A Partial Tumor Irradiation Approach for Complex Bulky Disease.

A large proportion of cancer patients present with unresectable bulky disease at baseline or following treatment failure. The data available in the literature suggest that the vast majority of these patients do not benefit from available standard therapies. Therefore the clinical outcomes are poor; patients are desperate and usually relegated to palliative or best supportive care as the only options. Large tumor masses are usually hypoxic, resistant to radiation and systemic therapy, with extensive regional infiltration of the surrounding critical organs, the presence of which makes it impossible to deliver a radical dose of radiation. Promising data in terms of improved therapeutic ratio where such complex tumors are concerned can be seen with the use of new emerging unconventional radiotherapy techniques known as spatially fractionated radiotherapies (SFRT). One of them is PATHY, or PArtial Tumor irradiation targeting HYpoxic segment, which is characterized by a very short treatment course offering a large spectrum of therapeutic benefits in terms of the symptom relief, quality of life, local tumor control, neoadjuvant and immunomodulatory effects.

The Value of PET/CT in Particle Therapy Planning of Various Tumors with SSTR2 Receptor Expression: Comparative Interobserver Study.

The overexpression of somatostatin receptor type 2 (SSTR2) is a property of various tumor types. Hybrid imaging utilizing [68Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (DOTA) may improve the differentiation between tumor and healthy tissue. We conducted an experimental study on 47 anonymized patient cases including 30 meningiomas, 12 PitNET and 5 SBPGL. Four independent observers were instructed to contour the macroscopic tumor volume on planning MRI and then reassess their volumes with the additional information from DOTA-PET/CT. The conformity between observers and reference volumes was assessed. In total, 46 cases (97.9%) were DOTA-avid and included in the final analysis. In eight cases, PET/CT additional tumor volume was identified that was not detected by MRI; these PET/CT findings were potentially critical for the treatment plan in four cases. For meningiomas, the interobserver and observer to reference volume conformity indices were higher with PET/CT. For PitNET, the volumes had higher conformity between observers with MRI. With regard to SBGDL, no significant trend towards conformity with the addition of PET/CT information was observed. DOTA PET/CT supports accurate tumor recognition in meningioma and PitNET and is recommended in SSTR2-expressing tumors planned for treatment with highly conformal radiation.

Proton or Carbon Ion Therapy for Skull Base Chordoma: Rationale and First Analysis of a Mono-Institutional Experience.

BACKGROUND: Skull base chordomas are radio-resistant tumors that require high-dose, high-precision radiotherapy, as can be delivered by particle therapy (protons and carbon ions). We performed a first clinical outcome analysis of particle therapy based on the initial 4-years of operation. METHODS: Between August 2017 and October 2021, 44 patients were treated with proton (89%) or carbon ion therapy (11%). Prior gross total resection had been performed in 21% of lesions, subtotal resection in 57%, biopsy in 12% and decompression in 10%. The average prescription dose was 75.2 Gy RBE in 37 fractions for protons and 66 Gy RBE in 22 fractions for carbon ions. RESULTS: At a median follow-up of 34.3 months (range: 1-55), 2-, and 3-year actuarial local control rates were 95.5% and 90.9%, respectively. The 2-, and 3-year overall and progression-free survival rates were 97.7%, 93.2%, 95.5% and 90.9%, respectively. The tumor volume at the time of particle therapy was highly predictive of local failure (p < 0.01), and currently, there is 100% local control in patients with tumors < 49 cc. No grade ≥3 toxicities were observed. There was no significant difference in outcome or side effect profile seen for proton versus carbon ion therapy. Five patients (11.4%) experienced transient grade ≤2 radiation-induced brain changes. CONCLUSIONS: The first analysis suggests the safety and efficacy of proton and carbon ion therapy at our center. The excellent control of small to mid-size chordomas underlines the effectiveness of particle therapy and importance of upfront maximum debulking of large lesions.

Normofractionated and moderately hypofractionated proton therapy: comparison of acute toxicity and early quality of life outcomes.

