Pediatric sarcoma in Central America

BACKGROUND:

Children with cancer in middle‐income countries have inferior outcomes compared with similar children in high‐income countries. The magnitude and drivers of this survival gap are not well understood. In the current report, the authors sought to describe patterns of clinical presentation, magnitude of treatment abandonment, and survival in children with sarcoma in Central America.

METHODS:

A retrospective review was conducted of hospital‐based registries from national pediatric oncology referral centers. Patients with newly diagnosed osteosarcoma, Ewing sarcoma, rhabdomyosarcoma (RMS), and soft tissue sarcoma (STS) between January 1, 2000 and December 31, 2009 were included. Survival analyses were performed first using standard definitions of overall survival (OS) and event‐free survival (EFS) and then with abandonment included as an event (abandonment‐sensitive OS and abandonment‐sensitive EFS).

RESULTS:

In total, 785 new cases of pediatric sarcoma were reported (264 diagnoses of osteosarcoma, 175 diagnoses of Ewing sarcoma, 240 diagnoses of RMS, and 106 diagnoses of STS). The rate of metastatic disease at presentation was high (osteosarcoma, 38%; Ewing sarcoma, 39%; RMS, 29%; and STS, 21%). The treatment abandonment rate also was high, particularly among patients with extremity bone sarcomas (osteosarcoma, 30%; Ewing sarcoma, 15%; RMS, 25%; and STS, 15%). Of 559 patients who experienced a first event, 59% had either recurrent or progressive disease. The 4‐year OS rate (±standard error) was 40% ± 3%, and the EFS rate was 30% ± 2%; however, these rates decreased further to 31% ± 2% and 24% ± 2%, respectively, when abandonment was taken into account.

CONCLUSIONS:

The current results indicated that high rates of metastases and treatment abandonment and difficulty with upfront treatment effectiveness are important contributors to the poor survival of children with pediatric sarcomas in Central America. Initiatives for early diagnosis, psychosocial support, quality improvement, and multidisciplinary care are warranted to improve outcomes. Cancer 2013. © 2012 American Cancer Society.     

Malignant sarcoma of the pelvic bones: treatment outcomes and prognostic factors vary by histopathology

BACKGROUND:

Treatment of malignant sarcomas of the pelvis poses a challenge for local disease control and oncologic outcome. Many reports have described the dismal outcomes. Most studies are retrospective series coming out of single centers, thus biased toward patient selection and are of limited statistical power.

METHODS:

The authors used the Surveillance, Epidemiology, and End Results database to analyze 1185 pelvic sarcoma cases from 1987 to 2006. Kaplan‐Meier and Cox regression were used to analyze the significance of prognostic factors. The analysis was repeated for different histopathological subtypes to determine specific prognostic factors in each case.

RESULTS:

Incidence of pelvic sarcoma in 2006 was 89 per 100,000 persons; it has significantly increased since 1973 (P < .05). The overall 5‐year survival for all the patients with pelvic sarcoma was 47%, with osteosarcoma having the worst 5‐year survival at 19% and patients with chordoma having the best 5‐year survival at 60%. Independent prognostic factors included age, stage, grade, size of primary lesion, histopathology, and treatment‐related factors. Comparing the patients only with high‐grade lesions, patients with Ewing sarcoma have the best prognosis.

CONCLUSIONS:

This is an analysis of patients with pelvic sarcomas derived from a population‐based registry. Survival and prognostics vary with histopathological diagnoses. Although surgical resection was associated with superior outcomes for osteosarcoma and chondrosarcoma, there was no significant difference in outcomes of patients with Ewing sarcoma treated with surgery and/or radiotherapy. Cancer 2011. © 2010 American Cancer Society.     

Clinical features and outcomes in patients with extraskeletal Ewing sarcoma

BACKGROUND:

Ewing sarcoma can arise in either bone or soft tissue. The purpose of this study was to investigate whether patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES).

METHODS:

Patients <40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor reported to the United States Surveillance, Epidemiology, and End Results Program database from 1973 to 2007 were evaluated based on skeletal (n = 1519) versus extraskeletal (n = 683) site of origin. Patient characteristics were compared using Fisher exact tests. Overall survival was estimated via the Kaplan‐Meier method and compared using log‐rank tests and Cox proportional hazard models.

