End Of Radiotherapy Research Articles

Increasing the effectiveness of total-skin electron beam therapy by reducing the manifestations of radiation dermatitis in patients with primary lymphomas. A comparative randomized prospective study

Background. One of the main adverse events that significantly reduce the quality of life of patients and limit the total focal dose is radiation-induced skin reactions (RISR). Their timely diagnosis, prevention, and treatment remain urgent tasks of modern radiotherapy. Aim. To improve the effectiveness of total skin irradiation (TSI) in patients with primary skin lymphomas by reducing the clinical manifestations of RISR by using additional therapy with a hydrogel containing active components with vasoprotective and anti-inflammatory action. Materials and methods. A comparative randomized prospective study was conducted, including data from 52 patients who received electron TSI by conventional fractionation at a total focal dose of 14 to 30 Gy for primary cutaneous lymphomas at the Granov Russian Research Center of Radiology and Surgical Technologies from September 2021 to January 2024. Before the first TSI session, during treatment and 2 weeks after the end of radiation therapy, all patients underwent assessment for RISR, quantitative assessment of various degrees of severity of radiodermatitis using instrumental methods and assessment scales; for the observation group, a therapeutic regimen for the prevention and treatment of RISR was used, including a hydrogel with troxerutin (2%) and trolamine (0.07%), and in the control group, basic skin care using moisturizers. Results. Analysis of the physiological parameters of the skin showed statistically significant differences between the study groups: patients of the study group (group I; 30 subjects receiving the above-mentioned therapeutic regimen) compared with the control group (group II; 28 subjects who did not receive specific treatment for radiodermatitis) reported significantly lower rates of erythema (386±12.3 and 572±14.4; p=0.005), transepidermal water loss (25±0.3 and 38±0.4 g/m2/h; p0.001) and a decrease in peak endothelial-dependent vasodilation of microvasculature and blood flow in the skin. A lower proportion of severe radiodermatitis (86.3 and 73.3%; p0.05) and a statistically significant difference in the subjective quality of life scores by the 29-point Skindex-29 scale by an average of 22.2% were also found. Conclusion. A comparative analysis of the quantitative indicators of radiodermatitis in the study group and the control group showed that the topical application of the hydrocolloid gel containing troxerutin and trolamine reduces the clinical manifestations of RISR concerning objectively measured physiological parameters of the skin and blood flow parameters of the microvasculature measured by high-frequency ultrasound, thus improving the quality of life of patients during and after the course of radiation therapy.

CTNI-17. A PHASE 2 STUDY OF SAFETY AND EFFICACY OF CONCURRENT ACT001 AND RADIATION TREATMENT FOLLOWED BY ACT001 MAINTENANCE THERAPY IN NEWLY DIAGNOSED PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract BACKGROUND ACT001, an oral parthenolide derivative targeting NF-κB and STAT3 pathways, has shown activity in preclinical DIPG model and dose-finding study in patients with diffuse midline glioma. We further evaluated safety and activity of ACT001 in newly diagnosed DIPG patients and presented the interim data from exploratory stage of this phase 2 study. METHODS Eligible patients ≥ 5 and ≤ 15 years old were treated with concurrent ACT001 and standard radiation followed by ACT001 single agent treatment in this single arm, open label, multicenter phase 2 study. Tumor lesions were evaluated at baseline, 4 weeks and then every 8 weeks after the end of radiation therapy per RAPNO criteria with ORR as primary endpoint. Interim data analysis was performed when data from approximately 20 efficacy evaluable patients became available during the exploratory stage of this study. RESULTS Among 30 patients enrolled since Sept, 2023, 27 took at least one dose of ACT001 by April 30th, 2024, the data cutoff date (with exception for May 15th as the MRI cutoff date). While 3 patients were quickly taken off study due to a disease progression or consent withdrawal, 17 out of 27 patients finished at least one post-radiation MRI exam whereas MRI results are pending for 7 other patients by this interim analysis. Median age was 8 years old and male to female patient ratio is 17:10. The median LPS score is 70.0. Among 17 efficacy evaluable subjects, 8 patients exhibited partial response (6 confirmed) including one with a deep tumor reduction (-91.7%) noted three months after end of radiation. Among 9 other evaluable patients, 5 and 4 exhibited ongoing stable disease and progressive disease respectively. Subject 05001 was considered PD despite confirmed objective response for the target lesion upon development of new lesions. Two patients withdrew consent after finishing first post-radiation MRI scans despite initial tumor burden reduction which were both close to PR criteria. Patients tolerated concurrent ACT001 and radiation well. In total, 289 TEAE and 184 TRAE events were reported in 23 and 22 patients respectively. There were two ACT001-related grade 3 or 4 adverse events including one grade 4 hemorrhagic tumor necrosis (a SUSAR event and the only ACT001 related SAE) likely due to a therapeutic effect of ACT001 and one clinically insignificant grade 3 decreased lymphocyte count. Most common TRAE were manageable grade 1 or 2 events such as weight loss (15/184), vomiting (71/184), decreased lymphocyte count (13/184) and abdominal bloating (7/184). No study discontinuation occurred due to ACT001 or radiation related TRAEs. Conclusion. Concurrent ACT001 and radiation treatment was well tolerated. Preliminary evidence of anti-tumor activity was shown in about 50% efficacy evaluable DIPG patients. It is worthwhile to explore ACT001 and temozolomide combination in future study based on safety and efficacy signal from DIPG and recurrent GBM studies. The confirmatory stage of this study is in planning to further evaluate the anti-tumor efficacy signal of this NF-κB and STAT3 dual inhibitor.

