Natia Esiashvili

Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data.

Purpose The US population-based cancer registry Surveillance, Epidemiology, and End Results (SEER) database provides an opportunity to evaluate the incidence and survival rates of Ewing sarcoma (ES) for the past 3 decades. This analysis reflects trends for the diagnosis of localized versus metastatic disease and changes in ES survival in a setting of wide-ranging cancer care institutions across the United States, which is expected to be different from clinical trials published to date. Materials/Methods Data from the SEER public-access database were reviewed for the diagnosis of ES of the bone among patients of 1 to 19 years of age between 1973 and 2004. Age-adjusted incidence was analyzed for the entire group and for localized and metastatic disease separately over the past 3 decades. Actuarial survival rates were examined for 3 intervals: 1973 to 1982, 1983 to 1992, and 1993 to 2004. Results The overall incidence of ES seemed to remain unchanged with an average of 2.93 cases/1,000,000 reported annually between 1973 and 2004. The proportion of patients with distant metastasis among all ES cases remained in the 26% to 28% range, whereas the percent of localized cases slightly increased from 57% in 1973 to 1982 to 67% in 1993 to 2004 and the proportion of unstaged cases decreased from 17% to 5%. The 5-year survival of localized disease increased from 44% in the first study decade to 68% in the period after 1993, whereas 5-year survival of metastatic disease increased from 16% to 39%. The corresponding 10-year survival increased from 39% to 63% for localized disease and from 16% to 32% for metastatic ES. Conclusions The incidence of ES has not increased appreciably over the last 30 years. A marked decrease in the proportion of unstaged cases may be reflective of diagnostic improvement or changes in reporting. There is a clear improvement in survival for both localized and metastatic disease. Poorer outcome of metastatic patients still warrants intensification of therapy, which is currently being tested in several ongoing trials.

Bone Mineral Density Deficits in Survivors of Childhood Cancer: Long-term Follow-up Guidelines and Review of the Literature

The development of curative therapy for most pediatric malignancies has produced a growing population of childhood cancer survivors who are at increased risk for a variety of health problems resulting from their cancer or its treatment. Because of the fact that many treatment-related sequelae may not become clinically apparent until the survivor attains maturity or begins to age, the ability of primary care providers to anticipate late effects of treatment is essential for providing timely interventions that prevent or correct these sequelae and their adverse effects on quality of life. Altered bone metabolism during treatment for childhood cancer may interfere with attainment of peak bone mass, potentially predisposing to premature onset of and more severe complications related to osteopenia and osteoporosis. Bone mineral deficits have been reported after treatment for a variety of pediatric malignancies and represent morbidity that can be reduced or prevented through lifestyle changes and attention to other common cancer-related sequelae such as hypogonadism. The Childrens Oncology Group long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers provide risk-based surveillance recommendations that are based on expert opinion and review of the scientific literature for potential late effects of pediatric cancer therapy including osteopenia. This review summarizes the existing literature that has defined characteristics of cancer survivors at risk for bone mineral deficits and contributed to the surveillance and counseling recommendations outlined in the Childrens Oncology group long-term follow-up guidelines.

TREATMENT OF PANCREATIC CANCER TUMORS WITH INTENSITY- MODULATED RADIATION THERAPY (IMRT) USING THE VOLUME AT RISK APPROACH (VARA): EMPLOYING DOSE-VOLUME HISTOGRAM (DVH) AND NORMAL TISSUE COMPLICATION PROBABILITY (NTCP) TO EVALUATE SMALL BOWEL TOXICITY

