoma trial that bortezomib was not effective in the treatment of sarcomas should not apply to osteosarcoma since the treatment arm including osteosarcoma was prematurely closed because of low accrual rate. We have previously reported that high level of MKP-1 was associated with cisplatin resistance in osteosarcoma cell lines. Since bortezomib has been reported to increase MKP-1 expression, we investigated the effect of bortezomib treatment on cisplatin sensitivity. Methods: U2OS and P16T osteosarcoma cell lines and mouse embryonic fibroblasts (MEFs) derived from target gene knockout (KO) mice of ATF-4, CHOP, IRE-1 and eIF2α and their paired wild type controls were used in this study. Results: Treatment with bortezomib indeed increased MKP-1 level in U2OS osteosarcoma cell line, but increase in cisplatin resistance was not observed, suggesting that increase in MKP-1 alone may not be adequate to induce cisplatin resistance. In contrast, concomitant exposure of U2OS cells to sub-therapeutic dose of bortezomib and therapeutic dose of cisplatin, which were both minimally cytotoxic when used alone, resulted in a striking increase in cytotoxicity, suggesting that bortezomib interacts synergistically with cisplatin in killing the osteosarcoma cells. Furthermore, bortezomib was more effective in killing cisplatin resistant U2OS than cisplatin sensitive P16T cells, and this increase in bortezomib sensitivity was in parallel with increased apoptosis and enhanced JNK activation in U2OS over P16T cells. While the most striking protective effect was observed in the CHOP K/O MEFs, which were almost completely protected from the bortezomib induced cell death, ATF-4 and IRE1a K/O also diminished the bortezomib cytotoxicity. In contrast, eIF2a K/O significantly enhanced the bortezomib lethality. Conclusions: The results support that bortezomib induced increase in ER stress indeed leads to increased cell death, and could be an effective novel agent in the treatment of cisplatin resistant osteosarcoma. No significant financial relationships to disclose.

Abstract 1655: Mechanism of the synergistic antiproliferative effect of gefitinib and interferon-alpha in sarcoma cell lines

Abstract A static 50% 5-year overall survival rate reflects inadequacy of currently available therapies and urgent need to develop treatment strategies for sarcoma. Single epidermal growth factor receptor (EGFR) inhibitor, gefitinib was reported in a phase II trial in synovial sarcoma with a low response rate and short sustained time. Identification of combinations with both a higher proportion of responders and potentially more sustained benefit is needed. One potential partner is interferon-alpha. We have shown in vitro that cell growth signals such as those from an activated EGFR increases resistance to interferon-alpha, and the combination of EGFR inhibitor and interferon-alpha has synergistic antitumor effect in some colon and bladder cancer cell lines. A recent phase II trial of gefitinib and pegylated interferon alfa 2b in previously-treated renal cell carcinoma has demonstrated significant and prolonged disease control benefit with acceptable toxicity. However the effect of the combination therapy in sarcoma is unreported. This study aimed to investigate the effect and mechanisms of this combination therapy in human sarcoma cell lines. Combination treatment using gefitinib and interferon-alpha was investigated in a panel of sarcoma cell lines (6 soft tissue sarcomas (STS) and 3 osteosarcomas (OS)) with synergy analysis based on the Chou-Talalay combination index. Mechanism studies examined a pair of synergistic and antagonistic liposarcoma cell lines using multiple techniques. All 9 cell lines expressed wild-type and/or activated EGFR and interferon-alpha receptors but no EGFR gene mutation was identified. Combination treatment of EGFR inhibition and interferon-alpha achieved synergistic antiproliferative effect (combination index (CI) &amp;lt;1 = synergism) in 6/9 sarcoma cell lines (CI for STS: GCT 0.1-0.3, SW684 0.3-0.7, and 778 0.1-0.7; for OS: MG63 0.3-0.7, U2OS 0.3-0.7, and SJSA 0.1-0.3), accompanied by apoptotic and necrotic cell death. The drug reduction index (DRI) at IC50 measures how much the dose of each drug may be reduced when drugs were combined at the IC50 effect level compared with the dose of drug alone. For the most synergistic GCT cell line, the DRI for gefitinib and interferon-alpha was 4.7 and &amp;gt;100. Characterisation of interferon-alpha and EGFR signaling interaction by both pathway inhibition and western blot detection of downstream factor expression discovered that interferon-alpha enhances gefitinib through affecting the ratio of the signal transducer and activator of transcription (STAT) family members (STAT1 up, STAT3 down) to favour tumor cell death. The activated Akt enhanced by interferon-alpha alone was significantly down regulated by combination therapy. EGFR inhibition combined with interferon-alpha is a worthwhile treatment to pursue in anti-sarcoma therapy. These results provide a rationale for the clinical evaluation of this treatment strategy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1655.

