End Of Concurrent Chemoradiotherapy Research Articles

Eosinophil Dynamics during Chemo-Radiation Correlate to Clinical Outcome in Stage II-IVA Nasopharyngeal Carcinoma Patients: Results from a Large Cohort Study

We investigated the dynamics of eosinophil depletion and recovery during definitive concurrent chemo-radiotherapy (CCRT) and how they affect the prognosis of stage II-IVA nasopharyngeal carcinoma (NPC) patients. A total of 1225 patients with pathologically proven NPC from 2013 to 2019 were enrolled. Fuzzy C-Means Clustering (FCM) was used to assess trends in eosinophil during CCRT longitudinally and to grade eosinophil decline during treatment in combination with absolute eosinophil counts (AECs) at the end of CCRT. Grade G0 refers to patients with no decreasing trend in eosinophils and AECs >0.05×109 cells/L, grade G1 refers to patients with a decreasing trend in eosinophils or AECs between 0-0.05×109 cells/L, grade G2 refers to patients with a decreasing trend in eosinophils and AECs between 0-0.05×109 cells/L. Progression-free survival (PFS) is the primary outcome measure, with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS) as secondary outcome measures. A Cox proportional risk model was used to determine the hazard ratio for adverse prognostic effects in declining grades of eosinophil. During a median follow-up of 4.1 years, 376 (30.69%) patients experienced disease progression events. The grade of eosinophil reduction after CCRT was significantly associated with PFS, OS, and DMFS but not with LRFS. After adjusting for demographics, clinical baseline indicators, tumor characteristics, and treatment characteristics, a 1.57-fold (p = 0.001), 1.69-fold (p = 0.007), and 1.51-fold (p = 0.019) increase in the risk of developing PFS, OS, and DMFS was observed for G1 compared with G0, whereas a 2.4-fold (p < 0.001), 2.76-fold (p < 0.001), and 2.31-fold (p < 0.001) increase in the risk of developing PFS, OS, and DMFS was observed for G2. Moreover, among patients with G0, treatment with CCRT with a cumulative dose of platinum-based chemotherapy < 200 mg/m2 resulted in PFS, OS, and DMFS that were not inferior to CCRT with cumulative doses ≥ 200 mg/m2. Eosinophil is an easily detectable and inexpensive biomarker that may be useful in the clinical setting to aid in assessing the prognosis for standard treatment of NPC.

Impact of Surveillance Imaging in Patients with HPV-Associated Oropharyngeal Carcinomas Treated with Definitive Radiation and Chemotherapy

Post-treatment surveillance imaging for HPV-associated oropharyngeal carcinomas (OPCs) differs among physicians and institutions. Surveillance imaging can detect disease progression earlier, but can also contribute to anxiety and cost, without proven disease-free or survival benefit. We sought to determine the number of surveillance scans needed to detect a recurrence in patients with HPV-associated OPCs. We included consecutive patients with locally advanced HPV-associated OPC that received definitive concurrent chemoradiotherapy (CRT) with 70 Gy between March 1, 2017 to July 31, 2019. First post-treatment scans were defined as the first scans following the end of CRT. Surveillance scans were defined as body FDG PET/CTs, neck or chest CTs, and neck MRIs taken after the first post-treatment scans showed no evidence of disease. Any scans ordered to follow suspicious lesions on first post-treatment scans were not counted as surveillance scans. Recurrences were classified as detected by first post-treatment scans, surveillance scans, clinical exam, or incidental findings. The number of surveillance scans needed to detect 1 recurrence was determined by dividing the number of surveillance scans by the number of recurrences detected by surveillance scans. There were a total of 275 patients with median follow-up of 39.8 months (Interquartile Range (IQR), 34.9-47.8). Surveillance scans were first taken at a median of 12.1 months (IQR, 9.2-16) post-CRT. There were 27 (9.8%) patients who had a recurrence: 7 (2.5%) had locoregional recurrence (LR), 19 (6.9%) had distant metastasis (DM), and 1 (0.4%) had both LR and DM. LR was detected at a median of 5.8 months (IQR, 3.4-10.6) post-CRT and DM was detected at a median of 9.5 months (IQR, 4.8-14.3) post-CRT. Of all recurrences, 11/27 (40.7%) were first post-treatment scan detected, 10 (37.0%) were surveillance scan detected, 5 (18.5%) were clinical exam detected, and 1 (3.7%) was incidentally detected on lung cancer screening. Four (50%) LRs were first post-treatment detected (median time to detection, MTD: 4.2 months), 3 (37.5%) were clinical exam detected (MTD: 6.7 months), and 1 (12.5%) was surveillance detected (MTD: 9.0 months). For DM, 9 (45%) were surveillance detected (MTD: 12.7 months), 8 (40%) were first post-treatment detected (MTD: 4.1 months), 2 (10%) were clinical exam detected (MTD: 18.9 months), and 1 (5%) was incidentally detected (MTD: 12.1 months). A total of 702 surveillance scans were taken during the follow-up period. The number of surveillance scans needed to detect 1 LR/DM was 71 overall, 50 within 2 years and 254 beyond 2 years from CRT. First post treatment scans detect most recurrences for HPV-associated OPC. A high burden of surveillance scans is needed to detect one recurrence, especially beyond 2 years from CRT.

