Tumor Dose Research Articles

Robust optimization of the Gross Tumor Volume compared to conventional Planning Target Volume-based planning in photon Stereotactic Body Radiation Therapy of lung tumors.

Robust optimization has been suggested as an approach to reduce the irradiated volume in lung Stereotactic Body Radiation Therapy (SBRT). We performed a retrospective planning study to investigate the potential benefits over Planning Target Volume (PTV)-based planning. Thirty-nine patients had additional plans using robust optimization with 5-mm isocenter shifts of the Gross Tumor Volume (GTV) created in addition to the PTV-based plan used for treatment. The optimization included the mid-position phase and the extreme breathing phases of the 4D-CT planning scan. The plans were compared for tumor coverage, isodose volumes, and doses to Organs At Risk (OAR). Additionally, we evaluated both plans with respect to observed tumor motion using the peak tumor motion seen on the planning scan and cone-beam CTs. Statistically significant reductions in irradiated isodose volumes and doses to OAR were achieved with robust optimization, while preserving tumor dose. The reductions were largest for the low-dose volumes and reductions up to 188 ccm was observed. The robust evaluation based on observed peak tumor motion showed comparable target doses between the two planning methods. Accumulated mean GTV-dose was increased by a median of 4.46 Gy and a non-significant increase of 100 Monitor Units (MU) was seen in the robust optimized plans. The robust plans required more time to prepare, and while it might not be a feasible planning strategy for all lung SBRT patients, we suggest it might be useful for selected patients.

Simplification strategies for a patient-specific CFD model of particle transport during liver radioembolization

BackgroundPatient-specific 3D computational fluid dynamics (CFD) simulations have been used previously to identify the impact of injection parameters (e.g. injection location, velocity, etc.) on the particle distribution and the tumor dose during transarterial injection of radioactive microspheres for treatment of hepatocellular carcinoma. However, these simulations are computationally costly, so we aim to evaluate whether these can be reliably simplified. MethodsWe identified and applied five simplification strategies (i.e. truncation, steady flow modelling, moderate and severe grid coarsening, and reducing the number of cardiac cycles) to a patient-specific CFD setup. Subsequently, we evaluated whether these strategies can be used to (1) accurately predict the CFD output (i.e. particle distribution and tumor dose) and (2) quantify the sensitivity of the model output to a specific injection parameter (injection flow rate). ResultsFor both accuracy and sensitivity purposes, moderate grid coarsening is the most reliable simplification strategy, allowing to predict the tumor dose with only a maximal deviation of 1.4 %, and a similar sensitivity (deviation of 0.7 %). The steady strategy performs the worst, with a maximal deviation in the tumor dose of 20 % and a difference in sensitivity of 10 %. ConclusionThe patient-specific 3D CFD simulations of this study can be reliably simplified by coarsening the grid, decreasing the computational time by roughly 45 %, which works especially well for sensitivity studies.

Dosimetry of lutetium-177-PSMA-I&T radioligand therapy in recurrent/metastatic adenoid cystic carcinoma.