The emergent use of a combined modality approach (chemotherapy and radiation) in pancreatic cancer is associated with increased gastrointestinal toxicity. Intensity-modulated radiation therapy (IMRT) has the potential to deliver adequate dose to the tumor volume while decreasing the dose to critical structures such as the small bowel. We evaluated the influence of IMRT with inverse treatment planning on the dose-volume histograms (DVHs) of normal tissue compared to standard 3-dimensional conformal radiation treatment (3D-CRT) in patients with pancreatic cancer. Between July 1999 and May 2001, 10 randomly selected patients with adenocarcinoma of the pancreatic head were planned simultaneously with 3D-CRT and inverse-planned IMRT using the volume at risk approach (VaRA) and compared for various dosimetric parameters. DVH and normal tissue complication probability (NTCP) were calculated using IMRT and 3D-CRT plans. The aim of the treatment plan was to deliver 61.2 Gy to the gross tumor volume (GTV) and 45 Gy to the clinical treatment volume (CTV) while maintaining critical normal tissues to below specified tolerances. IMRT plans were more conformal than 3D-CRT plans. The average dose delivered to one third of the small bowel was lower with the IMRT plan compared to 3D-CRT. The IMRT plan resulted in one third of the small bowel receiving 30.2+/-12.9 Gy vs. 38.5+/-14.2 Gy with 3D-CRT (p = 0.006). The median volume of small bowel that received greater than either 50 or 60 Gy was reduced with IMRT. The median volume of small bowel exceeding 50 Gy was 19.2+/-11.2% (range 3% to 45%) compared to 31.4+/-21.3 (range 7% to 70%) for 3D-CRT (p = 0.048). The median volume of small bowel that received greater than 60 Gy was 12.5+/-4.8% for IMRT compared to 19.8+/-18.6% for 3D-CRT (p = 0.034). The VaRA approach employing IMRT techniques resulted in a lower dose per volume of small bowel that exceeded 60 Gy. We used the Lyman-Kutcher models to compare the probability of small bowel injury employing IMRT compared to 3D-CRT. The BIOPLAN model predicted a small bowel complication probability of 9.3+/-6% with IMRT compared to 24.4+/-18.9% with 3D-CRT delivery of dose (p = 0.021). IMRT with an inverse treatment plan has the potential to significantly improve radiation therapy of pancreatic cancers by reducing normal tissue dose, and simultaneously allow escalation of dose to further enhance locoregional control.

Neuroblastoma in adults: Incidence and survival analysis based on SEER data†

Clinical data on survival outcomes of adult patients (defined as 20 years of age and older) with neuroblastoma are scarce due to the rarity of the disease. Small single institution reports have described worse outcomes for adults than pediatric patients.

Patterns of failure in advanced stage diffuse large B-cell lymphoma patients after complete response to R-CHOP immunochemotherapy and the emerging role of consolidative radiation therapy.

PURPOSE The role of consolidative radiation therapy (RT) after complete response (CR) to rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for stage III-IV diffuse large B-cell lymphoma (DLBCL) patients is unclear. We aimed to evaluate our institutional experience when consolidative RT is delivered to initial presenting sites or bulky sites in these patients. METHODS AND MATERIALS We identified 211 histologically confirmed stage III-IV DLBCL patients who received R-CHOP from January 2000 to May 2012 at our institution. Patterns of failure for patients who achieved CR to R-CHOP were analyzed. Local control (LC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier method and compared between patients who received R-CHOP alone versus R-CHOP plus consolidative RT using the log-rank test. Multivariate analyses were also performed using Cox proportional hazards model. RESULTS Detailed treatment records were available for 163 patients. After a median 6 cycles of R-CHOP, 110 patients (67.5%) achieved CR and were entered for analysis. Fourteen patients (12.7%) received consolidative RT. After median follow-up of 32.9 months, 43.8% of patients who received R-CHOP alone failed at the initial sites with or without distant recurrence (DR), whereas isolated DR only occurred in 3.7% of these patients. Consolidative RT was associated with significantly improved LC (91.7% vs 48.8%), DC (92.9% vs 71.9%), PFS (85.1% vs 44.2%), and OS (92.3% vs 68.5%; all Ps<.0001) at 5 years compared with patients with R-CHOP alone. On multivariate analysis, consolidative RT and nonbulky disease were predictive of increased LC and PFS, whereas bone marrow involvement was associated with increased risk of DR and worse OS. Consolidative RT was also associated with marginal improved OS. CONCLUSIONS Forty-four percent of patients with advanced stage DLBCL failed at initial presenting sites after achieving CR to R-CHOP. Incorporation of consolidative RT as part of upfront treatment in these patients was associated with improved LC, PFS, and a trend towards improved OS.

