Strategies to promote translational research within the European Organisation for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Group: a report from the Translational Research Subcommittee

Head and neck squamous cell cancer (HNSCC) is the sixth leading cause of cancer-related deaths worldwide. These tumors are commonly diagnosed at advanced stages and mortality rates remain high. Even cured patients suffer the consequences of aggressive treatment that includes surgery, chemotherapy, and radiotherapy. In the past, in clinical trials, HNSCC was considered as a single disease entity. Advances in molecular biology with the development of genomic and proteomic approaches have demonstrated distinct prognostic HNSCC patient subsets beyond those defined by traditional clinical-pathological factors such as tumor subsite and stage [Cho W (ed). An Omics Perspective on Cancer Research. New York/Berlin: Springer 2010]. Validation of these biomarkers in large prospective clinical trials is required before their clinical implementation. To promote this research, the European Organisation for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Program will develop the following strategies—(i) biobanking: prospective tissue collection from uniformly treated patients in the setting of clinical trials; (ii) a group of physicians, physician—scientists, and EORTC Headquarters staff devoted to patient-oriented head and neck cancer research; (iii) a collaboration between the basic scientists of the Translational Research Division interested in head and neck cancer research and the physicians of the Head and Neck Cancer Group; and (iv) funding through the EORTC Grant Program and the Network Core Institutions Consortium. In the present report, we summarize our strategic plans to promote head and neck cancer research within the EORTC framewor

Identifying patients who may benefit from adaptive radiotherapy:Does the literature on anatomic and dosimetric changes in head and neck organs at risk during radiotherapy provide information to help?

AbstractIn the last decade, many efforts have been made to characterize anatomic changes of head and neck organs at risk (OARs) and the dosimetric consequences during radiotherapy. This review was undertaken to provide an overview of the magnitude and frequency of these effects, and to investigate whether we could find criteria to identify head and neck cancer patients who may benefit from adaptive radiotherapy (ART). Possible relationships between anatomic and dosimetric changes and outcome were explicitly considered. A literature search according to PRISMA guidelines was performed in MEDLINE and EMBASE for studies concerning anatomic or dosimetric changes of head and neck OARs during radiotherapy. Fifty-one eligible studies were found. The majority of papers reported on parotid gland (PG) anatomic and dosimetric changes. In some patients, PG mean dose differences between planning CT and repeat CT scans up to 10Gy were reported. In other studies, only minor dosimetric effects (i.e. <1Gy difference in PG mean dose) were observed as a result of significant anatomic changes. Only a few studies reported on the clinical relevance of anatomic and dosimetric changes in terms of complications or quality of life. Numerous potential selection criteria for anatomic and dosimetric changes during radiotherapy were found and listed. The heterogeneity between studies prevented unambiguous conclusions on how to identify patients who may benefit from ART in head and neck cancer. Potential pre-treatment selection criteria identified from this review include tumour location (nasopharyngeal carcinoma), age, body mass index, planned dose to the parotid glands, the initial parotid gland volume, and the overlap volume of the parotid glands with the target volume. These criteria should be further explored in well-designed and well-powered prospective studies, in which possible relationships between anatomic and dosimetric changes and outcome need to be established

Delayed Effects of a Single Dose Whole-Brain Radiation Therapy on Glucose Metabolism and Myelin Density:a Longitudinal PET Study

