Opportunities in Cancer Therapies: Deciphering the Role of Cancer Stem Cells in Tumour Repopulation.

Tumour repopulation during treatment is a well acknowledged yet still challenging aspect of cancer management. The latest research results show clear evidence towards the existence of cancer stem cells (CSCs) that are responsible for tumour repopulation, dissemination, and distant metastases in most solid cancers. Cancer stem cell quiescence and the loss of asymmetrical division are two powerful mechanisms behind repopulation. Another important aspect in the context of cancer stem cells is cell plasticity, which was shown to be triggered during fractionated radiotherapy, leading to cell dedifferentiation and thus reactivation of stem-like properties. Repopulation during treatment is not limited to radiotherapy, as there is clinical proof for repopulation mechanisms to be activated through other conventional treatment techniques, such as chemotherapy. The dynamic nature of stem-like cancer cells often elicits resistance to treatment by escaping drug-induced cell death. The aims of this scoping review are (1) to describe the main mechanisms used by cancer stem cells to initiate tumour repopulation during therapy; (2) to present clinical evidence for tumour repopulation during radio- and chemotherapy; (3) to illustrate current trends in the identification of CSCs using specific imaging techniques; and (4) to highlight novel technologies that show potential in the eradication of CSCs.

Modelling the influence of radiosensitivity on development of second primary cancer in out-of-field organs following proton therapy for paediatric cranial cancer.

OBJECTIVE: Radiobiological modelling the risks of second primary cancer (SPC) after proton therapy (PT) for childhood cranial cancer remains largely unknown. Organ-specific dose-response risk factors such as radiosensitivity require exploration. This study compared the influence of radiosensitivity data (slope of ßEAR) on children's lifetime attributable risks (LAR) of SPC development in out-of-field organs following cranial scattering and scanning PT. METHODS: Out-of-field radiosensitivity parameter estimates for organs (α/ß and ßEAR) were sourced from literature. Physical distances for 13 out-of-field organs were measured and input into Schneider's SPC model. Sensitivity analyses were performed as a function of radiosensitivity (α/ß of 1-10 Gy) and initial slope (ßEAR) from Japanese/UK data to estimate the influence on the risk of radiation-induced SPC following scattering and scanning PT. RESULTS: Models showed similar LAR of SPC estimates for age and sex-matched paediatric phantoms, however, for breast there was a significant increase using Japanese ßEAR data. For most organs, scattering PT demonstrated a larger risk of LAR for SPC which increased with α/ß. CONCLUSION: Breast tissue exhibited the highest susceptibility in calculated LAR risk, demonstrating the importance for accurate data input when estimating LAR of SPC. ADVANCES IN KNOWLEDGE: The findings of this study demonstrated younger female patients undergoing cranial proton therapy have a higher risk of developing second primary cancer of the breast tissue. Long-term multicenter registries are important to improve predictive radiobiological modelling studies of side effects.

Proton-to-photon comparative treatment planning guidelines for the Australian context.

Proton-to-photon comparative treatment planning is a current requirement of Australian Government funding for patients to receive proton beam therapy (PBT) overseas, and a future requirement for Medicare funding of PBT in Australia. Because of the fundamental differences in treatment plan creation and evaluation between PBT and conventional radiation therapy with x-rays (XRT), there is the potential for a lack of consistency in the process of comparing PBT and XRT treatment plans. This may have an impact on patient eligibility assessment for PBT. The objective of these guidelines is to provide a practical reference document for centres performing proton-to-photon comparative planning and thereby facilitate national uniformity.

Lifetime attributable risk of radiation induced second primary cancer from scattering and scanning proton therapy - A model for out-of-field organs of paediatric patients with cranial cancer.

BACKGROUND AND PURPOSE: Proton therapy (PT) can reduce side effects for paediatric cranial malignancies. Despite the high number of paediatric patients treated with PT, radiation induced risk factors for second primary cancer (SPC) in out-of-field organs are unknown. This study estimated lifetime attributable risk (LAR) of SPC as a function of age and sex for out-of-field organs following passive scattering and scanning beam PT in paediatric brain tumours. MATERIALS AND METHODS: Measured neutron dose equivalent spectra for scattered and scanning PT were sourced from literature. The physical distance of 12 measured organs from paediatric CT dataset-based phantoms (5, 9 and 13 years-of-age) were applied to Schneider et al.'s analytical model using MATLAB (R2020B) to calculate the organ-specific LAR of SPC. RESULTS: Scanning beam PT demonstrated smaller LAR (per 10,000 person years) of SPC compared to scattering. This was prominent for more radiosensitive organs, including the lung (320 vs 50), breast (1000 vs 150) and thyroid (350 vs 75), but not for all (i.e., rectum and reproductive organs were <10). For most organs, LAR was highest for 5-year-old females (i.e., breast LAR was 1,000 higher than for 13-year-olds), however, outliers existed for distal organs (i.e., stomach and lung). CONCLUSION: There was large variation in LAR estimates of out-of-field organs based on measured neutron dose equivalents. Younger female cranial paediatric patients were found at higher risk compared to males, especially for passive scattering PT. Not all organs had improved LAR using scanning beam PT for younger age groups.

Normal tissue complication probability modeling to guide individual treatment planning in pediatric cranial proton and photon radiotherapy.

