5538 Background: To assess the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma (Chinese Clinical Trial Registry number, ChiCTR2000032879). Methods: Twenty-two locally advanced cervical cancer patients, regardless of programmed death ligand-1 status, received toripalimab treatment combined with concurrent chemoradiotherapy. Concurrent chemoradiotherapy(CCRT) includes cisplatin (40 mg/m2, once a week for 5 weeks), radiotherapy (external irradiation 45-50.4Gy/25-28Fx, 5 fractions a week, followed by brachytherapy 24-30Gy/3-5Fx) and toripalimab (240mg on days 1, 22 and 43). The primary end-point was safety and feasibility. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), overall survival (OS). Results: The median age was 55 years old (range, 42 to 72 years old), with 2 patients in FIGO stage II, 15 patients in stage IIIC, and 5 patients in stage IVA. All patients have received CCRT successfully. Grade III and higher adverse events (AEs) were observed in 10 patients (10/22, 45.5%), and no patient had a grade V AE. The most frequent grade III AE was leukopenia (8/22, 36.4%). The most common immunotherapy-related adverse reaction was hypothyroidism (2/22, 9.1%). The 3-month ORR rate was 95.5%. At data cutoff (Jan 31, 2022), the median follow-up was 10 months (range, 3.30 to 16.73 months). One patient developed multiple metastases 3 months after treatment, and 1 patient developed lung metastasis 6 months after treatment. The ORR was 100%, while the PFS rate was 90.1%, and the OS rate was 95.5%. Conclusions: Toripalimab combined with concurrent chemoradiotherapy demonstrated a manageable safety profile and promising anti-tumor activity in patients with locally advanced cervical cancer, thus might represent a novel treatment option for this patient population. Longer follow-up results and further phase II/III studies are expected. Clinical trial information: ChiCTR2000032879.

Radiotherapy combined with chemotherapy reported promising response rate and a favorable survival for patients with stage I-II nasal ENKTL. Anthracycline-based chemotherapy regimen and no remission after RT and CT were adverse factors of OS.

Nivolumab plus ipilimumab (N+I) therapy has shown promising antitumor efficacy and safety for advanced hepatocellular carcinoma (HCC) patients after sorafenib therapy. This study aimed to explore whether N+I may improve the treatment efficacy of HCC patients who are potentially eligible for curative surgery (NCT03510871). Eligible subjects must have had a histological diagnosis of HCC, measurable tumors (by RECIST 1.1), ECOG score 0 or 1, Child-Pugh class A, and fulfilling one of the following criteria of ‘potentially eligible for curative surgery’: (a) AJCC T3 tumor(s) (tumor with macrovascular invasion); (b) AJCC T2 tumors with multiple (>3) tumors or tumors in bilateral lobes; (c) AJCC T2 tumors with significant portal hypertension (splenomegaly, esophageal varices or platelet 10% tumor size reduction as per RECIST 1.1 after N+I treatment. Subjects who were considered eligible for curative surgery received surgery, while those considered not eligible for surgery received other anti-cancer therapy according to current practice guidelines. From February 2019 to January 2021, 29 subjects were enrolled (men/women 23/6, median age 62 years, HBsAg+/ anti-HCV+ 12/3, BCLC stage A/B/C 2/8/19, liver tumor single/multiple 3/26, median tumor size 11.1 cm (range 1.8 – 16.2), median alpha-fetoprotein 64.9 ng/mL (range 2-71560)). In the 28 subjects evaluable for response, 11 (39.3%) had > 10% tumor size reduction; 7 (25%) partial responses, 10 (35.7%) stable diseases, and 11 (39.3%) progressive diseases were documented. Fifteen subjects received surgery, and 5 (33.3%) had major pathological response (>90% of tumor necrosis). The most common all-grade adverse event (AE) was hepatitis (48.3%). Grade 3-4 AE occurred in 12 subjects (hepatitis 5, infection 2, lipase increase 2, pruritus/ leukocyte decrease/ pneumonitis (one for each)), 7 of which were considered immune-related AE and required steroid treatment. RNA-Seq analysis of the pre-treatment biopsy indicated that high expression of type I interferon response genes was associated with longer progression-free survival. As of February 2021, the progression-free survival was 13.4 months (95% CI, 1.4-not reached) and 3 subjects died, all due to tumor progression. N+I neoadjuvant therapy is feasible for patients with potentially resectable HCC. Long-term follow-up is needed to clarify its efficacy in terms of increasing resectability and reducing recurrence after surgery.

