Radiation-induced Toxicity Research Articles

Patient- and physician-reported radiation-induced toxicity of short-course radiotherapy with a prolonged interval to surgery for rectal cancer.

A prolonged interval (>4 weeks) between short-course radiotherapy (25 Gy in five fractions) (SCRT-delay) and total mesorectal excision for rectal cancer has been associated with a decreased postoperative complication rate and offers the possibility of organ preservation in the case of a complete tumour response. This prospective cohort study systematically evaluated patient-reported bowel dysfunction and physician-reported radiation-induced toxicity for 8 weeks following SCRT-delay. Patients who were referred for SCRT-delay for intermediate risk, oligometastatic or locally advanced rectal cancer were included. Repeated measurements were done for patient-reported bowel dysfunction (measured by the low anterior resection syndrome [LARS] questionnaire and categorized as no, minor or major LARS) and physician-reported radiation-induced toxicity (according to Common Terminology Criteria for Adverse Events version 4.0) before start of treatment (baseline), at completion of SCRT and 1, 2, 3, 4, 6 and 8 weeks thereafter. Fifty-one patients were included; 31 (61%) were men and the median age was 67 years (range 44-91). Patient-reported bowel dysfunction and physician-reported radiation-induced toxicity peaked at weeks 1-2 after completion of SCRT and gradually declined thereafter. Major LARS was reported by 44 patients (92%) at some time during SCRT-delay. Grade 3 radiation-induced toxicity was reported in 17 patients (33%) and concerned predominantly diarrhoea. No Grade 4-5 radiation-induced toxicity occurred. During SCRT-delay, almost every patient experiences temporary mild-moderate radiation-induced toxicity and major LARS, but life-threatening toxicity is rare. SCRT-delay is a safe alternative to SCRT-direct surgery that should be proposed when counselling rectal cancer patients on neoadjuvant strategies.

Lenvatinib Synergistically Promotes Radiation Therapy in Hepatocellular Carcinoma by Inhibiting Src/STAT3/NF-κB-Mediated Epithelial–Mesenchymal Transition and Metastasis

This study suggested that lenvatinib may incapacitate hepatocellular carcinoma (HCC) to radiation treatment by abrogating radiation-induced Src/signal transducer and the activator of transcription 3 signaling (STAT3)/nuclear factor-κB (NF-κB) to escalate radiation-induced extrinsic and intrinsic apoptosis. These findings uncover the role of targeting Src and its arbitrating epithelial-mesenchymal transition (EMT), which could increase the anti-HCC efficacy of radiation therapy (RT). Lenvatinib and sorafenib are multikinase inhibitors used to treat HCC. Lenvatinib is noninferior to sorafenib in the therapeutic response in HCC. However, whether lenvatinib intensifies the anti-HCC efficacy of RT is ambiguous. Several oncogenic kinases and transcription factors, such as Src, STAT3, and NF-κB, enhance the radiosensitivity of cancers. Therefore, we aimed to investigate the roles of the Src/STAT3/NF-κB axis in HCC after RT treatment and assessed whether targeting Src by lenvatinib may enhance the effectiveness of RT. Hep3B, Huh7, HepG2, and SK-Hep1 HCC cells and 2 types of animal models were used to identify the efficacy of RT combined with lenvatinib. Cellular toxicity, apoptosis, DNA damage, EMT/metastasis regulation, and treatment efficacy were validated by colony formation, flow cytometry, Western blotting, and in vivo experiments, respectively. Knockdown of Src by siRNA was also used to validate the role of Src in RT treatment. Silencing Src reduced STAT3/NF-κB signaling and sensitized HCC to radiation. Lenvatinib reversed radiation-elicited Src/STAT3/NF-κB signaling while enhancing the anti-HCC efficacy of radiation. Both lenvatinib and siSrc promoted the radiation effect of cell proliferation on suppression, inhibition of the invasion ability, and induction of apoptosis in HCC. Lenvatinib also alleviated radiation-triggered oncogenic and EMT-related protein expression. Our findings uncovered the role of the Src/STAT3/NF-κB regulatory axis in response to radiation-induced toxicity and confirmed Src as the key regulatory molecule for radiosensitization of HCC evoked by lenvatinib.

KS01.5.A Impact of reduced treatment volumes on pattern of tumor recurrence and radiation dose to normal brain parenchyma in glioblastoma

Abstract Background to analyze GBM recurrence pattern after standard chemoradiotherapy according to different target volume delineations. We hypothesized that reduced target volume margins may result in similar pattern of failure. Material and Methods 207 patients with GBM who recurred after standard chemoradiation were evaluated. According to the Advisory Committee for Radiation Oncology Practice (ACROP) committee of the European Organisation for Research and Treatment of Cancer (EORTC) target volume delineation guideline, the clinical target volume (CTV) used for treatment planning consisted of residual tumor and resection cavity plus 2-cm margin. MRI scans showing tumor recurrences were fused with the planning computed tomography (CT), and the patterns of failure were analyzed dosimetrically using dose-volume histograms. The recurrent lesions were defined as in-field, marginal, or distant if >80%, 20-80%, or <20% of the intersecting volume was included in the 95% isodose line. For each patient a theoretical plan consisting of a reduced CTV using 1-cm margin was created and patterns of failure evaluated. Results The median overall survival and progression-free survival were 15.3 months and 7.8 months, respectively, from the date of surgery. Recurrences were in-field in 180 patients, marginal in 5 patients, and distant in 22 patients. Analysis of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status showed different recurrence patterns of GBMs in patients with MGMT methylated compared with patients with MGMT unmethylated status. Recurrences occurred in-field and distant in 75.6% and 18.6% of methylated patients and in 91.8% and 6% of unmethylated patients, respectively (p=0.0046). Patterns of failure were similar between the different treatment plans. Reduced target volumes were associated with significantly lower doses of 20-50 Gy to normal brain and hippocampi (p=0.0001). Conclusion Most of patients treated with standard chemioradiotherapy have in-field recurrences; however, an increased risk of distant recurrences occurs in methylated tumors. The use of target delineation using 1-cm CTV margin is associated with smaller volumes of normal brain and hippocampi irradiated to high doses, without significant changes in the pattern of failure. The impact of different target delineation in terms of efficacy and risk of late radiation-induced toxicity should be assessed prospectively.