Purpose: Radiotherapy is an important treatment option for brain tumors, but the unavoidable irradiation of normal brain tissue can lead to delayed cognitive impairment. The mechanisms involved are still not well explained and, therefore, new tools to investigate the processes leading to the delayed symptoms of brain irradiation are warranted. In this study, positron emission tomography (PET) is used to explore delayed functional changes induced by brain irradiation. Materials and methods: Male Wistar rats were subjected to a single 25-Gy dose of whole brain X-ray irradiation, or sham-irradiation. To investigate delayed effects of radiation on cerebral glucose metabolism and myelin density, 18F-fluorodeoxyglucose (18F-FDG) PET scans were performed at baseline and on day 64 and 94, whereas N-11C-methyl-4,4′-diaminostilbene (11C-MeDAS) PET scans were performed at baseline and on day 60 and 90 post-irradiation. In addition, the open field test (OFT) and novel spatial recognition (NSR) test were performed at baseline and on days 59 and 89 to investigate whether whole brain irradiation induces behavioral changes. Results: Whole-brain irradiation caused loss of bodyweight and delayed cerebral hypometabolism, with 18F-FDG uptake in all brain regions being significantly decreased in irradiated rat on day 64 while it remained unchanged in control animals. Only amygdala and cortical brain regions of irradiated rats still showed reduced 18F-FDG uptake on day 94. 11C-MeDAS uptake in control animals was significantly lower on days 60 and 90 than at the baseline, suggesting a reduction in myelin density in young adults. In irradiated animals, 11C-MeDAS uptake was similarly reduced on day 60, but on day 90 tracer uptake was somewhat increased and not significantly different from baseline anymore. Behavioral tests showed a similar pattern in control and irradiated animals. In both groups, the OFT showed significantly reduced mobility on days 59 and 89, whereas the NSR did not reveal any significant changes in spatial memory over time. Interestingly, a positive correlation between the NSR and 11C-MeDAS uptake was observed in irradiated rats. Conclusions: Whole-brain irradiation causes delayed brain hypometabolism, which is not accompanied by white matter loss. Irradiated animals showed similar behavioral changes over time as control animals and, therefore, cerebral hypometabolism could not be linked to behavioral abnormalities. However, spatial memory seems to be associated with myelin density in irradiated rats

Deep learning prediction of proton and photon dose distributions for paediatric abdominal tumours

OBJECTIVE: Dose prediction using deep-learning networks prior to radiotherapy might lead to more efficient modality selections. The study goal was to predict proton and photon dose distributions based on the patient-specific anatomy and to assess their clinical usage for paediatric abdominal tumours. MATERIAL &METHODS: Data from 80 patients with neuroblastoma or Wilms' tumour was included. Pencil beam scanning (PBS) (5mm/3%) and volumetric-modulated arc therapy (VMAT) plans (5mm) were robustly optimized on the internal target volume (ITV). Separate 3-dimensional patch-based U-net networks were trained to predict PBS and VMAT dose distributions. Doses, planning-computed tomography images and relevant optimization masks (ITV, vertebra and organs-at-risk) of 60 patients were used for training with a 5-fold cross validation. The networks' performance was evaluated by computing the relative error between planned and predicted dose-volume histogram (DVH) parameters for 20 inference patients. In addition, the organs-at-risk mean dose difference between modalities was calculated using planned and predicted dose distributions (ΔDmean= DVMAT-DPBS). Two radiation oncologists performed a blind PBS/VMAT modality selection based on either planned or predicted ΔDmean. RESULTS: Average DVH differences between planned and predicted dose distributions were ≤|6%|for both modalities. The networks classified the organs-at-risk difference as a gain (ΔDmean>0) with 98% precision. An identical modality selection based on planned compared to predicted ΔDmean was made for 18/20 patients. CONCLUSION: Deep-learning networks for accurate prediction of proton and photon dose distributions for abdominal paediatric tumours were established. These networks allowing fast dose visualization might aid in identifying the optimal radiotherapy technique when experience and/or resources are unavailable

Model-based comparison of organ at risk protection between VMAT and robustly optimised IMPT plans

