The ROCOCO performance scoring system translates dosimetric differences into clinically relevant endpoints: Comparing IMPT to VMAT in an example pilocytic astrocytoma dataset.

BACKGROUND AND PURPOSE: Proton therapy is expected to outperform photon-based treatment regarding organs at risk (OAR) sparing but to date there is no method to practically measure clinical benefit. Here, we introduce the novel ROCOCO Performance Scoring System (RPSS) translating dose differences into clinically relevant endpoints and apply this to a treatment plan comparison of volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) in 20 pilocytic astrocytoma patients. MATERIAL AND METHODS: The RPSS was developed on the basis of expert-based weighting factors and toxicity scores per OAR. The imaging datasets of 20 pilocytic astrocytoma patients having undergone radiotherapy were included in this in silico dosimetric comparison trial as proof of principle. For each of these patients, treatment plans to a total dose of 54 Gy (RBE) were generated for VMAT and IMPT and these were compared regarding radiation dose to the clinical target volume (CTV) and OARs. The RPSS was calculated for each treatment plan comparing VMAT and IMPT. RESULTS: In 40 analysed treatment plans, the average and low dose volumes to various OARs were significantly reduced when using IMPT compared to VMAT (p < 0.05). Using the RPSS, a significant difference between both treatment modalities was found, with 85% of the patients having a lower RPSS in favour of the IMPT plan. CONCLUSION: There are dosimetric differences between IMPT and VMAT in pilocytic astrocytoma patients. In absence of clinically validated NTCP models we introduce the RPSS model in order to objectively compare treatment modalities by translating dosimetric differences in potential clinical differences.

Is radiotherapy required in first-line treatment of stage I diffuse anaplastic Wilms tumor? A report of SIOP-RTSG, AIEOP, JWiTS, and UKCCSG.

BACKGROUND: As a significant proportion of relapses occurred in the tumor bed or abdomen on patients with the fifth National Wilms Tumor Study stage I anaplastic Wilms tumor (WT), flank radiotherapy was added for stage I anaplastic WT in the subsequent study of the Children's Oncology Group (AREN0321). Preliminary results revealed reduction of relapse rate and improved survival. In cases treated with preoperative chemotherapy, such as in International Society of Pediatric Oncology (SIOP), the value of radiotherapy has never been studied. The aim of this observational study is to describe the pattern of recurrence and survival of patients with stage I diffuse anaplastic WT (DAWT) after induction chemotherapy. METHODS: Retrospective data analysis of the pattern of relapse and survival of all patients with stage I DAWT were included in recent SIOP, L'Associazone Italiana Ematologica Oncologia Pediatrica (AIEOP), Japan Wilms Tumor Study Group (JWiTS), United Kingdom Children's Cancer Study Group (UKCCSG) renal tumor registries. Postoperative treatment consisted of actinomycin D, vincristine, and doxorubicin for 28 weeks without local irradiation. RESULTS: One hundred nine cases with stage I DAWT were identified, of which 95 cases received preoperative chemotherapy. Of these, seven patients underwent preoperative true-cut biopsy. Sixteen of the 95 patients relapsed (17%), six locally, four at distant site, and six combined, and all treated according to SIOP 2001 relapse protocol, which resulted in a 5-year overall survival of 93%. CONCLUSION: Despite 13% locoregional relapse rate, an excellent rescue rate was achieved after salvage treatment, in patients with stage I DAWT whose first-line treatment comprised three-drug chemotherapy (including doxorubicin), without flank irradiation. Therefore, we continue not to advocate the use of radiotherapy in first-line treatment after preoperative chemotherapy in stage I DAWT in the next SIOP protocol.

Risk of benign meningioma after childhood cancer in the DCOG-LATER cohort: contributions of radiation dose, exposed cranial volume, and age.