P11.25.B Adjuvant high precision hypofractionated radiotherapy for resected brain metastases: single-institutional experience

Abstract Background The proportion of patients with solid tumor who develop brain metastases may be as high as 35%. Whenever possible, resection should be the first treatment option. Unfortunately, resection alone has recurrence rates up to 50-60%. In order to improve local control, adjuvant radiation to the surgical cavity is highly recommended. Single dose stereotactic radiosurgery (SRS) as well as hypofractionated stereotactic radiotherapy (HFSRT) have shown one-year local control rates from 70 to 90% with low incidence of radiation-induced toxicity. High precision hypofractionated radiotherapy (HFRT) using Volumetric Modulated Arc Therapy (VMAT) combines sharp dose gradients of SRS with a fractionated scheme, allowing high radiation doses per fraction while minimizing adverse events. Therefore, it could be used as an alternative to SRS for target volumes larger than 3 cm or close to sensitive brain areas. This study aims to analyze control parameters and toxicity of High precision HFRT after brain metastasis resection. Material and Methods We retrospectively analyzed 38 patients diagnosed with brain metastases underwent complete or subtotal surgical resection followed by adjuvant High precision HFRT between January and December 2019 at Catalan Institute of Oncology, Badalona. Radiation was delivered using VMAT technique with 6 MV photon beams. Patient immobilization was achieved using commercial radiotherapy-thermoplastic-mask and daily image guide control with CBCT (cone beam computed tomography) was performed. Statistical analysis was performed with SPSS.PASW.Statistics.v18. Results We identified 38 patients (47.4% men, 52.6% women) with a median age at diagnosis of 61 years [37 - 83 years]. Most of the primary neoplasms were from lung (50%) and breast cancer (24%). The median size of cavities was 10,5cc [0.4 - 75.5cc]. Radiation scheme was selected depending on size and location of the surgical cavity, primary tumor histology and patient’s performance status. Forty-two percent of patients received 27 Gy/3 fractions, 39% received 24 Gy/3 fractions and 7% received 18Gy/3fractions. The remaining four patients received 35 Gy/5fr (3%), 15 Gy/3fr (3%), 16 Gy/2fr (3%) and 30Gy/10fr (3%) respectively. With a median follow-up of 9.9 months, brain recurrence was observed in 23 patients (60%), with only 7 patients (18.4%) showing local relapse at surgical cavity. One-year local control rate was 81% for all patients. Radiation necrosis was confirmed by Positron Emission Tomography in 3 patients (7.8%). Leptomeningeal disease was observed in 5 patients (13.2%). No significant differences were observed between radiation schemes nor primary tumor histology. Conclusion Surgery followed by High precision HFRT delivered with VMAT technique is an effective and safe treatment alternative to SRS for selected patients with brain metastases.

Hypofractionated versus conventional intensity-modulated radiation irradiation (HARVEST-adjuvant): study protocol for a randomised non-inferior multicentre phase III trial

IntroductionShort course regimen has become the major trend in the field of adjuvant radiotherapy for patients with breast cancer. Hypofractionated radiotherapy (HF-RT) regimen of 40–42.5 Gy in 15–16 fractions has...

Risk of Cerebrovascular Events Among Childhood and Adolescent Patients Receiving Cranial Radiation Therapy: A PENTEC Normal Tissue Outcomes Comprehensive Review

Radiation-induced cerebrovascular toxicity is a well-documented sequelae that can be both life-altering and potentially fatal. We performed a meta-analysis of the relevant literature to create practical models for predicting the risk of cerebral vasculopathy after cranial irradiation. A literature search was performed for studies reporting pediatric radiation therapy (RT) associated cerebral vasculopathy. When available, we used individual patient RT doses delivered to the Circle of Willis (CW) or optic chiasm (as a surrogate), as reported or digitized from original publications, to formulate a dose-response. A logistic fit and a Normal Tissue Complication Probability (NTCP) model was developed to predict future risk of cerebrovascular toxicity and stroke, respectively. This NTCP risk was assessed as a function of prescribed dose. The search identified 766 abstracts, 5 of which were used for modeling. We identified 101 of 3989 pediatric patients who experienced at least one cerebrovascular toxicity: transient ischemic attack, stroke, moyamoya, or arteriopathy. For a range of shorter follow-ups, as specified in the original publications (approximate attained ages of 17 years), our logistic fit model predicted the incidence of any cerebrovascular toxicity as a function of dose to the CW, or surrogate structure: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy. At an attained age of 35 years, our NTCP model predicted a stroke incidence of 0.9% to 1.3%, 1.8% to 2.7%, and 2.8% to 4.1%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.2%-0.3%). At an attained age of 45 years, the predicted incidence of stroke was 2.1% to 4.2%, 4.5% to 8.6%, and 6.7% to 13.0%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.5%-1.0%). Risk of cerebrovascular toxicity continues to increase with longer follow-up. NTCP stroke predictions are very sensitive to model variables (baseline stroke risk and proportional stroke hazard), both of which found in the literature may be systematically erring on minimization of true risk. We hope this information will assist practitioners in counseling, screening, surveilling, and facilitating risk reduction of RT-related cerebrovascular late effects in this highly sensitive population.