Aim: Data on the safety of moderately hypofractionated proton beam therapy (PBT) are limited. The aim of this study is to compare the acute toxicity and early quality of life (QoL) outcomes of normofractionated (nPBT) and hypofractionated PBT (hPBT). Material and methods: We prospectively compared acute toxicity and QoL between patients treated with nPBT (dose per fraction 1.8-2.3 Gy, n = 90) and hPBT (dose per fraction 2.5-3.1 Gy, n = 49) in following locations: head and neck (H&N, n = 85), abdomen and pelvis (A&P, n = 43), and other soft tissue (ST, n = 11). The toxicities were grouped into categories-mucosal, skin, and other sites-and evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at baseline, treatment completion, and 3 months after PBT completion. QoL was evaluated with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scale for all locations and additionally with EORTC QLQ-HN35 for H&N patients. Results: Overall, the highest toxicity grades of G0, G1, G2, and G3 were observed in 7 (5%), 40 (28.8%), 78 (56.1%), and 15 (10.8%) patients, respectively. According to organ and site, no statistically significant differences were detected in the majority of toxicity comparisons (66.7%). For A&P, hPBT showed a more favorable toxicity profile as compared to nPBT with a higher frequency of G0 and G1 and a lower frequency of G2 and G3 events (p = 0.04), more patients with improvement (95.7% vs 70%, p = 0.023), and full resolution of toxicities (87% vs 50%, p = 0.008). Skin toxicity was unanimously milder for hPBT compared to nPBT in A&P and ST locations (p = 0.018 and p = 0.025, respectively). No significant differences in QoL were observed in 97% of comparisons for QLQ-C30 scale except for loss of appetite in H&N patients (+33.3 for nPBT and 0 for hPBT, p = 0.02) and role functioning for A&P patients (0 for nPBT vs +16.7 hPBT, p = 0.003). For QLQ-HN35, 97.9% of comparisons did not reveal significant differences, with pain as the only scale varying between the groups (-8.33 vs -25, p = 0.016). Conclusion: Hypofractionated proton therapy offers non-inferior early safety and QoL as compared to normofractionated irradiation and warrants further clinical investigation.

Novel Carbon Ion and Proton Partial Irradiation of Recurrent Unresectable Bulky Tumors (Particle-PATHY): Early Indication of Effectiveness and Safety.

BACKGROUND: We present the early results of a novel partial bulky-tumor irradiation using particles for patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments. METHODS: First, eleven consecutive patients were treated from March 2020 until December 2021. The targeted Bystander Tumor Volume (BTV) was created by subtracting 1 cm from Gross Tumor Volume (GTV) surface. It reflected approximately 30% of the central GTV volume and was irradiated with 30-45 Gy RBE (Relative Biological Effectiveness) in three consecutive fractions. The Peritumoral Immune Microenvironment (PIM) surrounding the GTV, containing nearby tissues, blood-lymphatic vessels and lymph nodes, was considered an organ at risk (OAR) and protected by highly conservative constraints. RESULTS: With the median follow up of 6.3 months, overall survival was 64% with a median survival of 6.7 months; 46% of patients were progression-free. The average tumor volume regression was 61% from the initial size. The symptom control rate was 91%, with an average increase of the Karnofsky Index of 20%. The abscopal effect has been observed in 60% of patients. CONCLUSIONS: Partial bulky-tumor irradiation is an effective, safe and well tolerated treatment for patients with unresectable recurrent bulky disease. Abscopal effects elucidate an immunogenic pathway contribution. Extensive tumor shrinkage in some patients might permit definitive treatment-otherwise previously impossible.

The Value of SSTR2 Receptor-Targeted PET/CT in Proton Irradiation of Grade I Meningioma.

Grade I meningioma is the most common intracranial tumor in adults. The standard imaging for its radiation treatment planning is MRI, and [68Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated PET/CT can further improve delineation. We investigated the impact of PET/CT on interobserver variability in identifying the tumor in 30 anonymized patients. Four radiation oncologists independently contoured residual tumor volume, first using only MRI and subsequently with the addition of PET/CT. Conformity indices (CIs) were calculated between common volumes, observer pairs and compared to the volumes previously used. Overall, 29/30 tumors (96.6%) showed [68Ga]Ga-DOTA avidity. With help of PET/CT, the participants identified six cases with new lesions not recognized in MRI, including two where new findings would critically alter the target volume used for radiation. The PET/CT-aided series demonstrated superior conformity, as compared to MRI-only between observer pairs (median CI = 0.58 vs. 0.49; p = 0.002), common volumes (CI = 0.34; vs. 0.29; p = 0.002) and matched better the reference volumes actually used for patient treatment (CI = 0.55 vs. 0.39; p = 0.008). Cis in the PET/CT-aided series were lower for meningiomas outside of the skull base (0.2 vs. 0.44; p = 0.03). We conclude that SSTR2 receptor-targeted PET/CT is a valuable tool for planning particle therapy of incompletely resected meningioma. It serves both as a workup procedure and an aid for delineation process that reduces the likelihood of marginal misses.

