Treatment Of Pediatric Sarcomas Research Articles

Combinatorial cellular therapy in pediatric solid tumors with natural killer (NK) and genetically engineered myeloid cells (GEMys).

2561 Background: Early human studies with Natural Killer (NK) cells have shown promise, harnessing their ability to infiltrate into tumors and be tumoricidal. However, these effects can be limited by adenosine, reactive oxygen species, and TGF-β in the highly immune suppressive tumor microenvironment (TME). TGF-β and downstream SMAD3 signaling in Natural Killer (NK) cells have been shown to cause decreased cytokine production, downregulation of activating cell surface receptors, and attenuated cytotoxic function against solid tumors. Exposure to TGF-β during cell culture generates expanded NK cells with increased resistance to TGF-β signaling, dubbed TGF-β imprinted NK cells. In vitrostudies have shown that these cells have increased cytokine production and cytotoxic function in the presence of TGF-β. However, their in vivo trafficking, modulation of the TME, and therapeutic efficacy remain understudied. Our lab has previously shown that when given to tumor-bearing mice, myeloid cells modified to produce IL-12 (IL-12-Genetically Engineered Myeloid cells, aka IL-12 GEMys) are effective at homing to tumor and metastatic sites and, via IL-12 secretion and TME modulation, increase NK cell presence and activation in these sites. They hold great promise as combination therapy, enhancing the effectiveness of other cellular therapies such as NK cell therapy. A current clinical trial exploring TGF-β Imprinted, Ex Vivo Expanded, Universal Donor NK Cell Infusions in relapsed sarcomas is underway (NCT05634369). Methods: In vitro experiments were conducted with the xCELLigence real-time cell analysis system. The human osteosarcoma cell line 143B and human rhabdomyosarcoma cell line RH-30 were evaluated for cell death after co-culture with healthy donor NK cells or TGF-β imprinted NK cells (E:T ratio of 5:1) in isolation and in combination with IL-12 GEMys (E:T ratio of 2:1). Results: TGF-β imprinted NK cells are significantly more effective at tumor cell killing of both 143B and RH30 cell lines in-vitro compared to regular expanded NK cells (WT NK cells), with >90% decrease in cell index compared to 50-60%, respectively, after 48 hours of co-culture. IL-12 GEMys also significantly enhance the cytotoxic effects of WT NK cells, increasing cell killing to 70-80% compared to co-culture with untransduced GEMy controls. Conclusions: These initial in-vitro experiments provide insight into the promising effectiveness of NK-myeloid cell combination therapies in the treatment of pediatric sarcomas. Ongoing in vitroexperiments include cytokine quantification by ELISA and flow cytometric analysis of NK cell activation and proliferation markers. Our preliminary results provide rationale to continue studying the in vivo efficacy of TGF-β imprinted NK cell monotherapy and in combination with IL-12 GEMys in the treatment of tumor-bearing NSG mice.

Evaluation of prevalence and outcomes of serial tyrosine kinase inhibitor use in pediatric patients with advanced solid tumors.

Multitargeted tyrosine kinase inhibitors (mTKIs) are increasingly utilized in the treatment of pediatric sarcomas and other solid tumors. It is unknown whether serial treatment with multiple TKIs provides a benefit and which patients are most likely to benefit from mTKI rechallenge. We performed a retrospective cohort study of pediatric cancer patients who received serial mTKI therapy off-study between 2007 and 2020 as either monotherapy or combination therapy. We report patient characteristics, clinical outcomes, dosing patterns, and treatment-associated toxicity. The study cohort included 25 patients. The overall prevalence of serial mTKI therapy among all patients treated for sarcoma at our institution was 3.7%, and the response rate to second mTKI was 9%. Median 6-month progression-free survival (PFS) and overall survival (OS) from start of second mTKI were 42.1% (95% CI: 20.4%-62.5%) and 79.1% (95% CI: 57.0%-90.8%), respectively. Patients who had received 4months or more (n=11) of therapy with first mTKI had significantly longer PFS versus those who received less than 4months (n=11; p=.001). Thirty-three percent of patients discontinued second mTKI due to toxicity. Six (40%) of 15 patients who discontinued the first mTKI due to progression had either a partial response or stable disease on the second mTKI. We observed a low response rate to mTKI rechallenge. However, we identified patients who had been treated with first mTKI for ≥4months as more likely to have prolonged stable disease with second mTKI. Several patients had a response or stable disease on the second mTKI despite having progressed on the first mTKI. Though toxicity was common, only a minority of patients discontinued the second mTKI due to toxicity.