The comparison between intensity-modulated proton therapy (IMPT) and volume-modulated arc therapy (VMAT) plans, based on models of normal tissue complication probabilities (NTCP), can support the choice of radiation modality. IMPT irradiation plans for 50 patients with head and neck tumours originally treated with photon therapy have been robustly optimised against density and setup uncertainties. The dose distribution has been calculated with a Monte Carlo (MC) algorithm. The comparison of the plans was based on dose-volume parameters in organs at risk (OARs) and NTCP-calculations for xerostomia, sticky saliva, dysphagia and tube feeding using Langendijk's model-based approach. While the dose distribution in the target volumes is similar, the IMPT plans show better protection of OARs. Therefore, it is not the high dose confirmation that constitutes the advantage of protons, but it is the reduction of the mid-to-low dose levels compared to photons. This work investigates to what extent the advantages of proton radiation are beneficial for the patient's post-therapeutic quality of life (QoL). As a result, approximately one third of the patients examined benefit significantly from proton therapy with regard to possible late side effects. Clinical data is needed to confirm the model-based calculations

Current Status and Application of Proton Therapy for Esophageal Cancer

Esophageal cancer remains one of the leading causes of death from cancer across the world despite advances in multimodality therapy. Although early-stage disease can often be treated surgically, the current state of the art for locally advanced disease is concurrent chemoradiation, followed by surgery whenever possible. The uniform midline tumor location puts a strong importance on the need for precise delivery of radiation that would minimize dose to the heart and lungs, and the biophysical properties of proton beam makes this modality potential ideal for esophageal cancer treatment. This review covers the current state of knowledge of proton therapy for esophageal cancer, focusing on published retrospective single- and multi-institutional clinical studies, and emerging data from prospective clinical trials, that support the benefit of protons vs photon-based radiation in reducing postoperative complications, cardiac toxicity, and severe radiation induced immune suppression, which may improve survival outcomes for patients. In addition, we discuss the incorporation of immunotherapy to the curative management of esophageal cancers in the not-too-distant future. However, there is still a lack of high-level evidence to support proton therapy in the treatment of esophageal cancer, and proton therapy has its limitations in clinical application. It is expected to see the results of future large-scale randomized clinical trials and the continuous improvement of proton radiotherapy technology

Using a reduced spot size for intensity-modulated proton therapy potentially improves salivary gland-sparing in oropharyngeal cancer

Purpose: To investigate whether intensity-modulated proton therapy with a reduced spot size (rsIMPT) could further reduce the parotid and submandibular gland dose compared with previously calculated IMPT plans with a larger spot size. In addition, it was investigated whether the obtained dose reductions would theoretically translate into a reduction of normal tissue complication probabilities (NTCPs). Methods: Ten patients with N0 oropharyngeal cancer were included in a comparative treatment planning study. Both IMPT plans delivered simultaneously 70 Gy to the boost planning target volume (PTV) and 54 Gy to the elective nodal PTV. IMPT and rsIMPT used identical three-field beam arrangements. In the IMPT plans, the parotid and submandibular salivary glands were spared as much as possible. rsIMPT plans used identical dose-volume objectives for the parotid glands as those used by the IMPT plans, whereas the objectives for the submandibular glands were tightened further. NTCPs were calculated for salivary dysfunction and xerostomia. Results: Target coverage was similar for both IMPT techniques, whereas rsIMPT clearly improved target conformity. The mean doses in the parotid glands and submandibular glands were significantly lower for three-field rsIMPT (14.7 Gy and 46.9 Gy, respectively) than for three-field IMPT (16.8 Gy and 54.6 Gy, respectively). Hence, rsIMPT significantly reduced the NTCP of patient-rated xerostomia and parotid and contralateral submandibular salivary flow dysfunction (27%, 17%, and 43% respectively) compared with IMPT (39%, 20%, and 79%, respectively). In addition, mean dose values in the sublingual glands, the soft palate and oral cavity were also decreased. Obtained dose and NTCP reductions varied per patient. Conclusions: rsIMPT improved sparing of the salivary glands and reduced NTCP for xerostomia and parotid and submandibular salivary dysfunction, while maintaining similar target coverage results. It is expected that rsIMPT improves quality of life during and after radiotherapy treatment.</p