Patients’ Perceived Valorization Toward Ringing the Cancer Bell at the End of Their Radiation Therapy

In recent times, "ringing the bell" at the end of cancer treatment has attracted the attention of health care providers with regard to how this experience impacts patients' mental and emotional health. In this context, a study was conducted at a radiation oncology center in Santiago, Chile, to assess the perceived valorization of patients toward "ringing the bell" at the end of their treatment. It was further determined whether this experience had a positive or negative impact on their mental health. Two hundred thirty-six patients were invited to respond to a printed anonymous survey that used a Likert scale to evaluate their perceived valorization of "ringing the bell" after radiation therapy. In this survey, patients were also asked questions regarding their background to examine possible trends related to different lifestyles and socioeconomic status. The results showed that 93.6% of participants classified the experience as "positive" or "very positive." There were 6 "negative" responses out of 708 (0.8%) to the 3 questions regarding perceived valorization of the experience and no "very negative" responses. "Ringing the bell" at the end of radiation therapy can be considered a psychological comfort that positively impacts patients' mental health. No trends related to socioeconomic status were observed.

QOL-05. MEMANTINE FOR PREVENTION OF COGNITIVE LATE EFFECTS IN CHILDREN RECEIVING CRANIAL RADIATION THERAPY FOR FOCAL BRAIN TUMORS: A PILOT STUDY

Abstract BACKGROUND Childhood brain tumor survivors treated with cranial irradiation are at significant risk for cognitive late effects that negatively impact quality of life. Memantine (an NMDA receptor antagonist), taken during radiotherapy for brain metastases in adults, resulted in reduced cognitive declines. This is the first investigation of feasibility, acceptability, and preliminary efficacy of memantine for reducing cognitive late effects in children undergoing radiation therapy. METHODS In a randomized, double-blind, controlled trial (MEMCRT; NCT03194906) children took memantine (20 mg/d) or placebo for 12 weeks. During the medication phase, participants received weekly phone calls to assess adherence using pill counts and monitor side effects using the SAFTEE structured interview. At baseline, 6 weeks (end of radiation therapy), and 12 weeks (end of medication), participants completed a brief battery of cognitive measures. RESULTS 30 patients (age at irradiation=11.93±2.87; 47% male) were included; memantine (n=16) and placebo (n=14) groups did not differ in age, sex, race, socioeconomic status or baseline IQ (ps>.26). Study participation (71% of those approached) and medication adherence (88% completed 12 weeks, with 97% of medication taken) were high. Side effects were minimal (only one CTCAE≥ 3; headache in the placebo group) with no difference between groups in change in side effect severity from baseline to any medication week, across any symptom inquiry (ps>.23). At 12 weeks, Cohen’s d effect sizes (ES) indicate the memantine group had better performance on measures of processing speed (Cogstate Identification ES=.61), academic fluency (Woodcock Johnson-IV Reading Fluency ES=.45; Math Fluency ES=.81), and fatigue (PedsQL Multidimensional Fatigue Scale ES=.72). CONCLUSIONS Study findings indicate memantine used as a neuroprotectant during radiation therapy for children with focal brain tumors is feasible and acceptable, with preliminary evidence for better cognitive outcomes that require validation in a larger, definitive trial.

C-reactive protein as robust laboratory value associated with prognosis in patients with stage III non-small cell lung cancer (NSCLC) treated with definitive radiochemotherapy

To evaluate the prognostic value of biomarkers from peripheral blood obtained as routine laboratory assessment for overall survival in a cohort of stage III non-small cell lung cancer (NSCLC) patients treated with definitive radiochemotherapy at a high-volume cancer center. Seven blood biomarkers from 160 patients treated with definitive radiochemotherapy for stage III NSCLC were analyzed throughout the course treatment. Parameters were preselected using univariable and multivariable proportional hazards analysis and were assessed for internal validity using leave-one-out cross validation. Cross validated classifiers including biomarkers in addition to important clinical parameters were compared with classifiers containing the clinical parameters alone. An increased C-reactive protein (CRP) value in the final week of radiotherapy was found as a prognostic factor for overall survival, both as a continuous (HR 1.099 (1.038–1.164), p < 0.0012) as well as categorical variable splitting data at the median value of 1.2 mg/dl (HR 2.214 (1.388–3.531), p < 0.0008). In the multivariable analysis, the CRP value-maintained significance with an HR of 1.105 (1.040–1.173) and p-value of 0.0012. The cross validated classifier using CRP at the end of radiotherapy in addition to clinical parameters separated equally sized high and low risk groups more distinctly than a classifier containing the clinical parameters alone (HR = 2.786 (95% CI 1.686–4.605) vs. HR = 2.287 (95% CI 1.407–3.718)). Thus, the CRP value at the end of radiation therapy has successfully passed the crucial cross-validation test. The presented data on CRP levels suggests that inflammatory markers may become increasingly important during definitive radiochemotherapy, particularly with the growing utilization of immunotherapy as a consolidation therapy for stage III NSCLC.

