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

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

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). 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

Stereotactic central/core ablative radiation therapy: results of a phase I study of a novel strategy to treat bulky tumor

PurposeBulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT). We intend to safely deliver an ablative dose to the core of the tumor and with a low dose at tumor edge. The purpose of the phase 1 study was to determine dose-limiting toxicities (DLT)s and the Maximum Tolerated Dose (MTD) of SCART.Methods and materialsWe defined a SCART-plan volume inside the tumor, which is proportional to the dimension of tumor. VMAT/Cyberknife technique was adopted. In the current clinical trial; Patients with biopsy proven recurrent or metastatic bulky cancers were enrolled. The five dose levels were 15 Gy X1, 15Gy X3, 18GyX3, 21GyX3 and 24GyX3, while keeping the whole tumor GTV’s border dose at 5Gy each fraction. There was no restriction on concurrent systemic chemotherapy agents.Results21 patients were enrolled and underwent SCART. All 21 patients have eligible data for study follow-up. Radiotherapy was well tolerated with all treatment completed as scheduled. The dose was escalated for two patients to 24GyX3. No grade 3 or higher toxicity was observed in any of the enrolled patients. The average age of patients was 66 years (range: 14–85) and 13 (62%) patients were male. The median SCART dose was 18Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.3 months (range: 1 - 25.6). The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.5% (SD: 40.89, p-value:0.009).ConclusionSCART was safely escalated to 24 GyX 3 fractions, which is the maximum Tolerated Dose (MTD) for SCART. This regimen will be used in future phase II trials

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

A Definitive IMRT-SIB with Concomitant Chemotherapy for Synchronous Locally Advanced Anal Canal Cancer and Prostate Cancer

Currently, there are no specific recommendations regarding the management of the synchronous tumours due to the lack of either specific guidelines or individuals’ clinical experiences relative to these clinical situations. In the presence of a locally advanced double primary tumour and with the lymph node metastases in addition, from the radiotherapeutical point of view, it must be challenging to manage this complicated situation that requires a more delicate treatment planning, due to higher doses prescribed to greater volumes concomitantly with the chemotherapy. A 68-year-old Caucasian male with a synchronous intermediate-risk prostate adenocarcinoma and locally advanced anal canal carcinoma underwent IMRT-SIB with concomitant chemotherapy at our institute. Two years after the treatment, the restaging CT and MRI scan showed no evidence of the disease and the patient reported no significant gastrointestinal or genitourinary toxicity. Our experience is unique, since it is the first report on using the IMRT-SIB technique simultaneously with chemotherapy in the management of the synchronous prostate and anal canal carcinomas. Therefore, we find it important to provide the current literature with the results from our experience which show good feasibility, efficacy, and tolerability of the definitive concomitant IMRT-SIB-chemotherapy for the synchronous anal canal cancer and prostate cancer

Abstract LB-370: Radiation and hypoxia-induced bystander effect in human lung cancer cells

Abstract Purpose: The bystander effects of radiation are well documented. However, it is shown that many cell lines that respire anaerobically do not show cytotoxic bystander effects. There is no existing data on the acute hypoxia-induced bystander effects. The purpose of this study was to investigate the status of radiation-induced bystander effect in normoxic, hypoxic and normoxic-hypoxic mixed conditions that are equivalent to in vivo tumor compartments as well as acute hypoxia-induced bystander effect. Methods: Two lung cancer cell lines, A549 and H460 were used. The cells were exposed either to real hypoxia (&amp;lt; 2 % oxygen) for 3 days or incubated in normoxic conditions and then irradiated (2 or 10Gy) after changing the media. After 24h (irradiated and unirradiated cells were continued to be in the hypoxic or normoxic environment respectively), unirradiated hypoxic (H-CM) or normoxic (N-CM) conditioned media and irradiated hypoxic (H-RCM) or normoxic (N-RCM) conditioned media was collected and cells were incubated with fresh media for another 24h before collecting the second respective CM. Unirradiated normoxic cells were exposed to H-CM, N-CM, H-RCM or N-RCM and cell growth was monitored dynamically in real time using real time cell electronic sensing system (RT-CES). Results: Our preliminary results in A549 cells showed that H-RCM was much more effective in inducing growth delay compared to N-RCM. For all the treatments except for 2Gy N-RCM, which promoted slight cellular growth, RCM induced significant growth delay compared to CM. Further, as expected N-RCM obtained after 10Gy irradiation was more cytotoxic/cytostatic than 2Gy N-RCM. Interestingly, H-RCM obtained after 2Gy and 10Gy irradiation did not show significant differences in the growth delay of A549 cells. During the first 48h under real hypoxic conditions (24 or 48h H-CM), the H-CM promoted slight increase in cellular growth followed by significant growth delay which were most pronounced at 96h. When, in addition to the bystander factors, the cells were exposed to 2Gy direct irradiation, the growth was severely affected. Currently, we are performing these experiments in more radiosensitive cell line, H460 and also investigating the effects of acute hypoxia and mixed normoxia-hypoxia on generation of bystander effects. Conclusions: The findings from this study demonstrate for the first time that irradiation of hypoxic cells and exposing the cells to acute hypoxia lead to significant bystander effect that has important clinical implications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-370. doi:10.1158/1538-7445.AM2011-LB-370</jats:p

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

Abstract 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. </jats:sec