High-dose Radiotherapy Research Articles

Higher radiation doses after partial laryngectomy may raise the incidence of pneumonia: A retrospective cohort study.

Currently, studies have shown that a high dose of radiotherapy to the throat have various harmful and adverse effects on the patients' laryngeal function, resulting in the development of pneumonia. This study aimed to explore how radiotherapy dose affected the probability of pneumonia following laryngeal cancer surgery. A retrospective analysis was done on patients diagnosed with laryngeal cancer between 2010 and 2020 and were treated surgically and with postoperative radiotherapy in the same institution. This study included 108 patients in total, 51 of who were in the low-dose group and 57 of whom were in the high-dose group. Age, gender, the location of laryngeal cancer, the presence or absence of lymph node metastasis, and other demographic and clinical characteristics were collected, and the prevalence of postoperative pneumonia was compared between the two groups. The total prevalence of postoperative pneumonia was 59.3%, but there was a significant difference between the two groups(high-dose group 71.9% VS low-dose group 45.1%; p=0.005). A total of 9.3% (10/108) of the patients had readmission due to severe pneumonia, and the rate of readmission due to pneumonia was significantly different between the two groups (high-dose group 15.8% VS low-dose group 2.0%, p=0.032). Additionally, the high-dose group's prevalence of Dysphagia was significantly higher than the low-dose group's. According to multivariate logistic modeling, high-dose radiation was a risk factor for pneumonia (OR=4.224, 95%CI =1.603-11.131, p=0.004). Pneumonia risk could increase with radiotherapy doses > 50 Gy in the treatment of laryngeal cancer. Therefore, we recommend that when the radiation dose surpasses 50Gy, doctors should pay particular attention to the lung health of patients with laryngeal cancer.

Linear-quadratic model in the description of the mechanisms of high-dose radiation therapy

Литературный обзор посвящен основным проблемам радиобиологии, определяющей основы лучевой терапии, описывающей реакции нормальных и патологических тканей на облучение и их механизмы. Внедрение различных вариантов гипофракционирования, высокодозного облучения, в том числе стереотаксической лучевой терапии и радиохирургии показало, что радиобиология опухолей и нормальных тканей при использовании этих методов не соответствует традиционным представлениям, характерным для классического фракционирования, а 4R/5R концепции радиобиологии и традиционная линейно-квадратичная модель не могут адекватно объяснить возникающие эффекты. Для устранения несоответствия биологически эффективных доз непрерывно предпринимаются попытки модифицировать линейно-квадратичную модель, однако пока ни одна из них не смогла обеспечить точную оценку выживаемости клеток в диапазоне высоких доз. Кривые выживаемости клеток значимо отклоняются от прогноза, что во многом связано с радиационно-индуцированными повреждениями эндотелия сосудов и активацией иммунных процессов. Модифицированные линейно-квадратичные модели нуждаются в дальнейшей проверке, и их следует с осторожностью использовать в клинической практике, совместно с инструментами QUANTEC. Основные понятия радиобиологии можно свести к нескольким взаимосвязанным моделям: линейно-квадратичной, сосудистой, иммунной и немишенной. Назрела необходимость создания единой комплексной модели, объединяющий предыдущие.

Advanced stage cutaneous T-cell lymphoma treated with high-dose external beam radiation therapy: A case report.

The treatment for advanced-stage or refractory cutaneous T-cell lymphoma (CTCL) is largely palliative. Due to the rarity of the disease, there are few randomized controlled trials and large-scale prospective studies. Therefore, the treatment of advanced-stage CTCL remains challenging. A 64-years-old man who had received narrowband UVB phototherapy for several years presented with a generalized rash with widespread polycyclic erosions and painful ulcers on his hands and feet. We restaged him as stage III CTCL. He was treated with high-dose radiation for curative purposes and 3-dimensional conformal radiation therapy to both hands and feet. At the 2-year follow-up after the end of radiotherapy, the irradiated skin had recovered to normal soft, smooth skin with localized fibrosis and hypopigmented skin. He reported an excellent quality of life, and his hands and feet were free to move. CTCL at an advanced stage could require dose escalation with local radiotherapy for curative purposes. High-dose 3-dementional conformal radiation therapy could be effective and has tolerable toxicities.

Dose-response relationship in patients with newly diagnosed atypical meningioma treated with adjuvant radiotherapy.

