Soft Tissue Sarcoma Group Research Articles

Outcome of First-Line Treatment of Elderly Advanced Soft Tissue Sarcoma (Sts) Patients: a Pooled Analysis of Eleven Eortc Soft Tissue and Bone Sarcoma Group Trials

ABSTRACT Aim: Half of patients (pts) diagnosed with STS are older than 65 years, yet little data is available on survival of elderly pts with metastatic disease receiving standard chemotherapy. We therefore investigated the outcome of STS pts, treated with standard chemotherapy within EORTC trials. Methods: Pts who had an indication for systemic treatment because of locally unresectable or metastatic disease were evaluated. The EORTC database contains information on 2636 pts who did not receive prior chemotherapy and who were treated with doxorubicin (DOX), epirubicin (EPI), ifosfamide (IFO) or a combination of doxorubicin and ifosfamide (DOX-IFO) in the context of 11 EORTC advanced STS clinical trials. Of these, 274 pts were older than 65 years. The end points of interest for this analysis are overall survival (OS), progression free survival (PFS) and response rate (RR). Results: 274 pts were eligible. Median age of the elderly pts was 68 years (IQR 67-70), with a maximum of 80 years. Almost half (49%) had performance status (PS) 1, 12% had PS of 2 or more; 27% had histological grade 3. The most frequently reported histology was leiomyosarcoma (LMS) (39%). For 48% of pts disease involved the primary site of origin, 47% had lung metastases, 19% liver metastases, 8% bone metastases and 26% had lesions of other origin. 91 (33%) pts were treated with DOX, 43 (16%) with EPI, 26 (9%) with IFO and 114 (42%) with DOX-IFO. Median OS of the elderly pts was 9.8 months(mo) (95% CI: 6.2-11.9) for DOX, 9.9 mo (95% CI: 5.9-11.8) for EPI, 9.7 mo (95% CI: 2.9-14.4) for IFO, 12 mo (95% CI: 6.6-14.9) for DOX-IFO. Median PFS was 2.8 mo (95% CI: 2.0-4.0) for DOX, 3.8 mo (95% CI 1.4-6.2) for EPI, 2.2 mo (95% CI: 1.4-3.8) for IFO and 5.2 mo (95% CI: 3.1-6.4) for DOX-IFO. 42 (15.4%) pts achieved a response (complete or partial). In comparison, median OS of the 2363 pts aged less than 65 (median 49 years, IQR 37-57) was 11.5 mo (95% CI: 10.3-12.4), 11.2 mo (95% CI: 9.3-12.2), 11.1 mo (95% CI: 10.2-12.6) and 13.2 mo (95% CI: 12.4-14.2), respectively. Median PFS was 3.5 mo (95% CI: 3.1-4.1), 2.9 mo (95% CI: 2.3-3.4), 2.8 mo (95% CI: 2.4-3.1) and 6.2 mo (95% CI: 5.6-6.6) respectively. Conclusions: The outcome of elderly pts is slightly worse. New strategies for elderly pts with advanced STS are urgently needed. These results can be used as benchmarks for developing new trials in this age group. Disclosure: All authors have declared no conflicts of interest.

This Month in Pediatric Urology

No AccessJournal of UrologyThis Month in Pediatric Urology1 Sep 2014This Month in Pediatric Urology Laurence S. Baskin Laurence S. BaskinLaurence S. Baskin More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.06.033AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "This Month in Pediatric Urology." The Journal of Urology, 192(3), pp. 632–633 References 1 : Resource utilization and costs associated with the diagnostic evaluation of nonrefluxing primary hydronephrosis in infants. J Urol2014; 192: 919. Link, Google Scholar 2 : Evaluation of prenatal hydronephrosis: novel criteria for predicting vesicoureteral reflux on ultrasonography. J Urol2014; 192: 914. Link, Google Scholar 3 : Evaluation of a mobile voiding diary for pediatric patients with voiding dysfunction: a prospective comparative study. J Urol2014; 192: 908. Link, Google Scholar 4 : Impact of hemiscrotectomy on outcome of patients with embryonal paratesticular rhabdomyosarcoma: results from the Cooperative Soft Tissue Sarcoma Group Studies CWS-86, 91, 96 and 2002P. J Urol2014; 192: 902. Link, Google Scholar © 2014 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 192Issue 3September 2014Page: 632-633 Advertisement Copyright & Permissions© 2014 by American Urological Association Education and Research, Inc.MetricsAuthor Information Laurence S. Baskin More articles by this author Expand All Advertisement PDF DownloadLoading ...

