Complications after proton radiotherapy in children, focusing on severe late complications. A complete Swedish cohort 2008-2019.

BACKGROUND: Proton radiotherapy (RT) is an attractive tool to deliver local therapy with minimal dose to uninvolved tissue, however, not suitable for all patients. The aim was to explore complications, especially severe late complications (grades 3-4), following proton RT delivered to a complete Swedish cohort of paediatric patients aged <18 years treated 2008-2019. MATERIAL AND METHODS: Data was downloaded from a national registry. Complications with a possible causation with RT are reported. Proton treatments until July 2015 was performed with a fixed horizontal 172 MeV beam (The Svedberg Laboratory (TSL), Uppsala) in a sitting position and thereafter with gantry-based pencil-beam scanning technique (Skandion Clinic, Uppsala) in a supine position. RESULTS: 219 courses of proton RT (77 at TSL and 142 at Skandion) were delivered to 212 patients (mean age 9.2 years) with various tumour types (CNS tumours 58%, sarcomas 26%, germ cell tumours 7%). Twenty-five patients had severe acute complications (skin, mucous membrane, pharynx/oesophagus, larynx, upper gastrointestinal canal, lower gastrointestinal canal, eyes, ears). Fifteen patients had severe late complications; with increased proportion over time: 4% at 1-year follow-up (FU), 5% at 3-year, 11% at 5-year. Organs affected were skin (1 patient), subcutaneous tissue (4), salivary glands (1), upper GI (1), bone (7), joints (2), CNS (2), PNS (1), eyes (1) and ears (5). Twenty-one of the 28 patients with 10-year FU had at least one late complication grades 1-4 and fourteen of them had more than one (2-5 each). CONCLUSION: The most important result of our study is the relatively low proportion of severe late complications, comparable with other proton studies on various tumours. Furthermore, the numbers of late complications are lower than our own data set on a mixed population of photon and proton treated paediatric patients, assuring the safety of using proton therapy also in the clinical practice.

A national study on the inter-observer variability in the delineation of organs at risk in the brain.

BACKGROUND: The Danish Neuro Oncology Group (DNOG) has established national consensus guidelines for the delineation of organs at risk (OAR) structures based on published literature. This study was conducted to finalise these guidelines and evaluate the inter-observer variability of the delineated OAR structures by expert observers. MATERIAL AND METHODS: The DNOG delineation guidelines were formed by participants from all Danish centres that treat brain tumours with radiotherapy. In a two-day workshop, guidelines were discussed and finalised based on a pilot study. Following this, the ten participants contoured the following OARs on T1-weighted gadolinium enhanced MRI from 13 patients with brain tumours: optic tracts, optic nerves, chiasm, spinal cord, brainstem, pituitary gland and hippocampus. The metrics used for comparison were the Dice similarity coefficient (Dice), mean surface distance (MSD) and others. RESULTS: A total of 968 contours were delineated across the 13 patients. On average eight (range six to nine) individual contour sets were made per patient. Good agreement was found across all structures with a median MSD below 1 mm for most structures, with the chiasm performing the best with a median MSD of 0.45 mm. The Dice was as expected highly volume dependent, the brainstem (the largest structure) had the highest Dice value with a median of 0.89 whereas smaller volumes such as the chiasm had a Dice of 0.71. CONCLUSION: Except for the caudal definition of the spinal cord, the variances observed in the contours of OARs in the brain were generally low and consistent. Surface mapping revealed sub-regions of higher variance for some organs. The data set is being prepared as a validation data set for auto-segmentation algorithms for use within the Danish Comprehensive Cancer Centre - Radiotherapy and potential collaborators.

RBE for proton radiation therapy - a Nordic view in the international perspective.