This study aimed to identify the radiation dose-response relationship in patients with newly diagnosed atypical meningioma (AM) treated with adjuvant radiotherapy (ART) using conventional fractionation. In total, 158 patients who underwent surgery and ART between 1998 and 2018 were reviewed. Among these patients, 135 with complete information on radiotherapy (RT) dose/fractionation and pathological reports were analyzed. We entered RT dose as a continuous variable into the Cox regression model using penalized spline to allow for a nonlinear relationship between RT dose and events. Local control (LC), progression-free survival (PFS), and overall survival (OS) were evaluated. The corresponding biological equivalent dose in 2Gy fractions (EQD2) was calculated using an α/β ratio of 4Gy. The median follow-up duration was 56.0months. The median ART dose delivered was 61.2Gy in 24-34 daily fractions, corresponding to a median EQD2 of 59.16Gy. In multivariate analysis, larger size and higher mitotic count were associated with significantly reduced LC (P < 0.001 and P = 0.002, respectively), PFS (P < 0.001 and P = 0.006, respectively), and OS (P = 0.006 and P = 0.001, respectively). Meanwhile, a higher RT dose was significantly associated with improved LC, PFS, and OS. Moreover, RT showed a dose-dependent effect on LC, PFS, and OS; local failure, tumor progression, and death were reduced by 12%, 12%, and 16%, respectively, per 1Gy increase in the dose (EQD2). The dose of ART in AM has a dose-response relationship with LC and survival outcomes.

Consolidative high-dose thoracic radiotherapy for limited metastatic nonsmall cell lung cancer: Focusing on oligo-progressive disease.

Prior clinical data have shown a significant survival benefit of consolidative local radiotherapy for patients with limited metastatic non-small cell lung cancer (NSCLC). Therefore, this study aimed to evaluate the impact of consolidative high-dose thoracic radiotherapy on local control rates and survivals in patients with limited metastatic NSCLC, especially focusing on oligo-progressive disease. We retrospectively reviewed the medical records of 45 patients with limited metastatic NSCLC who received consolidative high-dose thoracic radiotherapy at the Korea University Guro Hospital between March 2015 and December 2020. In the current study, we included patients who showed partial response, stable disease, or oligo-progressive disease on tumor response evaluation after systemic treatment. All patients underwent stereotactic body radiation therapy (23 patients) or intensity-modulated radiation therapy (IMRT, 22 patients). The median follow-up time was 42 months (range: 5-88 months). The overall 2-year disease-free survival (DFS) and overall survival (OS) rates were 80.7% and 88.4%, respectively. Among the 45 patients, only two patients treated with IMRT showed in-field local recurrence. There was no local failure among the patients who showed oligo-progressive disease after systemic treatment. In addition, the response to systemic treatment was not a significant factor for either DFS or OS rates (p=.471 and p=.414, respectively) in univariate analysis. Consolidative high-dose thoracic radiotherapy improves local control rates and helps achieve long-term survival in patients with limited metastatic NSCLC. It is also effective and should be considered in patients with oligo-progressive disease after systemic treatment.

Patterns of failure for hypopharynx cancer patients treated with limited high-dose radiotherapy treatment volumes.

Optimal radiotherapy treatment volumes for patients with locally advanced hypopharynx squamous cell carcinoma should ensure maximal tumor coverage with minimal inclusion of normal surrounding structures. Here we evaluated the effectiveness of a direct 3-mm high-dose gross tumor volume to planning target volume expansion on clinical outcomes for hypopharynx cancers. We performed a retrospective analysis of patients with hypopharynx carcinoma treated between 2004 and 2018 with primary radiotherapy using a direct high-dose gross tumor volume to planning target volume expansion and with or without concurrent systemic therapy. Diagnostic imaging of recurrences was co-registered with the planning CT. Spatial and volumetric analyses of contoured recurrences were compared with planned isodose lines. Failures were initially defined as in field, marginal, elective nodal, and out of field. Each failure was further classified as central high-dose, peripheral high-dose, central intermediate/low-dose, peripheral intermediate/low-dose, and extraneous. Clinical outcomes were analyzed by Kaplan-Meier estimation. Thirty-six patients were identified. At a median follow-up at 52.4 months, estimated 5-year overall survival was 59.3% (95% confidence interval [CI], 36.3%-74.1%), 5-year local and nodal control was 71.7% (95% CI, 47.1%-86.3%) and 69.9% (95% CI, 57.0%-82.6%), respectively. The most common failure was in the high-dose primary target volume. The gastrostomy tube retention rate at 1 year among patients without recurrence was 13.0% (95% CI, 3.2%-29.7%). Minimal high-dose target volume expansions for hypopharynx cancers were associated with favorable locoregional control. This approach may enable therapy intensification to improve clinical outcomes.