Vincristine, dactinomycin, cyclophosphamide (VAC) versus VAC/V plus irinotecan (VI) for intermediate-risk rhabdomyosarcoma (IRRMS): A report from the Children’s Oncology Group Soft Tissue Sarcoma Committee.

10004 Background: The long-term event free survival (EFS) for IRRMS is 65%. Since VI had significant activity in metastatic and recurrent RMS, we tested whether adding VI to VAC would improve EFS for IRRMS. Methods: Patients (pts) with alveolar (A)RMS or incompletely resected (Group III) embryonal (E)RMS arising in an unfavorable primary site (Stage 2/3), both without distant metastases, < 50 years, and adequate organ function were eligible to be randomized to 42 weeks of VAC (V=1.5 mg/m2, A=0.045 mg/kg, C=1.2 g/m2 every 3 weeks) vs VAC/VI (I=50 mg/m2/day x 5 days) intravenously; doses were adjusted for children < 3 years; radiation therapy (36-50.4 Gy) was started at week 4, with individualized local control for children < 2 years allowed. The primary study endpoint was EFS. The study was designed with 80% power (5% 1-sided alpha level) to detect an increase in 5 yr EFS from 65% to 76%, a relative risk of 0.64. Results: 481 pts were entered between 12/2006-12/2012, with 461 confirmed eligible. Clinical f...

‘Beware the lump in the foot!’: predictors of recurrence and survival in bone and soft‐tissue sarcomas of the foot and ankle

Although benign lumps around the foot and ankle are common, sarcomas in this area are frequently missed, and the consequences can be disastrous. Patients are often referred to tumour centres after suboptimal prior surgical excision. The predictors of local recurrence, metastasis and survival in this cohort have yet to be elucidated. We performed a retrospective review of 61 consecutive patients that were surgically treated for a bone (BS) or soft-tissue sarcoma (STS) of the foot and ankle between 1996 and 2012 at a specialist tumour centre. Factors such as tumour versus non-tumour centre surgery and BS versus STS were examined. Univariate and multivariate analyses were performed to determine which factors predicted local recurrence, metastasis and survival. The overall 5-year survival rates were 74% in the STS group and 90% in the BS group. Furthermore, 33 (54%) patients had STS. Non-tumour centre surgery was performed in 23 (38%) patients. Overall local recurrence rate was 6.6%. Intra-lesional margins predicted a local recurrence, whereas non-tumour centre surgery was a predictor for developing a metastasis post-treatment. Tumour size, STS, radical margins (i.e. entire anatomical compartment removed with tumour) and metastasis, either at the time of referral or post-treatment, were associated with higher mortality. STSs of the foot and ankle appear to have a worse prognosis than BSs. Early referral to a specialist tumour centre before surgical intervention is recommended.

Impact of Hemiscrotectomy on Outcome of Patients with Embryonal Paratesticular Rhabdomyosarcoma: Results from the Cooperative Soft Tissue Sarcoma Group Studies CWS-86, 91, 96 and 2002P

Children with paratesticular rhabdomyosarcoma have a favorable prognosis. Surgical treatment problems include inadequate primary transscrotal approaches, incomplete tumor resections and the need for secondary hemiscrotectomy. We evaluated the need for hemiscrotectomy regarding local relapse and outcome. A total of 173 patients with a diagnosis of paratesticular rhabdomyosarcoma were enrolled in the Cooperative Soft Tissue Sarcoma Studies between 1986 and 2008. Of the patients 17 were excluded due to an incomplete data set and alveolar histology. Thus, a total of 156 patients with embryonal subtype were analyzed. All patients were treated according to study protocols, which included multiagent chemotherapy, tumor resection and/or radiotherapy. Mean ± SD 5-year overall survival rate was 91.5% ± 2.4% for patients with embryonal rhabdomyosarcoma. A total of 28 patients underwent transscrotal approaches initially. Of these patients 12 were treated with hemiscrotectomy (mean ± SD 5-year event-free survival 91.7% ± 8%) and 16 without hemiscrotectomy (93.8% ± 6.1%). Additionally 13 of 156 patients underwent an inguinal approach with hemiscrotectomy due to suspicious tumor infiltration of the scrotal skin (mean ± SD 5-year event-free survival 84.6% ± 10%). Relapse was observed in 3 of 12 patients after transscrotal approach with hemiscrotectomy (locoregional lymph node in 1 and metastasis in 2). One metastatic relapse was observed in the group undergoing a transscrotal approach without hemiscrotectomy. One of 13 patients treated with an inguinal approach and hemiscrotectomy had locoregional relapse and died of disease. Hemiscrotectomy seems not to be mandatory in patients after transscrotal approaches regarding outcome and local relapse. Nevertheless, hemiscrotectomy probably should be performed if the scrotal skin is infiltrated.

