Geert O. Janssens

Position paper: Rationale for the treatment of Wilms tumour in the UMBRELLA SIOP–RTSG 2016 protocol

The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP–RTSG 2016 (the UMBRELLA protocol), to continue international collaboration in the treatment of childhood renal tumours. This protocol will support integrated biomarker and imaging research, focussing on assessing the independent prognostic value of genomic changes within the tumour and the volume of the blastemal component that survives preoperative chemotherapy. Treatment guidelines for Wilms tumours in the UMBRELLA protocol include recommendations for localized, metastatic, and bilateral disease, for all age groups, and for relapsed disease. These recommendations have been established by a multidisciplinary panel of leading experts on renal tumours within the SIOP–RTSG. The UMBRELLA protocol should promote international collaboration and research and serve as the SIOP–RTSG best available treatment standard.

Adverse effect of smoking on prognosis in human papillomavirus-associated oropharyngeal carcinoma.

The purpose of this retrospective study was to identify prognostic factors in a cohort of patients with oropharyngeal carcinoma treated with intensity‐modulated radiotherapy (IMRT).

Quality-of-life after radiotherapy for advanced laryngeal cancer: Results of a phase III trial of the Dutch Head and Neck Society

BACKGROUND/PURPOSE To report on health-related quality-of-life (HRQoL) of patients with laryngeal cancer, treated in a randomized trial comparing accelerated radiotherapy with carbogen and nicotinamide (ARCON) against accelerated radiotherapy alone (AR). MATERIAL/METHODS HRQoL was assessed using the HRQoL Questionnaire-C30 (QLQ-C30) and the Head & Neck cancer module (QLQ-H&N35) at baseline, at completion of radiotherapy and at 6, 12, and 24months post-baseline. RESULTS From 269/345 patients (AR: 136/174; ARCON: 133/171) data on HRQoL were available for analysis. Moderate to severe clinical impact of the treatment was observed for nearly all items of the QLQ-C30 and QLQ-H&N35 between baseline and end-of-treatment. At 6months, scores returned to baseline level with exception of dry mouth, sticky saliva, and taste/smell. No difference between AR and ARCON was observed. At 2years from baseline, the percentage of patients reporting moderate to severe complaints of dry mouth, sticky saliva, or changes in taste/smell was 30%, 22% and 18%, respectively, while the majority of patients had no or few complaints of swallowing (79%) or speech (64%). CONCLUSIONS With accelerated radiotherapy, high local tumor control was obtained while maintaining good speech and swallowing function. Long-term dry mouth, sticky saliva and changes in taste/smell are limited to one quarter of patients. (ClinicalTrials.gov number, NCT00147732).

Intra- and inter-fraction uncertainties during IGRT for Wilms’ tumor

Abstract Background and purpose: To assess intra- and inter-fraction motion uncertainties, due to displacements of the tumor bed (TB) and organs at risk (OAR), as well as intra- and inter-fraction patient set-up uncertainties, due to positioning variations, during image-guided radiation therapy (IGRT) in children with Wilms’ tumor. Material and methods: Four-dimensional computed tomography (4D-CT) and daily pre- and post-treatment cone-beam CT (CBCT)-scans of 15 patients (average 4, range 1–8 years) undergoing flank irradiation after nephrectomy were analyzed. TB (marked by four surgical clips) and OAR motion uncertainties were quantified by displacements of the center of mass in all orthogonal directions. Translational and rotational bone off-sets were recorded for patient set-up uncertainties assessment in all orthogonal directions. The average results, systematic and random errors were computed. Results: Average intra- and inter-fraction motion uncertainties were ≤1.1 mm (range: [−6.9;7.9] mm) for the TB and ≤3.2 mm (range: [−9.1;9.6] mm) for the OAR. Average intra- and inter-fraction patient set-up uncertainties were ≤0.1 mm (range: [−3.3;4.8] mm) and ≤0.9° (range: [0.0;2.8°]). Both motion and patient set-up uncertainties were larger for the cranio-caudal direction. Calculated systematic and random errors were ≤2.4 mm for the motion uncertainties and ≤0.8 mm/0.7° for the patient set-up uncertainties. Conclusions: Average motion and patient set-up uncertainties during radiotherapy treatment were found to be limited. However, uncertainties were larger for the cranio-caudal direction and outliers were found in all orthogonal directions. When having available 4D-CT and CBCT information, the use of patient-specific and anisotropic safety margin expansions is advised for both target volume and OAR.

Colorectal Adenomas and Cancers After Childhood Cancer Treatment: A DCOG-LATER Record Linkage Study