BACKGROUND: This paper presents an insight into the critical discussions and the current strategies of the Nordic countries for handling the variable proton relative biological effectiveness (RBE) as presented at The Nordic Collaborative Workshop for Particle Therapy that took place at the Skandion Clinic on 14th and 15th of November 2019. MATERIAL AND METHODS: In the current clinical practice at the two proton centres in operation at the date, Skandion Clinic, and the Danish Centre for Particle Therapy, a constant proton RBE of 1.1 is applied. The potentially increased effectiveness at the end of the particle range is however considered at the stage of treatment planning at both places based on empirical observations and knowledge. More elaborated strategies to evaluate the plans and mitigate the problem are intensely investigated internationally as well at the two centres. They involve the calculation of the dose-averaged linear energy transfer (LETd) values and the assessment of their distributions corroborated with the distribution of the dose and the location of the critical clinical structures. RESULTS: Methods and tools for LETd calculations are under different stages of development as well as models to account for the variation of the RBE with LETd, dose per fraction, and type of tissue. The way they are currently used for evaluation and optimisation of the plans and their robustness are summarised. A critical but not exhaustive discussion of their potential future implementation in the clinical practice is also presented. CONCLUSIONS: The need for collaboration between the clinical proton centres in establishing common platforms and perspectives for treatment planning evaluation and optimisation is highlighted as well as the need of close interaction with the research academic groups that could offer a complementary perspective and actively help developing methods and tools for clinical implementation of the more complex metrics for considering the variable effectiveness of the proton beams.

Ongoing and future clinical trials in particle therapy in the Nordic countries.

In the Nordic countries, as in the rest of the world, particle therapy as a radiotherapy modality, is evolving, albeit the hard evidence for the clinical benefit still is scarce. However, a common goal for the Nordic countries is to include a minimum of 80% of the patients treated with particle therapy into clinical trials. In this paper, we summarize the current status of clinical trials involving particle therapy in the Nordic countries, with an overview of both active and coming trials. So far, one is closed for inclusion and data are being analyzed, seven trials are actively recruiting patients and several more trials are underway. No common Nordic trial has yet been designed, nor is in the planning phase, and the authors will discuss the obstacles as well as the opportunities a common Nordic platform may represent.

Harmonization of proton treatment planning for head and neck cancer using pencil beam scanning: first report of the IPACS collaboration group.

Background and purpose: A collaborative network between proton therapy (PT) centres in Trento in Italy, Poland, Austria, Czech Republic and Sweden (IPACS) was founded to implement trials and harmonize PT. This is the first report of IPACS with the aim to show the level of harmonization that can be achieved for proton therapy planning of head and neck (sino-nasal) cancer.Methods: CT-data sets of five patients were included. During several face-to-face and online meetings, a common treatment planning protocol was developed. Each centre used its own treatment planning system (TPS) and planning approach with some restrictions specified in the treatment planning protocol. In addition, volumetric modulated arc therapy (VMAT) photon plans were created.Results: For CTV1, the average Dmedian was 59.3 ± 2.4 Gy(RBE) for protons and 58.8 ± 2.0 Gy(RBE) for VMAT (aim was 56 Gy(RBE)). For CTV2, the average Dmedian was 71.2 ± 1.0 Gy(RBE) for protons and 70.6 ± 0.4 Gy(RBE) for VMAT (aim was 70 Gy(RBE)). The average D2% for the spinal cord was 25.1 ± 8.5 Gy(RBE) for protons and 47.6 ± 1.4 Gy(RBE) for VMAT. The average D2% for chiasm was 46.5 ± 4.4 Gy(RBE) for protons and 50.8 ± 1.4 Gy(RBE) for VMAT, respectively. Robust evaluation was performed and showed the least robust plans for plans with a low number of beams.Discussion: In conclusion, several influences on harmonization were identified: adherence/interpretation to/of the protocol, available technology, experience in treatment planning and use of different beam arrangements. In future, all OARs that should be included in the optimization need to be specified in order to further harmonize treatment planning.

Recurrent papillary craniopharyngioma with BRAFV600E mutation treated with neoadjuvant-targeted therapy.

Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Here, we report on near-radical reduction of a growing residual BRAFV600E craniopharyngioma using the same neoadjuvant therapy.

Respiratory gating for proton beam scanning versus photon 3D-CRT for breast cancer radiotherapy.

