Prognostic Factors for Outcome in Localized Extremity Rhabdomyosarcoma. Pooled Analysis from Four International Cooperative Groups.

BACKGROUND: Extremity rhabdomyosarcomas do not always show satisfactory outcomes. We analyzed data from 643 patients treated in 14 studies conducted by European and North American groups between 1983 and 2004 to identify factors predictive of outcome. PROCEDURE: Clinical factors, including age; histology; site of primary (hand and foot vs. other); size; invasiveness (T stage); nodal involvement (N stage); and treatment factors, including post-surgical group; chemotherapy type and duration; radiotherapy; and treatment (before or after 1995); were evaluated for impact on overall survival (OS). RESULTS: 5-year OS were 67% (se 1.8). Multivariate analysis showed that lower OS correlated with age >3 years, T2 and N1 stage, incomplete initial surgery, treatment before 1995, and European cooperative group treatment. Patients with gross residual disease after initial incomplete resection/biopsy had similar outcomes in both continental groups. The better global survival of patients treated in American studies was accounted for by differences in outcome in the subset of those with grossly resected tumors (OS 86% [se 3] for COG patients vs. 68% [se 4] for European patients (P = 0.004)). When excluding chemotherapy duration from the model, analysis in this subset of patients showed that cooperative group (P = 0.001), site (P = 0.001), and T stage (P = 0.05) were all significant. However, after adding duration of chemotherapy (≥27 weeks) to the model, only primary site remained significant (P = 0.006). CONCLUSION: This meta-analysis confirms the role of many established prognostic factors but identifies for the first time that chemotherapy duration may have an impact on outcome in patients with grossly resected tumors.

Radiation therapy for Ewing's sarcoma: results from Memorial Sloan-Kettering in the modern era.

PURPOSE: To evaluate the outcomes of patients with Ewing's sarcoma family of tumors (ESFT) treated with modern radiotherapy techniques with MRI along with optimal chemotherapy. METHODS AND MATERIALS: The records of all 60 patients with ESFT who received radiation to the primary site between 1990 and 2004 were reviewed. All patients received chemotherapy, including vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Radiation was used as the sole modality for local control in 31 patients and was given either before (n=3) or after surgical resection (n=26) in the remainder. All patients had MRI and CT scan-based treatment planning, and 43% received intensity-modulated radiation therapy. Radiation doses ranged from 30 Gy to 60 Gy (median, 51 Gy), and 35% received hyperfractionated radiotherapy. RESULTS: Median age was 16 years (range, 2-40 years). Because of selection bias for radiotherapy, the majority of primary tumors were centrally located (72%): spine (n=18), pelvis (n=15), extremities (n=12), chest wall (n=5), head and neck (n=5), and other (n=5). Thirty-eight percent of patients presented with metastatic disease, and 52% of primary tumors were >or=8 cm. Actuarial 3-year local control was 77%. The presence of metastases at diagnosis was an adverse prognostic factor for local control (84% vs. 61%, p=0.036). No other predictive factors for local failure were identified. In patients without metastatic disease, 3-year disease-free and overall survival rates were 70% and 86%, respectively, whereas in patients with metastases they were both 21%. Follow-up of surviving patients was 6-178 months (median, 41 months). CONCLUSION: In this unfavorable cohort of ESFT patients, radiation therapy was an effective modality for local control, especially for patients without metastases. The presence of metastases at diagnosis is a predictive factor not only for death but also for local failure.

Prognostic value of metabolic tumor volume and velocity in predicting head-and-neck cancer outcomes.