Biology of NSCLC: Interplay between Cancer Cells, Radiation and Tumor Immune Microenvironment.

The overall prognosis and survival of non-small cell lung cancer (NSCLC) patients remain poor. The immune system plays an integral role in driving tumor control, tumor progression, and overall survival of NSCLC patients. While the tumor cells possess many ways to escape the immune system, conventional radiotherapy (RT) approaches, which are directly cytotoxic to tumors, can further add additional immune suppression to the tumor microenvironment by destroying many of the lymphocytes that circulate within the irradiated tumor environment. Thus, the current immunogenic balance, determined by the tumor- and radiation-inhibitory effects is significantly shifted towards immunosuppression, leading to poor clinical outcomes. However, newer emerging evidence suggests that tumor immunosuppression is an "elastic process" that can be manipulated and converted back into an immunostimulant environment that can actually improve patient outcome. In this review we will discuss the natural immunosuppressive effects of NSCLC cells and conventional RT approaches, and then shift the focus on immunomodulation through novel, emerging immuno- and RT approaches that promise to generate immunostimulatory effects to enhance tumor control and patient outcome. We further describe some of the mechanisms by which these newer approaches are thought to be working and set the stage for future trials and additional preclinical work.

The role of radiotherapy in patients with solid tumours after solid organ transplantation: a systematic review.

For patients diagnosed with cancer who have previously received an organ transplant, radiotherapy represents a challenging clinical scenario without well established care algorithms. Immunosuppressive therapy can be a cause for concern among clinicians treating this category of patients. Potential immune modulation following irradiation could affect recipient organ tolerance and the outcomes of the transplantation itself. The main aim of this systematic review was to define the safety and effectiveness of radiotherapy in patients diagnosed with cancer who have previously received an organ transplant. We searched PubMed and Embase for articles published between Jan 1, 1995, and April 30, 2020 for studies in patients who had undergone radiotherapy for post-transplantation malignancies. The Review is framed by the PICO (population, intervention, control, and outcomes) criteria, and primarily focuses on modern treatment techniques.

Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY).

Radiation-induced immune-mediated abscopal effects (AE) of conventional radiotherapy are very rare. Whole-tumor irradiation leads to lymphopenia due to killing of immune cells in the tumor microenvironment, resulting in immunosuppression and weak abscopal potential. This limitation may be overcome by partial tumor irradiation sparing the peritumoral immune-environment, and consequent shifting of immune-suppressive to immune-stimulatory effect. This would improve the radiation-directed tumor cell killing, adding to it a component of immune-mediated killing. Our preclinical findings showed that the high-single-dose irradiation of hypoxic tumor cells generates a stronger bystander effect (BE) and AE than the normoxic cells, suggesting their higher "immunogenic potential". This led to the development of a novel Stereotactic Body RadioTherapy (SBRT)-based PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) for induction of the immune-mediated BE and AE. Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects. This review discusses the current evidence on the safety and efficacy of SBRT-PATHY in the treatment of unresectable hypoxic bulky tumors and its bystander and abscopal immunomodulatory potential.

Oligometastasis and local ablation in the era of systemic targeted and immunotherapy.

BACKGROUND: During these last years, new agents have dramatically improved the survival of the metastatic patients. Oligometastases represent a continuous field of interest in which the integration of metastases-directed therapy and drugs could further improve the oncologic outcomes. Herein a narrative review is performed regarding the main rationale in combining immunotherapy and target therapies with SBRT looking at the available clinical data in case of oligometastatic NSCLC, Melanoma and Kidney cancer. MATERIAL AND METHOD: Narrative Review regarding retrospective and prospective studies published between January 2009 to November 2019 with at least 20 patients analyzed. RESULTS: Concerning the combination between SBRT and Immunotherapy, the correct sequence of remains uncertain, and seems to be drug-dependent. The optimal patients' selection is crucial to expect substantial benefits to SBRT/Immunotherapy combination and, among several factors. A potential field of interest is represented by the so-called oligoprogressed disease, in which SBRT could improve the long-term efficacy of the existing target therapy. CONCLUSIONS: A low tumor burden seems to be the most relevant, thus making the oligometastatic disease represent the ideal setting for the use of combination therapies with immunological drugs.