Efficacy and safety of pazopanib in the treatment of pediatric sarcoma: Retrospective cohort study.

e23526 Background: The presence of frequent genetic alterations activating the tyrosine kinase (TKI) signaling pathway has recently led to a more targeted therapeutic approach. We describe our institutional experience using pazopanib for pediatric sarcomas. Methods: We performed a retrospective, IRB approved, chart review of all patients with sarcoma treated with pazopanib off-study at Ankara University Pediatric Oncology Clinic between 2019–2021. Results: Twenty-five patients were identified. Median age at commencement of pazopanib treatment was 13 years old (range 4 to18 years; 15 male: 10 female). Median duration on treatment with pazopanib was 16 months (range, 2 to 33). The median duration between the diagnosis of sarcoma and the beginning of pazopanib was 17.0 months (range, 1 to 80 months). Twelve of 25 patients due to metastatic disease at diagnosis, pazopanib was started with first-line chemotherapy and/or continued as maintenance therapy (Group 1). In the remaining 13 of 25 patients, received a second-line chemotherapy with pazopanib was administrated due to relapsed disease (Group 2). Nine patients (36.0%) ( 2 patients in group 1 and 7 patients in group 2) had died from progressive disease ranging between 13 and 70 months (median 33 months) after the diagnosis. OS rate was 64,0% in the entire cohort; group 1 and group 2 were 83,3%, and 46,2%, respectively. The overall median OS was 69.4 months. No new pazopanib-related adverse effects were identified. Conclusions: Pazopanib appears to be an effective treatment for pediatric sarcoma. Treatment with pazopanib is well-tolerated and could have a role to maintain response in patients with pediatric sarcoma. Further studies are needed to better define the use of this regimen in the upfront management of those patients.

Abstract 5756: Next-generation sequencing (NGS) reveals different molecular profiles of pediatric sarcoma in children and adults

Abstract Background: Pediatric sarcomas represent approximately 12% of all pediatric cancers with over 100 subtypes. Although some molecular detection techniques can be used to assist the diagnosis and treatment of pediatric sarcoma, it still remains challenging due to overlapping morphological features and limited biopsy specimens. Here we performed next generation sequencing (NGS) to analyze the molecular profiles of pediatric and adult sarcomas in China. Methods: A total of 700 Chinese patients with sarcoma were collected. The tumor tissue and matching blood specimens were tested by the integrative DNA and RNA sequencing panel Onco Panscan plus࣪ at Genetronhealth. Results: Of the 700 sarcoma patients, there were 224 children (32%) and 476 adults (68%). Difference from the almost same ratio of men to women in adults, there were more males (n = 134) than females (n = 90) in children. Rhabdomyosarcoma was the most common soft tissue tumor in children, accounting for 24.1% (n = 54), followed by Ewing's sarcoma (9.8%, n = 22) and Osteosarcoma (8.5%, n = 34), while Angiosarcoma (3.8%, n = 18) and Fibrosarcoma (3.6%, n = 17) were the most common in adults. Based on mutation types, the frequent alterations were missense mutations (n = 326, 51.2%), fusions (n = 129, 20.3%) and copy number variants (n = 66, 10.4%) in children with a mean of 3 mutations per patient, and missense mutations (n = 1438, 66.8%), fusions (n = 221, 10.3%) and truncating mutations (n = 215, 10.0%) in adults with an average 5 mutations. TP53 (12.9%, n = 29), EWSR1 (8.9%, n = 20) and ALK mutations (6.7%, n = 15) were common in children, which was distinct from TP53 (29.4%, n = 140), NF1 (4.8%, n = 23), CTNNB1 (4.2%, n = 20) and RB1 (4.2%, n = 20) in adults. Based on NGS results, pathological subtypes could be confirmed in 40.2% (90/224) and 48.1% (229/476) of children and of adults sarcoma patients, respectively. In addition, we identified a total of 72 drug-targeted gene mutations in the 57 children patients, of which 35 (48.6%) gene mutations could be targeted by FDA-approved drugs. In adults, 256 drug-targeted gene mutations were detected and the proportion of actionable mutations was up to 78.9% (n = 202). Conclusion: The genomic landscape of pediatric sarcomas is different from that of adults. NGS aids in the subtype classification and clinical guidance of pediatric sarcomas, providing evidence for personalized treatments with clinical benefit. Citation Format: Weisong Cai, Fang Liu, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Shu Li. Next-generation sequencing (NGS) reveals different molecular profiles of pediatric sarcoma in children and adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5756.

