Tumor Control Dose Research Articles

Time to Next Treatment Following Sub-Ablative Progression Directed Radiation Therapy for Oligoprogressive Non-Small-Cell Lung Cancer

We aimed to evaluate whether progression-directed radiation therapy (PDRT) can prolong the initiation of a subsequent systemic therapy regimen in a cohort of patients with oligoprogressive NSCLC. A retrospective analysis was conducted on NSCLC patients who underwent PDRT for extracranial oligoprogressive NSCLC, defined as limited (up to five) progressing lesions following initial complete, partial, or stable response to systemic therapy according to REC1ST 1.1 and/or PERCIST 1.0 criteria. Cox proportional hazard regressions were performed to identify factors influencing time to next treatment (TTNT), which was considered the primary endpoint. Forty patients were analyzed. First, second, and ≥3 lines of systemic therapy were administered in 22 (58.2%), 14 (27.2%), and 4 (14.6%) cases, respectively. The median total dose was 36 Gy (range: 12–60) in five fractions (1–10), with a median biological effective dose for tumor control (BED10) of 52 Gy (26.4–151.2). After a median follow-up of 11 months (2–50), PDRT delayed further systemic therapy in 32 (80.0%) treatments. Median TTNT was not reached at 8 months (1–47) with a one-year Kaplan–Meier estimate of 81.4% (95% CI: 75.0% to 87.8%). No >grade 3 adverse event was observed. On multivariate analysis, patients with ≥3 lines of systemic therapy and/or with larger CTV volumes did not benefit from PDRT. Despite the use of sub-ablative doses, our findings show that PDRT represents an effective, safe, and viable option for oligoprogressive NSCLC. Patients irradiated early during their systemic treatment course, with a low volume of disease and nonmetastatic oligoprogression, could derive substantial benefits from PDRT.

Mathematical modeling of radiotherapy: impact of model selection on estimating minimum radiation dose for tumor control.

Radiation therapy (RT) is one of the most common anticancer therapies. Yet, current radiation oncology practice does not adapt RT dose for individual patients, despite wide interpatient variability in radiosensitivity and accompanying treatment response. We have previously shown that mechanistic mathematical modeling of tumor volume dynamics can simulate volumetric response to RT for individual patients and estimation personalized RT dose for optimal tumor volume reduction. However, understanding the implications of the choice of the underlying RT response model is critical when calculating personalized RT dose. In this study, we evaluate the mathematical implications and biological effects of 2 models of RT response on dose personalization: (1) cytotoxicity to cancer cells that lead to direct tumor volume reduction (DVR) and (2) radiation responses to the tumor microenvironment that lead to tumor carrying capacity reduction (CCR) and subsequent tumor shrinkage. Tumor growth was simulated as logistic growth with pre-treatment dynamics being described in the proliferation saturation index (PSI). The effect of RT was simulated according to each respective model for a standard schedule of fractionated RT with 2 Gy weekday fractions. Parameter sweeps were evaluated for the intrinsic tumor growth rate and the radiosensitivity parameter for both models to observe the qualitative impact of each model parameter. We then calculated the minimum RT dose required for locoregional tumor control (LRC) across all combinations of the full range of radiosensitvity and proliferation saturation values. Both models estimate that patients with higher radiosensitivity will require a lower RT dose to achieve LRC. However, the two models make opposite estimates on the impact of PSI on the minimum RT dose for LRC: the DVR model estimates that tumors with higher PSI values will require a higher RT dose to achieve LRC, while the CCR model estimates that higher PSI values will require a lower RT dose to achieve LRC. Ultimately, these results show the importance of understanding which model best describes tumor growth and treatment response in a particular setting, before using any such model to make estimates for personalized treatment recommendations.

Intensity-modulated irradiation for superficial tumors by overlapping irradiation fields using intensity modulators in accelerator-based BNCT.

The distribution of the thermal neutron flux has a significant impact on the treatment efficacy. We developed an irradiation method of overlapping irradiation fields using intensity modulators for the treatment of superficial tumors with the aim of expanding the indications for accelerator-based boron neutron capture therapy (BNCT). The shape of the intensity modulator was determined and Monte Carlo simulations were carried out to determine the uniformity of the resulting thermal neutron flux distribution. The intensity modulators were then fabricated and irradiation tests were conducted, which resulted in the formation of a uniform thermal neutron flux distribution. Finally, an evaluation of the tumor dose distribution showed that when two irradiation fields overlapped, the minimum tumor dose was 27.4Gy-eq, which was higher than the tumor control dose of 20Gy-eq. Furthermore, it was found that the uniformity of the treatment was improved 47% as compared to the treatment that uses a single irradiation field. This clearly demonstrates the effectiveness of this technique and the possibility of expanding the indications to superficially located tumors.

