KẾT QUẢ HÓA XẠ TRỊ ĐỒNG THỜI PHÁC ĐỒ EP VÀ KĨ THUẬT XẠ ĐIỀU BIẾN LIỀU TRONG UNG THƯ PHỔI KHÔNG TẾ BÀO NHỎ GIAI ĐOẠN III

Mục tiêu: Đánh giá kết quả điều trị của phác đồ EP kết hợp với xạ trị điều biến liều trong ung thư phổi không tế bào nhỏ giai đoạn III và mô tả một số tác dụng không mong muốn của điều trị trên. Đối tượng nghiên cứu: Gồm 37 bệnh nhân UTPKTBN giai đoạn III được điều trị hoá xạ trị đồng thời bằng kĩ thuật xạ điều biến liều và phác đồ hoá chất etoposide-cisplatin tại Bệnh viện K từ 01/2019 đến 06/2021. Phương pháp nghiên cứu: mô tả cắt ngang. Kết quả: Đặc điểm nhóm nghiên cứu: Tuổi trung bình 57, tỉ lệ nam chiến 86,5%, bệnh nhân được lựa chọn có thể trạng tốt với 22 (59.5%) trong 37 bệnh nhân ECOG 0. Giai đoạn bệnh chủ yếu là giai đoạn IIIB chiếm 62,2%, mô bệnh học chủ yếu là carcinoma tuyến 64.9%. Kết quả điều trị: Đánh giá đáp ứng theo RECIST 1.1 cho thấy tỉ lệ đáp ứng toàn bộ, một phần tương ứng là 2,7% và 83,8%, tỉ lệ kiểm soát bệnh là 97,3%. Thời gian trung vị sống thêm không tiến triển là 14 ± 3,7 tháng. Sống thêm không tiến triển vào thời điểm 12 tháng là 54,7% là Độc tính: Có 24,3% bệnh nhân viêm phổi, 44,2% bệnh nhân viêm thực quản chỉ ở độ I, II. Độc tính trên hệ tạo huyết chủ yếu độ I, II, chỉ có 2,7% bệnh nhân xuất hiện độ III. Độc tính trên gan, thận, nôn, mệt mỏi, sụt cân đều ở mức độ 1-2. Kết luận: Phác đồ không những cho kết quả khả quan về đáp ứng và sống thêm không tiến triển, mà còn giảmđáng kể các độc tính liên quan đến xạ trị

Trends of Clinical Outcomes of Patients with Advanced Hepatocellular Carcinoma Treated with First-line Sorafenib in Randomized Controlled Trials

Background: Sorafenib has consistently served as the control arm in multiple RCTs evaluating novel therapies for advanced HCC for more than a decade. Analyzing trends in clinical outcomes of patients treated with sorafenib for the same indication over time offers the opportunity for unique insight into the evolution of clinical trial conduct and potential non-drug factors impacting outcomes. Methods: We identified RCTs in patients with treatment-naïve advanced HCC where sorafenib was compared to another systemic therapy or placebo. We extracted trial-level demographic, clinicopathologic, and outcome data (OS, progression-free survival (PFS), objective response rate (ORR) and duration of therapy). Sample-weighted linear regression was used to identify temporal trends with significance set at p0.05. Results: Sixteen RCTs (9 phase III and 7 phase II) enrolling 4086 patients treated with sorafenib were included in the analysis. Included trials enrolled patients from 2005-2019. OS has significantly improved by 4.5 months from 2005-2019 (p=0.048) over time. Thirteen studies provided data on PFS using RECIST 1.1, with no significant change over time (p=0.69). ORR assessed by RECIST 1.1 has significantly improved by 6.0% over time (p=0.003). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p=0.0037). There was no significant change in patient demographics were identified over time to explain the OS findings. Conclusion: The median OS of patients with advanced HCC treated with sorafenib has improved significantly over 15 years. At the same time, the median duration of therapy with sorafenib has decreased. The reason for these findings was not explained by changing demographics of patients enrolled in these trials and has implications for ongoing clinical trials.