Is iodine-125 seed strand brachytherapy suitable for ureteral carcinoma?

Long-term conventional high-dose radiation therapy can lead to retroperitoneal fibrosis and nerve damage in patients with advanced ureteral carcinoma (UC). The purpose of this study is to evaluate the safety and efficacy of nephrostomy combined with iodine-125 seed strand (ISS) brachytherapy for the treatment of UC. Twenty-one patients with UC were treated with nephrostomy combined with ISS brachytherapy. The following parameters were recorded: technical success rate, procedure time, complications, mean D90 (dose delivered to the 90% gross tumor volume), organ at risk (OAR) dose, local control rate (LCR), ureteral patency (UP), local tumor progression (LTP), and overall survival (OS). The hydronephrosis score (HS), visual analog score (VAS), Karnofsky score and maximum diameter (MD) were compared before and 8 weeks after the operation. The technical success rate was 100%, with a mean procedure time of 54.6 min. Three cases (14.5%) had bladder implant metastasis but no other major complications, such as ureteral perforation, infection, or severe bleeding, occurred. The mean D90 and OAR doses were 50.7 and 3.8 Gy, respectively. LCR was 100% with 28.6% UP at the 8-week evaluation. During the mean follow-up of 16.6 months, LTP occurred in 4 cases (19.1%), and the median OS was 25.0 months (95% CI 21.3-28.5). The HS, VAS, Karnofsky score and MD showed significant changes (all P < 0.01). UC can be safely and effectively treated by nephrostomy combined with ISS brachytherapy, a viable option for patients who cannot undergo or refuse surgical resection.

Oncology

The December 2022 Oncology Roundup360 looks at: Is high-dose radiation therapy associated with early revision with a cemented endoprosthesis?; Neoadjuvant chemotherapy and endoprosthetic reconstruction for lower extremity sarcomas: does timing impact complication rates?; Late amputation after treatment for lower extremity sarcoma; Osteosarcoma prediagnosed as another tumour: a report from the Cooperative Osteosarcoma Study Group; The influence of site on the incidence and diagnosis of solitary central cartilage tumours of the femur: a 21st century perspective.

High-dose extended-field radiotherapy plus chemotherapy improved survival in extranodal NK/T-cell lymphoma in a real-life setting: results from the multicenter T-Cell Brazil Project

Extranodal natural-killer/T-cell lymphoma (ENKTL) is a rare and aggressive Epstein-Barr virus related mature T-cell and natural-killer malignancy. Although highly prevalent in South America, few studies covering data from this geographic location have been published. Therefore, this study aims to report clinical characteristics, prognostic factors, and outcomes in a multicenter cohort of ENKTL patients from Brazil. This retrospective, observational and multicenter study included 98 ENKTL patients treated during two decades in Brazil. Data were extracted from the T-Cell Brazil Project database. In our cohort, 59/98 patients (60.2%) were male, with a median age of 50 years. Sixty-two patients (63.3%) had B-symptoms, 26/98 (26.5%) had Eastern Cooperative Oncology Group scale ≥ 2; 16/98 (16.3%) presented extranasal disease and 34.7% (34/98) were advanced-stage (Ann Arbor/Cotswolds III/IV). The median follow-up for the whole cohort was 49 months, with an estimated 2-year overall survival (OS) and progression-free survival (PFS) of 51.1% and 17.7%, respectively. In early-stage disease (IE/IIE), the median OS was 21.8 months for patients treated with concurrent radiotherapy plus chemotherapy (CCRT-VIPD [etoposide/vp-16, ifosfamide, cisplatin and dexamethasone), 16.2 months for sequential chemoradiotherapy (SCRT) followed by asparaginase-based regimens, and 56.7 months for SCRT followed by CHOP-like (cyclophosphamide, doxorrubicin, vincristine and prednisone) treatments, p = 0.211. CCRT was associated with higher rates of early-mortality, hematological toxicity, and mucositis. Median OS was 8.2 months for patients with advanced-stage disease receiving regimens containing asparaginase compared to 3.2 months for anthracycline-based therapy, p = 0.851. Chemo-radiotherapy (CRT) regimens demonstrated better OS (p = 0.001) and PFS (p = 0.007) than chemotherapy alone. Multivariate analysis revealed anemia, relapsed/refractory (R/R) disease and radiotherapy omission as poor outcome predictors for OS. Lymphopenia and radiotherapy omission adversely affected PFS. Concerning progression of disease within 24-months (POD-24), clinical stage III/IV was a poor outcome predictor. In this real-life Brazilian cohort, ENKTL presented dismal outcomes. Radiation therapy was an independent factor for increased OS and PFS, but CCRT regimens were associated with higher toxicities. Polychemotherapy based on anti-multi drug resistant agents was not associated with survival benefit in either early or advanced-stage disease in our patient cohort.