Radiation therapy in breast cancer: a narrative review on current standards and future perspectives

: Mastectomy and reconstructive procedures have been refined over the decades, allowing for aesthetic outcomes close to the native breast shape and in symmetry with the contralateral intact breast or even to improve breasts appearance and symmetry. Similarly, improvements in radiation oncology can help reduce treatment related toxicity and improve outcomes. However, postmastectomy radiation therapy (PMRT) is associated with poor cosmetic outcomes and increased rate complications in patients who undergo breast reconstruction. Radiation therapy planning should be guided by disease stage, risk of recurrence, correct definition of the target volumes and treatment objectives. Currently, there are guidelines endorsed by European Society for Radiotherapy and Oncology (ESTRO) for target volume delineation for breast cancer and elective nodal volumes, including after immediate reconstruction. Correct target volume delineation, along with meticulous radiation planning, total dose and fractionation, dose homogeneity, and organs at risk (OAR) doses are significant for reducing radiation-induced toxicity. Currently, tremendous efforts are done by different groups to improve aesthetic outcomes without compromising disease outcomes in breast cancer patients who are candidates for mastectomy and radiation therapy. The current paper summarizes key principles in PMRT, considering new surgical techniques for immediate breast reconstruction and new, partly experimental radiation techniques including future trials and proton beam irradiation.

Effect of Smoking on Treatment Efficacy and Toxicity in Patients with Cancer: A Systematic Review and Meta-Analysis.

Simple SummaryThe impact of smoking on cancer treatment efficacy and toxicity regardless of cancer type was investigated in this meta-analysis. Smoking during radiotherapy/chemoradiotherapy was associated with worse outcomes and a higher risk for toxicity. Smoking during treatment with EGFR tyrosine kinase inhibitors in lung cancer patients was associated with a worse prognosis, whereas smoking was associated with better outcomes in patients treated with checkpoint inhibitors. No association between smoking and treatment efficacy of chemotherapy was observed, though with low certainty of evidence. Our results can be used by oncology and radiotherapy staff to give patients more convincing information on the benefits that can be derived from smoking cessation before cancer treatment.Aim: The aim of the present systematic review and meta-analysis was to summarize the current evidence on the potential impact of smoking during cancer treatment on treatment efficacy and toxicity irrespective of cancer type. Methods: A systematic literature search was performed using two electronic databases for potentially eligible studies. Only studies based on multivariable analysis for the association between smoking, compared to non-smokers (never or former), and treatment efficacy or toxicity were included. Pooled Hazard Ratios (HRs) or Odds Ratios (ORs) and corresponding 95% Confidence Intervals (CIs) were estimated through random-effects meta-analyses. Results: In total, 97 eligible studies were identified, of which 79 were eligible for the pooled analyses. Smoking during radiation therapy, with or without chemotherapy, was associated with an increased risk of locoregional recurrence (pooled HR: 1.56; 95% CI: 1.28–1.91 for radiation therapy; pooled HR: 4.28; 95% CI: 2.06–8.90 for chemoradiotherapy) and worse disease-free survival (pooled HR: 1.88; 95% CI: 1.21–2.90 for radiation therapy; pooled HR: 1.92; 95% CI: 1.41–2.62 for chemoradiotherapy) as well as a higher risk for radiation-induced toxicity (pooled OR: 1.84; 95% CI: 1.32–2.56 for radiation therapy; pooled OR: 2.43; 95% CI: 1.43–4.07 for chemoradiotherapy) with low-to-moderate certainty of evidence. Smoking during treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with lung cancer was associated with worse progression-free survival compared to non-smokers (pooled HR: 1.43; 95% CI: 1.14–1.80; moderate certainty of evidence), whereas smoking was associated with improved progression-free survival in patients treated with checkpoint inhibitors (HR: 0.70; 95% CI: 0.58–0.84; moderate certainty of evidence). No statistically significant associations were observed between smoking and treatment efficacy or toxicity to chemotherapy. Conclusion: The present meta-analysis confirms earlier evidence of the negative impact of smoking during radiation therapy, with or without chemotherapy, on treatment efficacy and radiation-induced toxicity as well as a negative impact of smoking on the efficacy of EGFR-TKIs and a positive impact on the efficacy of checkpoint inhibitors. The evidence is too weak to draw firm conclusions on the potential association between smoking and chemotherapy, whereas there is no evidence for pooled analyses regarding other types of systemic oncological therapy.