Increased CD44s and decreased CD44v6 RNA expression are associated with better survival in myxofibrosarcoma patients: a pilot study

BackgroundNew prognostic markers may be of value in determining survival and informing decisions of adjuvant treatment in the heterogeneous group of soft tissue sarcomas known as malignant fibrous sarcomas (MFS). Increased CD44 expression has been associated with a better outcome in cancers such as bladder tumors and could potentially relate to cell-cell interaction as a marker for potential invasion/metastasis. The aim of this pilot study was to determine if there is a correlation between the expression rate of CD44 in adult patients with MFS and clinical outcomes.MethodsThe clinical outcome of 34 adult MFS patients (19 males and 15 females, average age 62 years, median 63 years, range: 38–88 years) who underwent surgical treatment were evaluated. Twenty-five of these patients had additional adjuvant radiotherapy. Extracted RNA from sarcoma tissues was used to measure the transcripts of CD44s (standard form) and isoform expression.The pooled data for each variant of CD44 was divided in half at the median expression value into two equally sized groups (low and high). Survival modeling and multivariate analysis were used with these two groups to determine if there were differences in survival times and whether this was independent of known factors such as tumor stage/grade, patient age and resection margin status.ResultsHigh CD44s and low of CD44v6 expression significantly correlated with an improved outcome (P <0.05 and P <0.02, respectively) whereas CD44v8 and hCD44 (isoforms) did not. Differences in survival were apparent within 6–12 months of operation with >30% difference in survival between low/high expressions at 5 years. These finding were independent of the other measured MFS survival predictors, though the group was homogenous.ConclusionsHigh CD44s and low CD44v6 expression may be an independent predictor of improved survival in MFS patients in this pilot data. This is contrary to other MFS data, which did not account for the CD44 isoforms but is confirmed by data from other cancer types. Further investigation is needed to confirm CD44 isoform expression data as a relevant survival biomarker and whether it could be used to inform clinical decisions such as adjuvant therapy.

Estimated incidence rate and distribution of tumours in 4,653 cases of archival submissions derived from the Dutch golden retriever population

BackgroundA genetic predisposition for certain tumour types has been proven for some dog breeds. Some studies have suggested that this may also be true for the Golden retriever breed. The present study aimed to examine a possible existence of a tumour (type) predisposition in the Dutch population of Golden retrievers by evaluating annual estimated incidence rates compared to incidence rates from previous publications. A second aim was to evaluate whether incidences of various tumours differed as related to the diagnostic method chosen, being either cytology or histology.ResultsTumours submitted to Utrecht University during the period 1998–2004 diagnosed either by means of cytology (n = 2,529) or histology (n = 2,124), were related to an average annual Dutch kennel club population of 29,304 Golden retrievers.Combining individual tumours from both the cytological and the histopathological data-set resulted in an annual estimated incidence rate of 2,242 for 100,000 dog-years at risk regarding tumour development in general.The most common cytological tumor diagnoses were ‘fat, possibly lipoma’ (35%), mast cell tumour (21%) and non-Hodgkin lymphoma (10%). The most commonly diagnosed tumours by histology were mast cell tumour (26%), soft tissue sarcomas (11%) and melanoma (8%). Both the cytological and histopathological data-sets, showed variation; in patient age distribution, age of onset and incidence of various tumours.ConclusionComparing our data with previous reports in non-breed-specified dog populations, the Golden retriever breed shows an increased risk for the development of tumours in general, as well as an increased risk for the development of specific tumour types, including the group of soft tissue sarcomas. Variations in age, location and incidence of various tumours were observed between the two data-sets, indicating a selection bias for diagnostic procedure.