6093 Background: There is a high unmet need for effective systemic therapies for recurrent and/or metastatic (R/M) adenoid cystic carcinoma (AdCC), as no standard-of-care exists. AdCC frequently expresses prostate-specific membrane antigen (PSMA), providing rationale for PSMA-targeted therapies, which have demonstrated significant efficacy in prostate cancer. In our phase 2 pilot trial (EudraCT 2019-003857-27), we assessed the safety, efficacy and feasibility of lutetium-177 (177Lu)-PSMA-I&T in R/M AdCC patients. Despite well-tolerated, the efficacy was limited. To gain further insight into causes of the limited efficacy, we measured absorbed 177Lu-PSMA-I&T radiation doses in tumors and organs at risk. Methods: Dosimetry was feasible and was performed in all 10 enrolled AdCC patients. They received 177Lu-PSMA-I&T with a median activity of 7.40 (range 6.78-7.49) GBq and a median of 4 (range 1-4) cycles. For bone marrow dosimetry, blood samples were collected during cycle 1. Single-photon emission CT/CT (SPECT/CT) was performed at 1, 24, 48, 72 and 168 hours after 177Lu-PSMA-I&T injection at cycle 1. Tumors >1 cm were categorized based on gallium-68 (68Ga)-PSMA PET mean standardized uptake value (SUVmean): above, at (±10%), and below liver SUVmean. Per site, up to 3 index lesions per category were selected. Volumes of interest with ~1 cm margin were drawn on SPECT/CT. Background correction was applied. Salivary gland and bone lesion volume were determined by iterative thresholding on 68Ga-PSMA PET. Other tumor volumes were determined on CT. Hermes dosimetry software and Olinda 2.2 software were used to estimate doses according to the Medical Internal Radiation Dose scheme. Results were reported as the absorbed dose at cycle 1 (Gy). Results: In total, 66 tumor lesions were analyzed. Tumor sites included lung (n=35), pleura (n=16), liver (n=5), bone (n=4), lymph node (n=3), local recurrence (n=2) and thoracic wall (n=1). The median 68Ga-PSMA PET tumor/liver SUVmean ratio was 0.94 (range 0.33-2.62). The median tumor-absorbed dose was 0.47 (range, 0.01-4.66) Gy. Highest median doses by tumor site were 1.84 (range, 0.76-2.92) Gy in local recurrences and 1.35 (range, 0.33-2.62) Gy in bone lesions. Lowest median doses by tumor site were 0.18 (range, 0.14-0.27) Gy in lymph node lesions and 0.21 (range, 0.12-0.79) Gy in liver lesions. In organs at risk, the absorbed dose was highest in the kidneys, followed by the salivary glands, with mean values of 6.29 (standard deviation [SD], 2.32) Gy and 5.07 (SD, 2.47) Gy, respectively. The mean bone marrow absorbed dose was 0.53 (SD, 0.14) Gy. Conclusions: Tumor-absorbed radiation doses in our AdCC patient cohort receiving 177Lu-PSMA-I&T were significantly lower than in prostate cancer (~10-40 Gy per cycle), likely due to lower and heterogeneous PSMA expression. This could explain the limited efficacy. Organ-absorbed doses aligned with studies in prostate cancer. Clinical trial information: NCT04291300 .

Dosimetry of lutetium-177 PSMA-targeted radiopharmaceutical therapies for prostate cancer patients: A comparative systematic review and meta-analysis.

e17033 Background: Novel theranostic approaches using radiopharmaceuticals targeting PSMA have emerged for treating metastatic castrate resistant prostate cancer (mCRPC). The physical properties and commercial availability of Lutetium-177 (Lu177) makes it one of the most used radionuclides for radiopharmaceutical therapy (RPT). In this review we aimed at comparing the dosimetry of the most used Lu177-PSMA RPT compounds. Methods: This is a systematic review and meta-analysis of Lu177-PSMA RPT (617, I&T, and J591) dosimetry for prostate cancer. Absorbed doses in Gy/GBq for each organ (kidney, parotid and submandibular glands, bone marrow, liver, lacrimal glands) and for tumor lesions (bone and non- bone lesions) were extracted. These were used to estimate the pooled average absorbed dose of each RPT, and normalize each to the respective injected activity (Gy/cycle) as determined by the dose per cycles used in VISION (7.4 GBq), SPLASH (6.8 GBq), and PROSTACT Trials (5.8 GBq). Results: 29 published manuscripts comprising 535 patients were included in the meta-analysis. The pooled dose was calculated for kidney based on (28 studies, 485 patients), parotid (20, 309), submandibular (7, 100) and lacrimal glands (9, 174), bone marrow (18, 293), and liver (14, 245) were 4.04 and 4.70, 5.85 and 2.62, 5.15 and 4.35, 11.03 and 19.23, 0.24 and 0.19 and 1.11 and 0.56 Gy respectively for Lu177-PSMA-617 and Lu177-PSMA-I&T. Lu177-PSMA-J591 reported absorbed doses to the kidney, bone marrow and liver were 3.95, 0.90, and 5.88 Gy respectively. There was no significant difference between Lu177-PSMA-I&T and Lu177-PSMA-617 for the dose to kidneys (p=0.10), submandibular glands (p=0.56), bone marrow (p=0.31), lacrimal glands (p=0.20), or tumors (p=0.16). However, parotid dose from Lu177-PSMA-617 was higher than that of Lu177-PSMA-I&T (p=<0.01). Average tumor doses tended to be higher for Lu177-PSMA-617 than for Lu177-PSMA-I&T, (27.94 vs. 21.31 Gy); p=0.16. Lu177-PSMA-J591 exposed the bone marrow and liver, to a significantly higher dose while resulting in a lower dose to the kidney than either of the two small molecule compounds. Absorbed doses to the salivary glands, lacrimal glands, and tumors after the treatment with Lu177-PSMA-J591 have not been published yet. Conclusions: The clinical impact of higher tumor to kidney dose ratio for Lu177-PSMA-617 than Lu177-PSMA-I&T has yet to be determined. Data for Lu177-PSMA-J591 are thus far too limited to draw firm conclusions.