RESULTS:

Patients with EES had a higher mean age (19.5 vs 16.3 years; P < .001) and were less likely to be male (53.4% vs 63.3%; P < .001) or white (84.8% vs 92.5%; P < .001) compared with patients with skeletal tumors. Extraskeletal tumors were more likely to arise in axial locations (72.9% vs 54.2%; P = .001) but were less likely to arise specifically in the pelvis (19.8% vs 26.6%; P < .001). Metastatic status or tumor size did not differ by group. Five‐year overall survival was superior for localized EES compared with localized skeletal tumors (69.7% vs 62.6%; P = .02). The hazard ratio for death in patients with localized skeletal tumors compared with localized EES was 2.36 (95% confidence interval, 1.61‐3.44) beyond 24 months from initial diagnosis.

CONCLUSIONS:

Patient characteristics and outcomes differ among patients with EES compared with patients with skeletal Ewing sarcoma. These findings may have important implications for patient care. Cancer 2011. © 2011 American Cancer Society.     

Ewing sarcoma demonstrates racial disparities in incidence‐related and sex‐related differences in outcome

BACKGROUND:

Previous reports of Ewing sarcoma cohorts suggested that there is a difference in incidence according to racial origin. However, to the authors' knowledge, this finding has never been tested in a population‐based database, and the impact of race on clinical outcome and the significance of known risk factors stratified to racial groups have not been reported.

METHODS:

Patients who had Ewing sarcoma diagnosed between 1973 and 2005 were identified in the Surveillance, Epidemiology, and End Results database. Patient demographic and clinical characteristics; incidence; year of diagnosis; tumor location, tumor size, and disease stage at diagnosis; treatment(s); cause of death; and survival were extracted. Kaplan‐Meier, log‐rank, and Cox regressions were used to analyze the significance of prognostic factors.

RESULTS:

Race‐specific incidence indicated that Caucasians have the highest incidence (0.155), followed by Asians/Pacific Islanders (0.082), and African Americans (0.017). The difference in incidence between Caucasians and African Americans was 9‐fold and significant (P < .001). The incidence of Ewing sarcoma increased over the past 3 decades among Caucasians (P < .05). Survival was not impacted by race. Local disease stage, primary tumor location in the appendicular skeleton, and tumor size ≤8 cm conferred a significant survival benefit. Women demonstrated improved survival among the Caucasian patients (P < .03).

CONCLUSIONS:

To the authors' knowledge, this is the first report focusing on racial disparity in incidence of Ewing sarcoma. Caucasians were affected more frequently, although outcomes were similar between races. It is noteworthy that being a woman constituted a survival benefit only among the Caucasian patients. Further studies will need to clarify the reasons for racial disparities in incidence and for sex differences in survival. Cancer 2009. © 2009 American Cancer Society.     

Risk stratification and pattern of cardiotoxicity in pediatric Ewing sarcoma

Introduction

Anthracycline chemotherapy contributes to improved outcomes in Ewing sarcoma; however, the most feared complication is cardiotoxicity. Echocardiograms were routinely used to monitor cardiac function after anthracycline treatment. Nevertheless, indices chosen to assess cardiac toxicity vary significantly among different centers, and no uniform protocol has been accepted as ideal.

Clinical outcome of children and adults with localized Ewing sarcoma

BACKGROUND:

As Ewing sarcoma (EWS) can affect children and adults, these patients can be treated at either a pediatric or an adult institution. This study investigated whether differences in therapeutic strategy undertaken in pediatric and adult specialty sarcoma centers correlated with clinical outcome.

METHODS:

Data from patients with localized EWS treated between 1990 and 2005 at tertiary care pediatric and adult institutions were reviewed.

