BACKGROUND
Both intensity‐modulated radiotherapy (RT) and passively scattered proton therapy have a risk of secondary malignant neoplasm (SMN) in children. To determine the influence of RT modality ...on the incidence of SMN after craniospinal irradiation (CSI), the authors compared the incidence of SMN in children who had medulloblastoma treated with either photon CSI plus an intensity‐modulated RT boost (group I) or passively scattered proton CSI plus a boost (group II).
METHODS
From 1996 to 2014, 115 children with medulloblastoma (group I, n = 63; group II, n = 52) received CSI followed by a boost to the tumor bed. Most patients had standard‐risk disease (63.5%). The median follow‐up was 12.8 years for group I and 8.7 years for group II.
RESULTS
The 5‐year and 10‐year overall survival (OS) rates were 88.8% and 85.1%, respectively, for standard‐risk patients and 63.1% and 57.3%, respectively, for high‐risk patients, with no OS difference by RT modality (P = .81). Six SMNs were identified (4 in group I, 2 in group II). The 5‐year and 10‐year SMN incidence rates were 1.0% and 6.9%, respectively (0.0% and 8.0%, respectively, in group I; 2.2% and 4.9%, respectively, in group II; P = .74). Two SMNs occurred in the clinical target volume in the brain, 2 occurred in the exit dose region from the photon spinal field, 1 occurred in the entrance path of a proton beam, and 1 occurred outside the radiation field. There were no reported cases of secondary leukemia.
CONCLUSIONS
This analysis demonstrates no difference in OS or SMN incidence between patients in groups I and II 10 years after RT.
LAY SUMMARY
One hundred fifteen children with medulloblastoma received radiotherapy (RT) with either photon craniospinal irradiation (CSI) and an intensity‐modulated RT boost (group I; n = 63) or passively scattered proton CSI and a boost (group II;, n = 52).
The majority of children had standard‐risk disease (63.5%).
The 5‐year and 10‐year overall survival rates were 88.8% and 85.1% for standard‐risk patients, respectively, and 63.1% and 57.3% for high‐risk patients, respectively, with no difference in overall survival by RT group (P = .81).
The 5‐year and 10‐year second malignant neoplasm incidence rates were 1.0% and 6.9%, respectively, with no difference in second malignant neoplasm incidence according to RT group (P = .74).
In total, 115 children with medulloblastoma who received surgery, chemotherapy, and radiotherapy (RT) with either 3‐dimensional RT followed by an intensity‐modulated boost (n = 63) or passively scattered proton therapy (n = 52) are assessed. At 10 years after RT, there are no differences in overall survival or secondary malignant neoplasms according to RT modality.
Purpose
WHO grade 4 gliomas are rare in the pediatric and adolescent and young adult (AYA) population. We evaluated prognostic factors and outcomes in the pediatric versus AYA population.
Methods
...This retrospective pooled study included patients less than 30 years old (yo) with grade 4 gliomas treated with modern surgery and radiotherapy. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analysis.
Results
Ninety-seven patients met criteria with median age 23.9 yo at diagnosis. Seventy-seven patients were ≥ 15 yo (79%) and 20 patients were < 15 yo (21%). Most had biopsy-proven glioblastoma (91%); the remainder had H3 K27M-altered diffuse midline glioma (DMG; 9%). All patients received surgery and radiotherapy. Median PFS and OS were 20.9 months and 79.4 months, respectively. Gross total resection (GTR) was associated with better PFS in multivariate analysis HR 2.00 (1.01–3.62), p = 0.023. Age ≥ 15 yo was associated with improved OS HR 0.36 (0.16–0.81), p = 0.014 while female gender HR 2.12 (1.08–4.16), p = 0.03 and DMG histology HR 2.79 (1.11–7.02), p = 0.029 were associated with worse OS. Only 7% of patients experienced grade 2 toxicity. 62% of patients experienced tumor progression (28% local, 34% distant). Analysis of salvage treatment found that second surgery and systemic therapy significantly improved survival.