Purpose: Radiation-induced temporal lobe necrosis (TLN) was once regarded as a progressive and irreversible disease in the era of two-dimensional radiotherapy. However, in the era of intensity-modulated radiotherapy (IMRT), the long-term development process of TLN remains unknown. We performed a prospective study to evaluate the dynamic changes in cognitive function in patients with TLN after definitive IMRT for nasopharyngeal carcinoma (NPC). Methods: The enrollment criteria were as follows: (1) patients must have had confirmed NPC and must have received only one course of definitive IMRT; (2) patients radiologically diagnosed with TLN during follow-up; (3) patients with TLN who had not undergone surgical resection; and (4) patients with TLN with a follow-up period of more than 2 years. Cognitive function was measured with the mini-mental state examination (MMSE) at an interval of every 3 months. Changes in the size of the necrotic mass in the temporal lobe were evaluated by magnetic resonance imaging. The treatment interventions included the wait-and-see policy or the administration of nerve growth factor (NGF) combined with pulsed steroids. Results: From January 2008 to December 2017, 86 patients with TLN entered this study. With a median follow-up of 32 months (26–50 months), 60 patients (70%) showed normal cognitive function as quantified by MMSE scores (≥27). Twenty-six patients (30%) demonstrated obvious cognitive impairment (MMSE scores ≤ 26) during follow-up. However, after receiving NGF combined with pulsed steroids, cognitive function improved significantly, and 21 of 26 patients demonstrated recovery to normal levels. Magnetic resonance imaging studies demonstrated that 10 patients had a complete response (CR), 13 had a partial response, and 3 had stable disease. Conclusions: In the IMRT era, TLN is not always a progressive disease. Most patients remain stable both in their cognitive function and in the size of the necrotic mass. For patients with progressive TLN, active intervention with the administration of NGF and pulsed steroids not only can improve cognitive function but also can decrease the size of the necrotic mass.

Radiation-induced heart disease (RIHD) remains main cause of non-cancer mortality in breast cancer (BC). Modern systemic therapy increases the challenge to cardiac toxicity after radiotherapy (RT). This study aims to evaluate risk of RIHD in BC pts receiving multidisciplinary therapy and optimal dose-volume histogram (DVH) constraints for heart. Patients treated with RT were eligible if they aged between 18 to 70 years, received adjuvant chemotherapy (CT) of anthracycline or taxanes and with baseline LVEF ≥50% before RT. Between Aug 4, 2017 and Aug 5, 2019, 233 pts from 12 centers were randomly assigned to study group, which requires DVH constraints for heart as Dmean ≤6Gy, V30≤20%, V10≤50%, and control group, with DVH constraints at the discretion of the participated center. Cardiac toxicity was evaluated at the baseline before RT and every 3 months within 1 year. The primary endpoint was any predefined clinical or subclinical cardiac toxicity events (NCT02942615). By Dec 31, 2019, 143 pts completed 1-year follow-up (FU) (77 in study group and 66 in control group). The median age was 50 (24-70) years. Patient characteristics and non-cancer cardiovascular risk factors were balanced between groups. Dmean of heart was 374.9 ± 205.3cGy and 376.7 ± 204.7cGy in the study and control group, respectively (P = 0.96). No clinical cardiac toxicity was observed. Subclinical cardiac events occurred to 29 pts in the study group and 29 in the control group (P = 0.45). No increase in subclinical cardiac events in 44 pts treated with concurrent trastuzumab and RT compared with those without trastuzumab (50% vs 36.4%, P = 0.13). In 40 pts with cardiovascular risk factors, there was a significant increase in subclinical cardiac events compared with those with no risk factors (57.5% vs 34%, P = 0.01). In the whole cohort, heart rate (HR) showed a trend of increasing after CT (74 before CT and 78 after CT, P<0.001) and decreasing after RT (P = 0.005, compared with before RT). There was no significant decrease in LVEF during FU (P = 0.30). Diastolic function index E/e' significantly increased after RT (P = 0.018). Significant increase in pro-BNP and CK-MB was observed after RT (all P<0.05). Significant correlation between heart V10 and pro-BNP increase at 6m (P = 0.04), between Dmean and CK-MB increase at 3m (p = 0.03) and between V10 and CK-MB increase at 3m (P = 0.03) were observed. Modern RT technique could keep DVH of heart at low level and guarantee cardiac safety with concurrent trastuzumab and RT. E/e', Pro-BNP and CK-MB might be more sensitive to cardiac toxicity, compared with LVEF. Patients with cardiovascular risk factors are more vulnerable to RIHD.Abstract 2080; TableRepeated measures analysis for the cardiac index changesBefore RT3m6m9m12mP valueHR78 ± 1177 ± 1174 ± 1072 ± 874 ± 140.005LVEF66 ± 466 ± 466 ± 466 ± 467 ± 40.3E/e'8.8 ± 2.49.2 ± 2.69.4 ± 3.19.4 ± 3.19.6 ± 3.20.018pro-BNP42.3 ± 37.855.2 ± 53.958.9 ± 49.655.2 ± 36.353.0 ± 39.5<0.001CK-MB1.0 ± 0.71.2 ± 0.91.3 ± 0.91.5 ± 1.81.5± 1.1<0.001 Open table in a new tab

