Andrea Hayes-Jordan

Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children's Oncology Group Study D9803

PURPOSE The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC). PATIENTS AND METHODS Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided alpha level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC. RESULTS A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups. CONCLUSION For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.

Novel treatment for desmoplastic small round cell tumor: hyperthermic intraperitoneal perfusion

BACKGROUND Less than 200 cases have been reported in the world literature since desmoplastic small round cell tumor (DSRCT) was first described in 1989. To date, chemotherapy, radiation therapy, and surgery have resulted in a poor survival of 30% to 55%. We used hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of complete tumor resection as an adjunct to treatment of pediatric and adolescent patients with DSRCT. PURPOSE The aim of this study was to assess survival as a function of disease burden and response to HIPEC in patients with DSRCT. METHODS Twenty-four patients with DSRCT from 1995 to 2008 were evaluated. Eight patients undergoing cytoreductive surgery and HIPEC were compared with 16 historical controls that had chemotherapy +/- radiation therapy or surgery alone. RESULTS Median age was 12 years in 8 patients who underwent HIPEC. Significant morbidity after HIPEC included renal insufficiency and gastroparesis. There were no operative mortalities. The estimated median overall 3-year survival for patients not undergoing surgery or HIPEC was 26% compared with 71% in patients who underwent HIPEC. Extraabdominal metastasis correlated with poor survival (P = .021). CONCLUSION Hyperthermic intraperitoneal chemotherapy is safe in children with DSRCT. It may prolong disease-free survival in selected cases of DSRCT. It may have a limited role as an adjunct to local control in patients with DSRCT.

The diagnosis and management of desmoplastic small round cell tumor: a review

Purpose of review Desmoplastic small round cell tumor (DSRCT) is a rare disease of children, adolescents and young adults, which begins in the abdominal cavity. Less than 200 cases are reported in the world literature. Because of the rarity of this disease, little is known about optimal treatment. Patients may present with dozens to hundreds of tumors studding the peritoneal cavity. Despite this presentation, it is not primarily considered metastatic but multifocal. It can metastasize to the liver or lung. Chemotherapy, radiotherapy, and surgical approaches have not been standardized. Neoadjuvant chemotherapy often yields a partial response; however, tumors may remain surgically un-resectable. An aggressive approach to treatment is required to maximize long-term remission. This review is designed to outline the evidence-based multidisciplinary approach to DSRCT. Recent findings Complete surgical resection, including 1–2 mm implants, is necessary to achieve long-term disease control. Hyperthermic intraperitoneal chemotherapy using cisplatin has recently been found to be a low morbidity treatment option for DSRCT patients. Yttrium microspheres have been used successfully to treat liver metastasis from DSRCT. Summary DSRCT is a rare tumor that requires a multidisciplinary approach which includes aggressive surgical extirpation to provide long-term disease control.

Rhabdomyosarcoma in children

Purpose of review Rhabdomyosarcoma is a rare childhood cancer that affects only approximately 300 children per year in the United States. The purpose of this review is to provide the reader a greater understanding of the complex diagnosis, assessment and treatment of rhabdomyosarcoma in children. Recent findings This review focusses on the new risk classification that is the foundation of all present rhabdomyosarcoma protocols developed by the Childrens Oncology Group of the United States and Canada. The new risk classification of low, intermediate and high encompasses the staging and grouping categories that were previously utilized. Summary This review also provides a complete list of diagnostic tests and imaging required to identify rhabdomyosarcoma in any body site. Rapid diagnosis and recognition of this rare disorder will facilitate long-term survival. Rhabdomyosarcoma today has an overall survival of 70%, depending on the site, and in orbital and other sites survival is as high as 90%. The treatment approaches that have led to this doubling in survival over the last 25 years are reviewed. For a practitioner, this review can be used as a reference when a child with a suspicious mass is encountered.