Resin-Based 90 Y Tumor Dose as a Predictor of Duration of Response and Survival in Patients With Surgically Unresectable Hepatocellular Carcinoma : A Prospective Single-Arm Study.

Personalized dosimetry improves overall survival (OS) in patients with hepatocellular carcinoma (HCC) treated with glass 90 Y radioembolization. This study evaluated personalized tumor dose (TD) as a predictor of OS, progression-free survival (PFS), and local duration of response (DOR) in patients with surgically unresectable HCC treated with resin 90 Y radioembolization. This prospective, single-center, single-arm clinical trial (NCT04172714) evaluated the efficacy of scout activity of resin 90 Y versus 99m Tc-MAA for treatment planning. A secondary aim of this study was to evaluate personalized dosimetry as a predictor of OS, PFS, and DOR. Partition dosimetry model was utilized for nonsegmental therapies with targeted TD >200 Gy and nontumoral liver dose <70 Gy. Single compartment dose of 200 Gy was used for segmentectomies. OS, PFS, and local DOR from 90 Y was estimated using Kaplan-Meier estimation with log-rank analysis used to determine predictors of prolonged survival. Thirty patients with treatment-naive HCC and 33 tumors (19 segmental and 14 nonsegmental) were included. Overall, 18 patients underwent segmental Y90-RE and 12 underwent non-segmental/lobar therapies. The mean 90 Y TD was 493 Gy. The median follow-up since enrollment into the study was 37 months. The mean OS was 32.2 months for the entire cohort. A total of 5 patients underwent orthotopic liver transplantation post 90 Y and were excluded from further survival analysis. The mean OS for the remainder of the cohort was 30.1 months (median not reached). The mean TD >250 Gy resulted in prolonged mean OS and PFS. The median local DOR was 32.7 months with mean TD 330 Gy predicting prolonged DOR. For patients with surgically unresectable HCC treated with resin 90 Y, there is mean TD threshold predicting prolonged OS, PFS, and local DOR. Therefore, there should be further emphasis on personalized dosimetry for optimization of patient outcomes.

Valuation of advanced Dosimetry in Transarterial Radioembolization of Hepatocellular Carcinoma with 90Y microspheres

Objective : The aim of our study was to analyze the relationships between tumor (T) and normal tissue (N) absorbed dose in relation to the clinical outcomes in hepatocellular carcinoma (HCC) patients treated with 90Y microspheres. Materials and methods : After transarterial radioembolization of HCC with 90Y microspheres, 62 patients (10 females: 52 males, mean age 68.2±8.2 years) were imaged using a four-ring, time-of-flight (TOF), PET/CT system. Low dose, non-diagnostic CT images from PET/CT were utilized for localization of the 90Y microspheres and attenuation correction of PET images. Response assessment was conducted using mRECIST criteria on MRI one month post treatment and subsequently every three months after 90Y treatment. Results : Among 62 patients, mean liver, tumor, and normal tissue doses (mean ± SD) were 51.38±23.32 Gy, 682.60±785.19 Gy and 45.54±21.19 Gy, respectively. Out of these patients, 39 exhibited complete response (CR), 11 showed partial response (PR), 2 had stable disease (SD), and 10 showed progression of the disease (PD). For CR+PR patients the mean T was 824.63±833.10 Gy, whereas for PD patients, the mean T was significantly lower at 205.70±183.22 Gy. The mean liver and normal tissue doses were comparable; for CR+PR patients had liver and normal tissue doses of 51.01±22.55 Gy and 45.18±20.68 Gy, respectively, and for PD patients, these values were 54.34±26.73 Gy and 49.10±22.97 Gy, respectively. Conclusion : Despite not considering the partial volume effect and having a limited number of PD cases, our data indicates a statistically significant lower (P = 0.0001) tumor dose in patients with disease progression compared to those with complete and partial response. These results suggest that post-therapy personalized, and image-based dosimetry provides promising predictive outcomes in 90Y microsphere radiation therapy for liver cancers.

Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.

Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer. This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial. MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials. clinicaltrials.gov, identifier NCT04431674.

Are survival outcomes dependent on the tumour dose threshold of 139 Gy in patients with chemorefractory metastatic colorectal cancer treated with yttrium-90 radioembolization using glass particles? A real-world single-centre study.

