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Challenges of Using High-Dose Fractionation Radiotherapy in Combination Therapy.

ABSTRACT: Radiotherapy is crucial and substantially contributes to multimodal cancer treatment. The combination of conventional fractionation radiotherapy (CFRT) and systemic therapy has been established as the standard treatment for many cancer types. With advances in linear accelerators and image-guided techniques, high-dose fractionation radiotherapy (HFRT) is increasingly introduced in cancer centers. Clinicians are currently integrating HFRT into multimodality treatment. The shift from CFRT to HFRT reveals different effects on the tumor microenvironment and responses, particularly the immune response. Furthermore, the combination of HFRT and drugs yields different results in different types of tumors or using different treatment schemes. We have reviewed clinical trials and preclinical evidence on the combination of HFRT with drugs, such as chemotherapy, targeted therapy, and immune therapy. Notably, HFRT apparently enhances tumor cell killing and antigen presentation, thus providing opportunities and challenges in treating cancer.

SUBMITTER: Yang YC

PROVIDER: S-EPMC4927577 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Challenges of Using High-Dose Fractionation Radiotherapy in Combination Therapy.

Yang Ying-Chieh YC Chiang Chi-Shiun CS

Frontiers in oncology 20160630

Radiotherapy is crucial and substantially contributes to multimodal cancer treatment. The combination of conventional fractionation radiotherapy (CFRT) and systemic therapy has been established as the standard treatment for many cancer types. With advances in linear accelerators and image-guided techniques, high-dose fractionation radiotherapy (HFRT) is increasingly introduced in cancer centers. Clinicians are currently integrating HFRT into multimodality treatment. The shift from CFRT to HFRT r ...[more]

PMID: 27446811

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Project description:The paper considers the fractionation problem in intensity modulated proton therapy (IMPT). Conventionally, IMPT fields are optimized independently of the fractionation scheme. In this work, we discuss the simultaneous optimization of fractionation scheme and pencil beam intensities.This is performed by allowing for distinct pencil beam intensities in each fraction, which are optimized using objective and constraint functions based on biologically equivalent dose (BED). The paper presents a model that mimics an IMPT treatment with a single incident beam direction for which the optimal fractionation scheme can be determined despite the nonconvexity of the BED-based treatment planning problem.For this model, it is shown that a small α∕β ratio in the tumor gives rise to a hypofractionated treatment, whereas a large α∕β ratio gives rise to hyperfractionation. It is further demonstrated that, for intermediate α∕β ratios in the tumor, a nonuniform fractionation scheme emerges, in which it is optimal to deliver different dose distributions in subsequent fractions. The intuitive explanation for this phenomenon is as follows: By varying the dose distribution in the tumor between fractions, the same total BED can be achieved with a lower physical dose. If it is possible to achieve this dose variation in the tumor without varying the dose in the normal tissue (which would have an adverse effect), the reduction in physical dose may lead to a net reduction of the normal tissue BED. For proton therapy, this is indeed possible to some degree because the entrance dose is mostly independent of the range of the proton pencil beam.The paper provides conceptual insight into the interdependence of optimal fractionation schemes and the spatial optimization of dose distributions. It demonstrates the emergence of nonuniform fractionation schemes that arise from the standard BED model when IMPT fields and fractionation scheme are optimized simultaneously. Although the projected benefits are likely to be small, the approach may give rise to an improved therapeutic ratio for tumors treated with stereotactic techniques to high doses per fraction.

Project description:Statins are the frontline in cholesterol reduction therapies; however, their use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in low-density lipoprotein cholesterol. Thirty-nine patients were treated with either 80 mg simvastatin (n=20) or 10 mg simvastatin plus 10 mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable low-density lipoprotein cholesterol reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (eg, eicosanoids and endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. After statistical analysis and orthogonal projections to latent structures multivariate modeling, no changes were observed in lipid mediator levels, whereas global structural lipids were reduced in response to both monotherapy (R(2)Y=0.74; Q(2)=0.66; cross-validated ANOVA P=7.0×10(-8)) and combination therapy (R(2)Y=0.67; Q(2)=0.54; cross-validated ANOVA P=2.6×10(-5)). Orthogonal projections to latent structures modeling identified a subset of 12 lipids that classified the 2 treatment groups after 6 weeks (R(2)Y=0.65; Q(2)=0.61; cross-validated ANOVA P=5.4×10(-8)). Decreases in the lipid species phosphatidylcholine (15:0/18:2) and hexosyl-ceramide (d18:1/24:0) were the strongest discriminators of low-density lipoprotein cholesterol reductions for both treatment groups (q<0.00005), whereas phosphatidylethanolamine (36:3e) contributed most to distinguishing treatment groups (q=0.017). Shifts in lipid composition were similar for high-dose simvastatin and simvastatin/ezetimibe combination therapy, but the magnitude of the reduction was linked to simvastatin dosage. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that pleiotropic effects are not associated with eicosanoid production. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (q=0.008), suggesting a pleiotropic effect previously associated with a reduced risk of cardiovascular disease.

Dataset Information

Challenges of Using High-Dose Fractionation Radiotherapy in Combination Therapy.

Publications

Challenges of Using High-Dose Fractionation Radiotherapy in Combination Therapy.

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