RESULTS:

Fifty‐three patients (24 adult and 29 pediatric) were treated. Pediatric patients received a median of 16 cycles of chemotherapy comprised of doxorubicin, vincristine, cyclophosphamide, ifosfamide, and etoposide. Adult patients received a median of 10 cycles of treatment, and a significantly lower total cumulative dose of ifosfamide and cyclophosphamide (P < .0001). There was no difference noted with regard to the total dose of doxorubicin, or in the type of local therapy offered (surgery or radiotherapy, vs both). However, local therapy occurred earlier in pediatric patients compared with adults (3.7 months vs 7.4 months; P = .0003). The 3‐year event‐free survival (EFS) rate in pediatric and adult patients was 70% ± 9% and 43% ± 13% (P = 0.1), respectively. The 3‐year overall survival rate was 81% ± 7.7% and 59% ± 12% (P = .02) for pediatric and adult patients, respectively. Factors found to be significantly associated with EFS on univariate analysis included pelvic site, cyclophosphamide dose, and time to local therapy. On multivariate analysis, only pelvic disease (hazard ratio [HR] 4.26; P = .018) and time to local therapy (HR, 1.19; P = .002) were found to be significant.

CONCLUSIONS:

Adults with localized EWS have an inferior outcome compared with pediatric patients. This difference may be related to lower doses of alkylating agents and the timing of local therapy. Cancer 2010. © 2010 American Cancer Society.     

Cancer-testis antigens expressed in osteosarcoma identified by gene microarray correlate with a poor patient prognosis

BACKGROUND:

From 30% to 40% patients with osteosarcoma eventually experience medical failure; and few biomarkers of prognostic significance have been established. High‐throughput methods like gene microarray analysis can help to identify molecular biomarkers that are useful for diagnosing osteosarcoma and targeting its treatment.

METHODS:

Oligonucleotide microarrays were used to compare expression profiles of osteosarcoma cell lines and osteoblasts. Differentially expressed genes were confirmed by real‐time polymerase chain reaction (PCR) analysis. Corresponding proteins were evaluated by flow cytometry and Western blot analysis in osteosarcoma cell lines and by immunohistochemistry in osteosarcoma tissues. The association between staining intensity and clinical outcome was analyzed further.

RESULTS:

Cancer‐testis antigens, including melanoma antigen family A (MAGEA), chondrosarcoma‐associated gene family, member 2 (CSAG2), and preferentially expressed antigen in melanoma (PRAME), were increased significantly in all osteosarcoma cell lines that were analyzed. Real‐time PCR examinations indicated that cancer‐testis antigen expression was frequent and coordinated in patients with osteosarcoma. The expression of MAGEA was confirmed by Western blot and flow cytometry analyses in osteosarcoma cell lines. Furthermore, immunohistochemical staining analysis suggested that MAGEA expression may be used to predict distant metastasis and poor survival. The adjusted relative risk for lung metastasis was 2.79 (95% confidence interval, 1.12‐6.93; P = .028) for MAGEA‐positive patients. Five‐year survival rates for patients with and without MAGEA expression were 39.6% ± 8.4% and 80% ± 8.9%, respectively (log‐rank test; P = .01).

CONCLUSIONS:

The combined use of an oligonucleotide microarray, a clinical database, and a tissue bank was useful for identifying molecular tumor markers. The frequent expression of MAGEA and other cancer‐testis antigens in osteosarcoma indicates that they may be useful as diagnostic markers and targets of immunotherapy that warrant further investigation. Cancer 2012. © 2011 American Cancer Society.     

Fine‐needle aspiration biopsy of high‐grade sarcoma

BACKGROUND.

To the authors' knowledge, few studies exist demonstrating the reliability of fine‐needle aspiration (FNA) biopsy for high‐grade sarcoma (HGS).

METHODS.

In the current study, the authors reviewed their cytopathology database (March 2001 through January 2007) and identified all FNA cases diagnosed as HGS. They also searched their tissue database for all HGS cases that had prior FNA biopsy findings.

RESULTS.