Incidence, Risks, and Sequelae of Posterior Fossa Syndrome in Pediatric Medulloblastoma

PURPOSE To investigate the incidence, risks, severity, and sequelae of posterior fossa syndrome (PFS) in children with medulloblastoma. METHODS AND MATERIALS Between 1990 and 2007, 63 children with medulloblastoma at Emory University and Childrens Healthcare of Atlanta were treated with craniectomy followed by radiation. Fifty-one patients were assigned to a standard-risk group, and 12 patients were assigned to a high-risk group. Five patients had <1.5-cm(2) residual tumor, 4 had >or=1.5-cm(2) residual tumor, and the remainder had no residual tumor. Eleven patients had disseminated disease. Patients received craniospinal irradiation at a typical dose of 23.4 Gy or 36 Gy for standard- or high-risk disease, respectively. The posterior fossa was given a total dose of 54 or 55.8 Gy. Nearly all patients received chemotherapy following cooperative group protocols. RESULTS Median follow-up was 7 years. PFS developed in 18 patients (29%). On univariate analysis, brainstem invasion, midline tumor location, younger age, and the absence of radiographic residual tumor were found to be predictors of PFS; the last two variables remained significant on multivariate analysis. From 1990 to 2000 and from 2001 to 2007, the proportions of patients with no radiographic residual tumor were 77% and 94%, respectively. During the same eras, the proportions of patients with PFS were 17% and 39%. Only 4 patients had complete recovery at last follow-up. CONCLUSIONS The incidence of PFS increased in the latter study period and is proportional to more aggressive surgery. Children with midline tumors exhibiting brainstem invasion are at increased risk. With the increased incidence of PFS and the permanent morbidity in many patients, the risks and benefits of complete tumor removal in all patients need to be reexamined.

Infant brain tumors: Incidence, survival, and the role of radiation based on surveillance, epidemiology, and end results (SEER) data

PURPOSE To evaluate the incidence of infant brain tumors and survival outcomes by disease and treatment variables. METHODS AND MATERIALS The Surveillance, Epidemiology, and End Results (SEER) Program November 2008 submission database provided age-adjusted incidence rates and individual case information for primary brain tumors diagnosed between 1973 and 2006 in infants less than 12 months of age. RESULTS Between 1973 and 1986, the incidence of infant brain tumors increased from 16 to 40 cases per million (CPM), and from 1986 to 2006, the annual incidence rate averaged 35 CPM. Leading histologies by annual incidence in CPM were gliomas (13.8), medulloblastoma and primitive neuroectodermal tumors (6.6), and ependymomas (3.6). The annual incidence was higher in whites than in blacks (35.0 vs. 21.3 CPM). Infants with low-grade gliomas had the highest observed survival, and those with atypical teratoid rhabdoid tumors (ATRTs) or primary rhabdoid tumors of the brain had the lowest. Between 1979 and 1993, the annual rate of cases treated with radiation within the first 4 months from diagnosis declined from 20.5 CPM to <2 CPM. For infants with medulloblastoma, desmoplastic histology and treatment with both surgery and upfront radiation were associated with improved survival, but on multivariate regression, only combined surgery and radiation remained associated with improved survival, with a hazard ratio for death of 0.17 compared with surgery alone (p = 0.005). For ATRTs, those treated with surgery and upfront radiation had a 12-month survival of 100% compared with 24.4% for those treated with surgery alone (p = 0.016). For ependymomas survival was higher in patients treated in more recent decades (p = 0.001). CONCLUSION The incidence of infant brain tumors has been stable since 1986. Survival outcomes varied markedly by histology. For infants with medulloblastoma and ATRTs, improved survival was observed in patients treated with both surgery and early radiation compared with those treated with surgery alone.

Excellent Local Control From Radiation Therapy for High-Risk Neuroblastoma

PURPOSE Local recurrence has been demonstrated in previous studies to be one of the obstacles to cure in neuroblastoma. Radiation therapy indications, optimal dose, and technique are still evolving. Here we report our experience of high-risk neuroblastoma patients who received local radiation therapy as part of their cancer management. METHODS AND MATERIALS We conducted a retrospective study of 34 high-risk neuroblastoma patients who received radiation therapy to local sites of disease from March 2001 until February 2007 at our institution as part of their multimodality therapy. RESULTS At a median follow-up of 33.6 months, 6 patients died of disease, 7 patients were alive with disease, and 21 patients were in clinical remission. Eleven patients relapsed, all distantly. Two patients failed locally in addition to distant sites. Both of these patients had persistent gross disease after induction chemotherapy and surgery. Our 3-year local control, event-free survival, overall survival were 94%, 66%, and 86%, respectively. CONCLUSION Patients with high-risk neuroblastoma in our series achieved excellent local control. Doses of 21-24 Gy to the primary tumor site appear to be adequate for local control for patients in the setting of minimal residual disease after induction chemotherapy and surgery. Patients with significant residual disease may benefit from radiation dose escalation, and this should be evaluated in a prospective clinical trial.