Targeting Tumor-Associated Macrophages in the Pediatric Sarcoma Tumor Microenvironment.

For many pediatric sarcoma patients, multi-modal therapy including chemotherapy, radiation, and surgery is sufficient to cure their disease. However, event-free and overall survival rates for patients with more advanced disease are grim, necessitating the development of novel therapeutic approaches. Within many pediatric sarcomas, the normal immune response, including recognition and destruction of cancer cells, is lost due to the highly immune suppressive tumor microenvironment (TME). In this setting, tumor cells evade immune detection and capitalize on the immune suppressed microenvironment, leading to unchecked proliferation and metastasis. Recent preclinical and clinical approaches are aimed at understanding this immune suppressive microenvironment and employing cancer immunotherapy in an attempt to overcome this, by renewing the ability of the immune system to recognize and destroy cancer cells. While there are several factors that drive the attenuation of immune responses in the sarcoma TME, one of the most remarkable are tumor associated macrophage (TAMs). TAMs suppress immune cytolytic function, promote tumor growth and metastases, and are generally associated with a poor prognosis in most pediatric sarcoma subtypes. In this review, we summarize the mechanisms underlying TAM-facilitated immune evasion and tumorigenesis and discuss the potential therapeutic application of TAM-focused drugs in the treatment of pediatric sarcomas.

Modulation of u-PA, MMPs and their inhibitors by a novel nutrient mixture in pediatric human sarcoma cell lines

Pediatric sarcomas are highly aggressive tumors that are characterized by high levels of matrix metalloproteinase (MMP)-2 and -9 secretions that degrade the ECM and basement membrane, allowing cancer cells to spread to distal organs. Proteases play a key role in tumor cell invasion and metastasis by digesting the basement membrane and ECM components. Strong clinical and experimental evidence demonstrates association of elevated levels of u-PA and MMPs with cancer progression, metastasis and shortened patient survival. MMP activities are regulated by specific tissue inhibitors of metalloproteinases (TIMPs). Our main objective was to study the effect of a nutrient mixture (NM) on activity of u-PA, MMPs and TIMPs in various human pediatric sarcomas. Human osteosarcoma MNNG-HOS, osteosarcoma U-2OS and rhabdomyosarcoma RD cell lines (ATCC) were cultured in their respective media and treated at confluence with NM at 0, 50, 100, 250, 500 and 1,000 µg/ml. Analysis of u-PA activity was carried out by fibrin zymography, MMPs by gelatinase zymography and TIMPs by reverse zymography. All sarcoma cell lines studied expressed u-PA, which was inhibited by NM in a dose-dependent manner. On gelatinase zymography, osteosarcoma MNNG-HOS showed a band corresponding to MMP-2 and induction of MMP-9 with PMA (100 ng/ml) treatment. U-2OS osteosarcoma cells showed strong bands corresponding to inactive MMP-2 and MMP-9 and faint bands corresponding to active MMP-2 and MMP-9 dimer; PMA treatment enhanced MMP-9 and MMP-9 dimer activity. Rhabdomyosarcoma showed MMP-2 and faint MMP-9 bands; PMA treatment enhanced MMP-9 expression. NM inhibited their expression in a dose-dependent manner. Activity of TIMPs was upregulated by NM in all cancer cell lines in a dose-dependent manner. Analysis revealed a positive correlation between u-PA and MMPs and a negative correlation between u-PA/MMPs and TIMPs. These findings suggest the therapeutic potential of NM in treatment of pediatric sarcomas.

Abstract 2753: Targeting bromodomain and extra-terminal (BET) family member BRD4 for treatment of pediatric sarcomas.