Prognostic Significance and Tumor Biology of Regional Lymph Node Disease in Patients With Rhabdomyosarcoma: A Report From the Children's Oncology Group

PURPOSE Regional lymph node disease (RLND) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of RLND to prognosis for patients with RMS. PATIENTS AND METHODS Patient characteristics and survival outcomes for patients enrolled onto Intergroup Rhabdomyosarcoma Study IV (N = 898, 1991 to 1997) were evaluated among the following three patient groups: nonmetastatic patients with clinical or pathologic negative nodes (N0, 696 patients); patients with clinical or pathologic positive nodes (N1, 125 patients); and patients with a single site of metastatic disease (77 patients). RESULTS Outcomes for patients with nonmetastatic alveolar N0 RMS were significantly better than for patients with N1 RMS (5-year failure-free survival [FFS], 73% v 43%, respectively; 5-year overall survival [OS], 80% v 46%, respectively; P < .001). Patients with a single site of alveolar metastasis had even worse FFS and OS (23% FFS and OS, P = .01) when compared with patients with N1 RMS; however, the differences was not as large as the differences between patients with N0 RMS and N1 RMS. For embryonal RMS, there was no statistically significant difference in FFS or OS (P = .41 and P = .77, respectively) for patients with N1 versus N0 RMS. Gene array analysis of primary tumor specimens identified that genes associated with the immune system and antigen presentation were significantly increased in N1 versus N0 alveolar RMS. CONCLUSION RLND alters prognosis for alveolar but not embryonal RMS. For patients with N1 disease and alveolar histology, outcomes were more similar to distant metastatic disease rather than local disease. Current data suggest that more aggressive therapy for patients with alveolar N1 RMS may be warranted.

TRAIL and Doxorubicin Combination Induces Proapoptotic and Antiangiogenic Effects in Soft Tissue Sarcoma In vivo

Purpose: Novel therapeutic approaches for complex karyotype soft tissue sarcoma (STS) are crucially needed. Consequently, we assessed the efficacy of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), in combination with chemotherapy, on local and metastatic growth of human STS xenografts in vivo. Experimental Design: TRAIL was evaluated alone and combined with low-dose doxorubicin in two human STS severe combined immunodeficient mouse xenograft models using fibrosarcoma (HT1080; wild-type p53) and leiomyosarcoma (SKLMS1; mutated p53), testing for effects on local growth, metastasis, and overall survival. Magnetic resonance imaging was used to evaluate local growth and bioluminescence was used to longitudinally assess lung metastases. Tissues were evaluated through immunohistocemistry and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining for treatment effects on tumor cell proliferation, apoptosis, angiogenesis, angiogenic factors, and TRAIL receptor expression. Quantitative real-time polymerase chain reaction (QRTPCR) angiogenesis array was used to assess therapy-induced gene expression changes. Results: TRAIL/doxorubicin combination induced marked STS local and metastatic growth inhibition in a p53-independent manner. Significantly increased (P < 0.001) host survival was also demonstrable. Combined therapy induced significant apoptosis, decreased tumor cell proliferation, and increased TRAIL receptor (DR4 and DR5) expression in all treated tumors. Moreover, decreased microvessel density was observed, possibly secondary to increased expression of the antiangiogenic factor CXCL10 and decreased proangiogenic interleukin-8 cytokine in response to TRAIL/doxorubicin combination, as was also observed in vitro. Conclusions: Given the urgent need for better systemic approaches to STS, clinical trials evaluating TRAIL in combination with low-dose chemotherapy are potentially warranted. Clin Cancer Res; 16(9); 2591–604. ©2010 AACR.

Outcomes in pediatric melanoma: Comparing prepubertal to adolescent pediatric patients