The future of radiation-induced abscopal response: beyond conventional radiotherapy approaches.

Advances in the immunological pharmaceuticals, such as checkpoint inhibitors and agonists, have positive implications for the future of the radiotherapy abscopal response. A once rare phenomenon, whereby distant nonirradiated tumor sites regressed after radiotherapy alone, may become more common when combined with the immune modulating agents. Radiotherapy can increase neoantigen expression, increased tumor PD-L1 expression, increase MHC class I expression, reverse exhausted CD8 T cells and increase tumor-infiltrating tumors within the tumor microenvironment. These changes in the tumor and the tumor microenvironment after radiotherapy could potentiate responses to anti-CTL-4, anti-PD-L1/PD-1 and other immunotherapy agents. Thus, advances in checkpoint inhibitors have increased interest in re-evaluation of the role of conventional radiotherapy approaches on the immune system. We reviewed newer nonconventional approaches such as SBRT-PATHY, GRID, FLASH, carbon ion and proton therapy and their role in eliciting immune responses. We believe that combining these novel radiation methods may enhance the outcome with the newly US FDA approved immune modulating agents.

Time-synchronized immune-guided SBRT partial bulky tumor irradiation targeting hypoxic segment while sparing the peritumoral immune microenvironment.

BACKGROUND: A novel unconventional SBRT-based PArtial Tumor irradiation targeting HYpoxic clonogenic cells (SBRT-PATHY) for induction of the tumoricidal bystander (BE) and abscopal effects (AE) was developed by translating our preclinical findings to a clinic in 2016. In order to further improve BE/AE response rate, SBRT-PATHY was upgraded in 2018 by the sparing of peritumoral immune microenvironment as a new OAR, defined by its own dose-constraints. Considering the anti-tumor immune response homeostatic fluctuation, which is cyclically suppressed and incited ("switched off and on"), we synchronized SBRT-PATHY with its most excitable phase, in order to overcome tumor tolerance locally and systemically. The aim of this study, therefore, was to report on the initial results of our latest innovation aimed to further improve BE/AE response rate by testing the effectiveness of the time-synchronized immune-guided SBRT-PATHY. MATERIALS AND METHODS: In order to serially map the homeostatic anti-tumor immune response-fluctuations, High Sensitive C-Reactive Protein (HS-CRP), Lactate Dehydrogenase (LDH) and Lymphocyte/Monocyte Ratio (LMR) were analyzed using high-order polynomial trend analysis as surrogate of immune system response. After the biomarker data analysis detected the immune fluctuations and related idiosyncratic immune cycle periodicity, we determined the "most favourable" and "least favourable" treatment time-positions in the immune cycle. In order to evaluate the impact of an idiosyncratic immune cycle on treatment outcomes, our first consecutive four patients were treated on the "most favourable" while the remaining four on the "least favourable" day. RESULTS: The median follow-up was 11.8 months. The biomarker data analysis showed periodic immune response fluctuations of regular frequency. The "right" synchronization of SBRT-PATHY with the "most favorable day" of anti-tumor immune response was accompanied with improved clinical outcomes in terms of BE/AE-response rate. CONCLUSION: We believe the right synchronization of radiotherapy with the homeostatically oscillating immune response may improve the probability of inducing BE/AE. Present study has been retrospectively registered on 18th of October 2019 by the ethic committee for Austrian region "Kärnten "in Klagenfurt (AUT), under study number A 37/19.

Mono-institutional phase 2 study of innovative Stereotactic Body RadioTherapy targeting PArtial Tumor HYpoxic (SBRT-PATHY) clonogenic cells in unresectable bulky non-small cell lung cancer: profound non-targeted effects by sparing peri-tumoral immune microenvironment.