Radiation-induced soft tissue sarcoma of the neck after radiation therapy for Hodgkin's lymphoma: a clinical case

Background. Radiation-induced malignancies are one of the long-term complications of radiation therapy, which is widely used to treat some tumors. The latency period before a second tumor develops varies from 3 to 60 years. Epithelial tumors and hemoblastoses occur after low-dose radiation therapy and sarcomas after high-dose radiation therapy.&#x0D; Aim. To present a case of radiation-induced soft tissue angiosarcoma of the neck after the cure of Hodgkin's disease.&#x0D; Materials and methods. A 41-year-old patient with Hodgkin's nodular lymphoma with the lymphoid predominance of stage IIIA with involvement of the right cervical and clavicular lymph nodes, mediastinum, and abdominal lymph nodes was followed-up. In 2004 the patient underwent four cycles of polychemotherapy per ABVD regimen followed by radiotherapy of the right cervical and clavicular lymph nodes and mediastinum, with a total focal dose of 40 Gy.&#x0D; Results. Seventeen years after the treatment for Hodgkin's disease, including radiation therapy, the patient presented with painful swelling of the neck soft tissues in the radiation area with the transition to the anterior thoracic wall and an enlarged cervical lymph node. A lymph node dissection was performed. According to the combined positron emission tomography and X-ray computed tomography (PET/CT), histological and immunohistochemical studies, epithelioid angiosarcoma of soft tissues of the neck and thoracic wall stage IV cT2N1M1G3 with metastases to the skeleton bones, neck lymph nodes, left adrenal gland was established. Surgical treatment was not performed due to advanced disease. The patient received six cycles of polychemotherapy with doxorubicin + ifosfamide. PET/CT confirmed partial tumor regression.&#x0D; Conclusion. Radiation-induced soft tissue sarcoma is a late iatrogenic complication of radiation therapy for Hodgkin's lymphoma. The tumor occurred in the radiation area. PET/CT is the method of choice in diagnosing and evaluating the extent of cancer and response to treatment. Chemotherapy, as an option for complex treatment, can achieve adequate disease control when surgery is not feasible.

CArdiac and REspiratory adaptive Computed Tomography (CARE-CT): a proof-of-concept digital phantom study

Current respiratory 4DCT imaging for high-dose rate thoracic radiotherapy treatments are negatively affected by the complex interaction of cardiac and respiratory motion. We propose an imaging method to reduce artifacts caused by thoracic motion, CArdiac and REspiratory adaptive CT (CARE-CT), that monitors respiratory motion and ECG signals in real-time, triggering CT acquisition during combined cardiac and respiratory bins. Using a digital phantom, conventional 4DCT and CARE-CT acquisitions for nineteen patient-measured physiological traces were simulated. Ten respiratory bins were acquired for conventional 4DCT scans and ten respiratory bins during cardiac diastole were acquired for CARE-CT scans. Image artifacts were quantified for 10 common thoracic organs at risk (OAR) substructures using the differential normalized cross correlation between axial slices (ΔNCC), mean squared error (MSE) and sensitivity. For all images, on average, CARE-CT improved the ΔNCC for 18/19 and the MSE and sensitivity for all patient traces. The ΔNCC was reduced for all cardiac OARs (mean reduction 21%). The MSE was reduced for all OARs (mean reduction 36%). In the digital phantom study, the average scan time was increased from 1.8 ± 0.4 min to 7.5 ± 2.2 min with a reduction in average beam on time from 98 ± 28 s to 45 s using CARE-CT compared to conventional 4DCT. The proof-of-concept study indicates the potential for CARE-CT to image the thorax in real-time during the cardiac and respiratory cycle simultaneously, to reduce image artifacts for common thoracic OARs.

High vs. low radiotherapy dose in locally advanced esophageal squamous cell carcinoma patients treated with neoadjuvant concurrent chemoradiotherapy: an endemic area population-based study

BackgroundThe optimal radiotherapy dose for locally advanced esophageal squamous cell carcinoma in endemic areas treated with neoadjuvant concurrent chemoradiotherapy is unclear.MethodsEligible patients diagnosed between 2010 and 2019 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders. The hazard ratio (HR) of death was compared between high dose (50–50.4 Gy) and low dose (40–41.4 Gy) radiotherapy. We also evaluated other outcomes and performed supplementary analyses via an alternative approach.ResultsOur study population consisted of 644 patients. The PS weight-adjusted HR of death was 0.92 (95% confidence interval: 0.7–1.19, p = 0.51). There were no statistically significant differences for other outcomes or supplementary analyses.ConclusionsIn this population-based study from an endemic area, we found no significant difference in overall survival between high vs. low radiotherapy doses.