Utero-Ovarian “out of field” Transposition Before Pelvic Radiation in a Patient with Rectal Cancer: A First Swiss Experience

Abstract Background Colorectal cancer represents the third most common cancer and the second leading cause of cancer-related mortality worldwide. The incidence of rectal cancer is rising faster and is increasing among young adults. Due to advances in diagnosis and treatment, most young patients with rectal cancer present long-term survival. Treatment-related infertility represents a largely unaddressed problem. Fertility preservation is essential in managing young women requiring chemo- and radiotherapy for rectal cancer. Ovaries and oocytes are very sensitive to radiation and chemotherapeutic agents, and current fertility preservation strategies include oocytes, embryos, or ovarian tissue cryopreservation and ovarian transposition out of the radiation field. Nevertheless, patients have little probability of procreating due to irreversible uterine radiation damages. Utero-ovarian “out of filed” Transposition [UOT] represent an interesting perspective specially in countries were pregnancy surrogacy is not allowed. Aims Demonstrate feasibility of an innovative surgical procedure permitting uterine functional preservation after long course neoadjuvant therapy for low rectal cancer including total chemo and radio-chemotherapy. Methods First Clinical Swiss experience case presentation. In addition, of a systematic review of the literature available to date on all cases of UOT was realized, and 13 patients from 9 articles were included. Results A 28-year-old nulligravida patient was diagnosed with a low-grade rectal adenocarcinoma. Before neoadjuvant therapies, the patient underwent laparoscopic UOT. The intervention was performed without complications, and the patient received neoadjuvant treatments as planned. TaTME and uterus repositioning were completed six weeks after the radiotherapy's end. No complications were observed during the first 9 postoperative months. Adequate utero-ovarian perfusion was assessed by Doppler ultrasound, cervicovaginal anastomosis appeared healed correctly, and the patient experienced menstrual bleeding. Data from the literature review of reported cases of UOT were presented. Conclusion UOT represents a valuable option to preserve fertility in patients requiring pelvic radiotherapy. This study provides additional evidence on the feasibility and safety of UOT.

Stereotactic ultrahypofractionated MR-guided radiotherapy for localized prostate cancer – Acute toxicity and patient-reported outcomes in the prospective, multicenter SMILE phase II trial

BackgroundDue to superior image quality and daily adaptive planning, MR-guided stereotactic body radiation therapy (MRgSBRT) has the potential to further widen the therapeutic window in radiotherapy of localized prostate cancer. This study reports on acute toxicity rates and patient-reported outcomes after MR-guided adaptive ultrahypofractionated radiotherapy for localized prostate cancer within the prospective, multicenter phase II SMILE trial. Materials and methodsA total of 69 patients with localized prostate cancer underwent MRgSBRT with daily online plan adaptation. Inclusion criteria comprised a tumor stage ≤ T3a, serum PSA value ≤ 20 ng/ml, ISUP Grade group ≤ 4. A dose of 37.5 Gy was prescribed to the PTV in five fractions on alternating days with an optional simultaneous boost of 40 Gy to the dominant intraprostatic lesion defined by multiparametric MRI. Acute genitourinary (GU-) and gastrointestinal (GI-) toxicity, as defined by CTCAE v. 5.0 and RTOG as well as patient-reported outcomes according to EORTC QLQ-C30 and -PR25 scores were analyzed at completion of radiotherapy, 6 and 12 weeks after radiotherapy and compared to baseline symptoms. ResultsThere were no toxicity-related treatment discontinuations. At the 12-week follow-up visit, no grade 3 + toxicities were reported according to CTCAE. Up until the 12-week visit, in total 16 patients (23 %) experienced a grade 2 GU or GI toxicity. Toxicity rates peaked at the end of radiation therapy and subsided within the 12-week follow-up period. At the 12-week follow-up visit, no residual grade 2 GU toxicities were reported and 1 patient (1 %) had residual grade 2 enteritic symptoms. With exception to a significant improvement in the emotional functioning score following MRgSBRT, no clinically meaningful changes in the global health status nor in relevant subscores were reported. ConclusionDaily online-adaptive MRgSBRT for localized prostate cancer resulted in an excellent overall toxicity profile without any major negative impact on quality of life.