Background Respiratory gating and proton therapy have both been proposed to reduce the cardiopulmonary burden in breast cancer radiotherapy. This study aims to investigate the additional benefit of proton radiotherapy for breast cancer with and without respiratory gating. Material and methods Twenty left-sided patients were planned on computed tomography (CT)-datasets acquired during enhanced inspiration gating (EIG) and free-breathing (FB), using photon three-dimensional conformal radiation therapy (3D-CRT) and scanned proton beams. Ten patients received treatment to the whole breast only (WBO) and 10 were treated to the breast and the regional lymph nodes (BRN). Dosimetric parameters characterizing the coverage of target volumes and the cardiopulmonary burden were compared using a paired, two-tailed Student's t-test. Results Protons ensured comparable or better target coverage than photons in all patients during both EIG and FB. The heterogeneity index decreased from 12% with photons to about 5% with protons. The mean dose to the ipsilateral lung was reduced in BRN patients from 12 Gy to 7 Gy (RBE) in EIG and from 14 Gy to 6-7 Gy (RBE) in FB, while for WBO patients all values were about 5-6 Gy (RBE). The mean dose to heart decreased by a factor of four in WBO patients [from 1.1 Gy to 0.3 Gy (RBE) in EIG and from 2.1 Gy to 0.5 Gy (RBE) in FB] and 10 in BRN patients [from 2.1 Gy to 0.2 Gy (RBE) in EIG and from 3.4 Gy to 0.3 Gy (RBE) in FB]. Similarly, the mean and the near maximum dose to the left anterior descending artery (LAD) were significantly lower (p < 0.05) with protons in comparison with photons. Conclusion Proton spot scanning has a high potential to reduce the irradiation of organs at risk and other normal tissues for most patients, beyond what could be achieved with EIG and photon therapy. The largest dose sparing has been seen for BRN patients, both in terms of cardiopulmonary burden and integral dose.

Radiation dose distribution in coronary arteries in breast cancer radiotherapy.

BACKGROUND: Women irradiated for left-sided breast cancer (BC) have an increased risk of coronary artery disease compared to women with right-sided BC. We describe the distribution of radiation dose in segments of coronary arteries in women receiving adjuvant radiotherapy (RT) for left- or right-sided BC. MATERIAL AND METHODS: Fifteen women with BC, seven left-sided and eight right-sided, who had received three-dimensional conformal radiotherapy (3DCRT), constituted the study base. The heart and the segments of the coronary arteries were defined as separate organs at risk (OAR), and the mean and maximum radiation doses were calculated for each OAR. RESULTS: In women with left-sided BC, irrespective of if regional lymph node RT was given or not, maximum dose in mid and distal left anterior descending artery (mdLAD) was approximately 50 Gy in 6/7 patients, whereas women with right-sided BC mainly received low doses of radiation. In women with left-sided BC, 6/7 patients had substantially higher mean dose to the distal LAD than to the heart, ranging from 30 to 55 Gy and 3 to13 Gy, respectively. CONCLUSION: We found a pronounced difference of radiation dose distribution in the coronary arteries between women with left- and right-sided BC. Women with left-sided BC had almost full treatment dose in parts of mdLAD, regardless of if regional lymph node irradiation was given or not, while women with right-sided BC mainly received low doses to the coronary arteries.

[Paraganglioma (glomus tumour) of the head and neck, a rare and demanding diagnosis]. / Huvud­halsparagangliom är en ovanlig och utmanande diagnos.

Paragangliomas of the head and neck are rare tumours arising from extraadrenal ganglia. They are highly vascular lesions and are normally benign and not hormone secreting. Symptoms are usually discreet and the tumours often present as a lump in the neck or are diagnosed incidentally. Evaluation of paragangliomas of the head and neck, and surgery when indicated, is highly specialized care to be performed at two hospitals nationwide (in Region Uppsala and Region Skåne). Historically, treatment has mainly been surgical. However, with a multidisciplinary evaluation of each case recommendations can be individualized and treatment options may include surgery, radiotherapy or watchful waiting (wait-and-scan). When surgery is recommended for paragangliomas of the neck, it is best performed in collaboration between head-neck surgeons and vascular surgeons. Follow up in benign cases is mainly done through imaging.

Evaluation of skin reactions during proton beam radiotherapy - Patient-reported versus clinician-reported.