Abstract A185: Phase I clinical, pharmacokinetic, and pharmacodynamic study of SB939, an oral histone deacetylase inhibitor (HDACi), in patients with advanced solid tumors

Abstract Background: SB939 is an orally available, potent, competitive HDACi selective for Class I, II and IV histone deacetylases. Preclinical evaluation of SB939 in a broad spectrum of xenograft mouse models revealed dose-dependent tumor growth inhibition. In the HCT116 colorectal cancer model, SB939 showed superior activity compared to other HDACi and prolonged histone H3 acetylation (acH3) in tumor tissues lasting ≥ 24 hours. Methods: Patients (pts) with advanced solid malignancies were enrolled into 7 dose levels (DL). At DL1, SB939 was taken on days 1-3 and 15-17 every 4 weeks, then on days 1-5 and 15-19 for other DLs. Detailed PK sampling was performed on cycle 1 days 1 and 5 (for DL1 on days 1 and 3). Peripheral blood mononuclear cells (PBMC) were collected on cycle 1 at various time points for determination of acH3 levels using a validated Western blot assay. MTD was defined as dose with ≥ 2/3–6 pt with DLT. Results: To date, 28 pts have received a total of 72 cycles: median age 62 (range 48–88); F:M = 10:18; ECOG 0:1:2 = 7;17:4; tumor types = colorectal (15), neuroendocrine (3), gastric (2), lung (2) and others (6); prior chemotherapy regimens 0:1:2:3+ = 5:1:6:16. The most frequent non-hematologic adverse events (AE) of at least possible attribution to SB939 were (% of pts with all grade/gr 3+): fatigue (46%/7%), nausea (29%/0%), anorexia (21%/4%), vomiting (18%/4%) and diarrhea (11%/0%). Hematologic AE were all mild to moderate. DLT occurrence is described below, with the 90 mg DL declared MTD. PK analysis showed dose-proportional increases in AUC and Cmax. Elimination half-life is 6–9 hours. PBMC analysis for acH3 (lysine9/14) showed highest levels at 3 hours post-dose with return to baseline by 24 hours. The average relative acH3 levels at 70 mg dose level in this study are comparable to those obtained at 60 mg dose level in another phase I study of SB939, which evaluates a different schedule of thrice weekly (every other day) for 3 out of 4 weeks. Four pts (14%) received 4 or more 4-week cycles of SB939 (range 6–10). Conclusions: SB939 is well tolerated at up to 70 mg on this schedule of 5 consecutive days every 2 weeks. The 70 mg DL is being expanded and will likely be the RP2D. Phase II trials in prostate cancer and sarcoma are planned. Dose level Schedule Total no of cycles No of pts with DLT/Total no of pts DLT Other significant toxicity 10 3 days 6 0/3 - - Q2W 10 5 days 16 1/6^ - - Q2W 20 5 days 18 1/6 Gr 3 - Q2W myositis 30 5 days 19 0/4 - - Q2W 50 5 days 6 0/4 - - Q2W 70 5 days 5 0/3 - - Q2W 90 5 days 2 1/2* Gr 3 2 gr 2 N/V Q2W fatigue 1 gr 2 QTc ^ gr 3 bilirubin rise subsequently declared not drug related * neither pt completed a full cycle Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A185.

Soft Tissue Sarcoma Trials: One Size No Longer Fits All

Soft Tissue Sarcoma Trials: One Size No Longer Fits All

Does the time‐point of relapse influence outcome in pediatric rhabdomyosarcomas?

Childhood rhabdomyosarcoma (RMS), a soft tissue malignant tumor of skeletal muscle origin, accounts for approximately 3.5% of the cases of cancer among children 0-14 years and 2% of the cases among adolescents and young adults 15-19 years of age. We evaluated survival (SUR) after first relapse depending on the time to relapse (TTR) in RMSs of childhood and adolescence. Early, intermediate, and late relapsing patients were evaluated for prognostic risk factors. Two hundred thirty-four patients with RMS enrolled in the German sarcoma trial CWS-81, CWS-86, CWS-91, and CWS-96 met selection criteria. Of the 234 patients, 35%, 32%, and 33% relapsed within 6 (early), 6-12 (intermediate), and more than 12 (late) months respectively after the end of primary therapy. Four-year SUR was 12%, 21%, and 41% for early, intermediate, and late relapse respectively (P < 0.001). Four-year SUR after local relapse was 18% (early), 38% (intermediate), and 49% (late). Embryonal RMS showed four year SUR of 16%, 30%, and 46% (P < 0.001) whereas alveolar histology showed four year SUR of 8%, 6%, and 23% (P < 0.01) for early, intermediate, and late relapse respectively. TTR has significant influence on prognosis in relapsed RMS. It influences SUR independent of other features such as type of relapse, histology, tumor site, primary treatment time or irradiation in primary treatment.