BACKGROUND: Radiotherapy-induced lymphopenia may be limiting the success of therapy and could also negatively affect the ability of immune system in mediating the bystander (BE) and abscopal effects (AE). A novel SBRT-based PArtial Tumor irradiation of HYpoxic clonogenic cells (SBRT-PATHY) for induction of the tumoricidal BE and AE by sparing the peritumoral immune microenvironment and regional circulating lymphocytes has been developed to enhance the radiotherapy therapeutic ratio of advanced lung cancer. The aim of this retrospective review of prospectively collected mono-institutional phase 2 study was to compare the outcomes between unconventional SBRT-PATHY and standard of care in unresectable stage IIIB/IV bulky NSCLC. MATERIALS AND METHODS: Sixty patients considered inoperable or unsuitable for radical radio-chemotherapy were enrolled and treated using the following 3 regimens: SBRT-PATHY (group I, n = 20 patients), recommended standard of care chemotherapy (group II, n = 20 patients), and institutional conventional palliative radiotherapy (group III, n = 20 patients). RESULTS: Median follow-up was 13 months. The 1-year overall survival was 75, 60, and 20% in groups 1, 2 and 3, respectively (p = 0.099). The 1-year cancer specific survival was 90, 60, and 20% in groups 1, 2, and 3, respectively (p = 0.049). Bulky tumor control rate was 95% for SBRT-PATHY compared with 20% in the other two groups. BE and AE were seen by SBRT-PATHY in 95 and 45% of patients, respectively. Multi-variate analysis for cancer specific survival was significant for treatment effect with SBRT-PATHY (p < 0.001) independent of age, sex, performance status, histology, stage, treated bulky site and tumor diameter. SBRT-PATHY resulted in lower toxicity (p = 0.026), and improved symptom control (p = 0.018) when compared to other two treatment options. CONCLUSION: SBRT-PATHY improved treatment outcomes in unresectable NSCLC and should be investigated in larger trials. Present study has been retrospectively registered on 8th of August 2019 by the ethic committee for Austrian region "Kärnten "in Klagenfurt (AUT), under study number A 31/19.

Novel stereotactic body radiation therapy (SBRT)-based partial tumor irradiation targeting hypoxic segment of bulky tumors (SBRT-PATHY): improvement of the radiotherapy outcome by exploiting the bystander and abscopal effects.

BACKGROUND: Despite the advances in oncology, patients with bulky tumors have worse prognosis and often receive only palliative treatments. Bulky disease represents an important challenging obstacle for all currently available radical treatment options including conventional radiotherapy. The purpose of this study was to assess a retrospective outcome on the use of a newly developed unconventional stereotactic body radiation therapy (SBRT) for PArtial Tumor irradiation of unresectable bulky tumors targeting exclusively their HYpoxic segment (SBRT-PATHY) that exploits the non-targeted effects of radiotherapy: bystander effects (local) and the abscopal effects (distant). MATERIALS AND METHODS: Twenty-three patients with bulky tumors received partial bulky irradiation in order to induce the local non-targeted effect of radiation (bystander effect). The hypoxic tumor segment, called the bystander tumor volume (BTV), was defined using PET and contrast-enhanced CT, as a hypovascularized-hypometabolic junctional zone between the central necrotic and peripheral hypervascularized-hypermetabolic tumor segment. Based on tumor site and volume, the BTV was irradiated with 1-3 fractions of 10-12 Gy prescribed to 70% isodose-line. The pathologic lymph nodes and metastases were not irradiated in order to assess the distant non-targeted effects of radiation (abscopal effect). No patient received any systemic therapy. RESULTS: At the time of analysis, with median follow-up of 9.4 months (range: 4-20), 87% of patients remained progression-free. The bystander and abscopal response rates were 96 and 52%, respectively. Median shrinkage of partially irradiated bulky tumor expressing intensity of the bystander effect was 70% (range 30-100%), whereas for the non-irradiated metastases (intensity of the abscopal effect), it was 50% (range 30-100%). No patient experienced acute or late toxicity of any grade. CONCLUSIONS: SBRT-PATHY showed very inspiring results on exploitation of the radiation-hypoxia-induced non-targeted effects that need to be confirmed through our ongoing prospective trial. Present study has been retrospectively registered by the local ethic committee under study number A 26/18.

Radiation and hypoxia-induced non-targeted effects in normoxic and hypoxic conditions in human lung cancer cells.

