Impact of COVID-19 pandemic on delivery of pediatric radiotherapy: A critical review.

The COVID-19 pandemic has prevented the timely diagnosis and treatment of many diseases, including pediatric cancer. Its impact on pediatric oncologic treatments warrants investigation. As radiotherapy is an integral component of cancer care, we reviewed the published data regarding the impact of COVID-19 on the delivery of pediatric radiotherapy to inform actions for future global events. We found that disruptions in radiotherapy were reported amongst interruptions in other therapies. Disruptions were more common in low-income countries (78%) and low middle-income countries (68%) compared with upper middle-income countries (46%) and high-income countries (10%). Several papers included recommendations for mitigation strategies. Altered treatment regimens were common, including increasing the use of active surveillance and systemic therapy to delay local therapies, and accelerated/hypofractionated dose delivery. Our findings suggest that COVID-19 has impacted radiotherapy delivery in the pediatric population globally. Countries with limited resources may be more affected. Various mitigation strategies have been developed. The efficacy of mitigation measures warrants further investigation.

Recommendations for the treatment of children with radiotherapy in low- and middle-income countries (LMIC): A position paper from the Pediatric Radiation Oncology Society (PROS-LMIC) and Pediatric Oncology in Developing Countries (PODC) working groups of the International Society of Pediatric Oncology (SIOP).

Pediatric radiotherapy is a critical part of pediatric oncology protocols and the quality of the radiotherapy may determine the future quality of life for long-term survivors. Multidisciplinary team decision making provides the basis for high-quality care. However, delivery of high-quality radiotherapy is dependent on resources. This article provides guidelines for delivery of good quality radiation therapy in resource-limited countries based on rational procurement and maintenance planning, protocol development, three-dimensional planning, quality assurance, and adequate staff numbers and training.

Challenges in Treating Childhood Infratentorial Ependymoma: A Low- and Middle-Income Country Experience.

PURPOSE: Patients and physicians in low- and middle-income countries (LMICs) face challenges owing to limited expertise and suboptimal access to appropriate diagnostic and treatment modalities. We report our experience in treating posterior fossa ependymoma (PFE) at MAHAK, a charity organization in Iran whose radiation oncology department is the only one exclusively dedicated to childhood cancer in the whole country. METHODS AND MATERIALS: Pediatric patients with PFE referred to MAHAK between November 2008 and January 2016 were identified. Details on investigations and management done before referral were collected. Management at MAHAK and patient outcomes were analyzed. RESULTS: Of 80 patients diagnosed as having ependymoma, 54 with PFE were identified. Forty-three patients received adjuvant radiation therapy, and 11 were irradiated initially after recurrence. At a median follow-up of 5.1 years (range, 0.3-9.7 years), the latter group had the worst outcome, with a 5-year overall survival (OS) rate of 27% (95% CI, 7%-54%). Patients who started radiation therapy within 77 days after initial surgery had a better outcome compared with those who started later (5-year OS: 74% vs 32%; P = .05). Compliance with follow-up recommendations was poor. Only 22% of the patients had at least 2 IQ test assessments, and 50% showed some decline over time. Three cases of growth hormone deficiency were detected, but none of the patients received replacement therapy. CONCLUSIONS: Access to pediatric neurosurgery, anesthesia, and timely radiation therapy are among the most challenging obstacles to be overcome in LMICs. Our series confirmed that chemotherapy is not an appropriate option for delaying radiation therapy, especially in young children. The importance of long-term follow-up should be acknowledged by the parents and medical team.

The Effects of Physical Activity and Exercise Therapy on Pediatric Brain Tumor Survivors: A systematic review.

Pediatric brain tumors are commonly established with late effects such as poor Gross Motor ability, cerebellar motor dysfunction and cognitive deficits that can significantly affect the children's physical and mental ability as well as their quality of life. The aim of the present systematic review is to investigate the effects of exercise therapy on the complications and late effects arising from the nature of brain tumor and its different treatments in survivors from pediatric brain tumors. Six databases, of Embase, Med line, Cochrane Central Database, PubMed, CINAHL and Elsevier from 2000 up to October 2020 were searched for the studies focusing on the effects of exercise therapy in pediatric brain tumor following different treatment procedures. After applying the inclusion and exclusion criteria, nine out of 224 articles were included for the present systematic review. The articles were rated based on PEDro scales for methodological assessment. The study revealed that the children who survived from brain tumors commonly suffer from damage to hippocampus, cortex and the white matter. The results of systematic analysis also showed that physical exercises would likely help the formation of normal sensorimotor experiences, justifying children's better performance in cognitive tests and eventually promoting their quality of life. The literature also indicated that improvements in motor proficiency and physical fitness after exercise therapy were consistent with such MRI results as increase in the right somatosensory cortical thickness, increased FA in corpus callosum, in the right corticospinal pathway as well as in cingulum. Research voids and recommendations for further investigations were finally presented.