RECIST 1.1, mRECIST 1.1: RADIOLOGICAL ASSESSMENT OF TUMOR RESPONSE TO CHEMOTHERAPY (literature review)

Определение изменений опухолевого роста является важной характеристикой клинической оценки терапии рака - как уменьшение размеров опухоли (объективный ответ), так и прогрессирование заболевания являются полезными конечными точками клинических исследований. Критерии RECIST были впервые опубликованы в 2000 г. и с тех пор начали применяться в мировой онкологической практике для оценки эффективности лечения. В 2009 году критерии RECIST 1.0 были пересмотрены и дополнены новыми данными RECIST 1.1 (2009 г.). Учитывая применение химиотаргетной терапии и особенности ответа на нее опухоли, предложены SACT критерии, модифицированные критерии RECIST (mRECIST) как способ адаптации критериев RECIST. Современные знания критериев оценки лечения солидных опухолей поможет лучевым диагностам правильно интерпретировать результаты исследований. В работе представлен обзор научных исследований по критериям оценки опухолевого ответа на лечение по данным радиологических исследований. Determining of tumor changes is an important characteristic of the clinical evaluation of cancer therapy - both tumor shrinkage (objective response) and disease progression are useful endpoints of clinical trials. The RECIST criteria were first published in 2000 and since then have been used in the global oncological practice to assess the effectiveness of treatment. In 2009, the RECIST 1.0 criteria were revised and supplemented with new data from RECIST 1.1 (2009). Taking into account the use of target chemotherapy and the peculiarities of the tumor response to it, the SACT criteria and modified RECIST criteria (mRECIST) are proposed as a way to adapt the RECIST criteria. Modern knowledge of the criteria for ASSESSMENT OF TUMOR RESPONSE will help radiologyst to correctly interpret the research results. The paper provides an overview of scientific studies on the criteria for evaluating tumor response to treatment based on radiological studies.

Response Evaluation and Survival Prediction Following PD‐1 Inhibitor in Patients With Advanced Hepatocellular Carcinoma: Comparison of the RECIST 1.1, iRECIST, and mRECIST Criteria

BackgroundPrecise evaluation of the efficacy of immunotherapy is critical in the effective management and treatment of advanced hepatocellular carcinoma (HCC). Therefore, the purpose of this study was to compare the response assessments achieved by different criteria and to evaluate the correlation between survival outcome and response assessment in HCC treated with programmed cell death protein 1 (PD-1) inhibitor.MethodsFifty patients with advanced HCC treated with first-line PD-1 inhibitor with baseline and follow‐up CT images were analyzed. The patients were categorized into responders and nonresponders according to the criteria.ResultsWhen the response assessments between RECIST 1.1 and mRECIST were compared, no statistically significant differences were observed. Overall response rate was 16% by RECIST 1.1 and iRECIST and was 24% by mRECIST. According to RECIST 1.1 and mRECIST, overall survival (OS) and progression-free survival (PFS) were not statistically different between the complete response (CR) and partial response (PR) groups and the stable disease (SD) and progressive disease (PD) groups. The OS and PFS were significantly different between responders and nonresponders according to mRECIST. The Cohen’s Kappa for RECIST 1.1, iRECIST, and mRECIST was 0.534, 0.438, and 0.363, respectively.ConclusionThe mRECIST criteria have a powerful ability to discriminate between responders and nonresponders and demonstrated significantly longer OS and PFS in responders than in nonresponders. However, mRECIST needs to be further improved in order for it to be widely used in the clinical evaluation of immunotherapy in HCC.

Assessment of Response to Chemotherapy in Pancreatic Cancer with Liver Metastasis: CT Texture as a Predictive Biomarker

In this paper, we assess changes in CT texture of metastatic liver lesions after treatment with chemotherapy in patients with pancreatic cancer and determine if texture parameters correlate with measured time to progression (TTP). This retrospective study included 110 patients with pancreatic cancer with liver metastasis, and mean, entropy, kurtosis, skewness, mean of positive pixels, and standard deviation (SD) values were extracted during texture analysis. Response assessment was also obtained by using RECIST 1.1, Choi and modified Choi criteria, respectively. The correlation of texture parameters and existing assessment criteria with TTP were evaluated using Kaplan-Meier and Cox regression analyses in the training cohort. Kaplan-Meier curves of the proportion of patients without disease progression were significantly different for several texture parameters, and were better than those for RECIST 1.1-, Choi-, and modified Choi-defined response (p < 0.05 vs. p = 0.398, p = 0.142, and p = 0.536, respectively). Cox regression analysis showed that percentage change in SD was an independent predictor of TTP (p = 0.016) and confirmed in the validation cohort (p = 0.019). In conclusion, CT texture parameters have the potential to become predictive imaging biomarkers for response evaluation in pancreatic cancer with liver metastasis.