Abstract Background. Potent inhibitors of histone binding modules have the potential to suppress, selectively, transcription of specific genes, including MYC family of transcription factors. JQ1 binds competitively to acetyl-lysine recognition motifs, or bromodomains. JQ1 inhibits BET bromodomain, and down-regulates MYC transcription. Ewing sarcoma (EWS) and alveolar rhabdomyosarcoma (ARMS) are associated with high expression of c-MYC and MYCN, respectively (Delmore JE, Cell 2011; Filippakopoulos P, Nature 2010). Consequently, we have evaluated sensitivity of EWS and ARMS cell lines and xenograft models to JQ1. Methods. EWS and ARMS cells were incubated with JQ1, or JQ1R (non-active enantiomer) for 96 hrs. Cell viability was determined by Alamar Blue staining. C-MYC and MYCN were determined by immunoblotting. Xenograft tumor lines were grown in CB17 female SCID mice. JQ1 was administered P.O. at 30 mg/kg (BID) or 50 mg/kg (SID) for up to 3 weeks. Assessment of JQ1 activity was as described (Houghton P, Ped Blood & Cancer, 2007). The effect of JQ1 on proliferation and tube formation of human umbilical vascular endothelial cells (HUVECs) was as described (Bid H, Mol Cancer Ther, 2012). Results. For all cell lines, the IC50 concentration for JQ1R (inactive enantiomer) was > 10 microM. EWS cell lines (n=9) segregated into two distinct groups with IC50 < 1 microM, (ES-1, ES-2, ES-3, ES-4, ES-7, ES-8) and cell lines with significantly higher IC50s (IC50 > 7 microM ES-6, EW8, CHLA-258). Seven of 9 ARMS cell lines demonstrated sensitivity to JQ1 (IC50 < 1 microM) whereas 2 lines were insensitive (IC50 > 10 microM Rh18, Rh30). JQ1 (500 nM, 24 hr) markedly down-regulated c-MYC in Rh41, and to a lesser extent in Rh36. MYCN expression in Rh5 ARMS cell line was also suppressed by JQ1. Of interest, JQ1 did not suppress c-MYC in any EWS cell line. In vivo, BID and SID dosing was well tolerated (mortality 1.2%) and gave similar antitumor activity. JQ1 significantly retarded growth of all 4 sarcoma models (Rh10, Rh28 ARMS and EW5, EW8 EWS lines. T/C at day 21 range 0.30 – 0.43). Of note, while EW8 cells in vitro were resistant to JQ1 (IC50 > 10 microM), the xenografts were equally sensitive as other lines to JQ1 treatment, suggesting JQ1 exerted effects on stroma/angiogenesis. In vitro, JQ1 (500 nM) suppressed tube formation of HUVECs without decreasing viability. Conclusions. JQ1 potently inhibited proliferation of EWS and ARMS cells in vitro, with distinct groups demonstrating either sensitivity or resistance. Sensitivity was associated with decreased levels of MYCN or c-MYC in some cell lines. In vivo, JQ1 demonstrated significant antitumor activity in 4 xenograft lines, including EW8 derived from cells resistant to JQ1 in vitro. The potential for JQ1 to exert anti-angiogenic effects is suggested by its potent inhibition of HUVECs differentiation. Supported through a grant from SWOG Citation Format: Linlin Xiao, Doris A. Phelps, Laurence A. Baker, Jun Qi, Hemant K. Bid, Peter J. Houghton. Targeting bromodomain and extra-terminal (BET) family member BRD4 for treatment of pediatric sarcomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2753. doi:10.1158/1538-7445.AM2013-2753

Survivin expression in Ewing sarcoma family of tumors.

9558 Background: Despite significant advances in treatment of pediatric sarcomas, the 5-year survival rates for metastatic and relapsed sarcomas remain dismal. Novel therapies are needed for such patients. Survivin, an inhibitor of apoptosis protein, is over expressed in several human cancers including lung, breast, colon, brain tumors, melanoma, neuroblastoma and soft tissue sarcomas and increased survivin expression is associated with reduced overall survival. The goal of the current study was to evaluate the role of survivin in Ewing sarcoma (ES), the second most common pediatric bone sarcoma. Methods: The goal of this study was to evaluate the expression of survivin in ES cell lines and tissue samples and to correlate the degree of expression with conventional clinical parameters. Survivin protein expression was determined in ES cell lines using Western Blot analysis. To examine a functional role for survivin in growth of ES cells, cells were treated with four siRNAs targeting survivin and cell growth and viability was assessed following survivin inhibition with the siRNAs. Immunohistochemical analysis was performed on paraffin-embedded patient samples using an anti-survivin antibody. Staining was scored from 0-3 depending on the percentage of positive cells. The degree of expression was correlated with clinical parameters such as tumor site, presence or absence of metastases, event-free and overall survival. Results: Survivin is overexpressed in a panel of ES cell lines. Gene silencing of survivin in the Ewing's sarcoma cell line TC-71 decreased cell growth by more than 50% for each survivin siRNA compared to non-silencing control siRNA. Survivin is overexpressed in majority of the ES tumor samples with a higher degree of expression noted in patients with metastatic disease and patients with relapsed disease. Further statistical analysis is currently underway to confirm the effect on survival rates. Conclusions: Our results show that survivin is overexpressed in ES cell lines and patient samples. Further, it plays an important role in cell growth and viability in-vitro. Higher degree of expression in patients with advanced and relapsed disease may indicate that survivin plays an imporatant role in ES pathogenesis and overall patient outcome.