OBJECTIVES:To compare the treatment outcomes between young and adult patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS:We conducted a retrospective case-matched analysis of all patients with non-metastatic NPC ≤20 years treated in our institution between January 2010 and July 2016. Adult patients ≥35 years treated over the same time period were included and matched at a ratio of 1:1 according to N classification, T classification, treatment modality, year of diagnosis, and gender. Survival outcomes and late toxicities were compared between the two groups. RESULTS:Overall 112 young patients with NPC were included, and 112 out of 3105 consecutive patients with NPC aged ≥35 years were matched. The 5-year overall survival (OS), progression-free survival, locoregional control and distant control of young and control cohorts were 89.1% vs. 79.3% (p = 0.03), 80.3% vs. 67.0% (p = 0.02), 96.4% vs. 84.3% (p < 0.01), and 82.9% vs. 82.8% (p = 0.94), respectively. Multi-variate analysis showed that age ≤20 years was the only significant factor predicting for better OS (HR = 0.5, CI 0.3-0.97, p = 0.04). A trend of higher rate of hypothyroidism (grade 1-2) was observed in the young cohort (67.9% vs. 46.2%, p = 0.08). CONCLUSION:Young patients with NPC treated with modern multimodality therapy have better survival outcomes. Age was an independent favorable prognostic factor for NPC in the IMRT era. Further prospective studies are needed to establish optimal management for the young population to minimize and manage long-term side-effects without compromising survival.

Introduction/BackgroundThe human body anatomical axes (HBAAs) interaction shows an anti-inflammatory effect (Ou MC decrescendo phenomenon, OuDP, Am J Emerg Med. 2012) which indicates a normalization of dysfunctional cells and has shown to induce tumor regression (TJOG, 2017; Cancer arch, 2019).MethodologyOuDPt is performed by putting the contralateral hand over the lesion along human body anatomical axis of left-right, dorsoventral or vertical axis by the patient.ResultsTen patients with cancer diseases including gynecological cancers as uterine leiomyosarcoma (1/10), endometrial cancer (2/10), ovarian cancer (1/10) and breast cancer (1/10) showed initial cancer suppression or regression. However, long term follow up showed tumor regrowth in endometrial cancer (2/10) and the ovarian cancer.ConclusionThe signaling system of embryonic axes has shown to impart polarization of individual cells in Drosophila. Normal cell polarity is essential for normal cell function. The effect of OuDP is rapid, which indicates a direct mending effect on cell function (ICST, 2015).Normalizing the tumor cells and microenvironment function may make tumor cells conform to the regulations with apoptosis, metastasis suppression, preventing uninhibited proliferation, minimizing angiogenesis and supervision by host immunological systems. Long term follow up of advanced cancer diseases treated with OuDP showed tumor regrowth after initial regression, which may be due to poor accessibility, insufficient efficacy or escape phenomenon. However, OuDP may be availed for an active prevention for cancer.DisclosureNothing to disclose