Paclitaxel liposome, cisplatin and 5-fluorouracil-based induction chemotherapy followed by de-escalated intensity-modulated radiotherapy with concurrent cisplatin in stage IVA–IVB childhood nasopharyngeal carcinoma in endemic area: a phase II, single-arm trial

Previous studies demonstrated that induction chemotherapy (IC) followed by de-escalated chemoradiotherapy adapted to tumor response was effective in treating childhood nasopharyngeal carcinoma (NPC), but the toxicity profile of this treatment strategy, and whether childhood patients with advanced stages can obtain enough benefits from it requires further investigation. We conducted a single-center phase II trial (NCT03020329). All participants received 3 cycles of paclitaxel liposome, cisplatin and 5-fluorouracil (TPF)-based IC. Patients who showed complete or partial response received de-escalated radiotherapy of 60Gy with 3 cycles of concurrent cisplatin, and those who showed stable or progressive disease received standard-dose radiotherapy of 70Gy with concurrent cisplatin. The primary endpoint was the complete response (CR) rate at the end of concurrent chemoradiotherapy (CCRT). From November 2016 to March 2021, 44 patients were recruited in the cohort. The CR rate was 80% (35/44, 95% CI, 65-90) of the whole cohort. All patients achieved CR 3 months after CCRT. By the last follow-up, the 3-year progression-free survival and overall survival were 91% (95% CI, 82-99) and 100% respectively. Dry mouth was the most common late toxicity, with an incidence of 41% (18/44), followed by skin fibrosis and hearing impairment. No patient suffered from severe late toxicity and growth retardation. Our results proved the efficacy and safety of TPF regimen followed by de-escalated radiotherapy with concurrent cisplatin in treating stage IVa-b childhood NPC patients. A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Efficacy and safety of camrelizumab and apatinib combined with neoadjuvant concurrent chemoradiation for MSS locally advanced rectal cancer.

e15647 Background: Long-term neoadjuvant concurrent chemoradiotherapy (CRT) is the standard therapy for local advanced rectal cancer (LARC).However, the pCR rate is only about 15 %. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in advanced rectal cancer, but their efficacy in the neoadjuvant setting is unclear. In this exploratory trial, we evaluate the efficacy and safety of a combination of ICI (Camrelizumab), anti-angiogenesis (Apatinib) and CRT for neoadjuvant treatment of microsatellite-stable (MSS) LARC. Methods: Patients in experimental group received Camrelizumab injection combined with Apatinib tablets and concurrent CRT. Radiotherapy dose: 5040cGy/28f/180cGy; Capecitabine 825 mg/m2 bid on the radiotherapy day; Apatinib 250mg qd d1-d60; Camrelizumab 200 mg q3w, d22, d43, d64. Surgery with total mesorectal excision was performed 7-9 weeks after the end of CRT. The primary endpoint was pCR rate and the secondary endpoints included major pathological response (MPR) rate, R0 resection rate, 2-year DFS rate, 3-year OS rate and safety. Results: From July/2022 to October/2022, a total of 11 patients were recruited and assessed, 90.91% (10/11) of which is at high-risk (cT3 with any MRF involved, any cT4a/b, lateral node +, HLARC). Out of the 11 patients evaluable for pathological response, 4 (36.36%) patients achieved a pCR (AJCC grade 0) and 7 (63.64%) obtained a MPR(AJCC grade 0+1)(table). All patients achieved R0 resection and downstaging. Treatment-related severe adverse events were observed in 3 patients (grade 3-4 transaminase elevations); all fully recovered and received radical surgery. No treatment-related deaths were observed. Conclusions: A promising pCR rate of 36.36%, with mild toxicities, was shown in MSS LARC patients treated with neoadjuvant Camrelizumab combined with Apatinib and long-term CRT plus radical surgery, suggesting the candidate therapy for the future non-surgical approach. Clinical trial information: ChiCTR2100053040 . [Table: see text]