The modern management of untreated large (>2 cm) brain metastases: a narrative review.

Our objective was to identify contemporary management options for large brain metastases reported in literature, specifically evaluating local control and risk of toxicity. Large brain metastases are typically defined as lesions >2 cm in diameter, and historically conferred poor outcomes due to the high rates of radiation necrosis and less local control in comparison to smaller brain metastases. A literature search examining modern management of large brain metastases was performed using ovid-MEDLINE. A total of 18 articles met criteria for review, evaluating single fraction radiosurgery [stereotactic radiosurgery (SRS)] and multi-fraction stereotactic radiation therapy (MFSRT) in both the definitive and post-operative cavity setting, as well as targeted therapies. Multi-fractionated radiosurgery represents a modern and attractive treatment approach in the definitive management of patients with large brain metastases, with equivalent local control and reduced rates of radionecrosis less than 13% in comparison to single fraction SRS. In cases where surgery is indicated, fractionated cavity radiation should be considered for large tumor bed volumes. More research is needed for the optimal dose and fractionation regimen for optimal tumor control with reduced risk of radiation toxicity, but common regimens include 3-5 fractions while meeting appropriate biologically effective dose (BED) goals. Future areas of interest include targeted therapies in the initial management of brain metastases as well as pre-operative radiation therapy to reduce risk of leptomeningeal disease (LMD).

Boron Neutron Capture Therapy (BNCT) for Cutaneous Malignant Melanoma Using 10B-p-Boronophenylalanine (BPA) with Special Reference to the Radiobiological Basis and Clinical Results.

BNCT is a radiotherapeutic method for cancer treatment that uses tumor-targeting 10B-compounds. BNCT for cutaneous melanoma using BPA, a phenylalanine derivative, was first initiated by Mishima et al. in 1987. This article reviews the radiobiological basis of melanoma control and damage to normal tissues as well as the results of clinical studies. Experimental studies showed that the compound biological effectiveness (CBE) values of the 10B (n, α)7Li reaction for melanoma control ranged from 2.5 to 3.3. The CBE values of the 10B (n, α)7Li reaction for skin damage ranged from 2.4 to 3.7 with moist desquamation as the endpoint. The required single radiation dose for controlling human melanoma was estimated to be 25 Gy-Eq or more by analyzing the 50% tumor control dose data of conventional fractionated radiotherapy. From the literature, the maximum permissible dose to human skin by single irradiation was estimated to be 18 Gy-Eq. With respect to the pharmacokinetics of BPA in patients with melanoma treated with 85–350 mg/kg BPA, the melanoma-to-blood ratio ranged from 2.1–3.8 and the skin-to-blood ratio was 1.31 ± 0.22. Good local tumor control and long-term survival of the patients were achieved in two clinical trials of BNCT conducted in Japan.