Long-term survival of a patient with aggressive sporadic malignant peripheral nerve sheath tumour presenting as haemothorax

mour (MPNST) belongs to the group of rare soft tissue sarcomas. High his­ tological grade is a common feature, explaining its poor prognosis irrespec­ tive of the aggressiveness of local treat­ ment. Standard therapy of inoperable local relapses or distant metastases has not been established, as phase II or III clinical trials are lacking and treatment strategies are based on an­ ecdotal reports on the effectiveness of standard chemotherapy or different novel agents. Here we present a long­ term survivor of the sporadic type of MPNST – a giant thoracic tumour with an uncommon presentation of haemo­ thorax. Despite radical excision of the tumour, followed by high­dose ra­ diotherapy to the tumour bed, the patient was diagnosed with multiple metastases located in the postpneu­ monectomy thoracic cavity and the right lung. First­line doxorubicin fol low­ ed by somatostatin analogue resulted in a six­month PFS, while second­line ifosfamide­based chemo therapy result­ ed in good and long lasting symptom palliation.

Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: An European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group randomised phase II and pharmacogenetic study

AimBrostallicin is a DNA minor groove binder that has shown activity in patients with soft tissue sarcoma (STS) failing first-line therapy. The present study assessed the safety and efficacy of first-line brostallicin in patients with advanced or metastatic STS>60years or not fit enough to receive combination chemotherapy. A prospective explorative pharmacogenetic analysis was undertaken in parallel. MethodsPatients were randomised in a 2:1 ratio between IV brostallicin 10mg/m2 and doxorubicin 75mg/m2 once every 3weeks for a maximum of six cycles. Disease stabilisation at 26weeks (primary end-point) was considered a ‘success’. Further testing of brostallicin was warranted if ⩾35 ‘successes’ were observed in the first 72 eligible patients treated with brostallicin. In addition, patients were genotyped for glutathione S transferase (GST) polymorphisms. ResultsOne hundred and eighteen patients were included (79 brostallicin and 39 doxorubicin). Brostallicin was well tolerated in comparison to doxorubicin with less grade 3–4 neutropenia (67% versus 95%), grade 2–3 systolic dysfunction (0% versus 11%), alopecia (17% versus 61%) and grade 2–3 mucositis (0% versus 18%). For brostallicin versus doxorubicin, ‘successes’ were observed in 5/77 versus 10/36, progression free survival at 1year was 6.5% versus 15.6%, objective response rate was 3.9% versus 22.2% and overall survival at 1year was 50.5% versus 57.9%, respectively. Only GSTA1 genotype was significantly associated with success rate of doxorubicin treatment. ConclusionBrostallicin cannot be recommended at this dose and schedule in this patient population as first-line therapy. GSTA1 genotype may be predictive for doxorubicin efficacy but warrants further study.

NY-ESO-1 is a sensitive and specific immunohistochemical marker for myxoid and round cell liposarcomas among related mesenchymal myxoid neoplasms

Myxoid and round cell liposarcomas constitute approximately one-third of all liposarcomas, a relatively common group of fat-derived soft tissue sarcomas. The histomorphology is a continuum between highly differentiated myxoid and poorly differentiated round cell components. The gold standard of diagnosis is dependent on histomorphology and/or identification of t(12;16)(q13;p11) translocation by cytogenetics or demonstration of DDIT3 rearrangements by fluorescence in situ hybridization. There are currently no diagnostic immunohistochemical stains available. The broad range of myxoid neoplasms in the differential diagnosis includes a variety of sarcomas. Given the notable differences in disease biology among myxoid neoplasms, which range from benign to aggressive, an accurate diagnosis is imperative for proper treatment and prognostication. Prompted by our recent study showing frequent expression of the cancer testis antigen NY-ESO-1 in myxoid and round cell liposarcomas, we sought to evaluate the utility of NY-ESO-1 as an immunohistochemical marker for myxoid and round cell liposarcoma among mesenchymal myxoid neoplasms within the differential diagnosis. Formalin-fixed, paraffin-embedded blocks were obtained for the following mesenchymal myxoid neoplasms (n=138): myxoid and round cell liposarcoma (n=38); well-differentiated liposarcoma (n=12); lipoma (n=20; 4 with myxoid change); extra-cardiac soft tissue myxoma (n=39); extraskeletal myxoid chondrosarcoma (n=12); myxofibrosarcoma (n=10: 5 low grade, 2 intermediate grade, 3 high grade); and low-grade fibromyxoid sarcoma (n=7). Utilizing standard immunohistochemistry protocols, full sections were stained with NY-ESO-1 (clone E978), and staining was assessed for intensity (1–2+), percentage of tumor positivity, and location. In all, 36/38 (95%) of the myxoid and round cell liposarcomas demonstrated NY-ESO-1 immunoreactivity. The majority of the positive cases (34/36; 94%) showed strong, homogenous staining (>50% tumor positivity), and two cases (6%) showed weak (1+ intensity), patchy staining (20–30% tumor positivity). Immunoreactivity was predominantly cytoplasmic. All the other neoplasms evaluated were negative for NY-ESO-1. NY-ESO-1 appears to be a sensitive and a specific marker for myxoid and round cell liposarcoma among mesenchymal myxoid neoplasms. The assessment of NY-ESO-1 expression by immunohistochemistry in the appropriate setting provides a cheaper, faster, and more accessible confirmatory test.