Isotoxic High-Dose Stereotactic Body Radiotherapy (iHD-SBRT) Versus Conventional Chemoradiotherapy for Localized Pancreatic Cancer: A Single Cancer Center Evaluation.

Given the lack of direct comparative evidence, we aimed to compare the oncological outcomes of localized pancreatic ductal adenocarcinoma (PDAC) treated in the same tertiary cancer center with isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT) or conventional chemoradiotherapy (CRT). Biopsy-proven borderline/locally advanced patients treated with iHD-SBRT (35 Gy in 5 fractions with a simultaneous integrated boost up to 53 Gy) or CRT (45-60 Gy in 25-30 fractions) were retrospectively included from January 2006 to January 2021. The median overall survival (mOS) was evaluated trough uni- and multivariate analyses. The progression free survival (PFS) and the 1-year local control (1-yLC) were also reported. Eighty-two patients were included. The median follow-up was 19.7 months. The mOS was in favour of the iHD-SBRT group (22.5 vs. 15.9 months, p &lt; 0.001), including after multivariate analysis (HR 0.39 [CI95% 0.18-0.83], p = 0.014). The median PFS and the 1-yLC were also significantly better for iHD-SBRT (median PFS: 16.7 vs. 11.5 months, p = 0.011; 1-yLC: 75.8 vs. 39.3%, p = 0.004). In conclusion, iHD-SBRT is a promising RT option and may offer an improvement in OS in comparison to CRT for localized PDAC. Further validation is required to confirm the exact role of iHD-SBRT and the optimal therapeutic sequence for the treatment of localized PDAC.

Gadolinium-Bisphosphonate Nanoparticle-Based Low-Dose Radioimmunotherapy for Osteosarcoma.

Osteosarcoma is a malignant osteogenic tumor with a high metastatic rate commonly occurring in adolescents. Although radiotherapy is applied to treat unresectable osteosarcoma with radiation resistance, a high dose of radiotherapy is required, which may weaken the immune microenvironment. Therefore, there is an urgent need to develop novel agents to maximize the radiotherapeutic effects by eliciting immune activation effects. In this study, we synthesized therapeutic gadolinium-based metal-bisphosphonate nanoparticles (NPs) for osteosarcoma treatment that can be combined with radiotherapy. The gadolinium ion (Gd) was chelated with zoledronic acid (Zol), a commonly used drug to prevent/treat osteoporosis or bone metastases from advanced cancers, and stabilized by ovalbumin (OVA) to produce OVA-GdZol NPs. OVA-GdZol NPs were internalized into K7M2 osteosarcoma cells, showing a high sensitization effect under X-ray irradiation. Cell pretreatment of OVA-GdZol NPs significantly enhanced the radiation therapeutic effect in vitro by reducing the cell colonies and increased the signal of γH2AX-positive cells. More importantly, OVA-GdZol NPs promoted the maturation of bone marrow-derived dendritic cells (BMDCs) and M1 polarization of macrophages. The inhibitory effect on K7M2 osteosarcoma of OVA-GdZol NPs and X-ray radiation was evident, indicated by a significantly reduced tumor volume, high survival rate, and decreased lung metastasis. Meanwhile, both innate and adaptive immune systems were activated to exert a strong antitumor effect. The above results highly suggest that OVA-GdZol NPs serve as both radiosensitizers and immune adjuvants, suitable for the sequential combination of vaccination and radiotherapy.

Study of radiation enteritis in cervical cancer patients treated with definitive radiotherapy and adjuvant radiotherapy – A prospective study