PURPOSE: Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/ß ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT). METHODS: Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/ß ratio. RESULTS: IMPT plans resulted in lower NTCP compared to IMRT across all models (p < 0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (> 20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p < 0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p < 0.0001) across tested α/ß as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/ß of these pediatric tissues is higher than expected (α/ß âˆ¼ 3), the risk of tinnitus for IMRT can significantly increase (p < 0.0001). CONCLUSION: Due to the scarcity of pediatric NTCP data available, sensitivity analyses were performed using plausible ranges based on published adult data. In the clinical scenario where, if female pediatric patients were 20% more radiosensitive (lower TD50 value), they could be up to twice as likely to experience side-effects of brainstem necrosis and cochlea tinnitus compared to males, highlighting the need for considering the sex in NTCP models. Based on our sensitivity analyses, age and sex of a pediatric patient could significantly affect the resultant NTCP from cranial radiotherapy, especially at higher α/ß values.

Normal tissue tolerance amongst paediatric brain tumour patients- current evidence in proton radiotherapy.

BACKGROUND: Proton radiotherapy (PT) is used increasingly for paediatric brain cancer patients. However, as demonstrated here, the knowledge on normal tissue dose constraints, to minimize side-effects, for this cohort is limited. METHODS: A search strategy was systematically conducted on MEDLINE® database. 65 papers were evaluated ranging from 2013 to 2021. RESULTS: Large variations in normal tissue tolerance and toxicity reporting across PT studies makes estimation of normal tissue dose constraints difficult, with the potential for significant late effects to go unmeasured. Mean dose delivered to the pituitary gland varies from 20 to 30 Gy across literature. Similarly, the hypothalamic dose delivery ranges from 20 to 54.6 Gy for paediatric patients. CONCLUSION: There is a significant lack of radiobiological data for paediatric brain cancer patients undergoing proton therapy, often using data from x-ray radiotherapy and adult populations. The way forward is through standardisation of reporting in order to validate relevant dose constraints.

Influence of Target Location, Size, and Patient Age on Normal Tissue Sparing- Proton and Photon Therapy in Paediatric Brain Tumour Patient-Specific Approach.

BACKGROUND: Proton radiotherapy produces superior dose distributions compared to photon radiotherapy, reducing side effects. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Understanding these differences may help clinicians estimate the benefit and improve referral across available centres. Our aim was to compare intensity-modulated proton therapy (IMPT) and intensity-modulated photon radiotherapy (IMRT) radiation doses for select paediatric intracranial tumours. METHODS: IMPT and IMRT dose distributions for gender-matched paediatric cranial CT-datasets (ages 5, 9 and 13 years) were retrospectively calculated to simulate irradiation of supratentorial (ependymoma) and infratentorial (medulloblastoma) target volumes diameters (1-3 cm) and position (central and 1-2 cm shifts). RESULTS: Clinical dosimetric objectives were achieved for all 216 treatment plans. Whilst infratentorial IMPT plans achieved greater maximum dose sparing to optic structures (4.8-12.6 Gy optic chiasm), brainstem sparing was limited (~0.5 Gy). Mean dose difference for optic chiasm was associated with medulloblastoma target position (p < 0.0197). Supratentorial IMPT plans demonstrated greater dose reduction for the youngest patients (pituitary gland p < 0.001). CONCLUSIONS: Normal tissue sparing was achieved regardless of patient age for infratentorial tumours. However, for supratentorial tumours, there was a dosimetric advantage of IMPT across 9 vs. 13-year-old patients.

Clinical Limitations of Photon, Proton and Carbon Ion Therapy for Pancreatic Cancer.

INTRODUCTION: Despite improvements in radiation therapy, chemotherapy and surgical procedures over the last 30 years, pancreatic cancer 5-year survival rate remains at 9%. Reduced stroma permeability and heterogeneous blood supply to the tumour prevent chemoradiation from making a meaningful impact on overall survival. Hypoxia-activated prodrugs are the latest strategy to reintroduce oxygenation to radioresistant cells harbouring in pancreatic cancer. This paper reviews the current status of photon and particle radiation therapy for pancreatic cancer in combination with systemic therapies and hypoxia activators. METHODS: The current effectiveness of management of pancreatic cancer was systematically evaluated from MEDLINE® database search in April 2019. RESULTS: Limited published data suggest pancreatic cancer patients undergoing carbon ion therapy and proton therapy achieve a comparable median survival time (25.1 months and 25.6 months, respectively) and 1-year overall survival rate (84% and 77.8%). Inconsistencies in methodology, recording parameters and protocols have prevented the safety and technical aspects of particle therapy to be fully defined yet. CONCLUSION: There is an increasing requirement to tackle unmet clinical demands of pancreatic cancer, particularly the lack of synergistic therapies in the advancing space of radiation oncology.

A Retrospective Dosimetric Study of Radiotherapy Patients with Left-Sided Breast Cancer; Patient Selection Criteria for Deep Inspiration Breath Hold Technique.

BACKGROUND: Several studies have investigated cardiac dose reduction when utilizing the deep inspiration breath hold (DIBH) technique in patients undergoing radiotherapy for left-sided breast cancer. This paper aims to recommend potential selection criteria based on a retrospective single institute study of free breathing (FB) and DIBH computed tomography (CT) simulation planning scans. METHODS: Dosimetric comparisons were performed retrospectively for 20 patients correlating the dose reduction and patient anatomical factors (anatomical variation of chest shape, chest wall separation, total lung volume (TLV) and others). RESULTS: Paired t-tests demonstrated significant cardiac dose reduction for most patients but not all. Minimal cardiac dose reduction was observed for three patients using their DIBH plan, with one patient receiving a higher dose. Linear regression analysis identified a positive correlation between the patient's TLV (on the FB CT simulation scan) and the magnitude of dosimetric benefit received (0.4045 R²). CONCLUSION: The TLV measured on a FB plan could potentially be utilised to predict cardiac exposure and assist with patient selection for DIBH. This is important in resource allocation, as DIBH may be unnecessarily recommended for some patients with little dosimetric benefit.