S251 ESTRO 37other two signatures do also show increased HR values (albeit not significant) further supporting the role of EMT in HNSCC prognosis.Remarkably, these signatures only reached consensus for 55 out of 95 samples.Sub-analyses show that the prognostic value for the signatures was reduced in these remaining discordantly classified samples.In an attempt to optimize the EMT signatures for HNSCC, we therefore used the consensus samples to train a new classifier and tested it on the subgroup of discordantly classified patients.We show that this classifier was prognostic for distant metastasis-free survival in these samples (HR 10.6 ; p=0.004). Fig 1. The prognostic value of expression based EMT signatures in our HPV negative HNSCC cohort (n=96).Signatures are indicated by the first author of their respective publications.*: p= <0.05 **: p= <0.01 Conclusion HPV negative HNSCC patients with tumors that score high for EMT features showed increased metastasis rates, independent of known clinical risk factors.This suggests that biomarkers for EMT would be a valuable addition to estimate risks of metastasis in the clinic.

Purpose. - The role of postmastectomy radiotherapy following primary systemic treatment in patients with clinical T1-2N1 breast cancer remains a controversial issue. The purpose of this study was to evaluate the benefit of postmastectomy radiotherapy following primary systemic treatment. Patients and methods. - Between 2005 and 2012, in two independent institutions, female patients with T1-2N1 breast cancer receiving primary systemic treatment followed by mastectomy and lymph node dissection because bad response, then treated with or without chest wall and regional lymph node irradiation have been studied retrospectively. The patients received normofractionated radiotherapy using 3D conformal photons or electron techniques. Locoregional recurrence-free survival, distant metastasis free survival and disease-free survival were calculated using Kaplan-Meier method. Univariate analysis of potential prognostic factors was performed using log-rank test. Results. - Eighty-eight patients have been studied. Of them, 75 patients received postmastectomy radiotherapy. At surgery, 53 patients achieved ypNO. Median follow-up was 67 months. Postmastectomy radiotherapy significantly improved locoregional recurrence-free survival, with a 5-year rate of 96.9% versus 78.6% in the group that did not have postmastectomy radiotherapy. In the subgroup of 53 patients achieving ypNO, postmastectomy radiotherapy improved locoregional recurrence-free survival (a 5-year rate of 94.7% vs. 72.9%), distant metastasis-free survival (a 5-year rate of 92.8% vs. 75%) and disease-free survival (a 5-year rate of 92.9% vs. 62.5%). By univariate analysis, postmastectomy radiotherapy was the only significant prognostic factor affecting locoregional recurrence-free survival. Conclusions. - For patients with clinical T1-2N1 disease, postmastectomy radiotherapy could significantly improve locoregional recurrence-free survival after primary systemic treatment and be even more therapeutic in the subgroup of patients with good response for primary systemic treatment by improving locoregional recurrence-free, distant metastasis-free and disease-free survival. Larger prospective studies are needed to confirm our findings. (C) 2017 Societe francaise deradiotherapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.

PURPOSE:To evaluate the coverage of different levels of axillary lymph nodes and organs at risk according to the field design of AMAROS study (levels I-II-III-IV), breast tangents with supraclavicular and infraclavicular fields (levels II-III-IV) and high tangent fields to the breast after breast-conserving surgery. MATERIALS AND METHODS:We delineated the axillary lymph nodes levels I-IV in 34 patients treated with breast-conserving surgery and sentinel lymph nodes biopsy. Field design according to AMAROS study - levels I-IV in patients without axillary dissection - as well as irradiation of levels II-IV used in N+ patients after axillary dissection, and also high tangent fields was simulated. Mean dose levels and volumes covered by 95% or 80% isodoses were evaluated. Doses to ipsilateral lung, heart and brachial plexus were compared. Paired t test was used. RESULTS:AMAROS study and levels II-IV plans delivered therapeutic dose to high axilla (levels II-IV), but the high tangent fields showed inefficacy to cover these volumes, P<0.001). In terms of organs at risk, especially, ipsilateral lung, AMAROS study plan was found to significantly increase the volume receiving at least 10Gy (I-IV:46.8%, II-IV: 39%), but also the volume receiving at least 20Gy (I-IV: 39.3%, II-IV: 31.3%), and V30Gy (I-IV: 34.2% vs II-IV: 26.1%), as well as the mean dose (I-IV: 18.6Gy, II-IV: 15.2Gy, P<0.001). CONCLUSIONS:The omission of axillary dissection and the axilla irradiation need is associated with high dose irradiation of the lungs, and with higher toxicity. The indication of axillary dissection or irradiation of low axilla could be individualized in relation with individual comorbidities and factors of risk.