A total of 107 FNA samples from 98 patients (age range, 13–90 years, with a male:female ratio of 1:1) had an FNA diagnosis of HGS, or had HGS and a prior FNA diagnosis of another entity. Ten cases were nondiagnostic. Of the 97 remaining samples, 6 were diagnosed as something other than HGS (sensitivity of 94%). The positive predictive value of an FNA diagnosis of HGS was 97% (88 of 91 cases). Fifty‐four cases were diagnosed as HGS, not otherwise specified, 8 as myxofibrosarcoma, 8 as osteosarcoma, 5 as malignant peripheral nerve sheath tumor, 5 as leiomyosarcoma, 4 as Ewing sarcoma, 4 as liposarcoma, 2 as epithelioid sarcoma, and 1 as angiosarcoma. Approximately 71% of patients presented with a primary tumor, 23% with disease recurrence, and 7% with metastasis. Sites of disease included the lower extremity (59%), upper extremity (19%), trunk (15%), groin (4%), and head and neck (4%). FNA diagnosis was confirmed histologically in 88% of cases, clinically in 7% of cases, and cytogenetically in 1% of cases; 3% of cases had false‐positive results and 1 patient was lost to follow‐up. Sixteen of 19 patients received neoadjuvant chemotherapy based on the FNA diagnosis alone.

CONCLUSIONS.

A cytopathologic diagnosis of HGS was found to be accurate in 88 of 97 cases (91%) with follow‐up. A FNA biopsy diagnosis of HGS appears to be clinically reliable in a high percentage of cases when used in close conjunction with the orthopedic team. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.     

Relationship between height at diagnosis and bone tumours in young people: a meta-analysis

Objective  

Some evidence exists that patients with osteosarcoma and Ewing sarcoma are taller than the general population. However, previous studies are under-powered, lack comprehensive data and show inconsistencies.     

The value of local treatment in patients with primary,disseminated, multifocal Ewing sarcoma (PDMES)

BACKGROUND:

The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES) was investigated.

METHODS:

We analyzed 120 patients registered into the European Ewing Tumor Working Initiative of National Groups (EURO‐E.W.I.N.G. 99) trial at the trial center of Muenster from 1998 to 2006. Median age was 16.2 years. Local treatment of the primary tumor was surgery in 26 of 120 patients, surgery and radiotherapy in 21 patients, and definitive radiotherapy in 40 patients. For treatment of metastases, 6 of 120 patients received surgery; 9 patients, surgery and radiotherapy; and 33 patients, definitive radiotherapy. Forty‐seven (39%) patients had local treatment of both the primary tumor and metastases, 41 (34%) patients of either the primary tumor or metastases, and 32 (27%) received no local therapy.

RESULTS:

Event‐free survival (EFS) at 3 years was 0.24 (95% CI, 0.16‐0.33). Univariate analyses demonstrated the impact of local therapy given to the primary tumor: 3‐year EFS was 0.25 with surgery, 0.47 with surgery and radiotherapy, 0.23 with radiotherapy, and 0.13 when no local therapy was administered (P < .001). Three‐year EFS in PDMES was also influenced by the local treatment: surgery, 0.33; surgery and radiotherapy, 0.56; radiotherapy, 0.35; no local therapy, 0.16 (P = .003). Three‐year EFS was 0.39 in patients who received local treatment of both primary tumor and PDMES, compared with 0.17 in patients with any local treatment of either primary tumor or PDMES and 0.14 in patients with no local therapy (P < .001). Multivariate analysis showed absence of local treatment to be the major risk factor (HR = 2.21; P = .027; n = 20).

CONCLUSIONS:

Local therapy of involved sites is important for patients with PDMES and should complement systemic treatment whenever possible. Cancer 2010. © 2010 American Cancer Society.     

The ganglioside antigen G(D2) is surface-expressed in Ewing sarcoma and allows for MHC-independent immune targeting

Background:

Novel treatment strategies are needed to cure disseminated Ewing sarcoma. Primitive neuroectodermal features and a mesenchymal stem cell origin are both compatible with aberrant expression of the ganglioside antigen G_D2 and led us to explore G_D2 immune targeting in this cancer.

Methods:

We investigated G_D2 expression in Ewing sarcoma by immunofluorescence staining. We then assessed the antitumour activity of T cells expressing a chimeric antigen receptor specific for G_D2 against Ewing sarcoma in vitro and in vivo.

Results:

Surface G_D2 was detected in 10 out of 10 Ewing sarcoma cell lines and 3 out of 3 primary cell cultures. Moreover, diagnostic biopsies from 12 of 14 patients had uniform G_D2 expression. T cells specifically modified to express the G_D2-specific chimeric receptor 14. G2a-28ζ efficiently interacted with Ewing sarcoma cells, resulting in antigen-specific secretion of cytokines. Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, G_D2-specific cytolytic responses to allogeneic and autologous Ewing sarcoma, including tumour cells grown as multicellular, anchorage-independent spheres. G_D2-specific T cells further had activity against Ewing sarcoma xenografts.