Experience of using 1st line combination immunotherapy in patients with metastatic renal cell carcinoma

The study objective is to evaluate effectiveness and tolerability of 1st line combination immuno-oncological therapy with nivolumab and ipilimumab in patients with metastatic renal cell carcinoma (mRCC) in clinical practice.Materials and methods. The study included 38 patients with mRCC who received combination immunotherapy between July of 2019 and September of 2021. Median follow-up duration was 8 (2-25) months. Mean age of the patients was 58.3 (20-85) years. Previously 22 (57.9 %) patients underwent surgical treatment. Unfavorable physical status 2-3 per the ECOG scale was observed in 10 (26.3 %) patients. Clear-cell type of renal cell carcinoma was diagnosed in 34 (89.6 %) patients, non-clear-cell types in 4 (10.4 %). Sarcomatoid component in the tumor was detected in 8 (21.0 %) patients. G3-4 mRCC variant was verified in 16 (42.1 %) patients. Poor prognosis per the IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) scale was identified in 16 (42.1 %) patients, intermediate -in 20 (52.6 %) patients. All 4 administrations of combination immunotherapy were received by 29 (76.3 %) patients.Results. For median follow-up duration of 8 (2-25) months, 23 (60.5 %) patients continue treatment, 15 (39.5 %) completed therapy with nivolumab and ipilimumab due to various reasons including progression in 11 (28.9 %), death in 2 (5.3 %), intolerable toxicity in 2 (5.3 %) cases. Median duration of combination immunotherapy was 9 (2-24) months. Subsequent antitumor therapy was administered to 3 (7.9 %) patients. During induction course immune-mediated adverse event (grade III-IV hepatitis) developed in 3 (7.9 %) patients. Adverse events were observed in 81.6 % of patients, including grade III-IV in 23.7 % of patients. Objective response was observed in 44.8 % of cases, complete response in 5.3 % of cases, partial response in 39.5 % of cases; controlled disease was achieved in 84.3 % of patients. Median progression-free survival and overall survival were 8 months.Conclusion. In our study despite large number of patients with poor prognosis and poorly differentiated tumors, 64.0 % of patients are alive and 60.5 % of patients continue treatment without disease progression after 18 months of combination immunotherapy. Progression-free survival was significantly affected by sarcomatoid component in the tumor, number of unfavorable factors per the IMDC scale, best response per RECIST 1.1; overall survival was significantly affected by sarcomatoid component in the tumor, sum of measurable lesions, number of unfavorable factors per the IMDC scale, best response per RECIST 1.1, and presence of symptomatic metastases in the brain.

Dose Escalation Study of GCC19CART CoupledCAR ® Technology for Patients with Relapsed or Refractory Colorectal Cancer