To compare the survival and objective response rate (ORR) of the patients receiving estimated tumour absorbed dose (ETAD) <140 Gy versus ETAD ≥140 Gy in patients with advanced chemorefractory colorectal carcinoma liver metastases (CRCLM) treated with yttrium-90 transarterial radioembolization (90Y TARE). Between August 2016 and August 2023 adult patients with unresectable, chemorefractory CRCLM treated with 90Y TARE using glass particles, were retrospectively enrolled. Primary outcomes were overall survival (OS) and hepatic progression free survival (hPFS). Secondary outcome was ORR. A total of 40 patients with a mean age of 66.2 ± 7.8 years met the inclusion criteria. Mean ETAD for group 1 (ETAD <140 Gy) and group 2 (ETAD ≥140) were 131.2 ± 17.4 Gy versus 195 ± 45.6 Gy, respectively. The mean OS and hPFS for group 1 versus group 2 were 12 ± 10.3 months and 8.1 ± 9.3 months versus 9.3 ± 3 months and 7.1 ± 8.4 months, respectively and there were no significant differences (P = .181 and P = .366, respectively). ORR did not show significant difference between the groups (P = .432). In real-world practice, no significant difference was found in OS, hPFS, and ORR between patients who received ETAD <140 Gy versus ETAD ≥140 Gy in patients with CRCLM, in this series. This study demonstrated that increased tumour absorbed doses in radioembolization may not provide additional significant advantage for OS and hPFS for patients with CRCLM.

Relationship Between Absorbed Dose and Response in Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE.

Peptide receptor radionuclide therapy presents the possibility of tracing and quantifying the uptake of the drug in the body and performing dosimetry, potentially allowing individualization of treatment schemes. However, the details of how neuroendocrine tumors (NETs) respond to different absorbed doses are insufficiently known. Here, we investigated the relationship between tumor-absorbed dose and tumor response in a cohort of patients with NETs treated with [177Lu]Lu-DOTATATE. Methods: This was a retrospective study based on 69 tumors in 32 patients treated within a clinical trial. Dosimetry was performed at each cycle of [177Lu]Lu-DOTATATE, rendering 366 individual absorbed dose assessments. Hybrid planar-SPECT/CT imaging using [177Lu]Lu-DOTATATE was used, including quantitative SPECT reconstruction, voxel-based absorbed dose rate calculation, semiautomatic image segmentation, and partial-volume correction. Changes in tumor volume were used to determine tumor response. The volume for each tumor was manually delineated on consecutive CT scans, giving a total of 712 individual tumor volume assessments. Tumors were stratified according to grade. The relationship between absorbed dose and response was investigated using mixed-effects models and logistic regression. Tumors smaller than 4 cm3 were excluded. Results: In grade 2 NETs, a clear relationship between absorbed dose and volume reduction was observed. Our observations suggest a 90% probability of partial tumor response for an accumulated tumor-absorbed dose of at least 135 Gy. Conclusion: Our findings are in accordance with previous observations regarding the relationship between tumor shrinkage and absorbed dose. Moreover, our data suggest an absorbed dose threshold for partial response in grade 2 NETs. These observations provide valuable insights for the design of dosimetry-guided peptide receptor radionuclide therapy schemes.

Primary chemoradiation versus neoadjuvant chemotherapy followed by surgery as treatment strategy for locally advanced vulvar carcinoma (VULCANize2)

BackgroundCurrent treatment options for patients with locally advanced vulvar cancer are limited and associated with high morbidity. Therefore, it is important to develop new and safe treatment strategies for this...

Validation of the Elekta iBEAM Evo couchtop modeling in the Monaco treatment planning system