Conclusion:

G_D2 surface expression is a characteristic of Ewing sarcomas and provides a suitable target antigen for immunotherapeutic strategies to eradicate micrometastatic cells and prevent relapse in high-risk disease.     

Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil

BACKGROUND:

The inherited, low‐penetrance arginine‐to‐histidine substitution at codon 337 (R337H) of the tumor protein 53 gene (TP53) is clustered in southeast Brazil (estimated frequency, 0.3%). Although its tumorigenic effect initially appeared to be tissue‐specific, recent evidence suggests its association with a broader range of tumors. Therefore, the authors of this report investigated the spectrum of pediatric malignancies associated with the TP53 R337H mutation at a single referral institution in southeast Brazil.

METHODS:

Genomic DNA samples from 493 children with malignancies were screened for the R337H mutation. Available tumor samples from carriers were investigated for loss of heterozygosity (LOH) and nuclear p53 accumulation. Clinical data were obtained from medical records.

RESULTS:

Sixty‐five of 70 patients (93%) with adrenocortical tumors (ACTs), 9 of 13 patients (69%) with choroid plexus carcinoma (CPC), and 3 of 41 patients (7.3%) with osteosarcoma carried the mutation. The proportion of CPC to choroid plexus papilloma (CPP) was much higher than that reported elsewhere. Osteosarcoma in carriers had a significantly poorer outcome (P = .02). The mutation was not identified in patients who had acute lymphoblastic leukemia (ALL) (n = 187), recurrent ALL (n = 49), acute myeloid leukemia (n = 44), lymphoma (n = 30), non‐CPC central nervous system tumors (n = 26), Ewing sarcoma (n = 25), or rhabdomyosarcoma (n = 8). Among the tumors that were available for analysis, LOH with retention of the mutant allele was confirmed in 21 of 21 ACTs, in 2 of 2 CPCs, and in 2 of 3 osteosarcomas that were positive for R337H. CPCs and osteosarcomas that were positive for R337H had marked nuclear accumulation of p53.

CONCLUSIONS:

The current findings demonstrated compellingly that the TP53 R337H mutation is associated not only with ACT but also with CPC and, to a lesser extent, with osteosarcoma, both of which are core‐component tumors of the Li‐Fraumeni syndrome. Cancer 2011. © 2010 American Cancer Society.     

Prognostic factors and long‐term outcomes of childhood nasopharyngeal carcinoma

BACKGROUND:

The authors studied the survival and long‐term morbidities of children with nasopharyngeal carcinoma (NPC).

METHODS:

This was a retrospective review of children with NPC who were treated at St. Jude Children's Research Hospital between 1961 and 2004. Prognostic factors and long term effects of therapy were analyzed.

RESULTS:

Fifty‐nine patients (median age, 14.1 years) were identified. Most were male (66.1%) and black (54.2%) and had lymphoepithelioma (93.2%). Thirty‐five patients had stage IV disease (59.3%), 20 patients had stage III disease (33.9%), and 4 patients had stage II disease (6.8%). All patients received radiotherapy (RT) to the primary tumor, and most received cervical RT (98.3%) and chemotherapy (88.1%). The 15‐year survival and event‐free survival (EFS) rates were 67.2% ± 7.5% and 63.5% ± 7.8%, respectively. Five patients (8.5%) developed subsequent malignancies 8.6 to 27 years after NPC diagnosis. EFS was improved in patients who were diagnosed after 1980 (74.8% ± 10% vs 45.5% ± 10.1%; P = .031), in patients who had stage III disease compared with patients who had stage IV disease (79.3% ± 9.6% vs 56.2% ± 11.8%; P = .049), in patients who received cisplatin (81% ± 10.7% vs 45.8% ± 9.7%; P = .013), and in patients who received ≥50 grays of RT (71.4% ± 9.3% vs 43.8% ± 11.6%; P = .048). White patients had higher distant failure rates than black patients (41.7% ± 10.4% vs 15.6 ± 6.5%; P = .045). The 15‐year cumulative incidence (CI) of any morbidity was 83.7% ± 5.4%, the CI of sensorineural hearing loss was 52.9% ± 6.7%, the CI of primary hypothyroidism was 42.7% ± 6.6%, and the CI of growth hormone deficiency (GHD) was 14.1% ± 4.7%. Dose‐response relations were observed between the RT dose and primary hypothyroidism and GHD.