Chemotherapy in adult soft tissue sarcoma

Soft tissue sarcomas (STSs) are rare and histologically diverse neoplasms. Recent results of various meta-analyses and development of newer drugs have changed the medical management of soft tissue sarcoma. This review gives an outline of chemotherapy and the newer targeted therapies for the same. We have carried out an extensive search in PubMed, Medline for almost all relevant articles concerning chemotherapy of soft tissue sarcoma. The available data from the literature is mainly composed of the most recent reviews, meta-analyses, phase II, and randomized phase III trials published in various peer reviewed journals and various international conferences. The role of neoadjuvant and adjuvant chemotherapy has been found to be controversial. The recent meta-analysis for adjuvant therapy in STSs has shown an increase in the overall survival with combination of ifosfamide and adriamycin. In locally advanced and metastatic STSs, single agent adriamycin remains the basic standard of medication. The combination of ifosfamide and adriamycin may also be used for rapid symptom relief and in patients planned for curative resection for metastases. Newer combinations of docetaxel and gemcitabine appear promising in selected subgroups, especially in leiomyosarcoma and malignant fibrous histiocytoma. Some recent developments include the European Union's approval of trabectedin for advanced STSs patients who had progressed on adriamycin and ifosfamide therapy. The future of mTOR inhibitors, insulin like growth factor receptor inhibitors and anti-angiogenic drugs appear quite promising. Newer methodologies such as, Bayesian adaptive randomization and inclusion of newer end points like progression-free rate, time of progression rate, and tumor growth rate will improve the results of sarcoma trials. At the end of each section we have also presented recommendations from FNx01European Society of Medical Oncology and FNx08National Comprehensive Cancer Network guidelines v.1.2009 for better correlation with the present literature.

Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: An European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874)

The management of uterine sarcomas continues to present many difficulties. Primary surgery is the optimal treatment but the role of post-operative radiation remains uncertain. In the mid-1980s, the European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study proposed a trial to evaluate adjuvant radiotherapy, as previous non-randomised studies had suggested a survival advantage and improved local control when post-operative radiation was administered. The study opened in 1987 taking 13 years to accrue 224 patients. All uterine sarcoma subtypes were permitted. Patients were required to have undergone as a minimum, TAH and BSO and wahsings (166 patients) but nodal sampling was optional. There were 103 leiomyosarcomas (LMS), 91 carcinosarcomas (CS) and 28 endometrial stromal sarcomas (ESS). Patients were randomised to either observation or pelvic radiation, 51Gy in 28 fractions over 5 weeks. Hundred and twelve were recruited to each arm. The initial analysis has shown a reduction in local relapse (14 versus 24, p=0.004) but no effect on either OS or PFS. No unexpected toxicity was seen in the radiation arm. No difference in either overall or disease-free survival was demonstrated but there is an increased local control for the CS patients receiving radiation but without any benefit for LMS. Prognostic factor analysis shows that stage, age and histological subtype were important predictors of behaviour which may explain differences between CS and LMS. CS appears to show more kinship to poorly differentiated endometrial carcinomas in behaviour. LMS did not show the same benefit from radiation. These results will help shape future management and clinical trials in uterine sarcomas.

Other Endpoints in Screening Studies for Soft Tissue Sarcomas

Despite extensive research efforts over the past two decades to identify effective agents for the treatment of soft tissue sarcomas, few agents are available, and with modest utility. There is a high unmet medical need to develop novel therapies for the treatment of patients with soft tissue sarcomas. Clinical trials for soft tissue sarcomas should be optimally designed, and it is crucial that they identify and define the desired clinical outcome. Survival is often the ultimate endpoint; however, physiological and biological markers are often used to predict the potential therapeutic benefit of a new agent. These endpoints can be easily measured, but can lead to false-positive results and do not take into account the complicated nature of soft tissue sarcomas. Alternative endpoints that are currently being evaluated include the progression-free survival rate, time to progression, tumor growth rate, and progression arrest rate. This article discusses some of the limitations of current endpoint criteria and potential endpoint criteria that could be used to evaluate treatment options for patients with soft tissue sarcomas.

Induction of the Human Heat Shock Promoter HSP70B by Nutritional Stress: Implications for Cancer Gene Therapy

Background: We designed and tested, in vitro, an adenoviral construct containing the feline interleukin-12 (IL-12) gene under control of the heat-inducible promoter HSP70B. This construct, AdhspfIL12, was used in a phase I trial in feline soft tissue sarcomas. During the course of our experiments, we noted that IL-12 was being produced in the transfected Crandell Feline Kidney (CrFK) cells under certain conditions even in the absence of hyperthermia. This observation was further explored to identify the cause of this unintended HSP70B induction. Materials and Methods: We used real-time PCR as a sensitive method to quantitatively detect the presence of even small amounts of IL-12 mRNA. This served as a surrogate indicator of HSP70B induction. Various conditions were tested to induce the heat shock promoter, including nutritional deprivation, radiation and changes in pH. Results: Nutritional stresses, specifically the absence of glucose and glutamine, could induce the heat shock promoter, thus, resulting in production of the downstream gene product. Other factors known to trigger the heat shock response, pH change, and reactive oxygen species production were also studied but were not found to contribute to heat shock promoter induction in our setting. Conclusions: The human heat shock promoter (HSP70B) is reported to be an efficient and tightly regulated promoter. We discovered, using sensitive real-time PCR techniques, that it can also be induced in response to cellular nutrient stresses. The pros and cons of this phenomenon and its implications for cancer gene therapy are discussed.