The third most frequent type of cancer in the world is cervical cancer. Traditionally cervical cancer treatment is carried by either Radiation therapy alone and/or with chemotherapy. High doses of Radiation therapy can cause gastric enteritis. To study the incidence of radiation enteritis in cervical cancer patients of stage upto IIIA. A total of 94 patients receiving radiation therapy (RT) for cervical cancer treatment were enrolled for the study in our hospital from August 2018 to January 2020. The 94 patients were divided into definitive RT group (64 patients) and Adjuvant RT group (30 patients). The incidences of radiation enteritis were evaluated statistically.In all cervical cancer patients, early radiation enteritis (RE) observed in 68.08%, and late radiation enteritis observed in 21.1%. Patients treated with definitive RT showed more frequent radiation enteritis than in adjuvant RT. In the group treated with definitive RT, the occurrence of early (RE) is more in the Radical radiotherapy group (RRT), whereas late RE appeared more with concurrent chemoradiotherapy (CCRT) group. The late (RE) severe cases (Grade 3,4) observed more with the definitive RT group (only RRT) than in the adjuvant RT group. In the Definitive RT group, early and late RE occurrence is more than the Adjuvant RT group. The incidence of enteritis was correlated with the lengthening of total irradiation time. Methods to reduce small bowel intervention in RT and volume of irradiation will further decrease enteritis morbidity.

EXTH-84. A NOVEL DUAL-SPECIFIC CHIMERIC ANTIGEN RECEPTOR T CELL WITH HIGH SPECIFICITY FOR EGFR AND EGFRVIII IMPROVES SURVIVAL IN EGFR EXPRESSING MEDULLOBLASTOMA

Abstract BACKGROUND Medulloblastoma is the most common malignant brain tumor in children 0-19 years of age and current treatment requires surgical resection, followed by high dose chemotherapy and radiotherapy. Therapy carries high morbidity, with late effects including neurocognitive decline, endocrine dysfunction, and subsequent malignancies. Chimeric antigen receptor (CAR) T cell therapy presents the potential for less toxic and more effective treatment for medulloblastoma. Epidermal growth factor (EGFR) is expressed in medulloblastoma derived cell lines and appears to serve an important role in the metastatic potential of this tumor type. D2C7 is a recombinant monoclonal antibody short chain variable fragment (scFv) with dual specificity, binding to wild type EGFR (EGFRwt) and its mutant EGFR variant III (EGFRvIII). We previously developed a novel, third-generation chimeric antigen receptor T-cell construct utilizing the D2C7 scFv and performed analysis on both glioblastoma and medulloblastoma tumor models. METHODS U87 and U87vIII glioblastoma and DAOY medulloblastoma cell lines were characterized by flow cytometry to evaluate for EGFRwt and EGFRvIII expression. Cytotoxicity assays were performed utilizing flow cytometry on serially diluted effector: target ratios of U87, U87vII, and DAOY mixed with D2C7 CAR. DAOY was orthotopically implanted into the frontal lobe of NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. After tumor implantation, D2C7 CAR was introduced within the tumor bed. RESULTS EGFR was detected in U87, U87vIII, and DAOY on flow analysis. EGFRvIII was expressed only on U87vIII. D2C7 CAR demonstrated effective in vitro cytotoxicity against all three cell lines with &amp;gt;90% cytotoxicity achieved at an effector: target ratio of 2.5:1. In vivo, D2C7 CAR treatment significantly prolonged survival compared to treatment with mock CAR. CONCLUSION D2C7 CAR demonstrates efficacy in vitro and in mouse models of medulloblastoma and glioblastoma. Future steps in our work will set out to assess the D2C7 CAR in NSG mice with DAOY in the posterior fossa.

Definitive High-Dose Radiotherapy for Primary Vulvar Cancer: The DRIVE Multicenter Cohort Study