IntroductionRecently, carbon fiber (CF) has prevailed as the primary material used in radiotherapy couchtops. Modern couchtops incorporate the CF sandwich design, in which two thin CF plates sandwich an air-equivalent polymeric foam. Developments in radiotherapy necessitate irradiation from posterior angles through the couchtop. However, the presence of the couchtop needs proper modeling in the Treatment Planning System (TPS) due to attenuation; otherwise, the tumor dose is reduced. In the current study, an effort was made with the intent of finding the optimum electron density (ED) values for Elekta's iBEAM Evo couchtop components (CF and Foam Core (FC)) for its proper modeling in Monaco TPS. Also, the attenuation of the beam due to the couchtop's presence was investigated. Materials and MethodsA cylindrical phantom with an ionization chamber positioned at the isocenter was utilized for the measurements. The phantom was placed centrally on the iBEAM Evo couchtop and was irradiated with an Elekta Infinity linear accelerator's 6, 10, and 15 MV photon beams. The gantry angle was set at 0o and from 120o to 180o with an increment of 10o. The same procedure was designed and followed in Monaco TPS. Measured and calculated dose values were compared by calculating percentage deviation (PD). Attenuation has also been calculated using the measurements of the experimental setup and the Monaco calculations. ResultsThe values of ED that provided the optimum agreement between measured and Monaco-calculated dose values while minimizing PD were 0.55 g/cm3 for CF, and 0.1 g/cm3 for FC. The maximum values of PD for the beams of 6, 10, and 15 MV were -0.62%, +1,78%, and +2.35% , respectively, for a 5x5 cm2 field size. Furthermore, Monaco predicted attenuation from 1.83% to 6.26% (calculated values), while from the measurements, an attenuation from 1.44% to 5.75% (measured values) regarding the posterior angles was found. Thus, good agreement was verified between the TPS calculations and experimental measurements. ConclusionsElekta's iBEAM Evo couchtop modeling was successfully validated in Monaco TPS. The couchtop's presence alters the patient's dose regarding irradiation from the posterior angles. Due to the attenuation of the beam, proper incorporation, modeling, and validation of the couchtop are necessary to improve the radiotherapy outcome and ensure that each patient receives the optimal treatment.

Dosimetry and Biochemical Comparison of Early Radiation-Induced Lung Toxicity in Breast Cancer Patients Treated with 3D-CRT and IMRT: the Role of Serum Interleukin-6 and Pulmonary Surfactant Protein-D.

Radiation-induced lung disease is a potentially fatal, dose-limiting toxicity commonly seen after radiotherapy of thoracic malignancies, including breast cancer. To evaluate and compare the early lung toxicity induced by 3D-CRT and IMRT radiotherapy treatment modalities in breast cancer female patients using biochemical, dosimetry and clinical data. this study included 15 normal healthy controls, 15 breast cancer patients treated with IMRT, and 15 breast cancer patients treated with 3D-CRT. One blood sample was obtained from the control group and 3 blood samples were withdrawn from cases before RT, after RT and after 3 months of RT. IMRT delivered higher radiation dose to the breast tumor and lower doses to the lung as an organ at risk. There was a non-significant increase in the serum levels of IL-6 before IMRT and 3D-CRT compared with its levels in the control group. There were significant increases in serum levels of IL-6 after RT (IMRT and 3DCRT) compared with its levels before RT. There was a non-significant decrease in the serum levels of IL-6 after 3 months of RT (IMRT and 3D-CRT) compared with its serum levels immediately after RT. There was a non-significant increase in the serum levels of SP-D before RT (IMRT and 3D-CRT) compared with its levels in the control group. There were significant-increases in serum levels of SP-D after RT (IMRT and 3D-CRT) compared with its levels before RT. There was a non-significant decrease in the serum levels of SP-D after 3 months of radiotherapy (IMRT and 3D-CRT) compared with its serum levels immediately after RT. serum of levels IL-6 and SP-D can be used to diagnose the occurrence of early lung toxicity due to radiotherapy and the rate of recovery from radiation pneumonitis is apparent in case of IMRT than 3D-CRT.

Proton Therapy in Non-Rhabdomyosarcoma Soft Tissue Sarcomas of Children and Adolescents.

This paper provides insights into the use of Proton Beam Therapy (PBT) in pediatric patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). NRSTS are a heterogeneous group of rare and aggressive mesenchymal extraskeletal tumors, presenting complex and challenging clinical management scenarios. The overall survival rate for patients with NRSTS is around 70%, but the outcome is strictly related to the presence of various variables, such as the histological subtype, grade of malignancy and tumor stage at diagnosis. Multimodal therapy is typically considered the preferred treatment for high-grade NRSTS. Radiotherapy plays a key role in the treatment of children and adolescents with NRSTS. However, the potential for radiation-induced side effects partially limits its use. Therefore, PBT represents a very suitable therapeutic option for these patients. The unique depth-dose characteristics of protons can be leveraged to minimize doses to healthy tissue significantly, potentially allowing for increased tumor doses and enhanced preservation of surrounding tissues. These benefits suggest that PBT may improve local control while reducing toxicity and improving quality of life. While clear evidence of therapeutic superiority of PBT over other modern photon techniques in NRSTS is still lacking-partly due to the limited data available-PBT can be an excellent treatment option for young patients with these tumors. A dedicated international comprehensive collaborative approach is essential to better define its role within the multidisciplinary management of NRSTS. Shared guidelines for PBT indications-based on the patient's age, estimated outcome, and tumor location-and centralization in high-level referral centers are needed to optimize the use of resources, since access to PBT remains a challenge due to the limited number of available proton therapy facilities.