Material and MethodsPretreatment tumour biopsies from 100 OTSCC patients were immunostained for Aurora-A and Aurora-B.Log rang test and Kaplan Meier were performed for the analysis of survival.Aurora-kinases expression and additional clinicopathological variables were included in the multivariate analysis (MVA) using a backward Cox regression strategy. ResultsOf 89 patients initially treated with surgery, 57, 15, 4 and 13 were diagnosed with Stages I, II III and IV, respectively.Eleven patients with clinical stage IV were initially treated with chemoradiation.With a median follow-up of 75 months, the 5-year OS and DFS of all patients were 57% and 50%, respectively.Of 100 patients, 26 had Aurora-A positive tumours, whereas 47 tumours expressed Aurora-B.Median OS was significantly shorter in patients with Aurora-A positive (105 months vs 27 months, p=0.019) and Aurora-B positive (not reached vs 32 months, p=0.0037) tumours.No difference in DFS was observed.MVA identified Aurora-A expression, Aurora-B expression, age and stage as significant predictors of OS.The magnitudes of the hazards for OS associated with Aurora-A and Aurora-B were 2.7 (95%CI 1.17-6.27,p=0.02) and 2.43 (95%CI 1.13-5.26,p=0.02), respectively. ConclusionPretreatment Aurora-A and Aurora-B expression identifies a subset of OTSCC patients with increased risk of death.These findings could help in patient selection and represent an encouraging step toward the development of personalized therapeutic approaches.

Background We report the first study examining the clinical, numerical and biological properties of circulating tumor cells according to molecular subtypes of non-small-cell lung cancer. Patients and methods 125 patients with treatment-naïve stage IIIb-IV NSCLC were prospectively recruited for CellSearch analysis. Anti-vimentin antibody was included for examination of CTCs to assess their mesenchymal character. Associations of total CTCs and vimentin-positive (vim +) CTCs with clinical characteristics, tumor genotype, and survival were assessed. Results 51/125 patients (40.8%) were total CTC+ and 26/125 (20.8%) were vim CTC+ at baseline. Multivariate analysis showed patients with ≥5 total CTCs had significantly reduced OS (HR 0.55, 95% CI 0.33-0.92, P = 0.022) but not PFS (HR 0.68, 95% CI 0.42-1.1, P = 0.118) compared to patients with <5 total CTCs. No OS difference was evident between vim+ CTC and vim-negative CTC patients overall (HR 1.24, 95% CI 0.67-2.28, P = 0.494), but after subdivision according to NSCLC driver mutation, we found an increase of vim+ CTCs in the EGFR-mutated subgroup (N = 21/94 patients; mean 1.24 vs 1.22 vim+ CTCs, P = 0.013), a reduction of total CTCs in the ALK-rearranged subgroup (N = 13/90 patients; mean 1.69 vs 5.82 total CTCs, P = 0.029), and a total absence of vim+ CTCs in KRAS-mutated adenocarcinomas (N = 19/78 patients; mean 0 vs 1.4 vim+ CTCs, P = 0.006). Conclusions We validate that the baseline presence of ≥5 total CTCs in advanced NSCLC confers a poor prognosis. CTCs from EGFR-mutant NSCLC express epithelial-mesenchymal transition characteristics, not seen in CTCs from patients with KRAS-mutant adenocarcinoma.