Survivor and parent engagement in childhood cancer treatment in Iran.

In Iran (with a population of 83 million), 19,973 children were diagnosed with cancer from 2009 to 2019 (MAHAK Charity). This study was part of the International Society of Paediatric Oncology, Paediatric Oncology in Developing Countries Committee, 'Patient, Family and Stakeholder Engagement Task Force' engagement study in ten low- and middle-income countries in 2019. We documented childhood cancer survivors and parents' experiences and quality of engagement, including perceptions and expectations, during their cancer treatment journey in Iran. Fourteen in-depth interviews and three focus group discussions were conducted by three Iranian qualitative researchers with 29 participants: recent adolescent/young adult survivors (12-20 years), long-term survivors (21-30 years) and parents [36-61 years (six mothers and four fathers)] from diverse socio-economic and ethnic backgrounds. Data were recorded, transcribed and analysed, and then translated from Farsi into English. Participants' expectations included inter alia improved communication and information flow among the key stakeholders including doctors, nurses, parents and patients. A need for improved patterns of doctor-patient relationships and communication, more effective psychosocial support and the importance of peer support groups (for survivors and parents) were reported. Participants identified areas of satisfaction and dissatisfaction regarding their actual engagement and decision-making. The dominance of a medical-only approach instead of multidisciplinary approach in care, the shortage of psychosocial support, the lack of an integrated system for providing information and delivering a package of printed material about the treatment journey and the absence of patient navigator in childhood cancer care systems were among obstacles for successful engagement of patients and parents throughout their cancer journey.

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Heart and coronary artery protection in patients with mediastinal Hodgkin lymphoma treated with intensity-modulated radiotherapy: dose constraints to virtual volumes or to organs at risk?

BACKGROUND AND PURPOSE: To increase heart and coronary artery protection in patients with mediastinal Hodgkin lymphoma treated with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Twenty patients with early-stage mediastinal Hodgkin lymphoma entered the study. IMRT was delivered to the initially involved lymph node volumes. Various virtual volumes (VVs) were designed to improve the protection of the heart and the origin of the coronary arteries, which were the organs at risk (OARs), while preserving adequate PTV coverage. The results obtained with VVs were then compared with those obtained with dose constraints assigned to OARs. RESULTS: The most satisfactory VV was obtained using the PTV expansion concept. The best compromise between adequate PTV coverage and OAR protection was obtained with dose constraints assigned to the PTV expansion VV and to the origin of the coronary arteries. CONCLUSIONS: IMRT can be improved by using dose constraints assigned to the PTV expansion VV and/or to the origin of the coronary arteries.

The conundrum of Hodgkin lymphoma nodes: to be or not to be included in the involved node radiation fields. The EORTC-GELA lymphoma group guidelines.

PURPOSE: To develop easily applicable guidelines for the determination of initially involved lymph nodes to be included in the radiation fields. PATIENTS AND METHODS: Patients with supra-diaphragmatic Hodgkin lymphoma. All the imaging procedures were carried out with patients in the treatment position. The prechemotherapy PET/CT was coregistered with the postchemotherapy CT simulation for planning purposes. Initially involved lymph nodes were determined on fused prechemotherapy CT and FDG-PET imaging data. The initial assessment was verified with the postchemotherapy CT scan. RESULTS: The classic guidelines for determining the involvement of lymph nodes were not easily applicable and did not seem to reflect the exact extent of Hodgkin lymphoma. Three simple steps were used to pinpoint involved lymph nodes. First, FDG-PET scans were meticulously analysed to detect lymph nodes that were overlooked on CT imaging. Second, any morphological and/or functional asymmetry was sought on CT and FDG-PET scans. Third, a decrease in size or the disappearance of initially visible lymph nodes on the prechemotherapy CT scan as compared to the postchemotherapy CT scan was considered as surrogate proof of initial involvement. CONCLUSIONS: All the radiological procedures should be performed on patients in the treatment position for proper coregistration. It is highly advisable that all CT and/or CT/PET scans be performed with IV contrast. Using the above-mentioned three simple guidelines, initially involved lymph nodes can be detected with very satisfactory accuracy. It is also emphasized that the classic guidelines (2, 3, 4) can always be used when deemed necessary.