Patterns of Failure After SBRT Reirradiation for Recurrent Head and Neck Cancer

Stereotactic body radiotherapy (SBRT) is an emerging modality for the reirradiation of head and neck cancers (HNC). The need to use smaller reirradiation volumes to limit severe toxicity concerns represents a challenge in determining optimal target coverage. Herein, we investigate the associated patterns of failure after SBRT using previously defined spatial and dosimetric analysis (Mohamed et al, Radiat Oncol. 2017).SBRT reirradiation HNC cases treated between 2014-2019 and surveilled by CT, PET/CT, and/or MRI were reviewed retrospectively in this IRB approved study. Patients with radiographic evidence of recurrence within the head and neck region after SBRT were identified. Multifocal disease was defined as any non-contiguous FDG-avid or biopsy positive disease seen on imaging. Diagnostic scans were co-registered with planning CT scans (pCT) for manual segmentation of recurrent gross volumes (rGTV). rGTVs were then deformed to co-registered pCTs for failure classification. The classification followed a granular typology of 5 failure categories: central high-dose (type A or "in-field"), peripheral high-dose (type B), central low-dose (type C), peripheral low-dose (type D or "marginal"), and extraneous-dose (type E or "out of field"). Each type was determined based on the centroid location of rGTV relative to the planning target volumes plus the dose received by 95% of rGTV volume.A total of 106 SBRT cases were reviewed out of which 34 patients (32%) recurred after SBRT; 27 (79%) patients had squamous cell carcinomas, 7 (21%) received postoperative SBRT, and 24 (71%) received concurrent systemic therapy. Twenty-three (68%) patients received 42.5-45 Gy in 5 fractions (Fx) and 7 (21%) patients received 36 Gy in 6 Fx. Median time to failure was 5.5 months (range, 1-22 months). Twenty-two recurrences (65%) were out-of-field type E failures, 6 (18%) type A, 3 (9%) type C, and 3 (9%) type D. Fourteen of 16 (88%) multifocal SBRT reirradiation cases had Type E failures compared to 8 of 18 (44%) unifocal SBRT cases. Among the 6 in-field failures, 3 received 36 Gy in 6 Fx and 3 received 42.5-45 Gy in 5 Fx.Post SBRT reirradiation recurrences were seen in one-third of cases with the majority of failures being Type E (outside the treatment field), particularly in patients who were treated for multifocal disease. The use of 42.5-45 Gy in 5 Fx appears to be an effective biological dose for local tumor control. Marginal (Type C and D) failures may be reduced with larger margins, but limit feasibility of SBRT. Therefore, future reirradiation strategies should aim to improve patient selection, multimodal therapy, and margin definition in the HNC SBRT reirradiation setting.

Radiotherapy Response Assessment of Multiple Myeloma: A Dual-Energy CT Approach With Virtual Non-Calcium Images.

BackgroundLife expectancy of patients with multiple myeloma (MM) has increased over the past decades, underlining the importance of local tumor control and avoidance of dose-dependent side effects of palliative radiotherapy (RT). Virtual noncalcium (VNCa) imaging from dual-energy computed tomography (DECT) has been suggested to estimate cellularity and metabolic activity of lytic bone lesions (LBLs) in MM.ObjectiveTo explore the feasibility of RT response monitoring with DECT-derived VNCa attenuation measurements in MM.MethodsThirty-three patients with 85 LBLs that had been irradiated and 85 paired non-irradiated LBLs from the same patients were included in this retrospective study. Irradiated and non-irradiated LBLs were measured by circular regions of interest (ROIs) on conventional and VNCa images in a total of 216 follow-up measurements (48 before and 168 after RT). Follow-ups were rated as therapy response, stable disease, or local progression according to the MD Anderson criteria. Receiver operating characteristic (ROC) analysis was performed to discriminate irradiated vs. non-irradiated and locally progressive vs. stable/responsive LBLs using absolute attenuation post-irradiation and percentage attenuation change for patients with pre-irradiation DECT, if available.ResultsAttenuation of LBLs decreased after RT depending on the time that had passed after irradiation [absolute thresholds for identification of irradiated LBLs 30.5–70.0 HU [best area under the curve [AUC] 0.75 (0.59–0.91)] and -77.0 to -22.5 HU [best AUC 0.85 (0.65–1.00)]/-50% and -117% to -167% proportional change of attenuation on conventional and VNCa images, respectively]. VNCa CT was significantly superior for identification of RT effects in LBLs with higher calcium content [best VNCa AUC 0.96 (0.91–1.00), best conventional CT AUC 0.64 (0.45–0.83)]. Thresholds for early identification of local irradiation failure were >20.5 HU on conventional CT [AUC 0.78 (0.68–0.88)] and >-27 HU on VNCa CT [AUC 0.83 (0.70–0.96)].ConclusionTherapy response of LBLs after RT can be monitored by VNCa imaging based on regular myeloma scans, which yields potential for optimizing the lesion-specific radiation dose for local tumor control. Decreasing attenuation indicates RT response, while above threshold attenuation of LBLs precedes local irradiation failure.

Value of functional in-vivo endpoints in preclinical radiation research

BackgroundCancer research faces the problem of high rates of clinical failure of new treatment approaches after positive preclinical data. We hypothesize that a major confounding factor to this problem in radiooncology is the choice of the preclinical endpoint. MethodsWe present a comprehensive re-evaluation of large-scale preclinical in-vivo data on fractionated irradiation alone or simultaneously with Epidermal Growth Factor Receptor inhibition. Taking the permanent local tumour control assay as a gold standard, we evaluated different tumour volume dependent endpoints that are widely used for preclinical experiments. Results: The analysis showed the highest correlations between volume related and local tumour control endpoints after irradiation alone. For combined treatments, wide inter-tumoural variations were observed with reduced correlation between the endpoints. Evaluation of growth delay per Gray (GD/Gy) based on two or more dose levels showed closest correlation with local tumour control dose 50% (TCD50). ConclusionsGD/Gy with at least two dose groups correlates with TCD50, but cannot replace the latter as the goldstandard.