Purpose or ObjectiveRadio(chemo)therapy is a crucial treatment modality for head and neck squamous cell carcinoma (HNSCC) and radioresistance is a major reason for therapy failure and is related to tumour recurrence and poor prognosis.However, the underlying molecular mechanisms are largely unknown.In order to gain knowledge on this fundamental and clinically relevant feature, we established an in vitro model of CAL-33 HNSCC cell line subclones with different radiosensitivity.The main aim of the study was to identify signalling pathways and key regulators of radioresistance by static and dynamic global mRNA expression analyses followed by gene association network (GAN) reconstruction and pathway enrichment analyses. Material and MethodsSubclones with altered radiosensitivity were generated by fractionated irradiation of the parental CAL-33 cells and colony formation assays were performed to confirm the differences in radiosensitivity.Selected subclones were characterized at the genome and transcriptome levels by SKY, array CGH, and mRNA-microarray analyses.Temporally differentially expressed genes upon irradiation were identified using natural cubic spline regression modelling on time-course transcriptome data.Moreover, early and late responding genes were determined.GANs were reconstructed using a partial correlation-based approach.Pathway enrichment analyses were conducted employing the Reactome pathway database.Microarray gene expression data were technically validated by qRT-PCR. ResultsThe characterization of two subclones with enhanced radiation resistance (RP) and enhanced radiosensitivity (SP) revealed distinct genomic and transcriptomic changes compared to the parental cells.Interestingly, the expression of the endogenous retrovirus ERV3-1 in response to irradiation has been observed in all of the CAL-33 cells, suggesting a role in the radiation response of HNSCC cells.Differentially expressed genes after irradiation shared by both subclones pointed to important pathways of the early and late radiation response, including senescence, apoptosis, DNA repair, Wnt, PI3K/AKT, and Rho GTPase signalling.The analysis of the most important nodes of the GANs revealed pathways specific to the radiation response in different phenotypes of radiosensitivity.Exemplarily, for the RP subclone the senescence-associated secretory phenotype (SASP) together with GPCR ligand binding were considered as crucial. ConclusionOur study presents comprehensive gene expression data of CAL-33 subclones with different radiation sensitivity.Based on these data GANs have identified known to be linked to the radiation response phenotypes.The resulting GANs and pathways associated with the resistant phenotype are of special interest and include SASP together with GPCR ligand binding.The identified pathways may represent key players of radioresistance, which could serve as potential targets for molecularly designed, therapeutic intervention.

To explore prognostic and predictive value of radiomics and Human Papillomavirus (HPV) in patients with head and neck squamous cell carcinomas (HNSCC) treated with concurrent chemoradiotherapy (CRT) or bioradiotherapy (BRT). Data of 120 patients (CRT vs. BRT matched 2:1) were retrospectively analyzed. A total of 544 radiomics features of the primary tumor were extracted from radiotherapy planning computed tomography scans. Cox proportional hazards models were used to examine the association between survival and radiomics features with false discovery rate correction. HPV status was determined by p16 immunohistochemistry. The discriminatory performance was evaluated using receiver operating characteristic curve analysis. Twenty-four radiomics features were found to be correlated with overall survival (OS). Multivariate analysis showed the 24-feature based signature significantly predicted for OS (HR = 0.3, P = 0.02) and progression-free survival (PFS) (HR = 0.3, P = 0.01). Combining the radiomics signature with p16 status showed a significant improvement of prognostic performance compared with p16 (AUC = 0.78 vs. AUC = 0.64 at 5 years, P = 0.01) or radiomics signature (AUC = 0.78 vs. AUC = 0.67, P = 0.01) alone. When patients were stratified according to this combination, OS and PFS were significantly different according to the 4 sub-types (p16+ with low/high signature score; p16- with low/high signature score) (P < 0.001). Patients with high signature score significantly benefited from CRT (vs. BRT) in terms of OS (P = 0.004), while no benefit from CRT in patients with low signature score. Our analysis suggests an added value of radiomics features as prognostic and predictive biomarker in HNSCC treated with CRT/BRT. Moreover, the radiomics signature provided additional information to HPV/p16 status to further stratify patients. External validation of such findings is mandatory given the risk of overfitting.