CONCLUSIONS:

The outcome of children with NPC improved over the past 4 decades with the use of cisplatin‐based chemotherapy and higher RT doses. However, many survivors had long‐term treatment‐related morbidities. Cancer 2011. © 2010 American Cancer Society.     

Evaluation of neoadjuvant therapy and histopathologic response in primary,high‐grade retroperitoneal sarcomas using the sarcoma nomogram

BACKGROUND:

Patients with primary high‐grade retroperitoneal soft tissue sarcomas have a 5‐year disease‐specific survival (DSS) of <40%. The impact of neoadjuvant therapy on histopathologic response and DSS are unknown.

METHODS:

From 1987 to 2007, 55 patients with primary high‐grade retroperitoneal sarcoma received neoadjuvant therapy. All patients underwent surgical resection, and response was assessed histopathologically. Patients with ≥95% pathologic necrosis were classified as responders. Clinicopathologic variables were analyzed for association with DSS. Observed DSS was then compared with the Memorial Sloan‐Kettering Cancer Center Sarcoma Nomogram predicted DSS.

RESULTS:

The median tumor size was 15 cm, and the median follow‐up time for survivors was 68 months. The 5‐year DSS for all 55 patients was 47% and did not significantly differ from the 37% predicted by the sarcoma nomogram for such patients (P = .44). Fourteen (25%) of the patients had ≥95% pathologic necrosis and were defined as responders; 41 (75%) were nonresponders. The 5‐year DSS for responders was 83%. This was significantly better than the 5‐year DSS of 34% for nonresponders (P = .002) and the 39% predicted by the sarcoma nomogram for responders (P = .018). The 34% 5‐year DSS for nonresponders did not significantly differ from the 35% predicted by the sarcoma nomogram (P = .51).

CONCLUSIONS:

Neoadjuvant therapy was not associated with an overall improvement in DSS in patients with primary high‐grade retroperitoneal sarcoma compared with the sarcoma nomogram prediction. Histopathologic response to neoadjuvant therapy was associated with a significantly improved DSS compared with nonresponders and with the sarcoma nomogram prediction for such patients. Cancer 2010. © 2010 American Cancer Society.     

Dendritic and mast cell involvement in the inflammatory response to primary malignant bone tumours

Background

A chronic inflammatory cell infiltrate is commonly seen in response to primary malignant tumours of bone. This is known to contain tumour-associated macrophages (TAMs) and lymphocytes; dendritic cells (DCs) and mast cells (MCs) have also been identified but whether these and other inflammatory cells are seen commonly in specific types of bone sarcoma is uncertain.

Methods

In this study we determined the nature of the inflammatory cell infiltrate in 56 primary bone sarcomas. Immunohistochemistry using monoclonal antibodies was employed to assess semiquantitatively CD45+ leukocyte infiltration and the extent of the DC, MC, TAM and T and B lymphocyte infiltrate.

Results

The extent of the inflammatory infiltrate in individual sarcomas was very variable. A moderate or heavy leukocyte infiltrate was more commonly seen in conventional high-grade osteosarcoma, undifferentiated pleomorphic sarcoma and giant cell tumour of bone (GCTB) than in Ewing sarcoma, chordoma and chondrosarcoma. CD14+/CD68+ TAMs and CD3+ T lymphocytes were the major components of the inflammatory cell response but (DC-SIGN/CD11c+) DCs were also commonly noted when there was a significant TAM and T lymphocyte infiltrate. MCs were identified mainly at the periphery of sarcomas, including the osteolytic tumour-bone interface.

Discussion

Our findings indicate that, although variable, some malignant bone tumours (e.g. osteosarcoma, GCTB) are more commonly associated with a pronounced inflammatory cell infiltrate than others (e.g. chondrosarcoma. Ewing sarcoma); the infiltrate is composed mainly of TAMs but includes a significant DC, T lymphocyte and MC infiltrate.