BSCI-17 TOPIRAMATE DECREASES RADIATION-INDUCED CYTOTOXIC EDEMA IN HER2+ BRAIN METASTASES VIA AQUAPORIN 4 INHIBITION

Abstract Brain metastasis (BM) occurs in 30-40 % of breast cancer patients with Her2+ tumors, and radiation is part of the standard treatment for BM. About 10% of BM patients treated with radiation develop brain edema. We have shown that combination of Ado-trastuzumab Emtansine (T-DM1)-the main targeted therapy for metastatic Her2+ Breast Cancer- and radiation increases the risk of developing radionecrosis by 13.5-fold (Stump et al., 2019). We also showed that T-DM1 enhances radiation-induced astrocytic toxicity and cytotoxic edema through upregulation of aquaporin-4 water-transporter (AQP4). Here, we determined whether blockage of AQP4 would prevent astrocytic swelling –cytotoxic edema- in vitro and in vivo models of Her2+ BM. Results: Electron microscopy of brain cortex from mice treated with 35 Gy (single dose), showed acute astrocytic end-feet swelling and a significant increase in AQP4 expression compared with non-irradiated mice. Consistent with prior findings in murine astrocytes, primary human astrocytes (huAST) also upregulated AQP4 levels 24 h post-radiation (8 Gy), and T-DM1 treatment exacerbated this effect. AQP4 upregulation was concomitant with 4.8 fold increase in the astrocytic area (indicative of cytotoxic edema). The FDA-approved anti-epileptic and migraine prevention drug, Topiramate (TPM), which works as an AQP4 inhibitor, blocked radiation-induced astrocytic swelling in huAST in vitro. Thus, we tested whether pre-treatment with TPM could prevent radiation-induced edema in a mouse model of HER2+BMs. Mice were injected intracardially JmT1BR3 brain metastatic cells and ten days later randomized based on the total head flux to (1) Radiation + vehicle, (2) Radiation + TPM (2 days prior to irradiation), (3) Non-Radiation + vehicle, and (4) Non-radiation + TPM. TPM decreased brain-water content (a marker of brain edema) in irradiated mice as compared with vehicle-treated mice, without alteration of metastatic burden 21 days post-injection. These results suggest TPM could be repurposed as a preventive agent of radiation-induced brain edema.

Abstract 3319: Purified poloxamer 188 mitigates radiation-induced lung toxicity

Abstract The dose-limiting factor in radiation therapy (RT) is damage to healthy tissues, which presents as radiation-induced lung toxicity (RILT). Acute RILT, pneumonitis, is an early inflammatory-driven toxicity that develops within weeks to months following RT. Purified poloxamer 188 (PP188) is a triblock copolymer that associates with and protects cell membranes from oxidative insult, minimizing secondary inflammatory damage. This study aimed to investigate the effects of PP188 to mitigate the onset of acute radiation pneumonitis in a rat model of RILT, and to test the effect of PP188 on the efficacy of RT on tumor growth of a syngeneic CT26.WT murine colon carcinoma in Balb/c mice. To evaluate the efficacy of PP188 to mitigate RILT in healthy tissues, Sprague Dawley rats were given 200mg/kg PP188 or vehicle via IV 1hr prior to a single dose of partial volume (6mm) 20Gy X-irradiation to the right lung, and then were followed for 6 weeks. To validate PP188 treatment does not interfere with RT efficacy to reduce tumor volume, Balb/c mice were implanted with CT26.WT murine colon adenocarcinoma in the high axilla space, given 5Gy SARRP irradiation, and tumor volume was monitored. Rats were evaluated for histopathological changes indicative of acute RILT, including leakage of proteins into alveolar space, thickening of alveolar septa, and alteration of bronchial epithelium and capillaries; for presence of inflammatory infiltrate (Hanker-Yates Peroxidase Leukocyte kit); and for immunohistochemical expression of alpha-smooth muscle actin (SMA). Without PP188, significant inflammatory infiltrate was observed in all lungs bilaterally (p<0.001) contributing to significant bronchiole epithelium thickening (p<0.001) and alveolar septa thickening (p<0.001). Within the thickened alveoli there was significant SMA expression (p<0.001) indicative of cells undergoing a myofibroblast transition that was not observed in the PP188+RT animals or controls. Morphological assessment demonstrated that PP188 significantly attenuated pathological changes in the functional subunits of the lung, alveoli, as well as the vasculature including bronchiole epithelium and small capillaries, with no significant differences from control animals. Finally, it was shown that PP188 does not abrogate radiation-induced tumor volume reduction. The unique mechanism of PP188 provides radioprotection to healthy tissue without interfering with tumor control, and has the potential to mitigate radiation-induced toxicities in the majority of cancers treated with RT. Citation Format: Sarah G. Dennis-Little, Wilfred Ngwa, Marikki Laiho, Graham Warren, Michael J. Yost. Purified poloxamer 188 mitigates radiation-induced lung toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3319.

Abstract 3304: Gene expression profiling of full-thickness skin after FLASH proton radiotherapy