Association between incidental dose outside the prostate and tumor control after modern image-guided radiotherapy.

Background and purposeExternal beam radiotherapy for prostate cancer deposits incidental dose to a region surrounding the target volume. Previously, an association was identified between tumor control and incidental dose for patients treated with conventional radiotherapy. We investigated whether such an association exists for patients treated using intensity modulated radiotherapy (IMRT) and tighter margins.Materials and methodsComputed tomography scans and three-dimensional treatment planning dose distributions were available from the Dutch randomized HYPRO trial for 397 patients in the standard fractionation arm (39 × 2 Gy) and 407 patients in the hypofractionation arm (19 × 3.4 Gy), mainly delivered using online image-guided IMRT. Endpoint was any treatment failure within 5 years. A mapping of 3D dose distributions between anatomies was performed based on distance to the surface of the prostate delineation. Mean mapped dose distributions were computed for patient groups with and without failure, obtaining dose difference distributions. Random patient permutations were performed to derive p values and to identify relevant regions.ResultsFor high-risk patients treated in the conventional arm, higher incidental dose was significantly associated with a higher probability of tumor control in both univariate and multivariate analysis. The locations of the excess dose mainly overlapped with the position of obturator internus muscles at about 2.5 cm from the prostate surface. No such relationship could be established for intermediate-risk patients.ConclusionsAn association was established between reduced treatment failure and the delivery of incidental dose outside the prostate for high-risk patients treated using conventionally fractionated IMRT.

Inter/intra-tumoral dose response variations assessed using FDG-PET/CT feedback images: Impact on tumor control and treatment dose prescription

PurposeTo quantify inter/intra-tumoral variations of baseline metabolic activity and dose response. To evaluate their impact on tumor control and treatment dose prescription strategies. Methods and materialsTumor voxel baseline metabolic activity, SUV0, and dose response matrix, DRM, quantified using the pre-treatment and weekly FDG-PET/CT imaging feedback for each of 34 HNSCC patients (25 HPV+ and 9 HVP−) were evaluated. Inter/intra-tumoral variations of tumor voxel (SUV0, DRM) for each of the HPV− and HPV+ tumor groups were quantified and used to evaluate the variations of individual tumor control probabilities and the efficiency of uniform vs non-uniform treatment dose prescription strategies. ResultsTumor voxel dose response variation of all tumor voxels assessed using FDG-PET/CT imaging feedback had the mean(CV) = 0.47(47%), which was consistent with those of previously published in vitro tumor clonogenic assay. The HPV− tumors had the mean(CV) dose response, 0.53(49%), significantly larger than those of the HPV+ tumors, 0.45(43%). However, their baseline SUVs were opposite, 6.5(56%) vs 7.7(65%). Comparing to the inter-tumoral variations, both HPV−/+ tumor groups showed larger intra-tumoral variations, (53%, 58%) vs (20%, 31%) for the baseline SUV and (38%, 37%) vs (31%, 21%) for the dose response. Due to the large dose response variations, treatment dose to control the tumor voxels has very broad range with CV of TCD50 = 97% for the HPV− and 67% for the HPV+ tumor group respectively. As a consequence, heterogeneous prescription dose could potentially reduce the treatment integral dose for 92% of the HPV+ tumors and 78% of the HPV− tumors. ConclusionsThe study demonstrates that tumor dose response assessed using FDG-PET/CT feedback images had a similar distribution to those assessed conventionally using in vitro tumor clonogenic assay. Inter-tumoral dose response variation seems larger for HPV− tumors, but intra-tumoral dose response variations are similar for both HPV groups. These variations cause very large variation on the individual tumor control probability and limit the efficacy of dose escalation and de-escalation in conventional clinical practice. On the other hand, heterogeneous dose prescription guided by metabolic imaging feedback has a potential advantage in radiotherapy.

First experimental measurement of the effect of cardio-synchronous brain motion on the dose distribution during microbeam radiation therapy.