Multicenter Phase 1b/2a Clinical Trial of Radioprotectant BIO 300 Oral Suspension for Patients With Non-Small Cell Lung Cancer Receiving Concurrent Chemoradiotherapy

Radiation therapy is part of the standard treatment regimen for non-small cell lung cancer (NSCLC). Although radiation therapy is an effective tool to manage NSCLC, it can be associated with significant dose-limiting toxicities. These toxicities can lead to treatment interruption or early termination and worsening clinical outcomes in addition to reductions in patient quality of life. Based on preclinical efficacy for radioprotection of normal tissues, we evaluated the clinical utility of BIO 300 Oral Suspension (BIO 300; synthetic genistein nanosuspension) in patients with NSCLC. In this multicenter, open-label, single-arm, ascending dose phase 1b/2a study, patients were enrolled with newly diagnosed stage II-IV NSCLC planned for 60 to 70/1.8-2.0 Gy radiation therapy and concurrent weekly paclitaxel/carboplatin. Oral BIO 300 (cohort 1, 500 mg/d; cohort 2, 1000 mg/d; cohort 3, 1500 mg/d) was self-administered once daily starting 2 to 7 days before initiating concurrent chemoradiotherapy and continued until the end of radiation therapy. The primary endpoint was acute dose-limiting toxicities attributable to BIO 300. Secondary outcomes included pharmacokinetics, pharmacodynamics, overall toxicity profile, quality of life, local response rate, and survival. Twenty-one participants were enrolled. No dose-limiting toxicities were reported. BIO 300 dosing did not alter chemotherapy pharmacokinetics. Adverse events were not dose-dependent, and those attributable to BIO 300 (n=11) were all mild to moderate in severity (grade 1, n=9; grade 2, n=2) and predominantly gastrointestinal (n=7). A dose-dependent decrease in serum transforming growth factor β1 levels was observed across cohorts. Based on safety analysis, the maximum tolerated dose of BIO 300 was not met. Patient-reported quality of life and weight were largely stable throughout the study period. No patient had progression as their best overall response, and a 65% tumor response rate was achieved (20% complete response rate). The low toxicity rates, along with the pharmacodynamic results and tumor response rates, support further investigation of BIO 300 as an effective radioprotector.

Radiation Therapy of Patients with Regional Risk Group of Prostate Cancer

Relevance: Radiation therapy is one of the main local method of treatment for patients with prostate&#x0D; cancer and regional metastases of pelvic lymph nodes. However, unfortunately, some patients can be&#x0D; subject to development progression of disease as emergence regional lymph node’s metastasis of&#x0D; retroperitoneal space.&#x0D; Purpose: To develop a new more effective radical method of radiation therapy for patients with metastases in the regional lymph nodes.&#x0D; Material and methods: The radiotherapy department has developed a new method of radiation therapy&#x0D; for patients with prostate cancer and metastases in the regional lymph nodes, which includes prophylactic irradiation of retroperitoneal lymph nodes.&#x0D; Results: 20 patients with prostate cancer and metastases to the regional lymph nodes were treated&#x0D; from June 2020 to December 2022. The median follow-up was 17 months. In all patients, radiation&#x0D; therapy was carried out in combination with neoadjuvant, concomitant and adjuvant hormone therapy&#x0D; with analogues of luteinizing hormone releasing hormone. All patients received a course of radiation&#x0D; therapy without interruption. At the time of analysis, all patients are alive and stay by under active surveillance with no signs of progression. At the end of radiation therapy, all patients noted manifestations&#x0D; of toxicity of the I-II degree genitourinary and gastrointestinal systems. There is a gradual recovery of&#x0D; patients in the form of a decrease and relief of radiation reactions in 3-6 months after the end of radiation therapy.&#x0D; Conclusion: The first data evaluating the safety of the new developed method of radiation therapy by&#x0D; hypofraction mode with additional prophylactic irradiation of the retroperitoneal lymph nodes demonstrate good tolerability. However, further study and conducting the 3rd phase of randomized trial are required to determine clinical efficacy.

Prediction of Radiation-induced Lymphopenia following Exposure of the Thoracic Region and Associated Risk of Infections and Mortality

AimsLarge blood volumes are irradiated when the heart is exposed to radiation. The mean heart dose (MHD) may be a good surrogate for circulating lymphocytes exposure. We investigated the association between MHD and radiation-induced lymphopenia and explored the impact of the end-of-radiation-therapy (EoRT) lymphocyte count on clinical outcomes. Materials and methodsIn total, 915 patients were analysed: 303 patients with breast cancer and 612 with intrathoracic tumours: oesophageal cancer (291), non-small cell lung cancer (265) and small cell lung cancer (56). Heart contours were generated using an interactive deep learning delineation process and an individual dose volume histogram for each heart was obtained. A dose volume histogram for the body was extracted from the clinical systems. We compared different models analysing the effect of heart dosimetry on the EoRT lymphocyte count using multivariable linear regression and assessed goodness of fit. We published interactive nomograms for the best models. The association of the degree of EoRT lymphopenia with clinical outcomes (overall survival, cancer treatment failure and infection) was investigated. ResultsAn increasing low dose bath to the body and MHD were associated with a low EoRT lymphocyte count. The best models for intrathoracic tumours included dosimetric parameters, age, gender, number of fractions, concomitant chemotherapy and pre-treatment lymphocyte count. Models for patients with breast cancer showed no improvement when adding dosimetric variables to the clinical predictors. EoRT lymphopenia grade ≥3 was associated with decreased survival and increased risk of infections among patients with intrathoracic tumours. ConclusionAmong patients with intrathoracic tumours, radiation exposure to the heart contributes to lymphopenia and low levels of peripheral lymphocytes after radiotherapy are associated with worse clinical outcomes.