Indications et apport de la TEP au FDG dans les sarcomes de l’enfant en 2011

FDG-PET has boomed in recent years for diagnosis, staging and the search for recurrence of a large number of tumors. This is particularly true for soft tissue sarcomas and musculoskeletal sarcomas, for which the first publications on the potential role of FDG-PET dating back to the early 1990s. The majority of published studies on adult sarcomas confer, possibly a mixed population. Studies dedicated to pediatrics population are much rarer. The “Standards, Options and Recommendations” of the French Federation of Anticancer Centers published in 2003 on “The use of FDG-PET in oncology” and make recommendations and expert advices as part sarcomas of adult patients. After a first part dedicated to the particular interpretation of FDG PET in children, the purpose of this paper is to review the potential contribution of this exam in the treatment of pediatric sarcomas.

Abstract 5349: Angiotensin-(1-7) inhibits the growth of human pediatric rhabdomyosarcoma in a mouse xenograft model

Abstract Pediatric sarcomas are rare tumors encompassing a diversity of histology and can arise in almost any part of the body. Despite overall advances in pediatric cancer treatment, outcomes in sarcomas have improved little in the past 2 decades. Based on the rarity of these tumors and the growing body of knowledge on late effects of conventional therapies in pediatric cancer survivors, it is imperative to develop new targeted agents for the treatment of these childhood diseases. In published studies, we showed that angiotensin-(1-7) [Ang-(1-7)], an endogenous seven amino acid peptide hormone, inhibited the proliferation of human lung cancer cells through activation of a unique AT(1-7) receptor and significantly reduced the size of human A549 lung tumor xenografts, in association with a decrease in the density of blood vessels and pro-angiogenic factors. These studies are in agreement with our Phase I clinical trial in which adult patients displaying clinical benefit had reduced circulating levels of the angiogenic factor PlGF; two of the four patients showing a clinical response to Ang-(1-7) had a primary sarcoma. The purpose of this study was to determine whether Ang-(1-7) may serve as a targeted chemotherapeutic agent for the treatment of pediatric sarcoma. Ang-(1-7) significantly inhibited the growth of A673 cells, a pediatric rhabdomyosarcoma cell line which expresses the AT(1-7) receptor mas. More importantly, the heptapeptide significantly reduced the proliferation of human A673 tumor xenograft growth in vivo. A673 rhabdomyosarcoma cells were injected into the flank of athymic male mice; the tumors grew to approximately 100 mm3 followed by infusion of saline or 24 µg/kg/h Ang-(1-7) for 18 days. The average volume of the tumors from mice treated with the heptapeptide was approximately 6-fold less than the size of the tumors from control animals (4770.6 ± 860.4 mm3 versus 664.8 ± 190.9 mm3; n = 6, p < 0.001). In addition, Ang-(1-7) administration markedly reduced tumor weight, from 7.2 ± 1.5 g in the saline-treated mice to 2.2 ± 0.8 g in Ang-(1-7)-treated mice (n = 6, p < 0.02). The decrease in tumor growth from Ang-(1-7)-medicated mice was associated with an approximate 50% reduction in immunoreactive Ki67, suggesting that the heptapeptide reduces tumor cell proliferation. Tumors from mice treated with Ang-(1-7) also showed a marked decrease in vessel density as assessed by CD34 immunoreactivity and morphology (7.6 ± 0.9 to 3.6 ± 0.6 vessels/per field, p < 0.001), demonstrating that the observed reduction in tumor growth was due, in part, to inhibition of angiogenesis. These studies suggest that the heptapeptide has both anti-proliferative and anti-angiogenic properties and that Ang-(1-7) may be a new, first-in-class compound for the treatment of pediatric sarcoma targeting a specific AT(1-7) receptor mas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5349. doi:10.1158/1538-7445.AM2011-5349

Preclinical activity of palifosfamide lysine (ZIO-201) in pediatric sarcomas including oxazaphosphorine-resistant osteosarcoma