Abstract Purpose: To investigate the transcriptomic changes induced by FLASH proton radiotherapy (F-PRT) that could be responsible for the protection of normal epithelial tissues by radiation-induced toxicities as have been previously shown by us and others. Methods: C57BL/6J mice received 30 Gy of F-PRT or S-PRT to the hind leg at respective dose rates of 69-124 Gy/sec or 0.39-0.65 Gy/sec. RNA sequencing was performed using full-thickness leg skin at 5 days after radiation revealing major pathways regulated by F-PRT and S-PRT. In an endeavor to identify the full repertoire of cells and gene expression profiles that are involved in the sparing effects of FLASH PRT, we expanded our studies to include single-cell RNA sequencing (sc-RNA seq) and examined additional time points such as Day 2 and Day 10 after radiation. Single-cell transcriptome libraries were generated on a 10X Genomics Chromium system. Datasets were acquired from cell samples derived and sequenced from pooled skin samples of three mice per group. Skin from the sequenced mice was also embedded for spatial analysis of gene expression. Results: RNA sequencing revealed that F-PRT uniquely upregulates almost four times more genes compared to S-PRT (F-PRT-uniquely upregulated 489 genes vs S-PRT-uniquely upregulated 129 genes). Also, F-PRT uniquely downregulated 178 genes, compared to the 125 genes uniquely downregulated by S-PRT. GO analysis demonstrates that the keratinization and apoptosis pathways are uniquely upregulated by S-PRT, whereas F-PRT uniquely upregulates genes involved in vascular development pathway. During submission of the abstract, analysis of sc-RNA seq samples was pending. Conclusion: Our comprehensive studies inform on the transcriptomic profiling of skin cell populations that are affected by F-PRT vs S-PRT; this insight will further spur discoveries on the biology of FLASH radiotherapy effects. Citation Format: Anastasia Velalopoulou, Ilias V. Karagounis, Giorgos Skoufos, Ioannis I. Verginadis, Michele Kim, Khayrullo Shoniyozov, Artemis G. Hatzigeorgiou, Eric Diffenderfer, Lei Dong, James Metz, Constantinos Koumenis, Keith A. Cengel, Amit Maity, Theresa M. Busch. Gene expression profiling of full-thickness skin after FLASH proton radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3304.

Dose-Escalated Intensity-Modulated Radiotherapy for the Management of Locally Advanced Cervical Cancer.

ObjectiveIn this study, we aimed to assess the response and toxicity related to dose escalation in external beam radiation therapy (EBRT) using intensity-modulated radiation therapy (IMRT) with weekly concurrent cisplatin followed by de-escalated brachytherapy (BT) in locally advanced carcinoma cervix of International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IIB-IIIC1.Materials and methodsFifty-two patients diagnosed with cervical cancer FIGO 2018 stage IIB-IIIC1 were treated with curative intent from November 2019 to October 2021. The dose of 50 Gy was prescribed for the primary tumor volume and elective pelvic nodal volume followed by a primary boost to a dose of 20 Gy. Gross lymph node (LN) of size >1 cm after EBRT completion received a sequential nodal boost of 10 Gy. All patients received concurrent cisplatin to a dose of 40 mg/m2 for a total of five to six weekly cycles. All patients received two fractions of BT to a dose of 6 Gy after EBRT completion. Radiation-induced acute toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) criteria and hematologic toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0).ResultsA median follow-up of six months was available for the 40 eligible patients. All patients tolerated treatment with an acceptable toxicity profile. Grade III dermatitis, grade III gastrointestinal (GI) toxicity, and grade III genitourinary (GU) toxicity were seen in three (7.5%), six (17.5%), and three patients (7.5%) respectively. Grade I anemia was evident in all patients. At six months after EBRT completion, 37 patients (92.5%) had a complete response and only three patients (7.5%) had residual disease.ConclusionBased on our findings, patients with cervical cancer treated with dose-escalated IMRT have a satisfactory outcome with reasonably low levels of treatment-related acute GI and GU toxicities. The findings of the present study endorse the notion that the application of a high dose of external radiation to the pelvis by IMRT technique with image-guided delivery could be an acceptable alternative to the standard-dose management schedule.

Sexual dimorphism in gut microbiota dictates therapeutic efficacy of intravenous immunoglobulin on radiotherapy complications

IntroductionWith the mounting number of cancer survivors, the complications following cancer treatment become novel conundrums and starve for countermeasures. Intravenous immunoglobulin (IVIg) is a purified preparation for immune-deficient and autoimmune conditions. ObjectivesHere, we investigated whether IVIg could be employed to fight against radiation injuries and explored the underlying mechanism. MethodsHematopoietic or gastrointestinal (GI) tract toxicity was induced by total body or abdominal local irradiation. High-throughput sequencing was performed to analyze the gut microbiota configurations and gene expression profile of small intestine. The untargeted metabolomics of gut microbiome was assessed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses. Hydrodynamic-based gene delivery was used to knockdown the target genes in vivo. ResultsIntravenous injection of IVIg protected against radiation-induced hematopoietic and GI tract toxicity in female mice but not in males. IVIg structured sex-characteristic gut microbiota configurations in abdominal irradiated mice. The irradiation enriched gut Lachnospiraceae in female mice but reduced those in males. IVIg injection combined with oral gavage of Lachnospiraceae or its metabolite hypoxanthine, alleviated radiation toxicity in male mice however, Lachnospiraceae or hypoxanthine alone failed to ameliorate the injuries. Abdominal local irradiation drove sex-distinct gene expression signatures in small intestine. Mechanistic investigation showed that replenishment of Lachnospiraceae or hypoxanthine offset abdominal radiation-reduced PLD1 expression in male mice. In females, irradiation elevated PLD1 expression. Deletion of PLD1 in GI tract of female mice erased the radioprotective effects of IVIg. ConclusionIVIg battles against radiation injuries in a sex-specific, gut microbiome-dependent way through Lachnospiraceae/hypoxanthine/PLD1 axis. Our findings provide a sex-precise therapeutic avenue to improve the prognosis of cancer patients with radiotherapy in pre-clinical settings.