Complex Treatment of A Rare Non-Germinomatous Germ Cell Optic-Chiasmal Brain Tumor In An Adolescent Child-A Clinical Case With Literature Review

Non-germ cell tumours (NGCTs) are rare intracranial neoplasms occurring in adolescents and young adults. A multidisciplinary team including a neurosurgeon, oncologist, radiologist, pathohistologist, ophthalmologist, pediatric oncohematologist, neurologist and endocrinologist is required for diagnosis and treatment. We present a rarely diagnosed optic-chiasmal non-germinomatous germ cell tumour (NGGCT) in a 16-year-old boy, accompanied by pituitary insufficiency (diabetes insipidus and central hypothyroidism) and severely impaired vision bilaterally. The immunohistochemistry (IHC) of the tumor biopsy, as well as the level of tumor markers (human chorionic gonadotropin and alpha-fetoprotein) in the serum and cerebrospinal fluid are significant factors for determining the diagnosis-cranial GCT or cranial NGCT. Because the tumor was inoperable, we performed 3 courses of neoadjuvant chemotherapy followed by definitive radiotherapy to a total tumor dose of 55 Gy. In such rare childhood brain tumors, complex treatment achieves long-term local tumor control, requiring long-term monitoring by an ophthalmologist and endocrinologist.

Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma

BackgroundSoft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS.MethodsPhase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies.DiscussionThis is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS.Trial registrationNCT05301283.Trial statusThe trial started recruitment on March 17, 2022.

In-vivo inhibition of neutral endopeptidase 1 results in higher absorbed tumor doses of [177Lu]Lu-PP-F11N in humans: the lumed phase 0b study

BackgroundA new generation of radiolabeled minigastrin analogs delivers low radiation doses to kidneys and are considered relatively stable due to less enzymatic degradation. Nevertheless, relatively low tumor radiation doses in patients indicate limited stability in humans. We aimed at evaluating the effect of sacubitril, an inhibitor of the neutral endopeptidase 1, on the stability and absorbed doses to tumors and organs by the cholecystokinin-2 receptor agonist [177Lu]Lu-PP-F11N in patients. In this prospective phase 0 study eight consecutive patients with advanced medullary thyroid carcinoma and a current somatostatin receptor subtype 2 PET/CT scan were included. Patients received two short infusions of ~ 1 GBq [177Lu]Lu-PP-F11N in an interval of ~ 4 weeks with and without Entresto® pretreatment in an open-label, randomized cross-over order. Entresto® was given at a single oral dose, containing 48.6 mg sacubitril. Adverse events were graded and quantitative SPECT/CT and blood sampling were performed. Absorbed doses to tumors and relevant organs were calculated.ResultsPretreatment with Entresto® showed no additional toxicity and increased the stability of [177Lu]Lu-PP-FF11N in blood significantly (p < 0.001). Median tumor-absorbed doses were 2.6-fold higher after Entresto® pretreatment (0.74 vs. 0.28 Gy/GBq, P = 0.03). At the same time, an increase of absorbed doses to stomach, kidneys and bone marrow was observed, resulting in a tumor-to-organ absorbed dose ratio not significantly different with and without Entresto®.ConclusionsPremedication with Entresto® results in a relevant stabilization of [177Lu]Lu-PP-FF11N and consecutively increases radiation doses in tumors and organs.Trial registration clinicaltrails.gov, NCT03647657. Registered 20 August 2018.

Experimental and New Approaches for Bladder Preservation in Intermediate and High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC).

About 75% of bladder cancers are detected as non-muscle invasive. High-risk patients have high progression risk. Although the standard is transurethral resection of bladder tumor plus full dose intravesical BCG for one to 3 years, due to the high risk of progression, radical cystectomy may be considered in specific cases. Although radical cystectomy is still the best approach for high-grade NMIBC from an oncological perspective, its high morbidity and impact on quality of life motivate studies of new strategies that may reduce the need for cystectomy. We carried out a mini-review whose objectives were: 1 - to identify bladder-sparing alternatives that are being studied as possible treatment for patients with intermediate and high-risk NMIBC; 2 - understand the evidence that exists regarding success rate, follow-up, and side effects of different strategies. Several studies have sought alternatives for bladder preservation, including immunotherapy, intravesical chemotherapy, chemo-hyperthermia, antibody-drug conjugates, viral genetic therapy, and others with promising results. The selection of an optimal therapy for high-risk NMIBC that can reduce the need for cystectomy, with low toxicity and high efficacy, is of paramount importance and remains an issue, however, several known medications are being tested as bladder-preserving alternatives in this scenario and have shown promise in studies.