Microbeam radiation therapy (MRT) is an emerging radiation oncology modality ideal for treating inoperable brain tumors. MRT employs quasi-parallel beams of low-energy x rays produced from modern synchrotrons. A tungsten carbide multislit collimator (MSC) spatially fractionates the broad beam into rectangular beams. In this study, the MSC creates beams 50μm wide ("peaks") separated by a center-to-center distance of 400μm ("valleys"). The peak to valley dose ratio (PVDR) is of critical importance to the efficacy of MRT. The underlying radiobiological advantage of MRT relies on high peak dose for tumor control and low valley dose for healthy tissue sparing. Cardio synchronous brain motion of the order 100-200μm is comparable to microbeam width and spacing. The motion can have a detrimental effect on the PVDR, full width at half maximum (FWHM) of the microbeams, and ultimately the dose distribution. We present the first experimental measurement of the effect of brain motion on MRT dose distribution. Dosimetry in MRT is difficult due to the high dose rate (up to 15-20kGy/s) and small field sizes. A real-time dosimetry system based on a single silicon strip detector (SSSD) has been developed with spatial resolution ~10μm. The SSSD was placed in a water-equivalent phantom and scanned through the microbeam distribution. A monodirectional positioning stage reproduced brain motion during the acquisition. Microbeam profiles were reconstructed from the SSSD and compared with Geant4 simulation and radiochromic HD-V2 film. The SSSD is able to reconstruct dose profiles within 2μm compared to film. When brain motion is applied the SSSD shows a two time increase in FWHM of profiles and 50% reduction in PVDR. This is confirmed by Geant4 and film data. Motion-induced misalignment and distortion of microbeams at treatment delivery will result in a reduced PVDR and increased irradiation of additional healthy tissue compromising the radiobiological effectiveness of MRT. The SSSD was able to reconstruct dose profiles under motion conditions and predict similar effects on FWHM and PVDR as by the simulation. The SSSD is a simple to setup, real-time detector which can provide time-resolved high spatial resolution dosimetry of microbeams in MRT.

The CD98 Heavy Chain Is a Marker and Regulator of Head and Neck Squamous Cell Carcinoma Radiosensitivity.

The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein-mediated molecular mechanisms of tumor radioresistance. CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis, and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by IHC analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was locoregional tumor control (LRC). High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism, and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx. We found that CD98hc-associated signaling mechanisms play a central role in the regulation of HNSCC radioresistance and may be a promising target for tumor radiosensitization.

Residual gammaH2AX foci in head and neck squamous cell carcinomas as predictors for tumour radiosensitivity: Evaluation in pre-clinical xenograft models and clinical specimens

Background and purposePredictive biomarkers can be instrumental to treatment individualisation of cancer patients and improve therapy outcome. Residual γH2AX foci represent a promising biomarker to predict tumour radiosensitivity. In this pre-clinical study, the slope of the dose–response curve was evaluated for its predictive relevance in head and neck squamous cell carcinoma xenografts (HNSCC). Additionally, the feasibility of the translated assay was tested in a clinical setting in patient derived HNSCC samples, and associations between residual γH2AX foci and clinical parameters were analysed. Materials and methodsSeven HNSCC xenografts models (FaDu, SAS, SKX, UT-SCC-5, UT-SCC-14, UT-SCC-45, XF354) were used. Tumour bearing NMRI nude mice were randomly distributed to five treatment arms (0–8 Gy). Residual γH2AX foci (24 h post irradiation) were counted by visual scoring in a micromilieu dependent manner (assessed with BrdU and pimonidazole). The local tumour control values measured as TCD50 (tumour control dose 50%) have previously been published. Patient derived HNSCC biopsies were cultivated ex vivo for 24 h including 4 h of pimonidazole and BrdU treatment, subsequently irradiated with 0–8 Gy and fixed after 24 h. ResultsIn the pre-clinical study, the dose–response curve slopes negatively correlated with the tumour control dose after fractionated irradiation (TCD50,fx, R2 = 0.63, p = 0.032) and after single dose irradiation under homogeneous hypoxia (TCD50,SD,clamp, R2 = 0.66, p = 0.027). The γH2AX assay in clinical HNSCC samples showed a dose–response relationship, with the values of the slopes ranging from 0.099 Gy−1 to 0.920 Gy−1 (coefficient of variation = 52.8%). Slopes derived from patients were in the same ranges as the sensitive, moderate and resistant models of the pre-clinical study. Statistical analysis revealed a significant negative correlation between the slope and the patients’ age (R2 = 0.65, p = 0.001). ConclusionThese results further support the promise of the slope of the residual γH2AX foci dose–response as a biomarker for radiosensitivity. In the clinical samples, the variation in the slopes reveals patients’ specific repair capacities, which could hold potential value for treatment individualisation.