Conclusion

Tumours that contain a heavy inflammatory cell response, which includes DCs, TAMs and T lymphocytes, may be more amenable to immunomodulatory therapy. MCs are present mainly at the tumour edge and are likely to contribute to osteolysis and tumour invasion.

     

Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high‐risk osteosarcoma patients

BACKGROUND:

A phase 2 trial was carried out to assess the antineoplastic activity of 2 courses of cyclophosphamide‐etoposide in relapsed osteosarcoma patients.

METHODS:

Twenty‐six relapsed osteosarcoma patients with a median age of 18.5 years (8.3‐47.1) were enrolled. Seven patients were in first relapse (27%), 11 in second relapse (42%), 7 in third relapse (27%), and 1 in fourth relapse (4%). Eighteen patients had bone metastasis at study entry (69%). Cyclophosphamide was given at 4 g/m² on Day 1 followed by etoposide at 200 mg/m² on Days 2, 3, and 4. Second cyclophosphamide and etoposide was planned at 21 days to 28 days from the previous one. The primary endpoint of the study was the clinical benefit at 4 months measured as progression‐free survival.

RESULTS:

Progression‐free survival at 4 months was 42%. Five patients achieved responses (19%), 9 patients had stable disease (35%), and 12 had tumor progression (46%). Overall survival (OS) at 1 year was 50%. The only grade 4 extrahematological toxicities were fever (5%), acute bronchospasm (4%) and stomatitis (18%). Six patients (23%) underwent radical surgery after cyclophosphamide and etoposide ×2.

CONCLUSIONS:

Cyclophosphamide and etoposide ×2 may arrest osteosarcoma progression in a significant number of patients (54%). Osteosarcoma progression arrest after cyclophosphamide and etoposide ×2 translates in a better OS. Cyclophosphamide and etoposide ×2 had good tolerability and the toxicity was time‐limited and resolved in all cases. Cancer 2009. © 2009 American Cancer Society.     

Imatinib plus low‐dose doxorubicin in patients with advanced gastrointestinal stromal tumors refractory to high‐dose imatinib

BACKGROUND:

In KIT‐expressing Ewing sarcoma cell lines, the addition of doxorubicin to imatinib increases apoptosis, compared with imatinib or doxorubicin alone. On the basis of these in vitro data, the authors conducted a phase 1‐2 trial of doxorubicin with imatinib in patients with gastrointestinal sarcoma tumors refractory to high‐dose imatinib therapy.

METHODS:

Patients with metastatic gastrointestinal sarcoma tumor resistant to imatinib at 400 mg by mouth (p.o.) twice a day were eligible for this multicenter study, and received imatinib (400 mg p.o. every day [q.d.]) concomitantly with doxorubicin 15‐20 mg/m²/weekly for 4 cycles (monthly cycles), followed by imatinib (400 mg p.o. q.d.) maintenance in nonprogressive patients. Spiral computed tomography and positron emission tomography with F18‐fluorodeoxyglucose were done basally and after 2 months of therapy to evaluate response. An in vitro study assessed the effect of combining imatinib and doxorubicin.

RESULTS:

Twenty‐six patients with progressive gastrointestinal sarcoma tumor were entered in the study. Treatment was well tolerated. Three (14%) of 22 evaluable patients had partial responses per Response Evaluation Criteria in Solid Tumors, and 8 (36%) had clinical benefit (partial response or stable disease for ≥6 months). Median progression‐free survival (PFS) was 100 days (95% confidence interval [CI], 62‐138), and median survival was 390 days (95% CI, 264‐516). Interestingly, PFS was 211 days (95% CI, 52‐370) in patients with wild type (WT) KIT and 82 days (95% CI, 53‐111) in non‐WT patients (10 mutant, 6 not assessed). A synergistic effect on cell line proliferation and apoptosis was found with imatinib and doxorubicin combination.

CONCLUSIONS:

Low‐dose chemobiotherapy combination showed promising activity in heavily pretreated gastrointestinal sarcoma tumor patients, especially in those with WT‐KIT genotype. Cancer 2010. © 2010 American Cancer Society.     