Abstract 6024: A novel carbonic anhydrase IX targeting radiopeptide, 64Cu-PD-32766 and 177Lu-PD-32766, exhibit promising theranostic potential in ccRCC tumors

Abstract Introduction: Carbonic Anhydrase IX (CA9) is a zinc metalloenzyme that regulates the pH for cell growth. CA9 is considered an attractive target and is upregulated in a variety of cancers, especially, in 95% of clear cell renal cell carcinoma (ccRCC) where there remains a large clinical unmet need despite the availability of several newly approved medicines. PeptiDream has identified PD-32766, a novel macrocyclic peptide, targeting CA9 and can be labeled with radionuclides such as copper (64Cu) and lutetium (177Lu), which enables tumor-specific PET bioimaging and radiotherapy. Here we report the theranostic translational feasibility of PD-32766 for ccRCC. Materials and Methods: PD-32766 was discovered using Peptide Discovery Platform System (PDPS), a proprietary screening system of PeptiDream. Binding affinity of PD-32766, 63Cu-PD-32766 and 175Lu-PD-32766 to CA9 was measured by SPR. For in vivo evaluation, we used a xenograft model in which VMRC-RCW (ccRCC cell line with similar CA9 expression level to clinical samples) was subcutaneously transplanted into nude mice. To assess biodistribution, 64Cu-PD-32766 or 177Lu-PD-32766 was dosed to VMRC-RCW xenograft mice, and the percentage of injected dose in tumors and major organs was quantified by cut and count method. To evaluate whether PET imaging can detect tumors, 64Cu-PD-32766 was dosed to VMRC-RCW xenograft mice and after dosing, PET scanning was performed. For therapeutic experiments, 177Lu-PD-32766 was dosed to VMRC-RCW xenograft mice and tumor volume was measured for 45 days after dosing. Results: SPR analysis revealed that PD-32766, 63Cu-PD-32766 and 175Lu-PD-32766 exhibits an affinity of less than 0.2 nM for CA9. In in vivo biodistribution experiment, 64Cu-PD-32766 and 177Lu-PD-32766 showed specific and strong accumulation in tumors 4 hours after dosing (88 and 107% ID/g, for 64Cu-PD-32766 and 177Lu-PD-32766, respectively) and were highly retained in the tumors at 48 hours after dosing (37 and 51% ID/g, for 64Cu-PD-32766 and 177Lu-PD-32766, respectively). Maximal intensity in other normal tissues were 23 and 9 %ID/g (tumor/kidney=3.8 and 11.9 for 64Cu-PD-32766 and 177Lu-PD-32766, respectively at 4 hrs.). PET bioimaging of 64Cu-PD-32766 clearly detected only tumors, consistent with the biodistribution data. In therapeutic experiments, 177Lu-PD-32766 (30 MBq/mouse single or QW x3) was well tolerated and strikingly improved mouse survival compared with control animals for 45 days after transplantation, which suggests a robust tumor growth inhibition of 177Lu-PD-32766 dosing. Taken together, PD-32766 showed specific tumor accumulation and strong therapeutic effect in a clinically relevant xenograft model of ccRCC. Conclusion: PD-32766 has preferable properties for imaging and therapy with radionuclides and a great potential for theranostic use in ccRCC. Citation Format: Yoshihide Mizukoshi, Shota Tsuchida, Hiroko Inaba, Tatsuro Kotake, Takanori Aoki, Kai Orihara, Yuichi Funase, Naoki Kanazawa, Hikaru Shimizu, Kaita Sawano, Kentaro Suzuki, Hayato Yanagida, Takeru Ehara, Hidetomo Kitamura, Satoshi Matsushima, Masato Murakami. A novel carbonic anhydrase IX targeting radiopeptide, 64Cu-PD-32766 and 177Lu-PD-32766, exhibit promising theranostic potential in ccRCC tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6024.