Response of Children with Stage IV Soft Tissue Sarcoma to Topotecan and Carboplatin: A Phase II Window Trial of the Cooperative Soft Tissue Sarcoma Group

To investigate antitumor activity and toxicity associated with combined topotecan and carboplatin treatment in children and adolescents with metastasized, untreated soft tissue sarcoma (STS).Patients (n=34) less than 21 years old and untreated, stage IV STS. Patients were treated with topotecan (1 mg/m²/d for 4 days) and carboplatin (150 mg/m²/d for 4 days) (TC course) during week 1 and 4 of a chemotherapy window trial, which was followed by chemotherapy and local therapy from week 6 on. We evaluated the side effects, toxicity and tumor response (using RECIST criteria) 6 weeks after starting the 2 TC chemotherapy courses.The objective response rate (ORR) was 38% (n=13 patients with a partial response (PR)), and a stable disease (SD) was reached in 11 cases. No patient showed a complete response (CR) of all metastatic lesions, although 1 patient showed a CR of the target lesion. 2 patients died of progress of disease (PD). Toxicity was mainly hematological (grade III/IV toxicity 79%), and nonhematological toxicities mainly included infection, fever, nausea,and vomiting. Regarding adverse events, 4 probable and 8 possible events related to study medication occurred among the 66 courses of TC.In conclusion, TC was potent against high-risk STS, but results and toxicity data were not superior to former published monotherapeutic topotecan therapies.

The pathologic response of resected synovial sarcomas to hyperthermic isolated limb perfusion with melphalan and TNF-α: a comparison with the whole group of resected soft tissue sarcomas

BackgroundHyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan (TM-HILP) has been successfully used to treat limb soft tissue sarcomas (STSs) with high response rates. The data on the effectiveness of HILP-TM for the treatment of STSs are mainly based on various STS types. The aim of this study was to investigate the responses of synovial sarcomas (SS) to TM-HILP.MethodsA total of 125 TM-HILP-treated tumors (STSall), including 14 SSs, were included in the study. The tumors were subdivided into proximal and distal limb localizations. Tumor typing (using the WHO classification), resection status (using the UICC classification), and response to therapy were assessed using light microscopy. The SSs were tested for the SYT-SSX translocation using RT-PCR. The following tests were applied: a chi-squared test, a t test, and the Mann-Whitney U test.ResultsThe SSs were localized distally more often than were the STS cohort (STS−SS) (85.7% vs. 32.4%) and were smaller (5.8 cm vs. 10.7 cm). There were no differences in the responder/nonresponder ratios or the mean percentages of pathological regression between the SS and STS−SS cohorts (74.0% vs. 76.0%). A general localization-dependent difference in the tumor responses to TM-HILP could not be detected in the STSall cohort (distal, 72.0% vs. proximal, 78.0%); however, a UICC R0 status was more often observed in proximal tumors (distal, 50.0% vs. proximal, 71.4%). There was no association between the SYT-SSX type and SS responses to TM-HILP.ConclusionsBecause of the high response rates, TM-HILP is recommended for the treatment of SSs. The distal limb localization of TM-HILP-treated STSs was generally (STSall cohort) associated with fewer R0 resections.