PURPOSE: Many cell lines with anaerobic metabolism do not show cytotoxic abscopal effect (AE) following irradiation. Further, there is no existing data on the radiation- and hypoxia (H)-induced AE. The purpose of this study was to investigate and compare the status of radiation-induced abscopal effect (RIAE) in normoxic and hypoxic conditions. METHODS: Lung cancer cells (A549, H460) were exposed either to hypoxia or normoxia and then irradiated (2 or 10 Gy). After 24 h, unirradiated hypoxic (H-CM) or normoxic (N-CM) conditioned media (CM) and irradiated hypoxic (H-RCM) or normoxic (N-RCM) CM was collected. Hypoxia-resistant clones (HR: A549/HR, H460/HR) were generated by continuous exposure of the cells to hypoxia. Unirradiated parental cells or HR were exposed to H-CM, N-CM, H-RCM or N-RCM. In some groups, 24 h after exposure to CM, cells were directly irradiated with 2 Gy. Cell growth was monitored using real-time cell electronic sensing system. Further, levels of hypoxia and HIF1α regulated angiogenesis related growth factors, basic fibroblast growth factor (bFGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-1) and vascular endothelial growth factor (VEGF) were assessed in CM. RESULTS: In the radio-resistant A549 cells, H-RCM was much more effective in inducing growth delay compared to N-RCM. In the radio-sensitive H460 cells, both N-RCM and H-RCM induced growth delay. Interestingly, effects of N-RCM were completely reversed in HR cells. Exposure of cells to direct irradiation (2 Gy) 24 h after incubation with CM resulted in 50-60% reduction in cell proliferation in A549/HR cells and a very significant induction of death (>95%) in H460/HR cells. Direct irradiation of parental or HR clones of A549 and H460 cells exposed to H-CM 24 h with 2 Gy induced significant reduction in cell proliferation (from 40% to >95%) in all the cells. Further, levels of sFlt-1 correlated with growth delay in all the cells. CONCLUSIONS: These results for the first time demonstrate that irradiation of hypoxic cells and exposing the cells to acute hypoxia lead to significant AE.

Manipulation of radiation-induced bystander effect in prostate adenocarcinoma by dose and tumor differentiation grade: in vitro study.

PURPOSE: This in vitro study evaluated the ability of prostate adenocarcinoma (ADC) cells to induce radiation-induced bystander effect (RIBE) exploring the factors that may be responsible and affect its intensity. The idea was to mimic a strong, clinically applicable RIBE that could lead to the development of innovative approaches in modern radiotherapy of prostate cancer, especially for those patients with hormone-refractory ADC in which radiotherapy might have a limited role. MATERIALS AND METHODS: Two human prostate cancer cell lines of different differentiation, PC-3 and DU-145, have been irradiated using wide range of doses to obtain radiation-conditioned medium (RCM), which was used to treat the unirradiated cells and to evaluate the cytokines level. Using a trypan blue dye exclusion method, cell growth was assessed. RESULTS: Prostate ADC cells were able to induce RIBE; intensity depended on dose and cell differentiation. RIBE intensity of DU-145 was not correlated with the cytokines level, while for PC-3 Interleukin-6 (IL-6) correlates with strongest RIBE induced by 20 Gy. CONCLUSIONS: RIBE can be manipulated by modifying radiation dose and depends on cell differentiation status. IL-6 correlates with RIBE after exposure of PC-3 to a very high dose of radiation, thus indicates its possible involvement in bystander signaling.

Adjuvant chemoradiation with 5-fluorouracil or capecitabine in patients with gastric cancer after D2 nodal dissection.

AIM: To evaluate outcome and prognostic factors in patients with locally advanced gastric cancer. PATIENTS AND METHODS: From 2007 to 2011, 55 patients underwent adjuvant radiotherapy and concurrent chemotherapy with 5-fluorouracil (64%) or capecitabine (36%). D2 node resection was performed in all patients. The pathological stage was as follows: 13% IB; 29% II; 24% IIIA; 9% IIIB and 25% stage IV. RESULTS: The median follow up was 21 months. Five-years overall and disease-free survival were 44.5% and 48%, respectively. Eighteen patients experienced disease relapse after combined treatment; in five of these patients, relapse was both locoregional and systemic. The most common toxicity was grade 1-2 leukopenia, reported in 32% of cases. Six patients developed grade 3 toxicity. Nodal ratio ≥0.4 and N3 stage were significant prognostic factors for survival and relapse. CONCLUSION: Adjuvant conformal radiotherapy and concurrent chemotherapy is a feasible and well-tolerated treatment for patients with locally advanced gastric cancer.