Predictive modeling of hypoxic head and neck cancers during fractionated radiotherapy with gold nanoparticle radiosensitization.

PURPOSE: Intrinsic radioresistance and increased proliferation rates in head and neck cancers (HNCs) are associated with negative radiotherapy (RT) treatment responses. The use of gold nanoparticles (AuNPs) as radiosensitizers could enable total radiation dose reduction and lowered radiation toxicity. AuNP radiosensitization may overcome hypoxia-induced radioresistance and treatment-induced accelerated repopulation of cancer cells in HNCs, improving radiotherapy outcomes. METHODS: Tumor control was determined by considering individual cancer cell responses in probabilistic computational simulations using HYP-RT software for clinical radiotherapy doses and fractionation schedules along with three different nanoparticle administration schedules. Antagonistic tumor hypoxia and rapid tumor regrowth due to accelerated repopulation of cancers cells were taken into consideration. RESULTS: Simulations indicate that tumors that are conventionally uncontrollable can be controlled with AuNP radiosensitization. In simulations where the absence of AuNPs required radiotherapy doses above standard clinical prescriptions, reoccurring AuNP administration allowed for radiation dose reductions below standard clinical dose prescriptions. For example, considering a 2 Gy per fraction radiotherapy schedule, tumor control was achieved with 57.2 ± 5.1 Gy (P = <0.0001) for weekly AuNP administration and 53.0 ± 4.0 Gy (P = <0.0001) for biweekly AuNP administration compared to 69.9 ± 5.8 Gy with no radiosensitization. CONCLUSIONS: AuNPs decreased the predicted RT total doses required to achieve tumor control via total stem cell elimination, offering an optimistic prediction and method for which hypoxia-induced and rapidly growing radioresistant tumors are treated more effectively. Outcomes are also shown to be sensitive to the RT schedule with data for hyperfractionated RT indicating the greatest benefits from radiosensitization.

In silico modeling of cellular probabilistic nanoparticle radiosensitization in head and neck cancers.

Background: The use of gold nanoparticles (AuNPs) as radiosensitizers may offer a new approach in the treatment of head and neck cancers; minimizing treatment-associated toxicities and improving patient outcomes. AuNPs promote localized dose deposition; permitting improved local control and/or dose reduction. Aim: This work aimed to address the theoretical optimization of radiation doses, fractionation and nanoparticle injection schedules to maximize therapeutic benefits. Materials & methods: Probabilistic nanoparticle sensitization factors were incorporated into the individual cell-based HYP-RT computer model of tumor growth and radiotherapy. Results: Total dose outcomes across all radiation therapy treatment regimens were found to be significantly reduced with the presence of AuNPs, with bi-weekly injections showing the most decrease. Conclusion: Outcomes suggest the need for regular AuNP administration to permit effective radiosensitization.

Are further studies needed to justify the use of proton therapy for paediatric cancers of the central nervous system? A review of current evidence.

Clinical implementation of proton therapy demonstrated its potential to overcome some limitations of the more traditional, photon-based radiotherapy, due to physical and radiobiological advantages of protons. However, questions concerning the long-term effects of protons on paediatric patients need outcome analysis of the reported literature in order to be answered. The current paper has analysed the available clinical trials and comparative studies (protons vs photons) for paediatric cancers of the central nervous system (CNS) analysing the reported outcomes and follow-up times in order to evaluate the safety of proton therapy for this patient group. Based on the literature analysis, proton therapy for treatment of paediatric cancers of the CNS was found to provide survival and tumour control outcomes comparable, and frequently superior, to photon therapy. Furthermore, the use of protons was shown to decrease the incidence of severe acute and late toxicities, including reduced severity of endocrine, neurological, IQ and QoL deficits. Most commonly, the reported median follow-up time was up to 5 years. Only a few studies reported promising, longer follow-up results. Considering that these patients are likely to survive many of the malignancies reported on, the incidence of long term sequellae impacting growth, development and quality of life into adulthood, should be viewed longitudinally for completeness. The evidence surrounding proton therapy in paediatric tumour management supports its effectiveness and potential benefits in reducing the incidence of late-onset toxicities and second malignancies. For stronger evidence, it is highly desired for future studies to improve current reporting by (1) highlighting the paediatric patient cohort's outcome (in mixed patient groups), (2) reporting the follow-up time, (3) clearly indicating the toxicity criteria used in their evaluation, and (4) identifying the risk group. With this suggested clarity of future reporting, meaningful data to support treatment choice may then be available.

Current status of proton therapy outcome for paediatric cancers of the central nervous system - Analysis of the published literature.

INTRODUCTION: The most common solid tumours that develop in children are cancers of the central nervous system. Due to the increased rate of survival over the past decades, greater focus has been placed on the minimisation of long term side effects. In childhood cancer survivors, over 60% report one or more radiation-related late toxicities while half of these adverse events are graded as life-threatening or severe. Proton therapy enables high conformity with the planning target volume and a reduction in dose to areas beyond the target. Owing to the unique nature of dose delivery with proton therapy a reduction of low doses to normal tissues is achievable, and is believed to allow for a decrease in long-term treatment-related side effects. This paper aims to review the published literature around the effectiveness of proton therapy for the treatment of paediatric cancers of the central nervous system, with a focus on treatment outcomes and treatment-related toxicities. METHODS: A search strategy utilising the Medline database was created with the intent of including all articles reporting on proton therapy, paediatric cancers, CNS tumours and treatment outcomes. The final search strategy included the following limitations: limited to humans, English, published from 2000 onwards. The final article count total was 74. RESULTS AND CONCLUSIONS: Proton therapy for the treatment of paediatric cancers of the central nervous system was found to provide survival and tumour control outcomes comparable to photon therapy. Reduced incidence of severe acute and late toxicities was also reported with the use of proton therapy. This includes reduced severity of endocrine, neurological, IQ and QoL deficits. Currently, extensive follow-up of proton patient populations still needs to be made to determine incidences of late-onset toxicities and secondary malignancies. Current evidence surrounding proton therapy use in paediatric patients supports its effectiveness and potential benefits in reducing the incidence of severe toxicities in later life.