Targeting of BRM Sensitizes BRG1-Mutant Lung Cancer Cell Lines to Radiotherapy.

Targeting of epigenetic regulators as the chromatin remodeler SWI/SNF is proving to be a promising therapeutic strategy for individualized treatment of cancer patients. Here, we tested whether targeting one of the two mutually exclusive subdomains of the SWI/SNF complex BRM/SMARCA2 can sensitize specifically non-small cell lung carcinoma (NSCLC) cells with mutations in the other subunit BRG1/SMARCA4 toward ionizing radiation (IR). Knockdown of BRM with siRNA or shRNA and its consequences for radiation sensitivity as measured by clonogenic survival and plaque-monolayer control was studied in different NSCLC lines with or without BRG1 mutations and in primary fibroblasts. Furthermore, the effect on double-strand break (DSB) repair markers measured by immunofluorescence staining of 53BP1-, γ-H2AX-, and Rad51-foci was investigated. BRG1-mutated cell lines showed an increased surviving fraction compared with BRG1 proficient cells. Depletion of BRM (i) leads to a decreased proliferation rate and plating efficiency specifically in BRG1-mutated cells, (ii) specifically sensitized BRG1-mutant NSCLC cells toward IR as characterized by a survival reducing factor of 0.63 [95% confidence interval (CI), 0.57-0.69] in the dose range between 2 and 6 Gy, and (iii) decreased the tumor control doses after daily fractionation at 4 Gy in BRG1-mutant NSCLC cell lines A549 and H1299 in minimonolayers by 9.9% ± 1.3% and 13.6% ± 1.8%, respectively. In addition, an increase of residual Rad51-foci at 24 hours after irradiation in BRG1-mutant cells was demonstrated. Therefore, targeting of BRM in combination with radiotherapy is supposed to improve the therapeutic outcome of lung cancer patients harboring BRG1 mutations.The present study shows that the moderate radioresponsiveness of NSCLC cells with BRG1 mutations can be increased upon BRM depletion that is associated with a prolonged Rad51-foci prevalence at DNA DSBs.

Effectiveness of stereotactic ablative radiotherapy in patients with advanced hepatocellular carcinoma unsuitable for transarterial chemoembolization.

Background:Stereotactic ablative radiotherapy (SABR) can deliver tumoricidal doses and achieve long-term control in early hepatocellular carcinoma (HCC). However, limited studies have investigated the safety and effectiveness of SABR in patients with advanced diseases that is unsuitable for transarterial chemoembolization (TACE).Methods:In this observational study, we reviewed the medical records of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease treated with linear accelerator-based SABR between 2008 and 2016. Their tumors were either refractory to TACE or TACE was contraindicated. Overall survival (OS), in-field progression-free survival (IFPFS), and out-field progression-free survival were calculated using Kaplan–Meier analysis. The Cox regression model was used to examine the effects of variables. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03) and whether patients developed radiation-induced liver disease (RILD) after SABR.Results:This study included 32 patients. The mean maximal tumor diameter and tumor volumes were 4.7 cm and 135.9 ml, respectively. Patients received linear accelerator-based SABR with a median prescribed dose of 48 Gy (30–60 Gy) in three to six fractions. Based on the assessment of treatment response by using the Response Evaluation Criteria in Solid Tumors (version 1.1), 19% of patients achieved a complete response and 53% achieved a partial response. After a median follow-up of 18.1 months (4.0–65.9 months), 10, 19, and 9 patients experienced in-field failure, out-field hepatic recurrence, and extrahepatic metastases, respectively. The estimated 2-year OS and IFPFS rates were 54.4% and 62.7%, respectively. In a multivariate analysis, a pretreatment Cancer of the Liver Italian Program (CLIP) score of ⩾2 (p = 0.01) was a prognostic factor for shorter OS, and a biologically effective dose (BED) of < 85 Gy10 (p = 0.011) and a Child–Pugh score of ⩾6 (p = 0.014) were prognostic factors for inferior IFPFS. In this study five and eight patients developed classic and nonclassic RILD, respectively.Conclusions:SABR can serve as a salvage treatment for patients with HCC with BCLC stage C disease unsuitable for TACE, in particular, in those with a baseline CLIP score of ⩽1. A BED10 of ⩾85 Gy is an appropriate prescribed dose for tumor control. Because out-field relapse is the major cause of treatment failure, SABR in combination with novel systemic modalities should be investigated in future studies.