The effect of delayed primary treatment initiation on adverse events and recurrence in older head and neck cancer patients

Background and purposeAs a result of rapid tumor growth in head and neck squamous cell carcinoma (HNSCC), delay in treatment initiation can result in tumor progression and inferior outcome. Especially older and frail patients are prone to develop adverse events. The aim of this study was to assess the effect of delay on development of adverse events and recurrence in older HNSCC patients. Materials and methodsThis cohort study with prospectively collected data included all newly diagnosed, curatively treated HNSCC patients (≥60 years) between 2015 and 2017. Time-to-treatment interval and geriatric domains were assessed. Adverse events were defined as postoperative complications (Clavien-Dindo classification) and acute radiation-induced toxicity (Common Terminology Criteria of Adverse Events). Multivariable regression models were performed, using adverse events and recurrence as outcome variables. ResultsA total of 245 patients were included. Median time-to-treatment was 26 days for surgery patients and 40 days for radiotherapy patients (p < 0.001). Delayed treatment initiation was not associated with postoperative complications or acute radiation-induced toxicity.Delay was significantly associated with recurrence risk within two years after treatment initiation in a model adjusted for stage and tumor location in patients treated with initial surgery (HR:4.1, 95%CI:1.2–14.0, p = 0.024). For patients treated with radiotherapy, delay was not significantly associated with recurrence risk. ConclusionDelayed treatment initiation was independently associated with increased recurrence risk in patients treated with initial surgery. Delay was not associated with short-term adverse events. These findings highlight the importance of establishing fast-track care pathways to minimize delays and improve especially long-term outcome.

Cardiotoxicity model-based patient selection for Hodgkin lymphoma proton therapy

Introduction Hodgkin lymphoma (HL) is a highly curable hematological malignancy. Consolidation radiation therapy techniques have made significant progresses to improve organ-at-risk sparing in order to reduce late radiation-induced toxicity. Recent technical breakthroughs notably include intensity modulated proton therapy (IMPT), which has demonstrated a major dosimetric benefit at the cardiac level for mediastinal HL patients. However, its implementation in clinical practice is still challenging, notably due to the limited access to proton therapy facilities. In this context, the purpose of this study was to estimate the benefit of IMPT for HL proton therapy for diverse cardiac adverse events and to propose a general frame for mediastinal HL patient selection strategy for IMPT based on cardiotoxicity reduction, patient clinical factors, and IMPT treatment availability. Material and methods This retrospective dosimetric study included 30 mediastinal HL patients treated with VMAT. IMPT plans were generated on the initial simulation scans. Dose to the heart, to the left ventricle and to the valves were retrieved to calculate the relative risk (RR) of ischemic heart disease (IHD), congestive heart failure (CHF) and valvular disease (VD). Composite relative risk reduction (cRRR) of late cardiotoxicity, between VMAT and IMPT, were calculated as the weighted mean of relative risk reduction for IHD, CHF and VD, calculated across a wide range of cardiovascular risk factor combinations. The proportion of mediastinal HL patients who could benefit from IMPT was estimated in European countries, based on the country population and on the number of active gantries, to propose country-specific cRRR thresholds for patient selection. Results Compared with VMAT, IMPT significantly reduced average mean doses to the heart (2.36 Gy vs 0.99 Gy, p < 0.01), to the left ventricle (0.67 Gy vs 0.03, p < 0.01) and to the valves (1.29 Gy vs. 0.06, p < 0.01). For a HL patient without cardiovascular risk factor other than anthracycline-based chemotherapy, the relative risks of late cardiovascular complications were significantly lower after IMPT compared with VMAT for ischemic heart disease (1.07 vs 1.17, p < 0.01), for congestive heart failure (2.84 vs. 3.00, p < 0.01), and for valvular disease (1.01 vs. 1.06, p < 0.01). The median cRRR of cardiovascular adverse events with IMPT was 4.8%, ranging between 0.1% and 30.5%, depending on the extent of radiation fields and on the considered cardiovascular risk factors. The estimated proportion of HL patients currently treatable with IMPT in European countries with proton therapy facilities ranged between 8.0% and 100% depending on the country, corresponding to cRRR thresholds ranging from 24.0% to 0.0%. Conclusion While a statistically significant clinical benefit is theoretically expected for ischemic heart disease, cardiac heart failure and valvular disease for mediastinal HL patients with IMPT, the overall cardiotoxicity risk reduction is notable only for a minority of patients. In the context of limited IMPT availability, this study proposed a general model-based selection approach for mediastinal HL patient based on calculated cardiotoxicity reduction, taking into consideration patient clinical characteristics and IMPT facility availability.

The association of frailty and outcomes of geriatric assessment with acute radiation-induced toxicity in patients with head and neck cancer

Background and purposeGeriatric impairments and frailty are highly prevalent in patients with head and neck cancer (HNC). This study investigated the association of frailty and outcomes of geriatric assessment (GA) with radiation-induced toxicity (RIT) in patients undergoing (chemo)radiotherapy ((C)RT) for HNC. Materials and methodsBetween October 2014 and April 2016, patients with HNC were prospectively included in OncoLifeS, an institutional data-biobank. Before treatment initiation, patients underwent GA and frailty screening (Groningen Frailty Indicator and Geriatric 8). The main outcome of this study was RIT (weight loss, mucositis, salivary gland inflammation, oral pain, sore throat, hoarseness, dry mouth, dysgeusia, dysphagia and general pain) according to the common terminology criteria of adverse events (CTCAE) version 4.0. Linear mixed models were performed, to analyse factors associated with increasing mean RIT over time during the treatment period. Results160 patients were included. 114 (71.3%) were male and the mean age was 66.1 years. Age ≥ 65 (β = 0.03(95 %CI = 0.01;0.05), p = 0.01), regional RT (β = 0.05(95 %CI = 0.02;0.09), p = 0.004), and concurrent chemotherapy (β = 0.04(95 %CI = 0.02;0.07), p = 0.001), were independent factors associated with increasing toxicity during the 7-week treatment period, adjusted for relevant covariates. None of the single items of GA, as well as the frailty screening instruments, were associated with increasing RIT. ConclusionIn this study, frailty and GA were not associated with additional RIT during treatment. These results suggest that (C)RT is equally tolerated in frail and non-frail patients, with respect to acute RIT. RT could be a suitable alternative to surgery in selected frail patients.