Background Although colorectal adenomas serve as prime target for colorectal cancer (CRC) surveillance in other high-risk groups, data on adenoma risk after childhood cancer are lacking. We evaluated the risk of histologically confirmed colorectal adenomas among childhood cancer survivors. A secondary aim was to assess CRC risk. Methods The DCOG-LATER cohort study includes five-year Dutch childhood cancer survivors and a sibling comparison group (n = 883). Colorectal tumors were identified from the population-based Dutch Pathology Registry (PALGA). We calculated cumulative incidences of adenomas/CRCs for survivors and siblings. For adenomas, multivariable Cox regression models were used to evaluate potential risk factors. All statistical tests were two-sided. Results Among 5843 five-year survivors (median follow-up = 24.9 years), 78 individuals developed an adenoma. Cumulative incidence by age 45 years was 3.6% (95% confidence interval [CI] = 2.2% to 5.6%) after abdominopelvic radiotherapy (AP-RT; 49 cases) vs 2.0% (95% CI = 1.3% to 2.8%) among survivors without AP-RT (28 cases; Pdifference = .07) and vs 1.0% (95% CI = 0.3% to 2.6%) among siblings (6 cases) (Pdifference = .03). Factors associated with adenoma risk were AP-RT (hazard ratio [HR] = 2.12, 95% CI = 1.24 to 3.60), total body irradiation (TBI; HR = 10.55, 95% CI = 5.20 to 21.42), cisplatin (HR = 2.13; 95% CI = 0.74 to 6.07 for <480 mg/m²; HR = 3.85, 95% CI = 1.45 to 10.26 for ≥480 mg/m²; Ptrend = .62), a hepatoblastoma diagnosis (HR = 27.12, 95% CI = 8.80 to 83.58), and family history of early-onset CRC (HR = 20.46, 95% CI = 8.10 to 51.70). Procarbazine was statistically significantly associated among survivors without AP-RT/TBI (HR = 2.71, 95% CI = 1.28 to 5.74). Thirteen CRCs occurred. Conclusion We provide evidence for excess risk of colorectal adenomas and CRCs among childhood cancer survivors. Adenoma risk factors include AP-RT, TBI, cisplatin, and procarbazine. Hepatoblastoma (familial adenomatous polyposis-associated) and family history of early-onset CRC were confirmed as strong risk factors. A full benefit-vs-harm evaluation of CRC screening among high-risk childhood cancer survivors warrants consideration.

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

To evaluate the value of radiotherapy boost omission in patients with intermediate‐risk, stage III Wilms tumours (WT) with positive lymph nodes (LN).

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.

Position paper: Rationale for the treatment of children with CCSK in the UMBRELLA SIOP-RTSG 2016 protocol

The International Society of Paediatric Oncology–Renal Tumour Study Group (SIOP–RTSG) has developed a new protocol for the diagnosis, treatment, and follow-up monitoring of childhood renal tumours — the UMBRELLA SIOP–RTSG 2016 protocol (the UMBRELLA protocol). This protocol has been designed to continue international collaboration in the treatment of childhood renal tumours and will be implemented in over 50 different countries. Clear cell sarcoma of the kidney, which is a rare paediatric renal tumour that most commonly occurs in children between 2 and 4 years of age, is specifically addressed in the UMBRELLA protocol.

Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?

We would like to comment on the manuscript entitled: “Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?”, published March 2018. In order to design early phase clinical trials for DIPG at the time of disease progression, Lobon-Iglesias et al. try to define a subgroup of long-term (> 3 months) survivors among a group of 142 patients with DIPG treated at a single institution [1]. On multivariate analysis (two way ANOVA), steroid-independence (≥ 2 months) and favorable Lansky Play Scale (LPS > 50%) at disease progression best predicted survival after relapse and hence, patients eligibility for clinical trials. Although significant on univariate analysis, re-irradiation (n = 14) or presence of histone H3.1 mutation (n = 20) did not improve statistical significance for prediction. In a recently published European matched-cohort analysis, comprising 70 patients with DIPG and progression ≥ 90 days from end of upfront radiotherapy, interval to progression and the use of re-irradiation, remained prognostic for survival on multivariate analysis [2]. Re-irradiation was well tolerated while clinical improvement was observed in nearly 80% of patients. In this study, a risk score (RS) comprising five categories was developed to predict survival from first progression. Median survival ranges from 1.0 month (RS-1) to 6.7 months (RS-5). No information on duration of steroid-independency, LPS or histone H3 mutations was available for this analysis. In absence of a clinical trial, and according to SIOP-E recommendations, re-irradiation of children with DIPG at first progression can be considered when eligibility criteria are fulfilled and radio-necrosis after upfront radiotherapy is excluded [2]. Recently, this policy has been adopted by the National Cancer Institute (https ://www.cance r.gov/types /brain /hp/child -gliom a-treat ment-pdq#secti on/_55). Both studies demonstrate that at least four variables can impact survival from progression [1, 2]. At present time it will be difficult to bypass the role of re-irradiation at the time of disease progression, even in the absence of a randomized control trial, considered unfeasible for ethical, political and financial reasons within the SIOP-E community. Although we fully support the author’s statement that new and more efficient treatments in DIPG are needed, we want to express our concerns on the feasibility of new studies in DIPG at the time of progression for the number of reasons mentioned above.

EP-1099: Re-irradiation for head and neck tumors: efficacy versus late toxicity in 137 patients

Material and Methods: Patients with head and neck cancer that had completed IMRT to unilateral or bilateral neck with a minimum of 2 years of follow up were identified from a prospective database. All patients underwent clinical review as per local protocol which was commonly 6 weekly. The brachial plexus was contoured based on RTOG Atlas. Maximum dose (Dmax) to brachial plexus was recorded from DVH. All doses were converted to BED using an α/β ratio of 2. A review of electronic records was performed to determine brachial plexus toxicity using CTCAE v 3.0.