Radiotherapy of hodgkin lymphoma: indications, new fields, and techniques.

In recent years, radiotherapy in patients with Hodgkin lymphoma has evolved considerably because of sophisticated imaging technologies and radiation delivery techniques. Even more recently, a new radiation field concept has emerged to ensure better normal tissue protection while preserving an excellent clinical outcome. The role of radiation therapy is also rapidly changing because the concept of a risk-adapted treatment strategy, in which combined-modality treatments were the order of the day, is now expanding into a concept of response-adapted treatments.

Is FDG-PET scan in patients with early stage Hodgkin lymphoma of any value in the implementation of the involved-node radiotherapy concept and dose painting?

BACKGROUND AND PURPOSE: To evaluate the input of FDG-PET data in the implementation of the involved-node radiotherapy concept and dose painting. MATERIALS AND METHODS: Patients with early-stage Hodgkin lymphoma treated with combined modality treatments. First, patients underwent a PET/CT before chemotherapy in the treatment position using a head and shoulder immobilization mask. Second, all patients had a CT simulation for treatment planning. The CT simulation was coregistered with the prechemotherapy CT and FDG-PET scan. All prechemotherapy volumes were superimposed on the CT simulation. The initially involved lymph node areas to be irradiated were delineated on the CT simulation scan. Chemotherapy-induced shrinkage rates of the tumor masses visible on CT scan and on FDG-PET were determined and compared. RESULTS: Before chemotherapy, FDG-PET-avid areas represented 25% of the total volume on CT. After chemotherapy, the influence of initial FDG-PET data on the delineation of involved-node radiotherapy fields was significant and was due to the fact that in 36% of the patients, FDG-PET helped pinpoint lymph nodes that were undetected on CT. After chemotherapy, the rates of tumor volume shrinkage on CT and FDG-PET were similar. This finding suggests similar chemosensitivity for FDG-PET-avid and non-avid areas. There was no correlation between initial FDG-PET-avid volumes and the clinical outcome. CONCLUSION: Prechemotherapy FDG-PET data are essential for correctly implementing the involved-node radiotherapy concept but seem to be of minimal value for applying the concept of dose painting.

Is intensity-modulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy for mediastinal masses in patients with Hodgkin's disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes?

PURPOSE: To evaluate the role of beam orientation optimization and the role of virtual volumes (VVs) aimed at protecting adjacent organs at risk (OARs), and to compare various intensity-modulated radiotherapy (IMRT) setups with conventional treatment with anterior and posterior fields and three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: Patients with mediastinal masses in Hodgkin's disease were treated with combined modality therapy (three to six cycles of adriamycin, bleomycin, vinblastine, and dacarbazine [ABVD] before radiation treatment). Contouring and treatment planning were performed with Somavision and CadPlan Helios (Varian Systems, Palo Alto, CA). The gross tumor volume was determined according to the prechemotherapy length and the postchemotherapy width of the mediastinal tumor mass. A 10-mm isotropic margin was added for the planning target volume (PTV). Because dose constraints assigned to OARs led to unsatisfactory PTV coverage, VVs were designed for each patient to protect adjacent OARs. The prescribed dose was 40 Gy to the PTV, delivered according to guidelines from International Commission on Radiation Units and Measurements Report No. 50. Five different IMRT treatment plans were compared with conventional treatment and 3D-CRT. RESULTS: Beam orientation was important with respect to the amount of irradiated normal tissues. The best compromise in terms of PTV coverage and protection of normal tissues was obtained with five equally spaced beams (5FEQ IMRT plan) using dose constraints assigned to VVs. When IMRT treatment plans were compared with conventional treatment and 3D-CRT, dose conformation with IMRT was significantly better, with greater protection of the heart, coronary arteries, esophagus, and spinal cord. The lungs and breasts in women received a slightly higher radiation dose with IMRT compared with conventional treatments. The greater volume of normal tissue receiving low radiation doses could be a cause for concern. CONCLUSIONS: The 5FEQ IMRT plan with dose constraints assigned to the PTV and VV allows better dose conformation than conventional treatment and 3D-CRT, notably with better protection of the heart and coronary arteries. Of concern is the "spreading out" of low doses to the rest of the patient's body.

Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines.

BACKGROUND AND PURPOSE: To describe new concepts for radiation fields in patients with early stage Hodgkin lymphoma treated with a combined modality. PATIENTS AND MATERIALS: Patients receiving combined modality therapy with at least 2 or 3 cycles of chemotherapy prior to radiotherapy. Pre- and postchemotherapy cervical and thoracic CT scans are mandatory and should be performed, whenever possible, in the treatment position with the use of image fusion capabilities. A pre-chemotherapy PET scan is strongly recommended to increase the detection of involved lymph nodes. RESULTS: Radiation fields are designed to irradiate the initially involved lymph nodes exclusively and to encompass their initial volume. In some cases, radiation fields are slightly modified to avoid unnecessary irradiation of muscles or organs at risk. CONCLUSIONS: The concept of involved-node radiotherapy (INRT) described here is the first attempt to reduce the size of radiation fields compared to the classic involved fields used in adult patients. Proper implementation of INRT requires adequate training and an efficient prospective or early retrospective quality assurance program.

Prospective coronary heart disease screening in asymptomatic Hodgkin lymphoma patients using coronary computed tomography angiography: results and risk factor analysis.

PURPOSE: To prospectively investigate the coronary artery status using coronary CT angiography (CCTA) in patients with Hodgkin lymphoma treated with combined modalities and mediastinal irradiation. METHODS AND MATERIALS: All consecutive asymptomatic patients with Hodgkin lymphoma entered the study during follow-up, from August 2007 to May 2012. Coronary CT angiography was performed, and risk factors were recorded along with leukocyte telomere length (LTL) measurements. RESULTS: One hundred seventy-nine patients entered the 5-year study. The median follow-up was 11.6 years (range, 2.1-40.2 years), and the median interval between treatment and the CCTA was 9.5 years (range, 0.5-40 years). Coronary artery abnormalities were demonstrated in 46 patients (26%). Coronary CT angiography abnormalities were detected in nearly 15% of the patients within the first 5 years after treatment. A significant increase (34%) occurred 10 years after treatment (P=.05). Stenoses were mostly nonostial. Severe stenoses were observed in 12 (6.7%) of the patients, entailing surgery with either angioplasty with stent placement or bypass grafting in 10 of them (5.5%). A multivariate analysis demonstrated that age at treatment, hypertension, and hypercholesterolemia, as well as radiation dose to the coronary artery origins, were prognostic factors. In the group of patients with LTL measurements, hypertension and LTL were the only independent risk factors. CONCLUSIONS: The findings suggest that CCTA can identify asymptomatic individuals at risk of acute coronary artery disease who might require either preventive or curative measures. Conventional risk factors and the radiation dose to coronary artery origins were independent prognostic factors. The prognostic value of LTL needs further investigation.

Low-dose radiation treatment in pulmonary mucosa-associated lymphoid tissue lymphoma: a plausible approach? A single-institution experience in 10 patients.

PURPOSE: To propose an alternative approach for treatment of pulmonary marginal zone lymphoma, using a very small radiation dose (2 × 2 Gy) delivered exclusively to tumor sites. METHODS AND MATERIALS: Patients had localized pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma according to the World Health Organization classification. The 6-MV radiation treatments were delivered using tumor-limited fields, except in cases of diffuse bilateral involvement. Two daily fractions of 2 Gy were delivered to tumor-limited fields using a 6-MV linear accelerator. RESULTS: Ten patients with pulmonary MALT lymphoma entered the study. All but 1 had localized tumor masses. The median follow-up was 56 months (range, 2-103 months). Complete remission or an unconfirmed complete remission was obtained in 60% of patients within the first 2 months, and two additional partial responses were converted into a long-term unconfirmed complete remission. All patients are well and alive, no local progression was observed, and the 5-year progression-free survival rate was 87.5% (95% confidence interval 49%-97%). CONCLUSIONS: Our results suggest that extremely low radiation doses delivered exclusively to tumor sites might be a treatment option in pulmonary MALT lymphoma.

Dosimetric benefits of intensity-modulated radiotherapy combined with the deep-inspiration breath-hold technique in patients with mediastinal Hodgkin's lymphoma.