Conclusion
Age is a significant prognostic factor in WHO grade 4 glioma, which may reflect age-related molecular alterations in the tumor. DMG was associated with worse OS than glioblastoma. Reoperation and systemic therapy significantly increased survival after disease progression. Prospective studies in this population are warranted.
Central nervous system (CNS) tumors are the most common solid tumors in children. Findings on the role of maternal and perinatal factors on the susceptibility or outcome of these tumors are ...inconclusive. Therefore, we investigated the association between these early-life factors, risk, and survival of pediatric CNS tumors, using data from one of the world's largest and most diverse cancer registries. Information on pediatric CNS tumor cases (n = 1950) for the period 1995-2011 was obtained from the Texas Cancer Registry. Birth certificate controls were frequency-matched on birth year at a ratio of 10:1 for the same period. Evaluated maternal and perinatal variables were obtained from birth records. Unconditional logistic regression was used to generate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for etiological factors. Additionally, Cox proportional hazards regression was employed to assess adjusted hazard ratios (HRs) and 95% CIs for survival factors. The results indicated that Hispanic and non-Hispanic black mothers were less likely to have children with CNS tumors compared to non-Hispanic white mothers (OR 0.88 95% CI 0.78-0.98 P-value = 0.019; OR 0.79 95% CI 0.67-0.93 P-value = 0.004, respectively). Infants born large for gestational age (OR 1.26 95% CI 1.07-1.47 P-value = 0.004) and those delivered pre-term (OR 1.19 95% CI 1.04-1.38 P-value = 0.013) showed an increased risk of CNS tumors. Infants born by vaginal forceps or vacuum delivery had a higher risk of CNS tumors compared to those born by spontaneous vaginal delivery (OR 1.35 95% CI 1.12-1.62 P-value = 0.002). Additionally, offspring of Hispanic and non-Hispanic black mothers showed a higher risk of death (HR 1.45 95% CI 1.16-1.80 P-value = 0.001; HR 1.53 95% CI 1.12-2.09 P-value = 0.008, respectively). Infants born by cesarean had a higher risk of death compared to those delivered vaginally (HR 1.28 95% CI 1.05-1.57 P-value = 0.016). These findings indicate the important role of maternal and perinatal characteristics in the etiology and survival of these clinically significant malignancies.
Brain tumors Chintagumpala, Murali; Gajjar, Amar
The Pediatric clinics of North America,
02/2015, Letnik:
62, Številka:
1
Journal Article
Recenzirano
The past 2 decades have witnessed a revolution in the management of childhood brain tumors, with the establishment of multidisciplinary teams and national and international consortiums that led to ...significant improvements in the outcomes of children with brain tumors. Unprecedented cooperation within the pediatric neuro-oncology community and sophisticated rapidly evolving technology have led to advances that are likely to revolutionize treatment strategies and improve outcomes.
Background
A primary objective of Children's Oncology Group study AREN0534 (Treatment for Patients With Multicentric or Bilaterally Predisposed, Unilateral Wilms Tumor) was to facilitate partial ...nephrectomy in 25% of children with bilaterally predisposed unilateral tumors (Wilms tumor/aniridia/genitourinary anomalies/range of developmental delays WAGR syndrome; and multifocal and overgrowth syndromes). The purpose of this prospective study was to achieve excellent event‐free survival (EFS) and overall survival (OS) while preserving renal tissue through preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response.
Methods
The treating institution identified whether a predisposition syndrome existed. Patients underwent a central review of imaging studies through the biology and classification study AREN03B2 and then were eligible to enroll on AREN0534. Patients were treated with induction chemotherapy determined by localized or metastatic disease on imaging (and histology if a biopsy had been undertaken). Surgery was based on radiographic response at 6 or 12 weeks. Further chemotherapy was determined by histology. Patients who had stage III or IV disease with favorable histology received radiotherapy as well as those who had stage I through IV anaplasia.