<h3>Purpose/Objective(s)</h3> There is limited published data on definitive chemoradiation therapy for vulvar cancer. A retrospective multi-institutional cohort study was conducted to determine the efficacy, patterns of failure and long-term toxicity of high-dose radiation therapy (RT) for the primary treatment of vulvar carcinoma. <h3>Materials/Methods</h3> DRIVE (definitive radiation therapy for primary vulvar cancer) is a multicenter cohort study evaluating outcome for definitive high-dose conformal RT (dRT) for first line treatment of vulvar cancer. Treatment compliance, toxicity and patterns of failure were investigated. Actuarial locoregional control (LRC) and survival (OS) were estimated using Kaplan-Meier method and compared using log rank test. Herein, we present our preliminary results. <h3>Results</h3> In total, 48 patients [median (interquartile range) age, 57 (46-67) years] who received dRT between 2010 and 2020 were analyzed. Median follow-up was 28 (2–113) months. Cohort included 15 (31%) with stage I-II, and 33 (69%) patients with stage III-IV disease. Inguinal nodes alone were involved in 13 patients (27%); 19 (40%) had inguinal and/or pelvic node metastases. Elective surgical staging of groins was performed in 16 (33%) patients, of whom 7 had involved nodes. Intensity-modulated RT (IMRT) was used in 45 (94%) patients, and 3 (6%) received 3D-conformal RT. Median tumor dose was 64Gy (52-74.8Gy). Concurrent platinum-based chemotherapy was administered in 40 (83%) patients (1-8 cycles). Clinical complete response (CR) was achieved in 81.3% (39/48) patients at the primary site, and 84% (27/32) at involved nodes. Eight (16.7%) patients had persistent/recurrent disease following treatment, all within treatment volume; 5 (10%) patients developed distant metastasis. Actuarial 2 and 5-year LRC was 77.7% and 73%, respectively. Two and 5-year overall survival were 71% and 55%, respectively. On univariate analysis, determinants of inferior LRC were stage III/IV (p=0.04), non-IMRT technique (p=0.05) and <2 cycles of chemo (p=0.03). Treatment compliance included 90% (43 patients) completing planned treatment, 11/48 (23%) hospitalization, 6/48 (12.5%) blood transfusion, 12/48 (25%) with >5 days interruptions and median weight loss of 2.6Kg during RT. Of 40 evaluable patients, 25 (63%) developed significant vaginal stenosis. Vulvar necrosis was observed in 5 (10%) patients, all received ≥64Gy [2 treated with hyperbaric oxygen, 1 had musculocutaneous flap-reconstruction]. No acute/chronic grade 3 GI or GU toxicity, or any grade 5 toxicities were seen. <h3>Conclusion</h3> Definitive high-dose RT for vulvar cancer achieves high rates of local control, good compliance with acceptable dose dependent long-term toxicity. Use of IMRT does not result in increased geographic miss and was associated with improved locoregional control over existing prospective data from GOG 205 study.

Selective Agonism of Intermediate-Affinity IL-2 Receptor Promotes Systemic Antitumor Responses in Combination with Radiotherapy in Metastatic Lung Cancer

<h3>Purpose/Objective(s)</h3> For immune checkpoint inhibitor-resistant patients, adding interleukin-2 (IL-2) may aid antitumor responses by stimulating effector T cells and NK cells. Unfortunately, high-dose IL-2 therapy has limited clinical utility due to adverse events and stimulation of immunosuppressive regulatory T cells (T_regs). Nemvaleukin alfa (nemvaleukin) is a novel engineered cytokine that selectively binds to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8⁺ T and NK cells, with minimal expansion of T_regs. Thus, Nemvaleukin may be beneficial in combination with radiation therapy (RT) and immunotherapy. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462 (the murine ortholog of Nemvaleukin, a.k.a. mNemvaleukin), RT, and immunotherapy in multiple mouse tumor models. <h3>Materials/Methods</h3> In a bilateral 344SQ lung adenocarcinoma murine model, primary tumors were treated with high-dose RT (HDRT; 12 Gy per fraction for 3 fractions), and secondary tumors were observed for evidence of abscopal effects. In another model for low absolute lymphocyte count (ALC), we used 2 Gy total body irradiation (TBI) three days before HDRT and RDB 1462. In a third MC38-gp100 mouse model, tumors were irradiated with low-dose RT (LDRT; 3 fractions of 1 Gy each) followed by pmel-1 T cell infusion after 24 hours, and RDB 1462 administration 12 hours thereafter. We performed immune phenotyping by flow cytometry; analyzed 770 immune-related genes using a multiplex analysis platform; also performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit. <h3>Results</h3> In 344SQ-parental lung adenocarcinoma, we combined HDRT with escalating doses of RDB 1462 at various timepoints, resulting in significant tumor reduction in both irradiated and unirradiated (abscopal) tumors compared with HDRT or RDB 1462 therapy alone. HDRT+RDB 1462 increased the numbers and activity of tumor-specific CD8⁺ T cells, NK cells, and memory T cells without drastically increasing T_regs, as evidenced by peripheral and tumor-infiltrating immune phenotypic and functional analyses. T cells showed increased receptor clonality and diversity in groups receiving HDRT+RDB 1462. The addition of anti-PD-1 to HDRT+RDB 1462 further increased antitumor control of both irradiated and abscopal tumors, reduced lung metastases, and prolonged survival. The antitumor effects of HDRT and RDB 1462 persisted even in mice with low ALC. The addition of LDRT contributed to increased tumor-specific T cells that were expanded by RDB 1462 with increased infiltration of Thy1.1⁺ CD8⁺ T cells. <h3>Conclusion</h3> The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD-1 or adoptive T cell therapy.