Decreasing the Adverse Effects in Pelvic Radiation Therapy: A Randomized Controlled Trial Evaluating the Use of Probiotics

PurposeThe aim of this randomized controlled trial was to evaluate the potential benefit from 2 probiotic bacteria of the species Lactiplantibacillus plantarum against radiation therapy–induced comorbidities. Methods and MaterialsWomen (>18 years of age) scheduled for radiation therapy because of gynecologic cancer were randomly allocated to consume placebo or either low-dose probiotics (1 × 1010 colony-forming unit/capsule twice daily) or high-dose probiotics (5 × 1010 colony-forming unit/capsule twice daily). The intervention started approximately 1 week before the onset of radiation therapy and continued until 2 weeks after completion. During this period the participants were daily filling in a study diary documenting the incidence and severity of symptoms, intake of concomitant medication, and stool consistency. The primary endpoint was the probiotic effect on the mean number of loose stools during radiation therapy. ResultsOf the 97 randomized women, 75 provided data for the analysis of the results. The mean number of loose stools (sum of Bristol stool type 6 and 7) was not significantly reduced in the probiotic groups, but there was a significant reduction in the mean number of days with >1 loose stool with 15.04 ± 8.92 days in the placebo and 8.65 ± 5.93 days in the high-dose probiotics group (P = .014). The benefit was even more pronounced in the 2 weeks following the end of radiation therapy (P = .005). Moreover, intake of the probiotics resulted in a reduced severity of the symptoms grinding abdominal pain (P = .041) and defecation urgency (P = .08) and a reduced percentage of days with these symptoms (P = .023 and P = .042, respectively), compared with placebo. There were no differences regarding reported adverse events. ConclusionsIntake of the 2 probiotic bacteria was beneficial and reduced many measures or symptoms of the radiation-induced toxicity in women treated for gynecologic cancer.

Impact of a mobile application (reminder app) on acute toxicity during radiotherapy of head-and-neck cancer – results of a randomized phase III trial (RAREST-02)

BackgroundRadiotherapy of head-and-neck cancer (SCCHN) is often associated with acute toxicity. In a previous trial, daily reminders by staff members to perform skin care resulted in less dermatitis. This randomized trial investigated whether a mobile application can replace these reminders.MethodsPatients were stratified according to tumor site, treatment and center. Fifty-three patients were eligible for per-protocol-set (25 with, 28 without app). Primary endpoint was grade ≥ 2 dermatitis until 60 Gy. Secondary endpoints included dermatitis grade ≥ 2 until end of radiotherapy (EOT), dermatitis grade ≥ 3, and mucositis grade ≥ 2 and ≥ 3.ResultsAfter an interim analysis, the study was terminated (delayed and slow accrual). Until 60 Gy, grade ≥ 2 dermatitis rates were 72% with vs. 82% without app (p = 0.38), grade ≥ 3 dermatitis rates 20% vs. 11% (p = 0.45). Until EOT, grade ≥ 2 and ≥ 3 dermatitis rates were 72% vs. 86% (p = 0.22) and 24% vs. 18% (p = 0.58). Until 60 Gy, grade ≥ 2 and ≥ 3 mucositis rates were 76% vs. 82% (p = 0.58) and 20% vs. 36% (p = 0.20). Until EOT, corresponding mucositis rates were 76% vs. 82% (p = 0.58) and 28% vs. 43% (p = 0.26).ConclusionGiven the limitations of this trial, the reminder app led to non-significant reduction of grade ≥ 2 dermatitis, grade ≥ 2 mucositis and ≥ 3 mucositis. Additional studies are required to define the value of reminder apps during radiotherapy for SCCHN.

Subjective Global Assessment of Nutritional Status in Head and Neck Cancer Patients Treated with Radiotherapy – A Prospective Observational Study from North East India

Head and neck cancer (HNC) patients undergoing curative radiotherapy (RT) are at risk of malnutrition due to disease process as well as effects of therapy. Identifying the nutritional status of these patients at the earliest, helps to introduce adequate and timely interventions that can improve compliance and outcomes of treatment. Various tools for nutritional assessment in cancer patients have been proposed. In this prospective observational study we used the Subjective Global Assessment (SGA) questionnaire in a cohort of HNC patients receiving definitive RT at a regional cancer center of North East India. Recording of data was done at baseline, at two weekly intervals during treatment, at end of radiotherapy (EORT) and at follow-up upto 6 months. We observed that despite proper nutrition counseling, our patients suffered from malnutrition throughout their course of RT, which was at its peak by EORT but gradually improved over six months of follow-up. Pain on eating and swallowing were the most debilitating symptoms which caused significant decline of nutrient intake, body fat and muscle mass among patients together with deteriorating SGA ratings. Our results will hopefully help us design better strategies for nutrition management while delivering curative (chemo)radiotherapy for HNC patients of this region- which has one of the highest incidences of HNC in the world.