PURPOSE: We previously showed that metabolic tumor volume (MTV) on positron emission tomography-computed tomography (PET-CT) predicts for disease recurrence and death in head-and-neck cancer (HNC). We hypothesized that increases in MTV over time would correlate with tumor growth and biology, and would predict outcome. We sought to examine tumor growth over time in serial pretreatment PET-CT scans. METHODS AND MATERIALS: From 2006 to 2009, 51 patients had two PET-CT scans before receiving HNC treatment. MTV was defined as the tumor volume ≥ 50% of maximum SUV (SUV(max)). MTV was calculated for the primary tumor, nodal disease, and composite (primary tumor + nodes). MTV and SUV velocity were defined as the change in MTV or SUV(max) over time, respectively. Cox regression analyses were used to examine correlations between SUV, MTV velocity, and outcome (disease progression and overall survival). RESULTS: The median follow-up time was 17.5 months. The median time between PET-CT scans was 3 weeks. Unexpectedly, 51% of cases demonstrated a decrease in SUV(max) (average, -0.1 cc/week) and MTV (average, -0.3 cc/week) over time. Despite the variability in MTV, primary tumor MTV velocity predicted disease progression (hazard ratio 2.94; p = 0.01) and overall survival (hazard ratio 1.85; p = 0.03). CONCLUSIONS: Primary tumor MTV velocity appears to be a better prognostic indicator of disease progression and survival in comparison to nodal MTV velocity. However, substantial variability was found in PET-CT biomarkers between serial scans. Caution should be used when PET-CT biomarkers are integrated into clinical protocols for HNC.

Validation that metabolic tumor volume predicts outcome in head-and-neck cancer.

PURPOSE: We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment (18)F-fluorodeoxydeglucose positron emission tomography (FDG PET)/ computed tomography (CT) predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study was to validate these results on an independent dataset, determine whether the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16(INK4a) status as a surrogate marker for human papillomavirus (HPV). METHODS AND MATERIALS: The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan before receiving definitive radiotherapy. MTV and maximum standardized uptake value (SUV(max)) were calculated for the primary tumor, the involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor vs. nodal MTV. RESULTS: Similarly to our prior findings, an increase in total MTV of 17 cm(3) (difference between the 75th and 25th percentiles) was associated with a 2.1-fold increase in the risk of disease progression (p = 0.0002) and a 2.0-fold increase in the risk of death (p = 0.0048). SUV(max) was not associated with either outcome. Primary tumor MTV predicted progression-free (hazard ratio [HR] = 1.94; p < 0.0001) and overall (HR = 1.57; p < 0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR = 4.23; p < 0.0001) and overall (HR = 3.21; p = 0.0029) survival in patients with p16(INK4a)-positive oropharyngeal cancer. CONCLUSIONS: This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk-stratifying biomarker in future studies of HNC.

Regional nodal involvement and patterns of spread along in-transit pathways in children with rhabdomyosarcoma of the extremity: a report from the Children's Oncology Group.

PURPOSE: To evaluate the incidence and prognostic factors for regional failure, with attention to the in-transit pathways of spread, in children with nonmetastatic rhabdomyosarcoma of the extremity. METHODS AND MATERIALS: The Intergroup rhabdomyosarcoma studies III, IV-Pilot, and IV enrolled 226 children with rhabdomyosarcoma of the extremity. Failure at the in-transit (epitrochlear/brachial and popliteal) and proximal (axillary/infraclavicular and inguinal/femoral) lymph nodes was evaluated. The median follow-up for the surviving patients was 10.4 years. RESULTS: Of the 226 children, 55 (24%) had clinical or pathologic evidence of either in-transit and/or proximal lymph node involvement at diagnosis. The actuarial 5-year risk of regional failure was 12%. The prognostic factors for poor regional control were female gender and lymph node involvement at diagnosis. In the 116 patients with a distal extremity primary tumor, 5% had in-transit lymph node involvement at diagnosis. The estimated 5-year incidences of in-transit and proximal nodal failure was 12% and 8%, respectively. The in-transit failure rate was 0% for patients who underwent radiotherapy and/or underwent lymph node sampling of the in-transit nodal site but was 15% for those who did not (p = .07). However, the 5-year event-free survival rate did not differ between these two groups (64% vs. 55%, respectively, p = .47). CONCLUSION: The high incidence of regional involvement necessitates aggressive identification and treatment of regional lymph nodes in patients with rhabdomyosarcoma of the extremity. In patients with distal extremity tumors, in-transit failures were as common as failures in more proximal regional sites. Patients who underwent complete lymph node staging with appropriate radiotherapy to the in-transit nodal site, if indicated, were at a slightly lower risk of in-transit failure.