Validation of an Image Based Deep Neural Network Model for Individualized Radiotherapy in Lung Malignancies

<h3>Purpose/Objective(s)</h3> The current standard of thoracic stereotactic body radiotherapy (SBRT) relies on varied dose prescriptions and is not currently guided by individual tumor features. A deep neural network (DNN) was previously developed that queries thoracic computer tomography (CT)-derived feature space and identifies radiation sensitivity parameters. The DNN can predict treatment failure and provide predictive information for individualization of radiotherapy (RT) dose within a single institution. In this study, the internally tested DNN was applied to an external validation set across distinct systems with the hypothesis that deep learning (DL) scores would continue to predict local failure with a higher C-index than standard radiomic or clinical features. <h3>Materials/Methods</h3> Two distinct cohort-based registries from disparate health systems were used to identify 849 internal and 271 external patients with cancer in the thorax and who were treated with high dose RT using SBRT. Pre-therapy lung CT images from the internal cohort were input to a multi-task DNN to generate an image fingerprint with the primary objective of predicting time to event local treatment outcomes. These findings were subsequently tested in the external cohort. DL scores from each patient were combined with clinical variables to provide an individualized dose for RT that projects a treatment failure probability of <5% at 24 months. <h3>Results</h3> External and internal study populations were significantly different in baseline characteristics, permitting an assessment of model transportability. These included patient demographics, use of motion control, CT scanner model, stage of disease, histology, tumor axial diameter, and dose received (p<0.001). In the external study cohort, radiation treatments in patients with high deep learning scores failed at a significantly higher rate than in those with low scores. The 3-year cumulative incidences of local failure were 25.1% (95% CI: 17.6-33.2) and 10.2% (95% CI: 5.5-16.6), respectively. DL scores independently predicted local failure (hazard ratio 2.16, 95% CI: 1.05-4.44, p = 0.04). A multivariable model that included DL score and cancer types predicted treatment failures with a C-index of 0.71 (95% CI: 0.64-0.76), a significant improvement (<i>p</i> = <0.001) compared to 3D volume and cancer type (C-index: 0.69 [95% CI: 0.63-0.75]). External study patients with recommended RT doses less than or equal to the actual delivered dose had 3-year cumulative incidence of local failure of 0%. Greater discordance between the recommended dose and delivered dose (differences >0 Gy) was associated with higher rates of local failure (<i>p</i> = <0.0001). <h3>Conclusion</h3> The DNN accurately predicted treatment failures from pretreatment CT-images across two distinct clinical settings. Results indicate that our image based DNN can be successfully implemented across other appropriately related populations and provide a robust dose guidance framework for individualized RT in prospective clinical studies.

The role of radiation therapy in the treatment of spine metastases from hepatocellular carcinoma: a systematic review and meta-analysis.

Spine hepatocellular carcinoma (HCC) metastases severely worsen quality of life and prognosis, with the role of radiotherapy being controversial. The authors systematically reviewed the literature on radiotherapy for spine metastatic HCCs. The PubMed, Scopus, Web of Science, and Cochrane databases were searched according to the PRISMA guidelines to include studies of radiotherapy for spine metastatic HCCs. Outcomes, complications, and local control were analyzed with indirect random-effect meta-analyses. The authors included 12 studies comprising 713 patients. The median time interval from diagnosis of HCC to spine metastases was 12 months (range 0-105 months). Most lesions were thoracic (35.9%) or lumbar (24.7%). Radiotherapy was delivered with conventional external-beam (67.3%) or stereotactic (31.7%) techniques. The median dose was 30.3 Gy (range 12.5-52 Gy) in a median of 5 fractions (range 1-20 fractions). The median biologically effective dose was 44.8 Gy10 (range 14.4-112.5 Gy10). Actuarial rates of postradiotherapy pain relief and radiological response were 87% (95% CI 84%-90%) and 70% (95% CI 65%-75%), respectively. Radiation-related adverse events and vertebral fractures had actuarial rates of 8% (95% CI 5%-11%) and 16% (95% CI 10%-23%), respectively, with fracture rates significantly higher after stereotactic radiotherapy (p = 0.033). Fifty-eight patients (27.6%) had local recurrences after a median of 6.8 months (range 0.1-59 months), with pooled local control rates of 61.6% at 6 months and 40.8% at 12 months, and there were no significant differences based on radiotherapy type (p = 0.068). The median survival was 6 months (range 0.1-62 months), with pooled rates of 52.5% at 6 months and 23.4% at 12 months. Radiotherapy in spine metastatic HCCs shows favorable rates of pain relief, radiological responses, and local control. Rates of postradiotherapy vertebral fractures are higher after high-dose stereotactic radiotherapy.