SPAR: A randomized placebo-controlled phase 2 trial of simvastatin in addition to standard chemotherapy and radiation in preoperative treatment for rectal cancer: An AGITG clinical trial.

TPS3646 Background: In retrospective studies statin use during preoperative chemo-radiation (pCRT) for rectal cancer is associated with improved overall survival, pathological tumor response and treatment toxicity. In vivo preclinical studies show that statins radiosensitize cancer cells, with improved tumor control and reduced radiation-induced gastrointestinal (GI) and skin toxicities. A prospective randomized trial is justified to confirm these clinically important benefits. Tumor regression following pCRT has strong prognostic significance, as assessed radiologically (MRI-based tumor regression grading [mrTRG]) prior to, or pathologically (pathTRG) following, surgery. Using mrTRG after each treatment phase in total neoadjuvant therapy (TNT) programs could assess incremental tumor regression and optimize patient management including surgery. Methods: Design: This double-blind phase 2 trial is recruiting 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 17 sites in New Zealand and Australia. Patients are randomized to simvastatin 40mg or placebo daily for 90 days, starting 1 week prior to pCRT, with minimization for major prognostic variables. Pelvic MRI at baseline and 6-8 weeks after pCRT will assess mrTRG. A protocol amendment allows TNT using consolidation chemotherapy after pCRT; MRI timing is unchanged. Primary objective: comparison of rates of grades 1-2 mrTRG following pCRT with simvastatin or placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4-5). Secondary objectives: comparison of rates of grades 1-2 pathTRG in resected tumors; incidence of &gt; grade 2 acute GI and non-GI adverse events (AE); incidence of late GI AE; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection post-pCRT; 3-year local recurrence rate, disease-free and cancer-specific survival; and pathological scores for radiation colitis. Tertiary and correlative objectives: association between mrTRG and pathTRG grouping; inter-observer scoring agreement on mrTRG and pathTRG; comparison of the association between tumor CD3+ and/or CD8+ T-cell infiltrates in diagnostic biopsies and pathTRG; intensity and distribution of subsets of infiltrating T-cells in irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Eligibility criteria exclude statin use within 6 weeks prior to trial entry, patients intolerant of statins, and planned use of oxaliplatin or biological agents during pCRT. Trial recruitment commenced April 2018 and 95 of 222 patients have been recruited as at 21 January 2022. Clinical trial information: ACTRN12617001087347.

Prospective study of biomarkers predictive of radiation-induced bladder toxicity in patients treated with radiotherapy for localized prostate cancer: RABBIO (Radiotoxicity Bladder BIOmarkers).

TPS12142 Background: Despite improvements in irradiation techniques, pelvic radiotherapy is responsible for acute and late adverse events in the bladder, defined as radiation cystitis (CysR). The early symptoms of bladder lesions secondary to pelvic irradiation are likely to occur during treatment or after radiotherapy in approximately 50% of irradiated patients. Acute radiation-related injuries are the first step of the fibrosis process. Fibrosis causes loss of bladder function and has a significant impact on the quality of life of the patients.The pathophysiology of CysR is not well understood, in particular because of the risks of complications caused by accessing the bladder tissue after irradiation, thereby limiting our ability to investigate this process and develop treatments. The main objective of our study is to assess the correlation of biologic biomarkers with the intensity of acute CysR and the quality of life of patients, evaluated with the digital telemonitoring platform Cureety. Methods: Patients with intermediate-risk localized prostate cancer and eligible for localized radiotherapy will be included. Inflammatory biomarkers will be analyzed on urine and blood samples before the initiation of radiotherapy, at week 4, 12 and 48 of irradiation, by quantitative methods such as the Multiplex Luminex assay, cytometry in flow and enzyme-linked immunosorbent assay ELISA. We will also characterize the gut and urinary microbiota in stool and urine samples using 16S rRNA sequencing technology. This is in order to assess the impact of the fecal and urinary microbiota in acute CysR. Between sample collection visits, patients will answer various questionnaires relating to the symptoms of radiation cystitis (IPSS), adverse events and quality of life (FACT-P), using the digital telemonitoring platform Cureety. Upon receipt of the questionnaires, an artificial intelligence algorithm will process the information and classify the patients according to the severity of symptoms and adverse reactions reported in accordance with CTCAE / IPSS. This will ultimately allow us to correlate urinary, blood and fecal biomarker levels with the severity of acute CysR symptoms and the quality of life reported by the patients. Conclusion: This prospective study is the first to explore the overexpression of inflammatory proteins in fluid biopsies from patients with symptoms of acute CysR. In addition, the 1-year post-treatment follow-up will allow us to predict which patients are at risk for late CysR and to stratify these patients towards radioprotective treatment. The results of this study will allow us to develop strategies to limit radiation damage to the bladder and improve the quality of life of patients. Clinical trial information: 2021A0319635.