Histologic and Clinical Characteristics Can Guide Staging Evaluations for Children and Adolescents With Rhabdomyosarcoma: A Report From the Children's Oncology Group Soft Tissue Sarcoma Committee

To simplify the recommended staging evaluation by correlating tumor and clinical features with patterns of distant metastasis in newly diagnosed patients with embryonal rhabdomyosarcoma (ERMS) or alveolar rhabdomyosarcoma (ARMS). Patient data from the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group over two periods were analyzed: 1991 to 1997 and 1999 to 2004. We used recursive partitioning analyses to identify factors (including histology, age, regional nodal and distant metastatic status, tumor size, local invasiveness, and primary site) that divided patients into subsets with the most different rates of metastatic disease. Of the 1,687 patients analyzed, 5.7% had lung metastases, 4.8% had bone involvement, and 6% had bone marrow (BM) involvement. Rhabdomyosarcoma (RMS) without local invasion (T1) had a low rate of metastasis for all distant sites, especially ERMS (0% bone, 0% BM). ARMS with local invasion (T2) had a higher rate of metastasis for all distant sites (13% lung, 18% bone, 23% BM). ERMS, T2 also had a higher rate of metastatic lung involvement (9%). The likelihood of bone or BM involvement increased in the presence of lung metastases (41% with, 6% without). Regional nodal metastases (N1) predicted a high rate of metastasis in all distant sites (14% lung, 14% bone, 18% BM). A staging algorithm was developed. Staging studies in childhood RMS can be tailored to patients' presenting characteristics. Bone marrow aspirate and biopsy and bone scan are unnecessary in at least one third of patients with RMS.

P14ARF methylation is a common event in the pathogenesis and progression of myxoid and pleomorphic liposarcoma

Liposarcoma represents the most frequent group of soft tissue sarcomas. The group can be divided into three different classes: (1) differentiated/undifferentiated (WDLPS/DDLPS), (2) myxoid/round cell (MLPS/RCLPS) and (3) pleomorphic liposarcoma (PLS). It has become apparent that p53-p14 and Rb-p16 pathways play important roles in the pathogenesis of various sarcoma types. Molecular studies of the genes involved in these two pathways showed wide variations between the liposarcoma subtypes or even within the same subtype. We sought to examine mutational status of p53 and methylation status of p16 (INK4a) /p14 (ARF) genes in primary and recurrent liposarcoma tumors. There were twelve myxoid (12/18, 66.7%) and six pleomorphic liposarcoma (6/18, 33.3%) samples. Immunohistochemical analysis revealed that p53 protein was overexpressed in 3/12 MLPS (25%) and 6/6 PLS (100%). Mutational analysis showed that 2/11 MLPS (18.2%) and 2/6 PLS (33.3%) contained mutated p53 gene. On the other hand, 3/18 samples (16.7%) had methylated p16 promoter. However, the frequencies of the p14 (ARF) gene methylation were 83.3% (10/12) and 50% (3/6) in myxoid and pleomorphic group, respectively. Overall, 15 out of 18 (83.3%) samples had either p53 gene mutation or methylated p14 (ARF) promoter. The results from the current study suggest significant impact of the p14 (ARF) gene methylation on the pathogenesis and progression of myxoid and to a lesser extent pleomorphic liposarcoma. Despite the limited number of samples, our study points to necessity of further investigation of p53-p14 and Rb-p16 pathways in liposarcoma.

Patterns of toxicities and outcome in children versus adolescents/young adults (AYA) with metastatic rhabdomyosarcoma (RMS): A report from the Children’s Oncology Group (COG) Soft Tissue Sarcoma Committee.

10554 Background: Age at diagnosis is a prognostic factor in patients with RMS. We sought to determine whether AYA with metastatic alveolar (ARMS) or embryonal (ERMS) RMS had a different failure-free survival (FFS) compared to younger patients, and to identify treatment related factors that may be associated with outcome. Methods: COG ARST0431 patients were reviewed. The incidence of toxicities (AE, grade3/4 using CTCAEv3) by age was determined in 4 reporting periods (RP: wks 1-6; RP2:7-19; RP3: 20-34; RP4: 35-54). The AEs in younger patients (&lt;=13 years) were compared with those in AYA. Fisher’s exact test was used to compare differences between the groups. Results: Of 109 patients, 60 (55%) were AYA. In RP1, they were more likely to have nausea/vomiting (4.1 vs. 16.9%, p=0.06), pain (6.1 vs. 20.3%, p=0.05), and metabolic disturbances (4.1 vs. 20.3%, p=0.02) compared to younger patients. In RP4, older patients trended to have less infection (15.8 vs. 30.1, p=0.07). All other toxicities were similar between the two age cohorts in the other RPs. AYA were less likely to complete therapy (52 vs. 73%, p=0.03) and more likely (in RP 4) to have unplanned dose modifications (outside of protocol guidelines) (23 vs. 2.7%). Of patients that completed therapy, there was no age-related difference in the time to completion. As shown in the table, younger patients had better 3-yr FFS, driven by a lower FFS for AYA with ARMS. Conclusions: This evaluation suggests that AYA with RMS were less likely to complete therapy and experienced a higher prevalence of pain and nausea compared to younger patients; the role of reporting bias and reasons for treatment discontinuation need further study. Children were more likely than AYA to have infection. Inferior FFS was only seen in AYA with ARMS suggesting a clear need for novel therapies for these patients. This study may be underpowered to demonstrate significant differences in other toxicities or in FFS among ERMS patients. [Table: see text]