КОМБИНИРОВАННОЕ ЛЕЧЕНИЕ РАКА ПРЯМОЙ КИШКИ С ИСПОЛЬЗОВАНИЕМ ДВУХКОМПОНЕНТНОЙ РАДИОМОДИФИКАЦИИ В СХЕМАХ НЕОАДЪЮВАНТНОЙ ЛУЧЕВОЙ ТЕРАПИИ НА ФОНЕ ЛЕКАРСТВЕННОЙ ТЕРАПИИ

Purpose: to evaluate the effectiveness of a “short” course of neoadjuvant radiation therapy using two radio modifiers with different mechanisms of radio-modulating action together with a drug therapy. Material and methods: To increase the effectiveness of radiation therapy there was created a variant of combined treatment of patients with rectal cancer, using the concept of polyradiomodification. Two radio modifiers have been applied (local microwave hyperthermia and intrarectal Metronidazole administration as part of a polymer composition) together with neoadjuvant radiation therapy and oral administration of Capecitabine, followed by surgical intervention 4–6 weeks after the end of radiation therapy. For intrarectal delivery of Metronidazole to the tumor, a new medical device was created, which is a biopolymer composition in the form of a hydrogel with a Metronidazole substance physically immobilized in it (RF Patent No. 2007139304, 2007). Results: The study included 520 patients, of whom 114 underwent a new variant of combined treatment with modulation of the effect of irradiation with two different radiomodifiers together with a drug therapy (group-1), 193 patients underwent only single-mode radiation therapy (group-2), and 213 patients underwent a combination of radiation therapy with local microwave hyperthermia (group-3). Toxic manifestations in group-1 was diagnosed in 38 (33,3 %) of 114 patients, general toxic manifestations of the III degree – in 13 (11,4 %) of 114. Postoperative complications in the group-1 was observed in 21 (18,4 %) of 114 patients, which was significantly less than in the group-2 and group-3, where they occurred in 78 (40,4 %) of 193 (p=0,0001) and in 78 (36,6 %) of 213 (p=0,0006). With a median follow-up of 54,6 months. relapses of cancer in the group-1 was not detected in any of 114 patients, which is significantly less than in the group-2, in which cancer relapses were diagnosed in 17 (8,8 %) of 193 patients (p=0,0011), and in the group-3, where they were detected in 10 (4,7 %) of 213 patients (p=0,0188). This made it possible to increase the number of sphincter-preserving operations performed in the group-1 to 84,2 %, which is significantly more compared to 53,4 % in the group-2 (p=0,00001) and 56,8 % in the group-3 (p=0,00001). It was also possible to significantly increase the rate of five-year relapse-free survival in the group-1 up to 82,9 % compared to 65,3 % at group-2 (p=0,01106) and 61,1 % at group-3 (p=0,00276). Conclusion: The treatment option using polyradiomodification is effective in improving local antitumor control of the disease and increasing relapse-free survival rates compared to other combined treatment options.

Influence of late radiation complications on long-term survival of patients treated with irradiation of the pelvic organs

Background. Radiation therapy is one of the main treatments for locally advanced cancers of the rectum, cervix, and prostate. As a result of summing up high total doses, radiation damage occurs in patients.Aim. To determine the frequency of late radiation injuries in patients, their impact on overall survival and quality of life.Materials and methods. The study included 759 patients who received treatment in medical facilities in St. Petersburg and the Leningrad Region, of which 324 were men and 435 were women aged 27–88 years, with a diagnosis of rectal cancer – 257, cervical cancer – 327, prostate cancer – 175 patients. Irradiation was carried out on linear accelerators and brachytherapy devices. The quality of life of patients was assessed by questionnaires based on QLQ-30.Results. The overall toxicity was 35.01 % in patients with cervical cancer, 10.4 % in patients with rectal cancer and 7.6 % in patients with prostate cancer. Overall long-term 5 and 10 years survival in patients with late complications was 46.3 and 16.5 %versus66.5 and 33.4 % in patients without late complications (p= 0.001). In patients diagnosed with rectal cancer, it was significantly higher than in other groups (p&lt;0.05). 3–5 weeks after the end of radiation therapy, patients reported a significant deterioration in the quality of life.Conclusion. Late radiation damage is an important prognostic factor influencing long-term survival in patients diagnosed with cancer of the rectum, cervix and prostate. A decrease in the quality of life in patients who received irradiation of the pelvic organs 3–5 weeks after the end of radiation therapy has been proven.

Adjuvant Apatinib in Nasopharyngeal Carcinoma With Residual Epstein-Barr Virus DNA After Radiation Therapy: A Biomarker-Driven, Phase 2 Trial