Objective:The aim of this study was to determine the influence of age on outcome in pediatric melanoma patients and to identify factors associated with positive lymph node status in this population. Methods:A retrospective review of a prospective pediatric melanoma database, using sentinel lymph node biopsy (SLNB), from 1992 to 2006, identified 109 patients with the primary diagnosis of melanoma. Patient age was dichotomized as prepubescent (<10 years of age) and adolescent (≥10–18 years of age). Factors investigated included patient race, sex, and lymph node status and tumor thickness, Spitzoid or Non-Spitzoid histology, radial growth phase, and vascular invasion. The Fishers exact test was used to compare patient groups. Time-to-event analysis was performed using the Kaplan-Meier method. Results:There were 25 prepubescent and 84 adolescent patients. Prepubescent patients were more often non-White, had greater tumor thickness, more spitzoid tumors and more vascular invasion. Ten-year overall survival (OS) was 89% and 10-year event-free survival (EFS) was 73%. Among 57 patients who had an SLNB, prepubertal patients had a higher percentage of sentinel lymph node positivity. The odds having a positive SLNB decreased by 13% each year with increasing age. Patients with a tumor thickness ≥2.01 mm had higher odds of having a positive lymph node compared with those patients with a tumor thickness ⩽1.0. Conclusions:This is the largest known study of prepubertal melanoma patients. Although OS and EFS did not differ by age groups, younger ages showed increased risk of lymph node metastasis and thicker tumors. This suggests that the younger pediatric patients may have a disease that differs biologically from that of the older pediatric patients.

Local control and outcome in children with localized vaginal rhabdomyosarcoma: A report from the Soft Tissue Sarcoma committee of the Children's Oncology Group

The local control approach for girls with non‐resected vaginal rhabdomyosarcoma (RMS) enrolled onto Intergroup RMS Study Group (IRSG)/Childrens Oncology Group (COG) studies has differed from that used at other primary sites by delaying or eliminating radiotherapy (RT) based on response achieved with chemotherapy and delayed primary resection.

Prognostic Significance of Tumor Response at the End of Therapy in Group III Rhabdomyosarcoma: A Report From the Children's Oncology Group

PURPOSE Some patients with rhabdomyosarcoma (RMS) achieve less than a complete response (CR) despite receiving all planned therapy. We assessed the impact of best response at the completion of all therapy on patient outcome. PATIENTS AND METHODS We studied 419 clinical group III participants who completed all protocol therapy without developing progressive disease for Intergroup Rhabdomyosarcoma Study (IRS) IV. Response (complete resolution [CR], partial response [PR; > or = 50% decrease], or no response [NR; < 50% decrease and < 25% increase]) was determined by radiographic measurement and categorized by the best response. RESULTS At the end of therapy, 341 participants (81%) achieved a best response of CR and 78 (19%) had a best response of PR/NR. Five-year failure-free survival was similar for participants achieving CR (80%) and PR/NR (78%). After adjustment for age, nodal status, primary site, and histology, there was no significant indication of lower risk of failure (hazard ratio [HR], 0.77; 95% CI, 0.46 to 1.27; P = .3) nor death (HR, 0.63; 95% CI, 0.36 to 1.09; P = .1) for CR versus PR/NR participants. Seventeen participants with a best response of PR/NR had surgical procedures; eight (50%) of 16 with available pathology reports had residual viable tumor and only three achieved a complete resection. Resection of residual masses was not associated with improved outcome. CONCLUSION CR status at the end of protocol therapy in clinical group III participants was not associated with a reduction of disease recurrence and death. Aggressive alternative therapy may not be warranted for RMS patients with a residual mass at the end of planned therapy.

Melanoma incidence rises for children and adolescents: An epidemiologic review of pediatric melanoma in the United States

BACKGROUND/PURPOSE This study was conducted to determine the influence of age on disease presentation and evaluate the change in pediatric melanoma incidence between 1998 and 2007. METHODS We performed a retrospective review of all children ≤18 years with cutaneous melanoma who were included in the 2007 National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2007. RESULTS We identified a total of 1447 patients with cutaneous melanoma. The overall average annual melanoma incidence was 5.4 per 1 million children and adolescents in the U.S., which increased throughout the study period. Most patients (89%) were at least 10 years of age (average age 15 years). Melanoma in situ (21%), thin (<1 mm) lesions (37%), stage I disease (46%), and superficial spreading histology (25%) were common at presentation. Only 1% of patients presented with distant metastases. Preadolescents younger than age 10 were ethnically more diverse and more likely to present with non-truncal primaries and advanced disease (P<.01) compared to adolescents. CONCLUSIONS The incidence of pediatric melanoma in the U.S. is increasing. There are significant differences between children and adolescents which suggest age-based inherent differences in the biology of the disease may exist.