BACKGROUND: Pediatric cranial radiotherapy (CrRT) markedly increases risk of meningiomas. We studied meningioma risk factors with emphasis on independent and joint effects of CrRT dose, exposed cranial volume, exposure age, and chemotherapy. METHODS: The Dutch Cancer Oncology Group-Long-Term Effects after Childhood Cancer (DCOG-LATER) cohort includes 5-year childhood cancer survivors (CCSs) whose cancers were diagnosed in 1963-2001. Histologically confirmed benign meningiomas were identified from the population-based Dutch Pathology Registry (PALGA; 1990-2015). We calculated cumulative meningioma incidence and used multivariable Cox regression and linear excess relative risk (ERR) modeling. RESULTS: Among 5843 CCSs (median follow-up: 23.3 y, range: 5.0-52.2 y), 97 developed a benign meningioma, including 80 after full- and 14 after partial-volume CrRT. Compared with CrRT doses of 1-19 Gy, no CrRT was associated with a low meningioma risk (hazard ratio [HR] = 0.04, 95% CI: 0.01-0.15), while increased risks were observed for CrRT doses of 20-39 Gy (HR = 1.66, 95% CI: 0.83-3.33) and 40+ Gy (HR = 2.81, 95% CI: 1.30-6.08). CCSs whose cancers were diagnosed before age 5 versus 10-17 years showed significantly increased risks (HR = 2.38, 95% CI: 1.39-4.07). In this dose-adjusted model, volume was not significantly associated with increased risk (HR full vs partial = 1.66, 95% CI: 0.86-3.22). Overall, the ERR/Gy was 0.30 (95% CI: 0.03-unknown). Dose effects did not vary significantly according to exposure age or CrRT volume. Cumulative incidence after any CrRT was 12.4% (95% CI: 9.8%-15.2%) 40 years after primary cancer diagnosis. Among chemotherapy agents (including methotrexate and cisplatin), only carboplatin (HR = 3.55, 95% CI: 1.62-7.78) appeared associated with meningioma risk. However, we saw no carboplatin dose-response and all 9 exposed cases had high-dose CrRT. CONCLUSION: After CrRT 1 in 8 survivors developed late meningioma by age 40 years, associated with radiation dose and exposure age, relevant for future treatment protocols and awareness among survivors and physicians.

Outcome of Nonsurgical Management of Extra-Abdominal, Trunk, and Abdominal Wall Desmoid-Type Fibromatosis: A Population-Based Study in the Netherlands.

INTRODUCTION: Nonsurgical management of patients with desmoid-type fibromatosis (DF) is increasing. This study tries to provide insight on type, usage, and outcome of first-line nonsurgical management strategies. PATIENTS AND METHODS: From the Dutch Pathology Registry (PALGA), patients with extra-abdominal or trunk/abdominal wall DF, diagnosed between 1993 and 2013, were identified. First-line treatment was analyzed. Best response (BR) using RECIST criteria from start of treatment/surveillance until change of treatment or last follow-up was analyzed. RESULTS: Ninety-one of the 1141 identified patients had first-line nonsurgical management. The percentage of patients treated nonsurgically increased from 0.6% in 1993-1998 to 12.8% in 2009-2013. Thirty-seven patients had surveillance (41%), 35 radiotherapy (38%), and 19 systemic treatment (21%). BR for surveillance was complete response (CR) in 2/37, partial response (PR) in 4/37, stable disease (SD) in 21/37, progressive disease (PD) in 5/37, and unknown in 5/37 patients. BR for radiotherapy was CR in 4/35, PR in 11/35, SD in 16/35, and unknown in 4/35. BR for systemic treatment was CR in 1/19, PR in 1/19, SD in 10/19, PD in 2/19, and unknown in 5/19. Totally, 91% of patients did not progress. DISCUSSION: Given the low percentage (9%) of PD of nonsurgical management, these data can be used in shared decision making with the patient regarding optimal treatment.

Evaluation of boost irradiation in patients with intermediate-risk stage III Wilms tumour with positive lymph nodes only: Results from the SIOP-WT-2001 Registry.