Local therapy for rhabdomyosarcoma of the hands and feet: is amputation necessary? A report from the Children's Oncology Group.

PURPOSE: To evaluate the outcome of children with rhabdomyosarcoma (RMS) of the hand or foot treated with surgery and/or local radiotherapy (RT). METHODS AND MATERIALS: Forty-eight patients with nonmetastatic RMS of the hand or foot were enrolled on Intergroup Rhabdomyosarcoma Study III, IV-Pilot, and IV. Patients received multiagent chemotherapy with surgery and/or RT. Twenty-four patients (50%) underwent surgery without local RT, of whom 4 had complete resection and 20 had an amputation. The remaining 24 patients (50%) underwent local RT, of whom 2 required RT for microscopic residual disease after prior amputation. Median follow-up for surviving patients was 9.7 years. RESULTS: Actuarial 10-year local control was 100%; 10-year event-free survival and overall survival rates were 62% and 63%, respectively. Poor prognostic factors for recurrence included gross residual (Group III) disease and nodal involvement (p = 0.01 and 0.05, respectively). More patients in the RT group had alveolar histology, Group III disease, and nodal involvement, as compared with the surgery group. There was no difference in 10-year event-free survival (57% vs. 66%) or overall survival (63% vs. 63%) between patients who underwent surgery or local RT. Among relapsing patients, there were no long-term survivors. No secondary malignancies have been observed. CONCLUSIONS: Despite having high-risk features, patients treated with local RT achieved excellent local control. Complete surgical resection without amputation is difficult to achieve in the hand or foot. Therefore, we recommend either definitive RT or surgical resection that maintains form and function as primary local therapy rather than amputation in patients with hand or foot RMS.

Postradiation metabolic tumor volume predicts outcome in head-and-neck cancer.

PURPOSE: To explore the prognostic value of metabolic tumor volume measured on postradiation (18)F-fluorodeoxyglucose positron emission tomography (PET) imaging in patients with head-and-neck cancer. METHODS AND MATERIALS: Forty-seven patients with head-and-neck cancer who received pretreatment and posttreatment PET/computed tomography (CT) imaging along with definitive chemoradiotherapy were included in this study. The PET/CT parameters evaluated include the maximum standardized uptake value, metabolic tumor volume (MTV(2.0)-MTV(4.0); where MTV(2.0) refers to the volume above a standardized uptake value threshold of 2.0), and integrated tumor volume. Kaplan-Meier and Cox regression models were used to test for association between PET endpoints and disease-free survival and overall survival. RESULTS: Multiple postradiation PET endpoints correlated significantly with outcome; however, the most robust predictor of disease progression and death was MTV(2.0). An increase in MTV(2.0) of 21 cm(3) (difference between 75th and 25th percentiles) was associated with an increased risk of disease progression (hazard ratio [HR] = 2.5, p = 0.0001) and death (HR = 2.0, p = 0.003). In patients with nonnasopharyngeal carcinoma histology (n = 34), MTV(2.0) <18 cm(3) and MTV(2.0) ≥18 cm(3) yielded 2-year disease-free survival rates of 100% and 63%, respectively (p = 0.006) and 2-year overall survival rates of 100% and 81%, respectively (p = 0.009). There was no correlation between MTV(2.0) and disease-free survival or overall survival with nasopharyngeal carcinoma histology (n = 13). On multivariate analysis, only postradiation MTV(2.0) was predictive of disease-free survival (HR = 2.47, p = 0.0001) and overall survival (HR = 1.98, p = 0.003). CONCLUSIONS: Postradiation metabolic tumor volume is an adverse prognostic factor in head-and-neck cancer. Biomarkers such as MTV are important for risk stratification and will be valuable in the future with risk-adapted therapies.