PURPOSE: To assess the additional benefits of using the deep-inspiration breath-hold (DIBH) technique with intensity-modulated radiotherapy (IMRT) in terms of the protection of organs at risk for patients with mediastinal Hodgkin's disease. METHODS AND MATERIALS: Patients with early-stage Hodgkin's lymphoma with mediastinal involvement were entered into the study. Two simulation computed tomography scans were performed for each patient: one using the free-breathing (FB) technique and the other using the DIBH technique with a dedicated spirometer. The clinical target volume, planning target volume (PTV), and organs at risk were determined on both computed tomography scans according to the guidelines of the European Organization for Research and Treatment of Cancer. In both cases, 30 Gy in 15 fractions was prescribed. The dosimetric parameters retrieved for the statistical analysis were PTV coverage, mean heart dose, mean coronary artery dose, mean lung dose, and lung V20. RESULTS: There were no significant differences in PTV coverage between the two techniques (FB vs. DIBH). The mean doses delivered to the coronary arteries, heart, and lungs were significantly reduced by 15% to 20% using DIBH compared with FB, and the lung V20 was reduced by almost one third. The dose reduction to organs at risk was greater for masses in the upper part of the mediastinum. IMRT with DIBH was partially implemented in 1 patient. This combination will be extended to other patients in the near future. CONCLUSIONS: Radiation exposure of the coronary arteries, heart, and lungs in patients with mediastinal Hodgkin's lymphoma was greatly reduced using DIBH with IMRT. The greatest benefit was obtained for tumors in the upper part of the mediastinum. The possibility of a wider use in clinical practice is currently under investigation in our department.

Involved-node radiotherapy and modern radiation treatment techniques in patients with Hodgkin lymphoma.

PURPOSE: To assess the clinical outcome of the involved-node radiotherapy (INRT) concept using modern radiation treatments (intensity-modulated radiotherapy [IMRT] or deep-inspiration breath-hold radiotherapy [DIBH) in patients with localized supradiaphragmatic Hodgkin lymphoma. METHODS AND MATERIALS: All but 2 patients had early-stage Hodgkin lymphoma, and they were treated with chemotherapy prior to irradiation. Radiation treatments were delivered using the INRT concept according to European Organization for Research and Treatment of Cancer guidelines. IMRT was performed with the patient free-breathing. For the adapted breath-hold technique, a spirometer dedicated to DIBH radiotherapy was used. Three-dimensional conformal radiotherapy was performed with those patients. RESULTS: Fifty patients with Hodgkin lymphoma (48 patients with primary Hodgkin lymphoma, 1 patient with recurrent disease, and 1 patient with refractory disease) entered the study from January 2003 to August 2008. Thirty-two patients were treated with IMRT, and 18 patients were treated with the DIBH technique. The median age was 28 years (range, 17-62 years). Thirty-four (68%) patients had stage I - (I-IIA) IIA disease, and 16 (32%) patients had stage I - (I-IIB) IIB disease. All but 3 patients received three to six cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). The median radiation doses to patients treated with IMRT and DIBH were, respectively, 40 Gy (range, 21.6-40 Gy) and 30.6 Gy (range, 19.8-40 Gy). Protection of various organs at risk was satisfactory. Median follow-up was 53.4 months (range, 19.1-93 months). The 5-year progression-free and overall survival rates for the whole population were 92% (95% confidence interval [CI], 80%-97%) and 94% (95% CI, 75%-98%), respectively. Recurrences occurred in 4 patients: 2 patients had in-field relapses, and 2 patients had visceral recurrences. Grade 3 acute lung toxicity (transient pneumonitis) occurred in 1 case. CONCLUSIONS: Our results suggest that patients with localized Hodgkin lymphoma can be safely and efficiently treated using the INRT concept and modern radiation treatment techniques such as IMRT and DIBH.

The efficacy and toxicity of EGFR in the settings of radiotherapy: Focus on published clinical trials.

Basic research in solid malignant tumours has led to a wealth of knowledge about this disease process and about novel ways to more effectively target our therapies. Laboratory research continues to identify novel therapeutic targets and moreover, clinical research is identifying effective new treatment regimens. Many preclinical studies in this area have targeted the epidermal growth factor receptor (EGFR) signalling pathway to increase radiosensitivity. The in vitro rationale for targeting EGFR and concurrent ionising radiation is well established, but to date, rare clinical data could provide proof-of-principle. Here we report all the different published clinical trials focusing on efficacy and toxicity in order to clarify and to summarise the present state-of-the-art of this particularly promising combination in solid tumour management.