BACKGROUND: Skin reaction is a common side-effect of radiotherapy and often only assessed as clinician-reported outcome (CRO). The aim was to examine and compare patient-reported outcome (PRO) of skin reactions with CRO for signs of acute skin reactions for patients with primary brain tumour receiving proton beam radiotherapy (PBT). A further aim was to explore patients' experiences of the skin reactions. METHODS: Acute skin reactions were assessed one week after start of treatment, mid-treatment and end of treatment among 253 patients with primary brain tumour who underwent PBT. PRO skin reactions were assessed with the RSAS and CRO according to the RTOG scale. Fleiss' kappa was performed to measure the inter-rater agreement of the assessments of skin reactions. RESULTS: The results showed a discrepancy between PRO and CRO acute skin reactions. Radiation dose was associated with increased skin reactions, but no correlations were seen for age, gender, education, occupation, other treatment or smoking. There was a poor agreement between patients and clinicians (κ = -0.016) one week after the start of PBT, poor (κ = -0.045) to (κ = 0.396) moderate agreement at mid treatment and poor (κ = -0.010) to (κ = 0.296) moderate agreement at end of treatment. Generally, patients' symptom distress toward skin reactions was low at all time points. CONCLUSION: The poor agreement between PRO and CRO shows that the patient needs to be involved in assessments of skin reactions for a more complete understanding of skin reactions due to PBT. This may also improve patient experience regarding involvement in their own care.

Spatial correlation of linear energy transfer and relative biological effectiveness with suspected treatment-related toxicities following proton therapy for intracranial tumors.

PURPOSE: The enhanced relative biological effectiveness (RBE) at the end of the proton range might increase the risk of radiation-induced toxicities. This is of special concern for intracranial treatments where several critical organs at risk (OARs) surround the tumor. In the light of this, a retrospective analysis of dose-averaged linear energy transfer (LETd ) and RBE-weighted dose (DRBE ) distributions was conducted for three clinical cases with suspected treatment-related toxicities following intracranial proton therapy. Alternative treatment strategies aiming to reduce toxicity risks are also presented. METHODS: The clinical single-field optimized (SFO) plans were recalculated for 81 error scenarios with a Monte Carlo dose engine. The fractionation DRBE was 1.8 Gy (RBE) in 28 or 30 fractions assuming a constant RBE of 1.1. Two LETd - and α/ß-dependent variable RBE models were used for evaluation, including a sensitivity analysis of the α/ß parameter. Resulting distributions of DRBE and LETd were analyzed together with normal tissue complication probabilities (NTCPs). Subsequently, four multi-field optimized (MFO) plans, with an additional beam and/or objectives penalizing protons stopping in OARs, were created to investigate the potential reduction of LETd , DRBE , and NTCP. RESULTS: The two variable RBE models agreed well and predicted average RBE values around 1.3 in the toxicity volumes, resulting in an increased near-maximum DRBE of 7-11 Gy (RBE) compared to RBE = 1.1 in the nominal scenario. The corresponding NTCP estimates increased from 0.8%, 0.0%, and 3.7% (RBE = 1.1) to 15.5%, 1.8%, and 45.7% (Wedenberg RBE model) for the three patients, respectively. The MFO plans generally allowed for LETd , DRBE , and NTCP reductions in OARs, without compromising the target dose. Compared to the clinical SFO plans, the maximum reduction in the near-maximum LETd was 56%, 63%, and 72% in the OAR exhibiting the toxicity for the three patients, respectively. CONCLUSIONS: Although a direct causality between RBE and toxicity cannot be established here, high LETd and DRBE correlated spatially with the observed toxicities, whereas setup and range uncertainties had a minor impact. Individual factors, which might affect the patient-specific radiosensitivity, were however not included in these calculations. The MFO plans using both an additional beam and proton track-end objectives allowed the largest reductions in LETd , DRBE , and NTCP, and might be future tools for similar cases.

The Art of Living With Symptoms: A Qualitative Study Among Patients With Primary Brain Tumors Receiving Proton Beam Therapy.