OBJECTIVE: To evaluate the value of radiotherapy boost omission in patients with intermediate-risk, stage III Wilms tumours (WT) with positive lymph nodes (LN). METHODS AND MATERIALS: All patients with intermediate-risk, stage III (LN positive) WT consecutively registered in the SIOP-WT-2001 study were included in this analysis. Endpoints were 5-year event-free survival (EFS), loco-regional control (LRC) and overall survival (OS). RESULTS: Between June 2001 and May 2015, 2,569 patients with stage I to III WT after preoperative chemotherapy were registered in the SIOP-WT-2001 study. Five hundred and twenty-three (20%) had stage III disease, of which 113 patients had stage III due to positive LN only. Of those, 101 (89%) received radiotherapy, 36 of which (36%) received, apart from flank irradiation, a boost dose to the LN positive area. Four patients (4%) did not receive any adjuvant radiotherapy. In eight patients information on radiotherapy was not available. With a median follow-up of 71 months, no difference in 5-year EFS (84% vs. 83%, P = 0.77) and LRC (96% vs. 97%, P = 0.91) was observed between patients receiving a radiotherapy boost and those without boost, respectively. Five-year OS, including salvage therapy, was excellent (boost vs. no boost: 97% vs. 95%, P = 0.58). CONCLUSIONS: Outcome data demonstrate that omission of the radiotherapy boost to the loco-regional positive lymph nodes in patients with intermediate-risk, stage III WT who receive preoperative chemotherapy and postoperative flank irradiation (14.4 Gy) can be considered a safe approach for future SIOP protocols.

Are age and gender suitable matching criteria in organ dose reconstruction using surrogate childhood cancer patients' CT scans?

PURPOSE: The purpose of this work was to assess the feasibility of using surrogate CT scans of matched patients for organ dose reconstructions for childhood cancer (CC) survivors, treated in the past with only 2D imaging data available instead of 3D CT data, and in particular using the current literature standard of matching patients based on similarity in age and gender. METHODS: Thirty-one recently treated CC patients with abdominal CT scans were divided into six age- and gender-matched groups. From each group, two radiotherapy plans for Wilms' tumor were selected as reference plans and applied to the age- and gender-matched patients' CTs in the respective group. Two reconstruction strategies were investigated: S1) without field adjustments; S2) with manual field adjustments according to anatomical information, using a visual check in digitally reconstructed radiographs. To assess the level of agreement between the reconstructed and the reference dose distributions, we computed (using a collapsed cone algorithm) and compared the absolute deviation in mean and maximum dose normalized by the prescribed dose (i.e., normalized errors |NEmean | and |NE2cc |) in eight organs at risk (OARs): heart, lungs, liver, spleen, kidneys, and spinal cord. Furthermore, we assessed the quality of a reconstruction case by varying acceptance thresholds for |NEmean | and |NE2cc |. A reconstruction case was accepted (i.e., considered to pass) if the errors in all OARs are smaller than the threshold. The pass fraction for a given threshold was then defined as the percentage of reconstruction cases that were classified as a pass. Furthermore, we consider the impact of allowing to use a different CT scan for each OAR. RESULTS: Slightly smaller reconstruction errors were achieved with S2 in multiple OARs than with S1 (P < 0.05). Among OARs, the best reconstruction was found for the spinal cord (average |NEmean | and |NE2cc | ≤ 4%). The largest average |NEmean | was found in the spleen (18%). The largest average |NE2cc | was found in the left lung (26%). Less than 30% of the reconstruction cases (i.e., pass fraction) meet the criteria that |NEmean | < 20% and |NE2cc | < 20% in all OARs when using age and gender matching and a single CT to do reconstructions. Allowing other matchings and combining reconstructions for OARs from multiple patients, the pass fraction increases substantially to more than 60%. CONCLUSIONS: To conclude, reconstructions with small deviations can be obtained by using CC patients' CT scans, making the general approach promising. However, using age and gender as the only matching criteria to select a CT scan for the reconstruction is not sufficient to guarantee sufficiently low reconstruction errors. It is therefore suggested to include more features (e.g., height, features extracted from 2D radiographs) than only age and gender for dose reconstruction for CC survivors treated in the pre-3D radiotherapy planning era and to consider ways to combine multiple reconstructions focused on different OARs.