Use of recombinant Lactobacillus sakei for the prevention and treatment of radiation-induced enteritis

Radiation-induced enteritis is one of the most common complications in patients under radiotherapy at abdominal or pelvic cavity. Up to 50% of patients treated with pelvic radiotherapy has been reported radiation-induced acute enteritis, and half of them developed chronic enteritis. Overproduction of free radicals, activation of inflammatory pathways and vascular endothelial dysfunction were considered as the primary mechanisms of radiation-induced enteritis. Because probiotics have been demonstrated as a promising potential candidate for treating intestinal diseases, it may be a safer and more effective radioprotector for the enteritis compared to conventional chemical agents with inherent toxicities. Here, we propose that a recombinant Lactobacillus sakei would decrease the complications or symptoms significantly through against different pathogenic mechanisms simultaneously. Therefore, application of higher radiation dose for tumor control would be feasible when co-treating with recombinant Lactobacillus sakei.

Intraluminal brachytherapy boost following external beam radiotherapy with concurrent chemotherapy of oesophagus carcinoma: Results of a prospective observational study

PurposeThe main objective of our study is to evaluate response and toxicity profile in patients receiving external beam radiotherapy with concurrent chemotherapy followed by intraluminal brachytherapy boost for a carcinoma of the oesophagus. Material and methodsTwenty patients with biopsy-proven carcinoma of the oesophagus received external beam radiotherapy (50Gy in 25 fractions) with concurrent chemotherapy (cisplatin: 40mg/m2). After a gap of two to three weeks, intraluminal brachytherapy (10Gy in two fractions each 1 week apart by a high dose rate 60Co source) was given. Response was evaluated at 1 month and at 1 year of completion of treatment. In addition, acute and chronic toxicity was evaluated at 1 month and 6 months of treatment. ResultsComplete response were seen in 80% of patients and partial response in 20% at 1 month. Moreover, there were 65% complete response, 10% local recurrences, 15% patients showed local control with distant metastasis and 10% patients died at 1 year. Grade 1, grade 2 and grade 3 oesophagitis were seen in 10%, 70% and 20% of patients respectively. Stricture was seen in 40% of patients and fistula in 10% of patients. There was no spinal cord, cardiac and nephrotoxicity found. ConclusionsWith the concept that high tumoricidal dose for adequate tumor control achieved by intraluminal brachytherapy as a mean of dose escalation, while sparing surrounding normal tissue and potentially improving therapeutic ratio, external beam radiotherapy followed by intraluminal brachytherapy could be a better choice for oesophagus carcinoma.

Stereotactic Radiotherapy for Oligometastases in Lymph Nodes-A Review.

In recent years, the concept of oligometastases has become accepted and reports on stereotactic body radiotherapy as a treatment method have been published. Lesions in the brain, lung, and liver have been reported as target lesions. However, lymph node oligometastases could be a good candidate for stereotactic body radiotherapy as well. In this study, the usability of stereotactic body radiotherapy for oligometastases to lymph nodes is assessed by researching for each primary site. As a result, we could consider that stereotactic body radiotherapy could be almost well applied for lymph node oligometastases from the breast, gynecological organs, and prostate. However, doubts remain concerning the usefulness of stereotactic body radiotherapy for cervical node metastases from head and neck cancer or for mediastinal node metastases from lung or esophageal cancer since late toxicities have occurred with a large radiation dose at hypofractionation to major vessels or the central respiratory tract, especially in patients with irradiation histories. In addition, high-dose irradiation is required to control lymph node metastases from colorectal cancer due to its radioresistance, and severe late adverse events would therefore occur in adjacent organs such as the gastrointestinal tract. In cases of lymph node oligometastases with a primary tumor in the stomach or esophagus, stereotactic body radiotherapy should be used limitedly at present because this patient population is not so large and these metastases are often located close to organs at risk. Because of the varied status of recurrence and varied conditions of patients, it is difficult to determine the optimal dose for tumor control. It might be reasonable to determine the treatment dose individually based on dose constraints of adjacent organs. The oligometastatic state is becoming more frequently identified with more sensitive methods of detecting such oligometastases. In addition, there seems to be another type of oligometastases, so-called induced oligometastases, following successful systemic treatment. To determine the optimal indication of stereotactic body radiotherapy for lymph node oligometastases, further investigation about the mechanisms of oligometastases and further clinical studies including a phase III study are needed.