BACKGROUND: Symptom management in conjunction with proton beam therapy (PBT) from patient's perspective has not been explored. Such knowledge is essential to optimize the care in this relatively new treatment modality. OBJECTIVE: The aim of this study was to explore the process of symptom management in patients with brain tumor receiving PBT. METHODS: Participants were 22 patients with primary brain tumor who received PBT, recruited in collaboration with a national center for proton therapy and 2 oncology clinics at 2 university hospitals in Sweden. Interviews using open-ended questions were conducted before, during, and/or after treatment. Verbatim interview transcripts were analyzed using classic Grounded Theory. RESULTS: "The art of living with symptoms" emerged as the core concept. This encompassed 3 interconnected symptom management concepts: "Adapting to limited ability," "Learning about oneself," and "Creating new routines." These concepts were summarized in a substantive theoretical model of symptom management. Despite the struggle to manage symptoms, participants lived a satisfactory life. CONCLUSIONS: Symptom management in conjunction with PBT comprises a process of action, thoughts, and emotions. The concepts that emerged indicated patients' symptom management strategies were based on their own resources. IMPLICATIONS FOR PRACTICE: It is important that PBT facilities develop an approach that facilitates the symptom management process based on patients' experiences of symptoms, as well as their actions and available resources.

ESTRO ACROP consensus guideline for target volume delineation in the setting of postmastectomy radiation therapy after implant-based immediate reconstruction for early stage breast cancer.

Immediate breast reconstruction (IBR) rates after mastectomy are increasing. Postmastectomy radiation therapy (PMRT) contouring guidelines for target volumes in the setting of IBR are lacking. Therefore, many patients who have had IBR receive PMRT to target volumes similar to conventional simulator-based whole breast irradiation. The aim of this paper is to describe delineation guidelines for PMRT after implant-based IBR based on a thorough understanding of the surgical procedures, disease stage, patterns of recurrence and radiation techniques. They are based on a consensus endorsed by a global multidisciplinary group of breast cancer experts.

Patterns of proton therapy use in pediatric cancer management in 2016: An international survey.

PURPOSE: To facilitate the initiation of observational studies on late effects of proton therapy in pediatric patients, we report on current patterns of proton therapy use worldwide in patients aged less than 22 years. MATERIALS & METHODS: Fifty-four proton centers treating pediatric patients in 2016 in 11 countries were invited to respond to a survey about the number of patients treated during that year by age group, intent of treatment, delivery technique and tumor types. RESULTS: Among the 40 participating centers (participation rate: 74%), a total of 1,860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223). The numbers of patients per center ranged from 1 to 206 (median: 29). Twenty-four percent of the patients were <5 years of age, and 50% <10 years. More than 30 pediatric tumor types were identified, mainly treated with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors. About half of the patients were treated with pencil beam scanning. Treatment patterns were broadly similar across the three continents. CONCLUSION: To our knowledge, this survey provides the first worldwide assessment of proton therapy use for pediatric cancer management. Since previous estimates in the United States and Europe, CNS tumors remain the cancer types most commonly treated with protons in 2016. However, the proportion of extra-cranial tumors is growing worldwide. The typically low numbers of patients treated in each center indicate the need for international research collaborations to assess long-term outcomes of proton therapy in pediatric patients.

Normal tissue sparing potential of scanned proton beams with and without respiratory gating for the treatment of internal mammary nodes in breast cancer radiotherapy.

Proton therapy has shown potential for reducing doses to normal tissues in breast cancer radiotherapy. However data on the impact of protons when including internal mammary nodes (IMN) in the target for breast radiotherapy is comparatively scarce. This study aimed to evaluate normal tissue doses when including the IMN in regional RT with scanned proton beams, with and without respiratory gating. The study cohort was composed of ten left-sided breast patients CT-scanned during enhanced inspiration gating (EIG) and free-breathing (FB). Proton plans were designed for the target including or excluding the IMN. Targets and organs-at-risk were delineated according to RTOG guidelines. Comparison was performed between dosimetric parameters characterizing target coverage and OAR radiation burden. Statistical significance of differences was tested using a paired, two-tailed Student's t-test. Inclusion of the IMN in the target volume led to a small increase of the cardiopulmonary burden. The largest differences were seen for the ipsilateral lung where the mean dose increased from 6.1 to 6.6 Gy (RBE) (P < 0.0001) in FB plans and from 6.9 to 7.4 Gy (RBE) (P = 0.003) in EIG plans. Target coverage parameters were very little affected by the inclusion of IMN into the treatment target. Radiotherapy with scanned proton beams has the potential of maintaining low cardiovascular burden when including the IMN into the target, irrespective of whether respiratory gating is used or not.