Dosimetric comparison of five different techniques for craniospinal irradiation across 15 European centers: analysis on behalf of the SIOP-E-BTG (radiotherapy working group).

PURPOSE: Conventional techniques (3D-CRT) for craniospinal irradiation (CSI) are still widely used. Modern techniques (IMRT, VMAT, TomoTherapy®, proton pencil beam scanning [PBS]) are applied in a limited number of centers. For a 14-year-old patient, we aimed to compare dose distributions of five CSI techniques applied across Europe and generated according to the participating institute protocols, therefore representing daily practice. MATERIAL AND METHODS: A multicenter (n = 15) dosimetric analysis of five different techniques for CSI (3D-CRT, IMRT, VMAT, TomoTherapy®, PBS; 3 centers per technique) was performed using the same patient data, set of delineations and dose prescription (36.0/1.8 Gy). Different treatment plans were optimized based on the same planning target volume margin. All participating institutes returned their best treatment plan applicable in clinic. RESULTS: The modern radiotherapy techniques investigated resulted in superior conformity/homogeneity-indices (CI/HI), particularly in the spinal part of the target (CI: 3D-CRT:0.3 vs. modern:0.6; HI: 3D-CRT:0.2 vs. modern:0.1), and demonstrated a decreased dose to the thyroid, heart, esophagus and pancreas. Dose reductions of >10.0 Gy were observed with PBS compared to modern photon techniques for parotid glands, thyroid and pancreas. Following this technique, a wide range in dosimetry among centers using the same technique was observed (e.g., thyroid mean dose: VMAT: 5.6-24.6 Gy; PBS: 0.3-10.1 Gy). CONCLUSIONS: The investigated modern radiotherapy techniques demonstrate superior dosimetric results compared to 3D-CRT. The lowest mean dose for organs at risk is obtained with proton therapy. However, for a large number of organs ranges in mean doses were wide and overlapping between techniques making it difficult to recommend one radiotherapy technique over another.

Risk of Symptomatic Stroke After Radiation Therapy for Childhood Cancer: A Long-Term Follow-Up Cohort Analysis.

PURPOSE: Long-term childhood cancer survivors are at high risk of late adverse effects, including stroke. We aimed to determine the cumulative incidence of clinically validated symptomatic stroke (transient ischemic attack [TIA], cerebral infarction, and intracerebral hemorrhage [ICH]) and to quantify dose-effect relationships for cranial radiation therapy (CRT) and supradiaphragmatic radiation therapy (SDRT). METHODS AND MATERIALS: Our single-center study cohort included 1362 survivors of childhood cancer that were diagnosed between 1966 and 1996. Prescribed CRT and SDRT doses were converted into the equivalent dose in 2-Gy fractions (EQD2). Multivariate Cox regression models were used to analyze the relationship between the EQD2 and stroke. RESULTS: After a median latency time of 24.9 years and at a median age of 31.2 years, 28 survivors had experienced a first stroke: TIA (n=5), infarction (n=13), and ICH (n=10). At an attained age of 45 years, the estimated cumulative incidences, with death as competing risk, among survivors treated with CRT only, SDRT only, both CRT and SDRT, and neither CRT nor SDRT were, respectively, 10.0% (95% confidence interval [CI], 2.5%-17.0%), 5.4% (95% CI, 0%-17.0%), 12.5% (95% CI, 5.5%-18.9%), and 0.1% (95% CI, 0%-0.4%). Radiation at both locations significantly increased the risk of stroke in a dose-dependent manner (hazard ratios: HRCRT 1.02 Gy(-1); 95% CI, 1.01-1.03, and HRSDRT 1.04 Gy(-1); 95% CI, 1.02-1.05). CONCLUSIONS: Childhood cancer survivors treated with CRT, SDRT, or both have a high stroke risk. One in 8 survivors treated at both locations will have experienced a symptomatic stroke at an attained age of 45 years. Further research on the pathophysiologic processes involved in stroke in this specific group of patients is needed to enable the development of tailored secondary prevention strategies.

Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. METHODS: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 µg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. FINDINGS: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. INTERPRETATION: Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification. FUNDING: See Acknowledgments for funders.

Valvular abnormalities detected by echocardiography in 5-year survivors of childhood cancer: a long-term follow-up study.

PURPOSE: To determine the prevalence of valvular abnormalities after radiation therapy involving the heart region and/or treatment with anthracyclines and to identify associated risk factors in a large cohort of 5-year childhood cancer survivors (CCS). METHODS AND MATERIALS: The study cohort consisted of all 626 eligible 5-year CCS diagnosed with childhood cancer in the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 and treated with radiation therapy involving the heart region and/or anthracyclines. We determined the presence of valvular abnormalities according to echocardiograms. Physical radiation dose was converted into the equivalent dose in 2-Gy fractions (EQD2). Using multivariable logistic regression analyses, we examined the associations between cancer treatment and valvular abnormalities. RESULTS: We identified 225 mainly mild echocardiographic valvular abnormalities in 169 of 545 CCS (31%) with a cardiac assessment (median follow-up time, 14.9 years [range, 5.1-36.8 years]; median attained age 22.0 years [range, 7.0-49.7 years]). Twenty-four CCS (4.4%) had 31 moderate or higher-graded abnormalities. Most common abnormalities were tricuspid valve disorders (n=119; 21.8%) and mitral valve disorders (n=73; 13.4%). The risk of valvular abnormalities was associated with increasing radiation dose (using EQD2) involving the heart region (odds ratio 1.33 per 10 Gy) and the presence of congenital heart disease (odds ratio 3.43). We found no statistically significant evidence that anthracyclines increase the risk. CONCLUSIONS: Almost one-third of CCS treated with potentially cardiotoxic therapy had 1 or more asymptomatic, mostly mild valvular abnormalities after a median follow-up of nearly 15 years. The most important risk factors are higher EQD2 to the heart region and congenital heart disease. Studies with longer follow-up are necessary to investigate the clinical course of asymptomatic valvular abnormalities in CCS.

Nephron sparing surgery (NSS) for unilateral wilms tumor (UWT): the SIOP 2001 experience.

BACKGROUND: Total nephrectomy (TN) remains the standard treatment of unilateral Wilms tumors (uWT). The SIOP WT-2001 protocol allowed Nephron Sparing Surgery (NSS) for polar or peripherally non-infiltrating tumors. AIM: Inventory of the current SIOP NSS-experience. PROCEDURES: 2,800 patients with a unilateral, localized or metastatic and an unequivocal surgical technique recorded were included. All had neo-adjuvant chemotherapy and delayed surgery. In 91 (3%) NSS was performed and in 2709 TN. Data was retrieved from the SIOP WT 2001 database. RESULTS: NSS group contained 65% stage I tumours and the TN group 48%. Tumor volume (at diagnosis and surgery) was significantly smaller in the NSS group. Within stage III, after NSS, 7/12 (58%) had positive margins (M +), 5 with tumor negative lymph nodes (LN-). After TN, 355/712 (55%) had M + , 182 were LN-. Treatment of M+ in the NSS group resulted in two conversions to TN (one combined with radiotherapy), three patients had radiotherapy only and in two patients local therapy, if given, was not recorded. After NSS, four recurrences occurred. For localized disease the 5-year overall (OS) and event free survival (EFS) in NSS group was 100 and 94.8 (95% CI:89.9-99.9), respectively, while OS and EFS in the TN group were 94.4 (95% CI: 93.2-95.5, log-rank test P = 0.06) and 86.5 (95% CI:85.0-88.1, log-rank test P = 0.06), respectively. CONCLUSIONS: NSS was only performed in 3% of patients with uWT. Despite excellent survival with few relapses, the gain of nephrons needs to be weighed against the risk to induce stage III with intensified therapy.