We previously demonstrated that real-time monitoring of plasma Epstein-Barr virus DNA (EBV DNA) during chemoradiation therapy defined 4 distinct phenotypic clusters of nasopharyngeal carcinoma. In particular, the treatment-resistant group, defined as detectable EBV DNA at the end of radiation therapy, had the worst prognosis and is thought to have minimal residual disease. This is the first phase 2 trial to use a targeted agent, apatinib (an inhibitor of vascular endothelial growth factor receptor 2 tyrosine kinase), in the treatment-resistant group. Eligible patients had plasma EBV DNA > 0 copies/mL at the end of radiation therapy (±1 week). Patients received apatinib (500 mg, once daily) until disease progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint was disease-free survival (DFS). Twenty-five patients were enrolled and 23 patients who received apatinib were included in the analyses. Three-year DFS was 47.8% and overall survival was 73.9%. Patients with plasma vascular endothelial growth factor-A ≤150 pg/mL at 28 days after the initiation of treatment had significantly better 3-year DFS (66.7% vs 14.3%; P = .041) and overall survival (88.9% vs 42.9%; P = .033). The most common adverse event of grade ≥3 was nasopharyngeal necrosis (26%), oral/pharyngeal pain (22%), and hand-foot syndrome (22%). Nineteen patients had serial EBV DNA data. Fourteen patients had plasma EBV DNA clearance (turn to 0), and 5 (36%) of these 14 patients had disease recurrence or death, whereas all 5 patients without EBV DNA clearance had disease recurrence or death (3-year DFS: 64.3% vs 0%; P = .001). The use of antiangiogenic agents shortly after radiation therapy might increase the risk of necrosis. This approach needs to be avoided until translational and preclinical studies reveal the underlying mechanism of interaction between radiation therapy and antiangiogenic agents.

Abstract P4-11-21: Plasma cytokine levels in breast cancer-related lymphedema patients

Abstract Background: Breast cancer-related lymphedema (BCRL) is encountered by approximately 40% of breast cancer survivors. BCRL drastically affects quality of life, as the arm, breast, and trunk swelling, together with pain, depression, and cellulitis risk can make everyday functions difficult or impossible. Objective: To identify plasma biomarkers that can suggest targeted pharmacological treatments for breast cancer survivors who develop lymphedema (LE). Methods: In a prospective, ongoing, longitudinal clinical study (NCT02949726), peripheral blood, perometric arm volumes, and near-infrared fluorescence lymphatic images/videos (NIRF-LI) for the first 33 enrolled advanced breast cancer patients were collected pre-mastectomy/breast-conserving surgery with ALND, four weeks postoperatively, at the end of radiation therapy (RT), and at 6 months post-RT. 29 cytokines were measured at each time point using a MILLIPLEX MAP human cytokine/chemokine magnetic bead panel from isolated blood plasma. Cytokine levels in subjects with &amp;gt;5% perometric arm swelling at 6 months post-regional nodal RT were analyzed and compared to those with &amp;lt;5% perometric arm swelling at 6 months post-regional nodal RT. Additionally, subjects who exhibited LE-associated dermal backflow, identified by cloudy fluid masses, instead of linear vessels, with NIRF-LI, at 6 months post-regional nodal RT were compared to those without backflow at 6 months post-regional nodal RT. GraphPad/Prism 9 non-parametric Mann-Whitney t-test was used to compute the p-values of each cytokine. P-values less than 0.05 were deemed significant. Results: Out of the 33 subjects, 7 developed &amp;gt;5% perometric arm swelling 6 months post-regional nodal RT and 15 developed dermal backflow 6 months post-regional nodal RT. Of the 15 subjects that developed backflow, 7 also had &amp;gt;5% perometric arm swelling. G-CSF, GM-CSF, IL-10, IL-12p40, and IL-1R-alpha were found to be significantly higher in subjects with &amp;gt;5% perometric arm swelling at 6 months post-RT than in subjects with &amp;lt;5% perometric arm swelling while IL-1beta was identified to be significantly lower in subjects with backflow at 6 months post-regional nodal RT than those without backflow at 6 months post-regional nodal RT. Conclusions: G-CSF, GM-CSF, IL-10, IL-12p40, IL-1Ralpha, and IL-1beta are candidate biomarkers for detecting and directing pharmacological treatment for lymphedema in breast cancer survivors. Citation Format: Anna R Vang, Simona F Shaitelman, Eva M Sevick-Muraca, Chan Wen-yaw, John C Rasmussen, Sarah D DeSnyder, Melissa B Aldrich. Plasma cytokine levels in breast cancer-related lymphedema patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-21.

Integrate Sequence Information of Dose Volume Histogram in Training LSTM-based Deep Learning Model for Lymphopenia Diagnosis

We previously demonstrated that the mean doses of lung, heart, thymus, and thoracic duct are significant for radiation induced lymphopenia. Here we hypothesized that deep learning model based on LSTM can integrate the full dose volume histogram (DVH) data and the clinical information to predict lymphopenia more accurately in patients with non-small cell lung cancer.Patients with primary lung cancer treated with definitive or palliative radiotherapy, with pre and post with full DVH data and clinical information were eligible. Lymphopenia was defined as absolute counts. Patients were randomly split as train dataset containing 83 patients and validation dataset containing 21 patients. The models tested consisted Bi-directional LSTM neural networks, LSTM neural networks, and full connected networks, which can output the lowest level of lymphocyte count during radiotherapy and the level of the largest change in lymphocyte count compared with initial lymphocyte count at the same time. Additionally, the analysis was compared with random forest method with simple features of stage, chemotherapy, mean dose of lung, heart, thymus, and thoracic duct.A total of 104 patients were eligible (age median = 62.00 years). 83 out of 104 had lymphopenia at the end of radiation therapy. There were 84 patients that were male and 20 that were female. The number of patients in staged I, stage II, stage III and stage IV were 5, 5, 64, and 30, respectively. LSTM-based Deep Learning Model was generated in the training dataset with area under the receiver operating characteristic curve (AUC) of 0.80, and validated on validation dataset with AUC of 0.80. The AUC from the random forest model of the clinical factors plus simple mean doses of the organs were 0.62.This study suggests that the LSTM-based deep learning model of integrating the full dosimetric information with the clinical information to improve lymphopenia predictions in patients with lung cancer treated with radiotherapy. Independent validation is needed before this model can be used to guide clinical practice to reduce radiation lymphopenia.