Bone sarcomas of the head and neck in children: the St Jude Children's Research Hospital experience

BACKGROUND: Bone sarcomas of the head and neck are difficult to resect. The authors reviewed their institutional experience with these tumors to characterize patients' clinical findings and to assess the impact of surgical resection on outcome. METHODS: The records of the 28 patients with bone sarcomas originating in the head and neck treated at St. Jude Children's Research Hospital between March 1962 and January 1998 were reviewed. RESULTS: There were 10 males and 18 females (median age, 12.6 years) each with a single sarcoma: osteosarcoma (18), Ewing sarcoma (7), malignant fibrous histiocytoma (MFH) (2), and fibrosarcoma (1). Primary tumor sites included the maxilla (13), skull (10), mandible (2), and other sites (3). All but one patient with Ewing sarcoma had localized disease at the time of diagnosis. All patients underwent surgery: complete resection, 8; gross total resection, 4; incomplete resection, 14; and biopsy only, 2; 22 also received chemotherapy. Radiotherapy was given to all patients with Ewing sarcoma and to four patients with primary osteosarcoma. Twelve patients survived a median of 8.4 years after diagnosis, 14 died of disease, and 2 died of unrelated causes. Local disease progression was evident in 12 patients (9 with osteosarcoma, 2 with MFH, and 1 with Ewing sarcoma) who died of disease, 9 of whom had the initial treatment of biopsy alone or incomplete resection. Patients with osteosarcoma who had the initial treatment of incomplete resection or biopsy alone were more likely to experience local failure (P = 0.001) and had poorer survival (P = 0.014) than those who underwent complete or gross total resection. CONCLUSIONS: Bone sarcomas of the head and neck are rare among children and most often are localized at the time of diagnosis. Incomplete resection of osteosarcoma is associated with local failure and poor outcome. Although aggressive surgery is essential for the cure of osteosarcoma, its necessity in the treatment of Ewing sarcomas remains controversial.     

Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children's Research Hospital OS99 trial

BACKGROUND:

The standard treatment of osteosarcoma includes cisplatin and high‐dose methotrexate (HDMTX); both agents exert significant toxicity, and HDMTX requires complex pharmacokinetic monitoring and leucovorin rescue. In the previous OS91 trial, the treatment of localized disease with carboplatin, ifosfamide, doxorubicin, and HDMTX yielded outcomes comparable to those of cisplatin‐based regimens and caused less toxicity. To build on this experience, the authors conducted a multi‐institutional trial (OS99) that evaluated the efficacy of carboplatin, ifosfamide, and doxorubicin without HDMTX in patients with newly diagnosed, localized, resectable osteosarcoma.

METHODS:

Treatment was comprised of 12 cycles of chemotherapy administered over 35 weeks: 3 cycles of carboplatin (dose targeted to area under the concentration‐time curve of 8 mg/mL × min on Day 1) and ifosfamide (at a dose of 2.65 g/m² daily ×3 days) and 1 cycle of doxorubicin (at a dose of 25 mg/m² daily ×3 days) before surgical resection, followed by 2 additional cycles of the combination of carboplatin and ifosfamide and 3 cycles each of doxorubicin (25 mg/m² daily ×2 days) combined with ifosfamide or carboplatin.

RESULTS:

A total of 72 eligible patients (median age, 13.4 years) were enrolled between May 1999 and May 2006. Forty of the 66 (60.6%) evaluable patients had good histologic responses (>90% tumor necrosis) to preoperative chemotherapy. The estimated 5‐year event‐free survival rate was 66.7% ± 7.0% for the OS99 trial compared with 66.0% ± 6.8% for the OS91 trial (P = .98). The estimated 5‐year survival rate was 78.9% ± 6.3% for the OS99 trial and 74.5% ± 6.3% for the OS91 trial (P = .40).

CONCLUSIONS:

The regimen used in the OS99 trial was found to produce outcomes comparable to those of cisplatin‐containing or HDMTX‐containing regimens. This therapy offers a good alternative for patients, particularly those who demonstrate an intolerance of HDMTX, and for institutions that cannot provide pharmacokinetic monitoring for MTX. Cancer 2011. © 2011 American Cancer Society.