Histology and Fusion Status in Rhabdomyosarcoma

The International Classification of Rhabdomyosarcoma (ICR) has provided diagnostic criteria for rhabdomyosarcoma (RMS) and formed the basis of histologic risk stratification since its publication in 1995. However, the recognition of new variants of embryonal rhabdomyosarcoma (ERMS), shifts in the diagnostic criteria of alveolar rhabdomyosarcoma (ARMS), the increasing use of myogenin immunohistochemistry and recognition of the distinct biologic properties associated with fusion status all raised questions about the continued use of this classification system in the diagnosis and treatment of patients with RMS. Recent Children's Oncology Group Soft Tissue Sarcoma Committee analysis of histology and fusion status in the intermediate risk RMS study D9803 refined the histologic criteria of RMS. We validated the new diagnostic criteria against fusion status, allowing prospective examination of the prognostic value of histology compared with fusion status for risk-stratification of patients with RMS. This article summarizes the evolution of and current practices in the histologic and molecular classification of rhabdomyosarcoma.

The Future of Drug Development? Seeking Evidence of Activity of Novel Drugs in Small Groups of Patients

We increasingly recognize that our traditional classification of tumor types on the basis of the organ of origin and microscopy alone is inadequate. Tumors grouped according to histologic classification systems are diverse entities that differ greatly in their molecular characteristics, clinical course, and sensitivity to antitumor agents. Accordingly, many tumor types are currently divided into smaller subgroups on the basis of molecular characteristics that have therapeutic consequences. Examples include melanoma, breast cancer, colorectal cancer, gastric cancer, and non–small-cell lung cancer. Undoubtedly, most tumor types as we currently know them will be redefined into smaller subsets of clinically relevant, molecular entities. Soft tissue sarcomas (STS) are well-known to represent a heterogeneous group of tumors comprising more than 50 histotypes. As a result of their rare occurrence, which was thought to preclude the possibility of performing adequately powered studies in specific histotypes, and despite the recognized heterogeneity in clinical course and known differences in sensitivity to chemotherapy, all subtypes from this group were treated similarly until a decade ago. This started to change with the introduction of imatinib with impressive antitumor activity in GI stomal tumors 2 and later dermatofibrosarcoma protuberans, both harboring molecular targets affected by the agent. The activity of imatinib was not observed in any other STS subtype, which emphasized the relevance of the underlying genetic aberrations as the primary determinant of treatment benefit. The total group of STS involves only 1% of all malignancies, and the subtype of alveolar soft part sarcoma (ASPS) accounts for approximately 1% of all STS, making it an extremely rare tumor type with an estimated annual incidence of 100 new cases in the United States. Although ASPS generally exhibits indolent growth, the majority of patients develop metastases during the course of their disease, most frequently in the lungs and bones. Compared with other STS subtypes, ASPS may also have a greater likelihood of metastasizing to the brain. Given that the limited data available suggest that ASPS is relatively resistant to radiotherapy and conventional chemotherapeutic agents, radical surgery is the only meaningful option. For patients with metastatic disease not amenable for radical resection, the median overall survival is 30 months, which is much longer than that for other STS histotypes, consistent with its relatively indolent course. Importantly, ASPS features a specific translocation [t(X,17)(p11; q25)], which fuses the ASPL gene to the TFE2 transcription factor gene. The presence of this fusion protein results in uncontrolled transcription of TFE3-regulated genes such as c-MET and several proangiogenic factors. In the article accompanying this editorial, Kummar et al describe a single-arm phase II study of cediranib in patients with advanced ASPS not amenable to curative surgery. Cediranib is a tyrosine kinase inhibitor (TKI) that targets all three vascular endothelial growth factor receptors (VEGFRs) at low concentrations. The rationale for this study was based on the overexpression of angiogenesispromoting genes in ASPS, the vascular appearance at histopathologic examination, and promising antitumor activity reported in another VEGFR TKI–related small study and in a phase I study of cediranib. Using RECIST-classified response rate (RR) as a primary end point, a Simon optimal two-stage design was applied, in which an RR of 25% was deemed worthwhile for further exploration. In 43 patients evaluable for response, 15 (35%) experienced a partial response. Importantly, only two patients (5%) experienced progression as best response. The progression-free rate at 26 weeks was 84%, whereas some patients still on treatment had not yet reached this time-point. After a dose reduction from 30 to 20 to 15 mg/day, cediranib had a toxicity profile that was deemed tolerable. In view of the high, unprecedented RR in this rare disease and the tumor regressions seen in almost all patients on the study, it is obvious that cediranib exerts antitumor activity against advanced ASPS. However, the study was not randomized and thus the question can be raised whether the activity seen in this trial is sufficiently convincing for implementation into daily clinical practice. Clearly, randomized trials are the preferred cornerstone for approval and treatment decision making in daily clinical practice. Yet, some of the most successful drugs applied in medical oncology have been implemented on the basis of results from nonrandomized studies. Most recently vismodegib, a Hedgehog pathway inhibitor, received marketing approval in the United States for advanced basal cell carcinoma on the basis of a single-arm study with 96 patients. RRs were 30% and 43% in patients with metastatic (n 33) and locally advanced disease (n 63), respectively, with a median duration of response of 7.6 months in JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 18 JUNE 2

Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial

Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.

Does body mass index at diagnosis or weight change during therapy predict toxicity or survival in intermediate risk rhabdomyosarcoma? A report from the Children's Oncology Group soft tissue sarcoma committee

Weight loss prevalence and its impact on toxicities and survival in intermediate risk rhabdomyosarcoma (IRMS) patients are unknown. We evaluated the association between weight change during therapy and number of toxicities, hospital days, infections, and overall survival and between baseline body mass index (BMI) and survival in patients treated on Children's Oncology Group trial D9803. Four hundred sixty-eight IRMS patients age ≥2 and <21 years treated on D9803 had required data. Regression models evaluated association between weight loss from baseline and toxicities, hospital days, infections, and survival. Kaplan-Meier curves and regression models evaluated baseline BMI percentile's association with survival. Thirty-five percent and 37% of patients had >5% weight loss at 12 and 24 weeks, respectively, with 16% and 19% losing >10% weight respectively. Greater than 10% weight loss at 24 weeks was associated with more toxicities and hospital days during subsequent therapy but not infection rate or survival. Baseline underweight patients (<5th percentile BMI) had borderline inferior survival compared with baseline average weight patients while there was no difference in survival seen between average weight and overweight or obese patients. Nearly one in five IRMS patients experienced >10% weight loss on therapy. This was associated with increased toxicity but not decreased survival compared with patients who had less weight loss. Baseline BMI percentile trended toward a significant association with survival. Future studies might investigate nutritional impact on quality of life and if weight loss is preventable by early nutritional intervention.

Histology and Fusion Status in Rhabdomyosarcoma

The International Classification of Rhabdomyosarcoma (ICR) has provided diagnostic criteria for rhabdomyosarcoma (RMS) and formed the basis of histologic risk stratification since its publication in 1995. However, the recognition of new variants of embryonal rhabdomyosarcoma (ERMS), shifts in the diagnostic criteria of alveolar rhabdomyosarcoma (ARMS), the increasing use of myogenin immunohistochemistry and recognition of the distinct biologic properties associated with fusion status all raised questions about the continued use of this classification system in the diagnosis and treatment of patients with RMS. Recent Children's Oncology Group Soft Tissue Sarcoma Committee analysis of histology and fusion status in the intermediate risk RMS study D9803 refined the histologic criteria of RMS. We validated the new diagnostic criteria against fusion status, allowing prospective examination of the prognostic value of histology compared with fusion status for risk-stratification of patients with RMS. This article summarizes the evolution of and current practices in the histologic and molecular classification of rhabdomyosarcoma.