Potential determinants of radiation-induced lymphocyte decrease and lymphopenia in breast cancer patients by machine learning approaches.

e12567 Background: Radiation-induced lymphopenia accompanied with radiation therapy is associated with inferior clinical outcomes in a wide variety of solid malignancies. This study aimed to examine the potential determines of radiation-induced lymphocyte decrease and radiation-induced lymphopenia in breast cancer patients who underwent radiotherapy. Methods: Patients with breast cancer treated who underwent radiotherapy were enrolled in University of Hong Kong-Shenzhen Hospital (our cohort). Circulating lymphocyte levels were evaluated within 7 days prior to and end of radiation therapy. Feature groups including clinical data, tumor characteristics, radiotherapy dosimetrics, treatment regiments were also collected. We applied machine learning algorithms (Extreme Gradient Boosting, XGboost) to predict the ratio of lymphocyte level after radiotherapy to baseline lymphocyte level and the event of lymphopenia and compared with Lasso regression approaches. Next, we used Shapley additive explanation (SHAP) to explore the directional contribution of each feature for lymphocyte decrease and lymphopenia. For the purpose of model validation and proof-of-concept validation, an independent cohort of patients enrolled in prospective trial was eligible (IP cohort). Results: A total of 589 patients were enrolled in our cohort and 203 patients in IP cohort. XGboost models which trained in our cohort with performances of a mean RMSE: 0.157 and R2: 53.9% for the ratio of lymphocyte levels; a mean accuracy: 0.757 and ROC-AUC: 0.733 for the lymphopenia events, separately. These models can predict the ratio of lymphocyte levels with a mean RMSE: 0.175 and R2: 47%; predict the lymphopenia events with a mean accuracy: 0.739 and ROC-AUC: 0.737 in the totally independent IP cohort. The feature group of dosimetrics had the largest predictive power with RMSE: 0.192, R2: 29.8%, accuracy: 0.678 and ROC-AUC: 0.667; followed by the group of baseline blood cells with predictive power as RMSE: 0.207, R2: 18.9%, accuracy: 0.669 and ROC-AUC: 0.645. Next, by SHAP value analysis, we investigated that integral dose of the total body, V5 dose, mean lung dose and V20 dose of ipsilateral lung/bilateral lungs were in consequence important promote factors for lymphocyte decrease and for the event of lymphopenia, while the features of baseline monocyte, mean heart dose and tumor size played a role of protection at some extend. Conclusions: In this study, we constructed robust XGboost models for predicting the lymphocyte decrease and the event of lymphopenia in breast cancer patients who underwent radiation therapy. We also applied SHAP analysis for revealing the directional contribution of features. These results are important either for the understanding the contributions of dosimetrics on immune response or for the refine of radiation dosimetrics before treatment in future clinical usages.

Association of Epigenetic Age Acceleration With Risk Factors, Survival, and Quality of Life in Patients With Head and Neck Cancer.

Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival (PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiation therapy. Patients without distant metastasis were enrolled and followed before and at the end of radiation therapy and at 6 and 12 months after radiation therapy. EAA was calculated with DNAmPhenoAge at all 4 time points. Risk factors included demographic characteristics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020, and QOL was measured using Functional Assessment of Cancer Therapy-HNC. Increased comorbidity, symptoms unrelated to human papilloma virus, and more severe treatment-related symptoms were associated with higher EAA (P = .03 to P < .001). A nonlinear association (quadratic) between body mass index (BMI) and EAA was observed: decreased BMI (<35 kg/m2; P = .04) and increased BMI (≥35 kg/m2; P = .01) were linked to higher EAA. Increased EAA (per year) was associated with worse OS (hazard ratio [HR], 1.11 [95% confidence interval {CI}, 1.03-1.18; P = .004]; HR, 1.10 [95% CI, 1.01-1.19; P = .02] for EAA at 6 and 12 months after treatment, respectively) and PFS (HR, 1.10 [95% CI, 1.02-1.19; P = .02]; HR, 1.14 [95% CI, 1.06-1.23; P < .001]; and HR, 1.08 [95% CI, 1.02-1.14; P = .01]) for EAA before, immediately after, and 6 months after radiation therapy, respectively) and QOL over time (β = -0.61; P = .001). An average of 3.25 to 3.33 years of age acceleration across time, which was responsible for 33% to 44% higher HRs of OS and PFS, was observed in those who died or developed recurrence compared with those who did not (all P < .001). Compared with demographic and lifestyle factors, clinical characteristics were more likely to contribute to faster biological aging in patients with HNC. Acceleration in epigenetic age resulted in more aggressive adverse events, including OS and PFS. EAA could be considered as a marker for cancer outcomes, and decelerating aging could improve survival and QOL.