Oxazaphosphorines, such as ifosfamide (IFA), are frequently used in the treatment of pediatric sarcomas. They are pro-drugs and undergo hepatic metabolism into the active moiety and potentially toxic by-products such as acrolein and chloracetaldehyde, which may cause hemorrhagic cystitis and encephalopathy, respectively. In addition, resistance to oxazaphosphorines can be mediated by overexpression of enzymes involved in their catabolism. Isophosphoramide mustard (IPM, palifosfamide) is the active moiety of IFA. In the current study, the activity of palifosfamide lysine (ZIO-201), a stable form of palifosfamide, was evaluated in a panel of sarcoma cell lines and tumor xenografts including oxazaphosphorine-resistant xenografts. The cytotoxic effect of palifosfamide lysine was studied in osteosarcoma (OS), Ewing's sarcoma (ES) and rhabdomyosarcoma (RMS) cell lines using the MTT assay. In vivo, the maximum tolerated dose (MTD) of palifosfamide lysine was determined in SCID mice based on a 3-day intravenous (IV) administration schedule. The effect on tumor growth and event-free survival was assessed at the MTD in all three sarcoma xenografts. In OS, cyclophosphamide (CPA)-resistant and -sensitive xenografts (OS31 and OS33, respectively) were evaluated for palifosfamide lysine activity. ALDH1A1 and ALDH3A1 gene expression data for the OS xenografts were mined from the Pediatric Preclinical Testing Program gene expression data. ALDH3A1 enzyme levels were compared between the CPA-resistant and -sensitive xenografts. Palifosfamide lysine was cytotoxic against all the cell lines tested with the IC(50) ranging from 0.5 to 1.5 microg/ml except for OS222, which had an IC(50) of 7 microg/ml. The IV MTD of palifosfamide lysine in mice was 100 mg/kg per day for three consecutive days. Tumor growth inhibition was seen in both OS31 and OS33 xenografts and the RMS xenograft resulting in a significant difference in event-free survival between the control and the treated groups. Differential gene expression of ALDH3A1 but not ALDH1A1 was noted in the OS31 xenograft. This was confirmed by RT-PCR and the ALDH3A1 enzyme assay. ALDH3A1 enzyme activity was measured at 100 mIU/mg of protein in OS31 xenograft but no significant activity was seen in the OS33 xenograft. We conclude that palifosfamide lysine has broad activity in a panel of sarcoma cell lines. It inhibits tumor growth in OS and RMS xenografts. Furthermore, it is active against the CPA-resistant, ALDH3A1 overexpressing, OS xenograft suggesting that it might have the potential of overcoming this resistance mechanism against oxazaphosphorines and may be an active agent in resistant/relapsed sarcomas in patients.

Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol.

Following their previous report on the activity of vinorelbine in the treatment of rhabdomyosarcoma, the authors report the results of a pilot study aimed at defining the optimal dose of vinorelbine when this agent is used in conjunction with continuous, orally administered low-dose cyclophosphamide to treat patients with refractory or recurrent sarcoma. It is hoped that the combination of vinorelbine and low-dose cyclophosphamide can be used as a maintenance regimen in an upcoming European trial involving high-risk patients with rhabdomyosarcoma. In the current pilot study, the cyclophosphamide dose was fixed at 25 mg/m2 per day for 28 days. Vinorelbine was administered intravenously on Days 1, 8, and 15, with trial doses escalated from an initial level of 15 mg/m2 in steps of 5 mg/m2; intrapatient dose escalation was not allowed. Between April 2002 and November 2003, 18 patients ages 2-23 years were treated with the study regimen after having received 1-4 (median, 2) other regimens previously. Ninety cycles were administered in total (median, 5 cycles per patient; range, 1-10 cycles per patient). Two cases of dose-limiting toxicity (Grade 4 neutropenia in both cases) were observed among the 5 patients who received vinorelbine at a dose of 30 mg/m2. Of the 41 cycles in which vinorelbine was administered at a dose of 25 mg/m2, Grade > or = 3 neutropenia was observed in 15 (37%); no other major toxicity was documented in association with these cycles. One complete remission and 6 partial remissions were noted among the 17 patients who had measurable disease. Three of the eight assessable patients with rhabdomyosarcoma (which was embryonal in two cases and alveolar in one) had responses to treatment. Combination therapy involving vinorelbine and low-dose cyclophosphamide was found to be feasible and to possess activity against recurrent sarcomas. The maintenance therapy doses recommended for use in the upcoming European trial are cyclophosphamide 25 mg/m2 per day for 28 days and vinorelbine 25 mg/m2 on Days 1, 8, and 15.

Treatment of pediatric sarcomas of the chest wall using intensive combined modality therapy

Treatment of pediatric sarcomas of the chest wall using intensive combined modality therapy