Impact on xerostomia for patients with nasopharyngeal carcinoma treated with superficial parotid lobe-sparing intensity-modulated radiation therapy (SPLS-IMRT): A prospective phase II randomized controlled study.

6059 Background: In the intensity-modulated radiation therapy (IMRT) era, xerostomia remains one of the most common radiation-induced toxicities in nasopharyngeal carcinoma (NPC) patients. We first proposed the superficial parotid lobe–sparing IMRT (SPLS-IMRT) technique in NPC, which has been proved to significantly reduce the mean doses of bilateral entire parotid glands and superficial parotid lobes. To further validate its clinical benefits, we conducted a prospective phase II randomized controlled study to compare the incidence of xerostomia in NPC patients treated with SPLS-IMRT and conventional IMRT (C-IMRT). Methods: Patients with histologically confirmed NPC who met the eligibility criteria were randomly assigned in a 1:1 ratio to receive either SPLS-IMRT or C-IMRT. The V36 (the percentage volume receiving a dose of 36 Gy) of the entire parotid gland was constrained to be less than 40% in both groups. Additionally, V26 (the percentage volume receiving a dose of 26 Gy) of the superficial parotid lobe was constrained to be less than 30% in the SPLS-IMRT group. The primary endpoint was the incidence of xerostomia at 12 months post-IMRT. The secondary endpoints included the xerostomia questionnaire (XQ) score, unstimulated salivary flow rate (USFR), stimulated salivary flow rate (SSFR), and survival outcomes. Results: From January 2018 to September 2018, 90 patients were enrolled (45 per group). Eighty-two patients were included for xerostomia analysis (42 in the SPLS-IMRT group and 40 in the C-IMRT group). At 12 months post-IMRT, the incidence of xerostomia in the SPLS-IMRT group was significantly lower than that in the C-IMRT group (83.4% vs. 95.0%; P = 0.007), especially the grade 3 xerostomia (0% vs. 12.5%; P &lt; 0.001). However, the median change in XQ score (XQchange) was similar between the two groups (11.9 points vs. 14.1 points; P = 0.194). Moreover, there was a significantly higher median fractional USFR (0.67 vs. 0.35; P = 0.024) and SSFR (0.66 vs. 0.32; P = 0.021) in the SPLS-IMRT group than the C-IMRT group. All 90 patients were included for survival analysis. With a median follow-up time of 37.8 months (IQR, 33.9–38.5 months), the 3-year locoregional relapse-free survival, distant metastasis-free survival, and overall survival in the SPLS-IMRT and C-IMRT groups were 92.5% vs. 90.9% (hazard ratio [HR], 1.84; P = 0.477), 83.8% vs. 81.7% (HR, 1.13; P = 0.816), and 88.9% vs. 88.2% (HR, 0.96; P = 0.949), respectively. Conclusions: SPLS-IMRT significantly reduced the incidence of xerostomia at 12 months post-IMRT in NPC by recovering parotid gland function earlier than C-IMRT, without compromising survivals. Phase III clinical trials are needed to confirm this result. Clinical trial information: NCT05020067.

Ultra-Hypofractionated vs. Moderate Fractionated Whole Breast Three Dimensional Conformal Radiotherapy during the COVID-19 Pandemic.

Background and Objectives: Reducing time of treatment during COVID-19 outbreaks has been recommended by the leading Radiation Oncology societies. Still minimizing radiation induced tissue toxicity is one of the most important issues in breast cancer patients. The study aimed to investigate compliance, clinical and dosimetry normal tissue toxicity, and cosmetic results between moderated and ultra-fractionated regimes for breast cancer patients during COVID-19 pandemic. Materials and Methods: This pilot prospective randomized study included 60 patients with early breast cancer after preserving surgery, 27 patients advocated to ultra-hypofractionated whole-breast three dimensional (3D) conformal radiotherapy of 26 Gy in 5 fractions over 1 week and 33 patients with moderate fractionated breast 3D conformal radiotherapy patients between March 2020 and July 2020, during the COVID pandemic outbreak. The compliance to treatment, dosimetric parameters, acute and late skin toxicity, subcutaneous tissue toxicity, cosmetic results and clinical follow up for 18 months for the two regimes were analyzed and compared. Results: When two regimes were compared 5 fraction group had significantly lower prevalence of newly infected cases of SARS-CoV-2 and thus delayed/interrupted treatment (p = 0.05), comparable grade 1 CTCAE v5, acute skin toxicity (p = 0.18), Grade 1 Radiation Morbidity Scoring Scheme (RESS) subcutaneous tissue toxicity (p = 0.18), Grade 1 RESS late skin toxicity (p = 0.88) and cosmetic results (p = 0.46). Dosimetric results reveled that patients in 5 fraction group received significantly lower median ipsilateral lung doses (p < 0.01) in addition to left breast cancer patients that received significantly lower median heart dose (p < 0.01) and median left anterior descending artery (LAD) dose (p < 0.01). Conclusion: Ultra-hypofractionated radiotherapy for breast cancer is comparable to moderate hypofractionation regimen regarding grade 1 acute skin toxicity, grade 1 subcutaneous tissue toxicity, late skin toxicity and cosmetic results. Application of ultra-hypofractionated radiotherapy with significantly lower radiation doses for lung and heart could be crucial in reducing the risk of acute/late pulmonary and heart radiation-induced toxicity.