Results
In total, 34 patients were evaluable, including 13 males and 21 females with a mean age at diagnosis of 2.79 years (range, 0.49‐8.78 years). The median follow‐up was 4.49 years (range, 1.67‐8.01 years). The underlying diagnosis included Beckwith‐Wiedemann syndrome in 9 patients, hemihypertrophy in 9 patients, multicentric tumors in 10 patients, WAGR syndrome in 2 patients, a solitary kidney in 2 patients, Denys‐Drash syndrome in 1 patient, and Simpson‐Golabi‐Behmel syndrome in 1 patient. The 4‐year EFS and OS rates were 94% (95% CI, 85.2%‐100%) and 100%, respectively. Two patients relapsed (1 tumor bed, 1 abdomen), and none had disease progression during induction. According to Response Evaluation Criteria in Solid Tumor 1.1 criteria, radiographic responses included a complete response in 2 patients, a partial response in 21 patients, stable disease in 11 patients, and progressive disease in 0 patients. Posttherapy histologic classification was low‐risk in 13 patients (including the 2 complete responders), intermediate‐risk in 15 patients, and high‐risk in 6 patients (1 focal anaplasia and 5 blastemal subtype). Prenephrectomy chemotherapy facilitated renal preservation in 22 of 34 patients (65%).
Conclusions
A standardized approach of preoperative chemotherapy, surgical resection within 12 weeks, and histology‐based postoperative chemotherapy results in excellent EFS, OS, and preservation of renal parenchyma.
In children with bilaterally predisposed unilateral Wilms tumors, a standardized approach of preoperative chemotherapy, surgical resection within 12 weeks, and histology‐based postoperative chemotherapy results in excellent event‐free and overall survival and in the preservation of renal parenchyma.
Metastatic retinoblastoma has a poor prognosis when treated with conventional chemotherapy and radiation therapy (RT). Intensified therapy may improve the outcome.
A prospective, international trial ...enrolled patients with extraocular retinoblastoma. Patients with stage II or III (locoregional) retinoblastoma received four cycles of chemotherapy, followed by involved field RT (45 Gy). Patients with stage IVa or IVb (metastatic or trilateral) retinoblastoma also received four cycles of chemotherapy and those with ≥ partial response then received one cycle of high-dose carboplatin, thiotepa, and etoposide with autologous hematopoietic stem-cell support. Patients with stage IVa or IVb with residual tumor postchemotherapy received RT. The proportion of patients who achieved event-free survival would be reported and compared with historical controls separately for each of the three groups of patients.
Fifty-seven eligible patients were included in the analyses. Event-free survival at 1 year was 88.1% (90% CI, 66.6 to 96.2) for stage II-III, 82.6% (90% CI, 61.0 to 92.9) for stage IVa, and 28.3% (90% CI, 12.7 to 46.2) for stage IVb/trilateral. Toxicity was significant as expected and included two therapy-related deaths.
Intensive multimodality therapy is highly effective for patients with regional extraocular retinoblastoma and stage IVa metastatic retinoblastoma. Although the study met its aim for stage IVb, more effective therapy is still required for patients with CNS involvement (ClinicalTrials.gov identifier: NCT00554788).
Background
Endocrine deficiencies are common following Craniospinal irradiation (CSI) in children with brain tumors, but empirical data comparing outcomes following proton (PRT) and photon radiation ...therapy (XRT) are limited.
Methods
This retrospective chart review compared the incidence of hypothyroidism, Growth hormone deficiency (GHD), and Adrenal insufficiency (AI) in patients with medulloblastoma treated with XRT and PRT between 1997 and 2016. All patients received CSI and had routine endocrine screening labs to evaluate for thyroid dysfunction, GHD, and AI. We used proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) comparing the development of hypothyroidism, AI, and GHD between radiation modalities, adjusting for age at diagnosis, sex, race/ethnicity, and CSI dose.
Results
We identified 118 patients with medulloblastoma who were followed for a median of 5.6 years from the end of radiotherapy. Thirty-five (31%) patients developed hypothyroidism, 71 (66%) GHD, and 20 (18%) AI. Compared to PRT, XRT was associated with a higher incidence of primary hypothyroidism (28% vs. 6%; HR = 4.61, 95% CI 1.2–17.7, p = 0.03). Central hypothyroidism, GHD, and AI incidence rates were similar between the groups.