Background: Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in hematologic malignancies but limited success in solid tumors. GCC19CART, the first clinical candidate from the CoupledCAR ® solid tumor platform, targets guanylate cyclase-C (GCC) which is expressed in colorectal cancers. A Phase 1 investigator-initiated dose escalation trial is underway in China for patients with relapsed or refractory metastatic colorectal cancer. Data presented here are from a single participating institution. Methods: Subjects with relapsed or refractory metastatic colorectal cancer are screened for GCC expression, with 70% to 80% of subjects expected to demonstrate GCC per historical data. Subjects undergo leukapheresis, a single dose of lymphodepleting chemotherapy (fludarabine 30mg/m2 and cyclophosphamide 300mg/m2) 3 days prior to infusion, and then administration of a single infusion of GCC19CART at one of three doses of 1x10 6, 2x10 6, or 3x10 6 cells/kg. Endpoints are safety and preliminary evidence of efficacy as determined by CT or PET/CT per RECIST1.1 or PERCIST 1.0. Results: 5 subjects have been enrolled to dose level 1 (1x10 6 cells/kg) and 5 subjects have been enrolled to dose level 2 (2x10 6 cells/kg) and have a 1-month post-infusion imaging study available for review. The most common adverse events were cytokine release syndrome (CRS) in 10/10 subjects (Grade 1 9/10 (90%) or Grade 2 1/10 (10%)) and diarrhea in 10/10 subjects (Grade 1 3/10 (30%) Grade 2 1/10 (10%) Grade 3 6/10 (60%)). Neurotoxicity was observed in 1/10 (10%) subjects at Grade 4 and resolved with corticosteroids. The combined overall response rate (ORR) for both dose levels was 50% (5/10). For dose level 1, the overall response rate (ORR) per RECIST 1.1 was 40% (2/5). Two subjects demonstrated a partial response (PR) while an additional subject had partial metabolic response (PMR) on PET/CT with stable disease (SD) per RECIST 1.1. For dose level 2, The ORR per RECIST 1.1 was 60% (3/5). 3 subjects demonstrated a PR (2 at month 1, 1 at month 3 after being SD at month 1) and an additional subject had PMR on PET/CT with SD per RECIST 1.1. Conclusions: GCC19CART demonstrated meaningful clinical activity and an acceptable safety profile in relapsed or refractory metastatic colorectal cancer. This trial is ongoing and updated data will be presented. A United States based Phase 1 trial of GCC19CART is anticipated for early 2022. Disclosures Pu: Innovative Cellular Therapeutics: Current Employment. Zhu: Innovative Cellular Therapeutics: Current Employment. Huang: https://www.accme.org/accreditation-rules/standards-for-integrity-independence-accredited-ce/eligibility: Current Employment. Tang: Innovative Cellular Therapeutics: Current Employment. Jia: Innovative Cellular Therapeutics: Current Employment. Chen: Innovative Cellular Therapeutics: Current Employment. Kennedy: Innovative Cellular Therapeutics: Current Employment. Wu: Innovative Cellular Therapeutics: Current Employment. Xiao: Innovative Cellular Therapeutics: Current Employment.

961 Preliminary results of a phase 2 study of intratumoral administration of BO-112 with pembrolizumab in patients with advanced melanoma that have progressive disease on anti-PD-1-based therapy