A patient with scapular Ewing sarcoma; 5-year follow-up after extracorporeal irradiation and re-implantation of the scapula, a case report.

In 2007 a 9½-year-old boy was treated with resection, extracorporeal irradiation and re-implantation of the right scapula. He also received chemotherapy. During five year follow-up shoulder function remained largely intact. Subtotal resorption of the scapula occurred, leaving only the glenohumeral joint intact. Sensibility and strength are intact. To date there is no sign of local or metastatic recurrence.

Surveillance of hepatic late adverse effects in a large cohort of long-term survivors of childhood cancer: prevalence and risk factors.

BACKGROUND: Childhood cancer survivors (CCS) are a growing group of young individuals with a high risk of morbidity and mortality. We evaluated the prevalence and risk factors of hepatic late adverse effects, defined as elevated liver enzymes, in a large cohort of CCS. METHODS: The cohort consisted of all five-year CCS treated in the EKZ/AMC between 1966 and 2003, without hepatitis virus infection and history of veno-occlusive disease (VOD). Liver enzyme tests included serum levels of alanine aminotransferase (ALT) for hepatocellular injury and gamma-glutamyltransferase (γGT) for biliary tract injury. We performed multivariable linear and logistic regression analyses. RESULTS: The study population consisted of 1404 of 1795 eligible CCS, of whom 1362 performed liver enzyme tests at a median follow-up of 12 years after diagnosis. In total, 118 (8.7%) of 1362 CCS had hepatic late adverse effects defined as ALT or γGT above the upper limit of normal. Abnormal ALT and γGT levels were found in 5.8% and 5.3%, respectively. In multivariable regression analyses treatment with radiotherapy involving the liver, higher body mass index, higher alcohol intake and longer follow-up time were significantly associated with elevated ALT and γGT levels; older age at diagnosis was only significantly associated with elevated γGT levels (all p<0.05). CONCLUSION: One in twelve CCS showed signs of hepatic late adverse effects after a median follow-up of 12 years. Several risk factors have been identified. Future studies should focus on the course of long-term liver related outcomes and on the influence of radiotherapy and chemotherapy dose.

Dose-effect relationships for adverse events after cranial radiation therapy in long-term childhood cancer survivors.

PURPOSE: To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships. METHODS AND MATERIALS: The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD(2)). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 years after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD(2) in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy. RESULTS: There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD(2), we found significant dose-effect relationships for these and other AEs. CONCLUSION: Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD(2) instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.

Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis.

PURPOSE: Despite conventional radiation therapy, 54 Gy in single doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most children with diffuse intrinsic pontine glioma (DIPG) will die within 1 year after diagnosis. To reduce patient burden, we investigated the role of hypofractionation radiation therapy given over 3 to 4 weeks. A 1:1 matched-cohort analysis with conventional radiation therapy was performed to assess response and survival. METHODS AND MATERIALS: Twenty-seven children, aged 3 to 14, were treated according to 1 of 2 hypofractionation regimens over 3 to 4 weeks (39/3 Gy, n=16 or 44.8/2.8 Gy, n=11). All patients had symptoms for ≤3 months, ≥2 signs of the neurologic triad (cranial nerve deficit, ataxia, long tract signs), and characteristic features of DIPG on magnetic resonance imaging. Twenty-seven patients fulfilling the same diagnostic criteria and receiving at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort analysis. RESULTS: With hypofractionation radiation therapy, the overall survival at 6, 9, and 12 months was 74%, 44%, and 22%, respectively. Progression-free survival at 3, 6, and 9 months was 77%, 43%, and 12%, respectively. Temporary discontinuation of steroids was observed in 21 of 27 (78%) patients. No significant difference in median overall survival (9.0 vs 9.4 months; P=.84) and time to progression (5.0 vs 7.6 months; P=.24) was observed between hypofractionation vs conventional radiation therapy, respectively. CONCLUSIONS: For patients with newly diagnosed DIPG, a hypofractionation regimen, given over 3 to 4 weeks, offers equal overall survival with less treatment burden compared with a conventional regimen of 6 weeks.

Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial.

PURPOSE: To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy. PATIENTS AND METHODS: In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine. RESULTS: After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm(2) was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up. CONCLUSION: In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease.

Characteristics and outcome of stage II and III non-anaplastic Wilms' tumour treated according to the SIOP trial and study 93-01.

PURPOSE: To determine the prognosis of children with stage II and III of low or intermediate risk histology (SIOP classification) in unilateral localised Wilms tumour (WT) after neoadjuvant chemotherapy according to the trial and study of the International Society of Paediatric Oncology, SIOP 93-01. PATIENTS AND METHODS: Patients with unilateral localised WT and stage II or III with low (LR) or intermediate risk (IR) histology between 6 months and 18 years of age, were selected from the total sample of patients registered in the SIOP 93-01 study between June 1993 and December 2001. All patients received 4 weeks of actinomycin-D/vincristine before surgery. Postoperative chemotherapy consisted of actinomycin-D, vincristine and epirubicin/doxorubicin for 27 weeks. Flank or whole abdomen irradiation was given for stage III. Event-free survival (EFS) and overall survival (OS) were analysed for various subgroups. RESULTS: Of 1476 registered patients 594 (40%) met the inclusion criteria for this analysis. Four hundred and two (67%) had stage II disease and 563 (95%) had intermediate risk histology. Median tumour volume was 439 ml at diagnosis and 163 ml after preoperative chemotherapy. With a median follow-up of 8 years, 5-year EFS was 90% (95% confidence interval [95% CI]: 87-92%) and OS 95% (95% CI: 93-97%). Patients with stage III, blastemal type histology and a large volume at surgery had a worse outcome. CONCLUSION: Treatment for stage II and III LR or IR WT is successful in a neoadjuvant setting as advised by the SIOP. Stage, tumour volume and blastemal type histology are the most important prognostic factors.

Renal dysfunction and elevated blood pressure in long-term childhood cancer survivors.

BACKGROUND AND OBJECTIVES: Little is known about renal function and blood pressure (BP) in long-term childhood cancer survivors. This cross-sectional study evaluated prevalence of these outcomes and associated risk factors in long-term childhood cancer survivors at their first visit to a specialized outpatient clinic. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Estimated GFR; percentages of patients with albuminuria, hypomagnesemia, and hypophosphatemia; and BP were assessed in 1442 survivors ≥5 years after diagnosis. Multivariable logistic regression analyses were used to estimate effect of chemotherapy, nephrectomy, and radiation therapy on the different outcomes. RESULTS: At a median age of 19.3 years (interquartile range, 15.6-24.5 years), 28.1% of all survivors had at least one renal adverse effect or elevated BP. The median time since cancer diagnosis was 12.1 years (interquartile range, 7.8-17.5 years). High BP and albuminuria were most prevalent, at 14.8% and 14.5%, respectively. Sixty-two survivors (4.5%) had an estimated GFR <90 ml/min per 1.73 m(2). Survivors who had undergone nephrectomy had the highest risk for diminished renal function (odds ratio, 8.6; 95% confidence interval [CI], 3.4-21.4). Combined radiation therapy and nephrectomy increased the odds of having elevated BP (odds ratio, 4.92; 95% CI, 2.63-9.19), as did male sex, higher body mass index, and longer time since cancer treatment. CONCLUSION: Almost 30% of survivors had renal adverse effects or high BP. Therefore, monitoring of renal function in high-risk groups and BP in all survivors may help clinicians detect health problems at an early stage and initiate timely therapy to prevent additional damage.