Six degrees of freedom CBCT‐based positioning for intracranial targets treated with frameless stereotactic radiosurgery

Frameless radiosurgery is an attractive alternative to the framed procedure if it can be performed with comparable precision in a reasonable time frame. Here, we present a positioning approach for frameless radiosurgery based on in‐room volumetric imaging coupled with an advanced six‐degrees‐of‐freedom (6 DOF) image registration technique which avoids use of a bite block. Patient motion is restricted with a custom thermoplastic mask. Accurate positioning is achieved by registering a cone‐beam CT to the planning CT scan and applying all translational and rotational shifts using a custom couch mount. System accuracy was initially verified on an anthropomorphic phantom. Isocenters of delineated targets in the phantom were computed and aligned by our system with an average accuracy of 0.2 mm, 0.3 mm, and 0.4 mm in the lateral, vertical, and longitudinal directions, respectively. The accuracy in the rotational directions was 0.1°, 0.2°, and 0.1° in the pitch, roll, and yaw, respectively. An additional test was performed using the phantom in which known shifts were introduced. Misalignments up to 10 mm and 3° in all directions/rotations were introduced in our phantom and recovered to an ideal alignment within 0.2 mm, 0.3 mm, and 0.4 mm in the lateral, vertical, and longitudinal directions, respectively, and within 0.3° in any rotational axis. These values are less than couch motion precision. Our first 28 patients with 38 targets treated over 63 fractions are analyzed in the patient positioning phase of the study. Mean error in the shifts predicted by the system were less than 0.5 mm in any translational direction and less than 0.3° in any rotation, as assessed by a confirmation CBCT scan. We conclude that accurate and efficient frameless radiosurgery positioning is achievable without the need for a bite block by using our 6 DOF registration method. This system is inexpensive compared to a couch‐based 6 DOF system, improves patient comfort compared to systems that utilize a bite block, and is ideal for the treatment of pediatric patients with or without general anesthesia, as well as of patients with dental issues. From this study, it is clear that only adjusting for 4 DOF may, in some cases, lead to significant compromise in PTV coverage. Since performing the additional match with 6 DOF in our registration system only adds a relatively short amount of time to the overall process, we advocate making the precise match in all cases. PACS number: 87.55.tm; 87.55.Qr; 87.57.nj

Clinical Outcomes Among Children With Standard-Risk Medulloblastoma Treated With Proton and Photon Radiation Therapy: A Comparison of Disease Control and Overall Survival.

PURPOSE The purpose of this study was to compare long-term disease control and overall survival between children treated with proton and photon radiation therapy (RT) for standard-risk medulloblastoma. METHODS AND MATERIALS This multi-institution cohort study includes 88 children treated with chemotherapy and proton (n=45) or photon (n=43) RT between 2000 and 2009. Overall survival (OS), recurrence-free survival (RFS), and patterns of failure were compared between the 2 cohorts. RESULTS Median (range) age was 6 years old at diagnosis (3-21 years) for proton patients versus 8 years (3-19 years) for photon patients (P=.011). Cohorts were similar with respect to sex, histology, extent of surgical resection, craniospinal irradiation (CSI) RT dose, total RT dose, whether the RT boost was delivered to the posterior fossa (PF) or tumor bed (TB), time from surgery to RT start, or total duration of RT. RT consisted of a median (range) CSI dose of 23.4 Gy (18-27 Gy) and a boost of 30.6 Gy (27-37.8 Gy). Median follow-up time is 6.2 years (95% confidence interval [CI]: 5.1-6.6 years) for proton patients versus 7.0 years (95% CI: 5.8-8.9 years) for photon patients. There was no significant difference in RFS or OS between patients treated with proton versus photon RT; 6-year RFS was 78.8% versus 76.5% (P=.948) and 6-year OS was 82.0% versus 87.6%, respectively (P=.285). On multivariate analysis, there was a trend for longer RFS with females (P=.058) and higher CSI dose (P=.096) and for longer OS with females (P=.093). Patterns of failure were similar between the 2 cohorts (P=.908). CONCLUSIONS Disease control with proton and photon radiation therapy appears equivalent for standard risk medulloblastoma.