Spin Lattice Relaxation EPR pO2 Images May Direct the Location of Radiation Tumor Boosts to Enhance Tumor Cure.

Radiation treatment success and high tumor oxygenation and success have been known to be highly correlated. This suggests that radiation therapy guided by images of tumor regions with low oxygenation, oxygen-guided radiation therapy (OGRT) may be a promising enhancement of cancer radiation treatment. Before applying the technique to human subjects, OGRT needs to be tested in animals, most easily in rodents. Electron paramagnetic resonance imaging provides quantitative maps of tissue and tumor oxygen in rodents with 1 mm spatial resolution and 1 torr pO2 resolution at low oxygen levels. The difficulty of using mouse models is their small size and that of their tumors. To overcome this we used XRAD225Cx micro-CT/ therapy system and 3D printed conformal blocks. Radiation is delivered first to a uniform 15% tumor control dose for the whole tumor and then a boost dose to either hypoxic tumor regions or equal volumes of well oxygenated tumor. Delivery of the booster dose used a multiple beam angles to deliver radiation beams whose shape conforms to that of all hypoxic regions or fully avoids those regions. To treat/avoid all hypoxic regions we used individual radiation blocks 3D-printed from acrylonitrile butadiene styrene polymer infused with tungsten particles fabricated immediately after imaging to determine regions with pO2 less than 10 torr. Preliminary results demonstrate the efficacy of the radiation treatment with hypoxic boosts with syngeneic FSa fibrosarcoma tumors in the legs of C3H mice.

Radiosensitization of HRAS Mutated Head and Neck Cancer

To test the hypothesis that head and neck cancer with HRAS activating mutations can be radiosensitized by inhibition of the downstream MEK/ERK or PI3K/MTOR pathways. Mutations in HRAS, KRAS, and NRAS were analyzed using cBioPortal in a head and neck cancer cohort. The Illumina TruSeq Amplicon Cancer panel was used to screen a panel of head and neck cancer cell lines for mutations in RAS-family genes. Radiation survival was assessed by clonogenic survival assay. Immunoblots were used to confirm target activation/knockdown in overexpression and knockdown studies. A tumor control dose 50% (TCD50) assay was employed to investigate radiosensitization of a mutated-HRAS head and neck cancer cell line in a flank xenograft model in nude mice. Activating mutations in one of the three RAS genes are seen in 5-10% of head and neck cancer patients. Mutations in HRAS represent over 50% of these. Screening our panel of head and neck cancer cell lines identified a canonical activating mutation in HRAS (G12V). Consistent with known roles for activated HRASG12V, SCC22B is relatively insensitive to both cetuximab and radiation. Using both in vitro and in vivo studies, cetuximab failed to radiosensitize SCC22B. Cetuximab treatment decreased AKT, but not ERK activation. Direct inhibition of the MEK/ERK or PI3K/MTOR pathway by selumetinib or BEZ235, respectively, decreased target protein activation and resulted in significant growth inhibition compared to control (p<0.05). Treatment with either selumetinib or BEZ235 radiosensitized HRASG12V expressing cells (SER 1.3-1.8) but had no effects on cells expressing wildtype HRAS. siRNA knockdown of HRAS radiosensitized SCC22B, but not SCC1 or SCC6 cells relative to non-targeting control while overexpression of HRASG12Vresulted in less sensitivity to radiation in wildtype cell lines. In vivo assessment of the radiosensitizing effects of these compounds via a TCD50 assay (5 fractions of 0, 0.5, 2, 4, 7, and 10 Gy) is pending. More than 5% of head and neck cancers harbor activating mutations in one of the RAS family of genes. These mutations lead to resistance to cetuximab, either as a single agent, or as a radiosensitizer. Inhibition of downstream targets such as the MEK/ERK and PI3K/MTOR pathways can radiosensitize tumors harboring activating mutations in HRAS. Further investigation of the safety and efficacy of these drugs in combination with chemoradiation is warranted.