Conclusions
Primary hypothyroidism occurs less often after PRT CSI, compared to XRT CSI. This suggests that the thyroid and pituitary glands receive less radiation after spine and posterior fossa boost RT, respectively, using PRT.
Limiting the neurocognitive sequelae of radiotherapy (RT) has been an objective in the treatment of medulloblastoma. Conformal RT to less than the entire posterior fossa (PF) after craniospinal ...irradiation might reduce neurocognitive sequelae and requires evaluation.
Between October 1996 and August 2003, 86 patients, 3-21 years of age, with newly diagnosed, average-risk medulloblastoma were treated in a prospective, institutional review board-approved, multi-institution trial of risk-adapted RT and dose-intensive chemotherapy. RT began within 28 days of definitive surgery and consisted of craniospinal irradiation (23.4 Gy), conformal PF RT (36.0 Gy), and primary site RT (55.8 Gy). The planning target volume for the primary site included the postoperative tumor bed surrounded by an anatomically confined margin of 2 cm that was then expanded with a geometric margin of 0.3-0.5 cm. Chemotherapy was initiated 6 weeks after RT and included four cycles of high-dose cyclophosphamide, cisplatin, and vincristine.
At a median follow-up of 61.2 months (range, 5.2-115.0 months), the estimated 5-year event-free survival and cumulative incidence of PF failure rate was 83.0% +/- 5.3% and 4.9% +/- 2.4% (+/- standard error), respectively. The targeting guidelines used in this study resulted in a mean reduction of 13% in the volume of the PF receiving doses >55 Gy compared with conventionally planned RT. The reductions in the dose to the temporal lobes, cochleae, and hypothalamus were statistically significant.
This prospective trial has demonstrated that irradiation of less than the entire PF after 23.4 Gy craniospinal irradiation for average-risk medulloblastoma results in disease control comparable to that after treatment of the entire PF.
•Proton beam therapy (PBT) provides excellent local control for pediatric patients with head and neck rhabdomyosarcoma (RMS).•Tumor size greater than 5 cm predicted increased risk of local failure, ...supporting ongoing dose escalation trial efforts.•Tumors with intracranial extension (ICE) had high rates of local and leptomeningeal relapse.•Delayed delivery of local therapy may drive higher rates of relapse seen among patients with ICE tumors.•The late toxicity profile of patients treated with PBT compares favorably to that of prior series using IMRT.
Pediatric patients with rhabdomyosarcoma (RMS) of the head and neck (H&N) are treated with multimodal therapy, often with radiotherapy (RT) as definitive local therapy. We report on the patterns of failure following proton beam therapy (PBT) for H&N RMS.
Forty-six H&N RMS patients were enrolled on a prospective registry protocol between 2006 and 2015. All were treated with a combination of chemotherapy (ChT) and PBT. Most patients (25 patients, 54%) had parameningeal tumors, of which 11 (24%) had intracranial extension (ICE). Thirteen patients (28%) had primary tumors greater than 5 cm. Median total cyclophosphamide (CPM) equivalent dose was 13.2 g/m2 (range 0–16.8 g/m2). Median RT dose was 50.4 Gy(RBE) (range 36 GyRBE–50.8 GyRBE).
With median follow-up of 3.9 years, five-year overall survival was 76%, and five-year progression-free survival was 57%. Seventeen patients (37%) experienced relapse, including 7 with local failure (LF). Five-year local control (LC) was 84%. Tumor size greater than 5 cm predicted increased risk of LF (hazard ratio HR 6.49, p = 0.03), as did the presence of ICE at diagnosis (HR 5.21, p = 0.03). Six relapses occurred in patients with ICE; all included a component of central nervous system relapse, with leptomeningeal disease and/or LF with an intracranial component. Delayed RT delivery after week 4 of ChT predicted increased risk of relapse for ICE patients (HR 10.49, p = 0.006).
PBT confers excellent LC, and a favorable late toxicity profile as compared with prior photon RT data. Our observations support ongoing trial efforts to dose-escalate RT for patients with larger tumors. However, these data raise concerns regarding excess failures among patients with ICE.
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