High risk of symptomatic cardiac events in childhood cancer survivors.

PURPOSE: To evaluate the long-term risk for validated symptomatic cardiac events (CEs) and associated risk factors in childhood cancer survivors (CCSs). PATIENTS AND METHODS: We determined CEs grade 3 or higher: congestive heart failure (CHF), cardiac ischemia, valvular disease, arrhythmia and/or pericarditis (according to Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) in a hospital-based cohort of 1,362 5-year CCSs diagnosed between 1966 and 1996. We calculated both marginal and cause-specific cumulative incidence of CEs and cause-specific cumulative incidence of separate events. We analyzed different risk factors in multivariable Cox regression models. RESULTS: Overall, 50 CEs, including 27 cases of CHF, were observed in 42 survivors (at a median attained age of 27.1 years). The 30-year cause-specific cumulative incidence of CEs was significantly increased after treatment with both anthracyclines and cardiac irradiation (12.6%; 95% CI, 4.3% to 20.3%), after anthracyclines (7.3%; 95% CI, 3.8% to 10.7%), and after cardiac irradiation (4.0%; 95% CI, 0.5% to 7.4%) compared with other treatments. In the proportional hazards analyses, anthracycline (dose), cardiac irradiation (dose), combination of these treatments, and congenital heart disease were significantly associated with developing a CE. We demonstrated an exponential relationship between the cumulative anthracycline dose, cardiac irradiation dose, and risk of CE. CONCLUSION: CCSs have a high risk of developing symptomatic CEs at an early age. The most common CE was CHF. Survivors treated with both anthracyclines and radiotherapy have the highest risk; after 30 years, one in eight will develop severe heart disease. The use of potentially cardiotoxic treatments should be reconsidered for high-risk groups, and frequent follow-up for high-risk survivors is needed.

Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG.

BACKGROUND: The authors report preliminary results from a prospective multicenter study (Nasopharyngeal Carcinoma [NPC] 2003 German Society of Pediatric Oncology and Hematology/German Children's Oncology Group [NPC-2003-GPOH/DCOG]). METHODS: From 2003 to 2010, 45 patients (ages 8-20 years), including 1 patient with stage II NPC and 44 patients with stage III/IV NPC, were recruited to the study. The patient with stage II disease received radiotherapy (59.4 grays [Gy]). The patients with stage III/IV disease received 3 courses of neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and folinic acid. The cumulative irradiation dose was 54 Gy in 5 patients, who achieved complete remission after neoadjuvant chemotherapy, and 59.4 Gy in the remaining 40 patients. All patients received concomitant cisplatin during the first week and last week of irradiation. After irradiation, all patients received interferon beta for 6 months. Tumor response was evaluated by magnetic resonance imaging studies and positron emission tomography scans. RESULTS: After the completion of treatment, 43 of 45 patients were in complete remission. In 2 patients, only a partial response was achieved, followed by distant metastases (1 patient) or local progression and distant metastases (1 patient), 6 months and 10 months after diagnosis, respectively. Another patient developed a solitary pelvic bone metastasis 21 months after diagnosis. After a median follow-up of 30 months (range, 6-95 months), the event-free survival rate was 92.4%, and the overall survival was 97.1%. Acute toxicity consisted mainly of leucopenia, mucositis, and nausea; and late toxicity consisted of hearing loss and hypothyroidism. CONCLUSIONS: Combined therapy with neoadjuvant chemotherapy, radiochemotherapy, and interferon beta was well tolerated and resulted in a very good outcome that was superior to the outcomes of published results from all other pediatric NPC study groups.