BackgroundIntratumoral immunotherapies are being tested in different solid tumors. They trigger local and systemic responses.1 2 BO-112 is a double stranded RNA nanoplexed with polyethyleneimine (PEI), which mimics a viral infection and mobilizes the immune system.In preclinical models and in a first in human clinical trial BO-112 activated dendritic cells, induced CD-8 infiltration, apoptosis and enhancement of immunogenic cell death and achieved an objective response in 2 out of 10 patients with melanoma with primary resistance to antiPD-1.3 4MethodsIn this phase 2 study, BO-112 plus pembrolizumab is evaluated in patients with advanced melanoma, who have developed progressive disease while on or within 12 weeks after anti-PD1/PD-L1 based therapy (either as first line or as adjuvant treatment). BO-112 is administered intratumorally once weekly in 1 to 8 tumor lesions, total dose 1 to 2 mg, for the first 7 weeks and thereafter every three weeks; pembrolizumab 200 mg is administered intravenously every three weeks. Overall response rate (ORR) is analyzed as primary endpoint by independent reviewer. Secondary objectives include disease control rate (DCR), duration of response and progression free survival (PFS); response assessment is done by RECIST 1.1 and iRECIST; in addition, CD-8 and PD-L1 IHC, NGS, itRECIST and radiomics signatures are prospectively assessed. Key eligibility criteria include cutaneous or mucosal melanoma with known BRAF status; at least one lesion RECIST 1.1 measurable and amenable for IT injection. Enrollment has been completed on 26th August.ResultsWith 26 evaluable patients with a first response assessment, seven have progressive disease (PD), five have partial response (PR) and fourteen patients show stable disease (SD). Preliminary ORR is 19.2% and DCR is 73.1% at week 8. Three patients with PR at week 8 have undergone a second assessment at week 16, with further decrease in sum of diameters (SOD) in both injected and non-injected lesions. Three out of five patients with SD and a second assessment maintain SD, showing a decrease in SOD in two cases (figure 1). In addition, two patients with only skin lesions have a pathological complete response. CD8 and PD-L1 have increased in 8 and 7 out of 13 patients with paired biopsies, being related with clinical benefit (figure 2).Abstract 961 Figure 1Swimmer plot, efficacy data for evaluable patients undergoing at least one response assessmentAbstract 961 Figure 2Immunohistochemistry data for CPS and CD8 data from paired biopsiesConclusionsDespite these data being preliminary, there is a trend for benefit in terms of ORR and also in long lasting stable diseases. BO-112 is able to increase PD-L1 expression in tumor cells and increase CD8-T cell infiltrates.AcknowledgementsMerck, Pivotal SLU, Quibim radiomics, Pangaea laboratories, all participating sites and patientsTrial RegistrationNCT04570332ReferencesAznar MA, Planelles L, Perez-Olivares M, et al. Immunotherapeutic effects of intratumoral nanoplexed poly I:C. J Immunother Cancer. 2019 May 2;7(1):116.5. Hamid O, Ismail R, Puzanov I. Intratumoral immunotherapy-update 2019. The Oncologist 2020;25:e423–438.Márquez-Rodas I, Longo F, Rodríguez-Ruiz M, et al. Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors. Sci Transl Med 2020 Oct 14;12(565):eabb0391.Kalbasi A, Tariveranmoshabad M, Hakimi K, Kremer S, et al. A. Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma. Sci Transl Med 2020 Oct 14;12(565):eabb0152.Ethics ApprovalThe study obtained ethics approval by Spanish Health Agency (AEMPS), on 11th December 2020, and French Health Agency (ANSM) on 27th January 2021; study obtained approval from two Ethics Committee: Vall D’Hebron, Barcelona, Spain on 7th December 2020 (number 467), and Centre Léon Bérard, Lyon, France, CPP 20.11.10.38825 on 11th February 2021.For each study patient, written informed consent is obtained prior to any protocol-related activities. As part of this procedure, the principal investigator or one of his/her associates must explain orally and in writing the nature, duration, and purpose of the study, and the action of the study drug in such a manner that the patient is aware of the potential risks, inconveniences, or adverse effects that may occur. They should be informed that the patient may withdraw from the study at any time. They will receive all information that is required by the regulatory authorities and ICH guidelines. The ICF has been signed by the patient and a copy provided to them.ConsentN/A

Some aspects of conservative treatment of patients with laryngeal cancer

Topicality: According to the National Cancer Registry of Ukraine, the incidence of laryngeal cancer is 4.1%. The treatment of patients with laryngeal cancer depends on the stage of the tumor. The conservative therapy includes both radiation therapy and chemotherapy. Material and methods: The conservative treatment of 93 patients with laryngeal cancer was performed. All patients are divided into two groups according to the localization of cancer: glottis (n=57) and supraglottis (n=36). The course of radiation therapy was conducted in oncology centers. The course of chemotherapy was induction or combined with radiation therapy. The outcome of therapy was evaluated one month after its completion. Tumor response after therapy was assessed by RECIST 1.1. Statistical processing of the obtained results was performed in accordance with the recommendations of Glantz. Results: It was found that metastases to the lymph nodes of the neck were significantly more common in cancer of the supraglottic (χ2=16.074; φ=0.00012; р<0.05). The greater number of recurrences of the tumor of the glottis after conservative therapy (χ2=6.718; φ=0.01345; р<0.05). Three-year recurrence-free survival and overall survival of patients after conservative treatment of laryngeal cancer patients were the same in both groups. Conclusion: The treatment of 93 patients with laryngeal cancer gave an objective tumor response in 96% of patients. The conservative treatment of patients with laryngeal cancer revealed a lower number of tumor recurrences in the supraglottis cancer (20 of 36 patients) compared with the glottis (37 of 57) (χ2= 6.718; φ = 0.01345; p <0.05).