Abstract 1979: Preclinical characterization of NVL-330, a selective and brain penetrant HER2 tyrosine kinase inhibitor with broad activity on HER2 oncogenic alterations

Abstract Background: Oncogenic mutations and gene amplifications in the HER2 receptor tyrosine kinase are detected in approximately 2 - 4% and 1 - 5%, respectively, of non-small cell lung cancers (NSCLC) in the US. Exon 20 insertion mutations (exon20ins) are the predominant HER2 mutations in NSCLC, and ~50% of HER2-mutant metastatic NSCLC patients develop brain metastases. The antibody drug conjugate trastuzumab deruxtecan (T-DXd) has received FDA accelerated approval for HER2-mutant NSCLC, but currently there are no approved tyrosine kinase inhibitors (TKIs) for this indication. NVL-330 is a novel, brain-penetrant, HER2-selective TKI, designed to address the combined medical need of treating HER2-mutant tumors, avoiding treatment related adverse events due to off-target inhibition of wild-type EGFR, and treating brain metastases. Here we characterized the preclinical pharmacological profile of NVL-330 in comparison to other investigational HER2-targeting TKIs and T-DXd. Methods: TKIs were profiled in cellular phospho-HER2, phospho-EGFR, and viability assays. In vivo antitumor studies were performed in nude mice with HER2-altered subcutaneous or intracranial tumors. T-DXd concentration was measured in an ELISA assay. The unbound brain-to-plasma partitioning ratio (Κp,uu) was determined at one hour after oral 10 mg/kg dosing in Wistar Han rats. Results: NVL-330 broadly inhibited HER2 oncogenic alterations, including amplified wild-type HER2, HER2 exon20ins and non-exon20ins mutants, with potency and selectivity over wild-type EGFR comparable to investigational HER2-selective TKI zongertinib. By contrast, NVL-330 had a higher Kp,uu than zongertinib in rats. In a patient-derived xenograft model harboring HER2 exon20ins, treatment with NVL-330 suppressed phospho-HER2 and downstream signaling, increased total HER2 and caused dose-dependent tumor regression at well tolerated doses. In the HER2amp NCI-N87 subcutaneous xenograft model, oral administration of 30 mg/kg NVL-330 twice per day induced tumor regression, similar to that achieved by intravenous administration of 10 mg/kg T-DXd once every three weeks, a human-relevant dose in mice. By comparison, in the intracranial setting with the same tumor model and dosing regimens, NVL-330 induced tumor regression, whereas T-DXd provided tumor stasis. Pharmacokinetic analysis in these intracranial tumor bearing mice indicated that NVL-330 had significantly higher brain penetrance than T-DXd. Conclusions: NVL-330 was broadly and selectively active against HER2 oncogenic alterations in vitro and in vivo, and demonstrated brain penetrance in rodents exceeding that of HER2 investigational TKI zongertinib and T-DXd. This preclinical profile supports the potential for NVL-330 to address a medical need for patients with HER2-driven cancers, including those with brain metastases. Citation Format: Yuting Sun, Kristin L. Andrews, Anupong Tangpeerachaikul, Tuan M. Nguyen, Baudouin Gerard, Nancy E. Kohl, Joshua C. Horan, Henry E. Pelish. Preclinical characterization of NVL-330, a selective and brain penetrant HER2 tyrosine kinase inhibitor with broad activity on HER2 oncogenic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1979.

Heart and Lung Dose as Predictors of Overall Survival in Patients With Locally Advanced Lung Cancer. A National Multicenter Study

IntroductionIt is an ongoing debate how much lung and heart irradiation impact overall survival (OS) after definitive radiotherapy for lung cancer. This study uses a large national cohort of patients with locally advanced NSCLC to investigate the association between OS and irradiation of lung and heart. MethodsTreatment plans were acquired from six Danish radiotherapy centers, and patient characteristics were obtained from national registries. A hybrid segmentation tool automatically delineated the heart and substructures. Dose-volume histograms for all structures were extracted and analyzed using principal component analyses (PCAs). Parameter selection for a multivariable Cox model for OS prediction was performed using cross-validation based on bootstrapping. ResultsThe population consisted of 644 patients with a median survival of 26 months (95% confidence interval [CI]: 24–29). The cross-validation selected two PCA variables to be included in the multivariable model. PCA1 represented irradiation of the heart and affected OS negatively (hazard ratio, 1.14; 95% CI: 1.04–1.26). PCA2 characterized the left-right balance (right atrium and left ventricle) irradiation, showing better survival for tumors near the right side (hazard ratio, 0.92; 95% CI: 0.84–1.00). Besides the two PCA variables, the multivariable model included age, sex, body-mass index, performance status, tumor dose, and tumor volume. ConclusionsBesides the classic noncardiac risk factors, lung and heart doses had a negative impact on survival, while it is suggested that the left side of the heart is a more radiation dose–sensitive region. The data indicate that overall heart irradiation should be reduced to improve the OS if possible.