Metabolic tumor volume predicts for recurrence and death in head-and-neck cancer.

PURPOSE: To evaluate the prognostic value of metabolic tumor volume measured on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and other clinical factors in patients treated for locally advanced head-and-neck cancer (HNC) at a single institution. MATERIALS AND METHODS: Between March 2003 and August 2007, 85 patients received positron emission tomography (PET)/computed tomography-guided chemoradiotherapy for HNC. Metabolically active tumor regions were delineated on pretreatment PET scans semiautomatically using custom software. We evaluated the relationship of (18)F-fluorodeoxyglucose-PET maximum standardized uptake value (SUV) and total metabolic tumor volume (MTV) with disease-free survival (DFS) and overall survival (OS). RESULTS: Mean follow-up for surviving patients was 20.4 months. The estimated 2-year locoregional control, DFS, and OS for the group were 88.0%, 69.5%, and 78.4%, respectively. The median time to first failure was 9.8 months among the 16 patients with relapse. An increase in MTV of 17.4 mL (difference between the 75th and 25th percentiles) was significantly associated with an increased hazard of first event (recurrence or death) (1.9-fold, p < 0.001), even after controlling for Karnofsky performance status (KPS) (1.8-fold, p = 0.001), and of death (2.1-fold, p < 0.001). We did not find a significant relationship of maximum SUV, stage, or other clinical factors with DFS or OS. CONCLUSIONS: Metabolic tumor volume is an adverse prognostic factor for disease recurrence and death in HNC. MTV retained significance after controlling for KPS, the only other significant adverse prognostic factor found in this cohort. MTV is a direct measure of tumor burden and is a potentially valuable tool for risk stratification and guiding treatment in future studies.

Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4.

Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.

Long-term results of three-dimensional conformal radiation therapy for patients with rhabdomyosarcoma.

BACKGROUND: The authors evaluated the outcome of patients with rhabdomyosarcoma (RMS) who were treated with three-dimensional (3D) conformal radiation therapy (RT) at a single institution. METHODS: The records of all 69 patients with RMS who received 3D RT from 1989 to 2001 were reviewed. All patients received multiagent chemotherapy with or without surgical resection. Follow-up of surviving patients ranged from 1.0 year to 12.8 years (median, 4.3 years). RESULTS: The median patient age was 6 years (range, 1-29 years), and there was a male:female ratio of 1.5:1. Forty-eight patients had embryonal sarcomas, 14 patients had alveolar sarcomas, and 7 patients had undifferentiated sarcomas. The parameningeal area (n = 22 patients) and the trunk (n = 21 patients) were the most common sites. Twelve percent of patients had Stage I disease, 10% of patients had Stage II disease, 51% of patients had Stage III disease, and 27% of patients had Stage V disease. Nine percent of patients were in clinical Group II, 64% of patients were in Group III, and 27% of patients were in Group IV. Regional lymph nodes were involved in 33% of patients, and 77% of tumors measured > or = 5 cm in greatest dimension. The actuarial 5-year local and regional control rates were 90% and 91%, respectively. No predictive factors for local failure were identified; however, alveolar histology was correlated with regional recurrence (29% compared with 4%; P = 0.02). The disease free and overall survival rates were 60% and 63% at 5 years, respectively. Disease stage was most predictive of 5-year survival (76% of patients with Stage I-III disease compared with 24% of patients with Stage IV disease; P < 0.001). CONCLUSIONS: High rates of local control were achieved in patients with RMS using 3D RT. Regional lymph node failure was increased significantly among patients with alveolar histology. Control of metastatic disease remains a formidable problem for patients with Stage IV RMS.