Efficacy and safety of immunonutrition in preventing oral mucositis during concurrent chemoradiotherapy in patients with nasopharyngeal carcinoma.

e18056 Background: To assess the efficacy of immunonutrition on severe radiotherapy-induced mucositis (RIOM) during concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC). Methods: In total, 30 patients with NPC undergoing CCRT were enrolled in our study. Patients in immunonutrition group (n = 15) receive an immunonutrient formula containing omega-3-fatty acids, arginine, nucleotides from five days before radiotherapy until the end of radiotherapy. Patients in control group (n = 15) receive isocaloric isonitrogenous product. The incidence of grade 3 or 4 RIOM was compared between two groups. Results: Although there was no difference of the incidence of grade 3-4 oral mucositis between the two groups (p = 0.050), the rate of severe mucositis were 13.3% (2/15) in immunonutrients, which was much lower than 53.33% (8/15) in control group. A significant improvement in body fat mass was observed in immunonutrition group than that in control group during the CCRT (3.476, 95CI% 0.015~6.937, P = 0.049) and at the end of CCRT (4.115, 95%CI 0.872~7.359, p = 0.015). And the levels of interleukin 6 (-6.765, 95%CI -16.104~2.573, p = 0.148) and C-reactive protein (CRP) (-7.937, 95%CI -20.395~4.520, p = 0.201) at the end of radiotherapy were lower in immunonutritions even though no statistical difference was reached. In addition, immunonutrition has the potential to improve the life of the patient in the EORTC QLQ-H&amp;N35 scales in painkillers (-13.332, 95%CI -22.612~-4.052, p = 0.007), pain (-15.873, 95%CI -32.131~0.384, p = 0.055), dysphagia (-15.516, 95%CI -34.136~3.104, p = 0.099) and dry mouth (-12.860, 95%CI -31.135~5.415, p = 0.160) at the end of radiotherapy. No patients died of treatment-related causes. Conclusions: Our study indicates that immunonutrition may reduce severe oral mucositis and improved quality of life for patients with NPC during CCRT. Further studies with a larger sample size on the role of immunonutrition in oral mucositis are required to substantiate the result of the study.

Toxicity, Disease Control, and Survival Outcomes of Intensified Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer: A Single-Institution Study.

The standard treatment regimen of preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) is still controversial. The purpose of this study was to analyze the efficacy and safety of preoperative intensive CRT in our institution. A retrospective data collection and analysis of 181 LARC patients receiving oxaliplatin (85%) of standard doses in capecitabine-based preoperative CRT and two additional cycle of neoadjuvant chemotherapy between the end of concurrent CRT and surgery. The compliance of the preoperative CRT was satisfactory with 99.4%patients completed radiotherapy and 97.19%patients completed all 2 cycles of concurrent chemotherapy. Except for 20 patients diagnosed clinical complete remission (cCR) managed according to watch and wait strategy, 160 patients received R0 radical surgery. The pathological complete response (pCR) rate was 23.75% (38/160) and tumor regression grade (TRG) 0/1 was 40% (72/180). In terms of tumor downstaging, 89 (55.63%) had T downstaging while 115 (71.88%) had N downstaging. The 1-overall survival (OS),2-OS,3-OS and 5-OS were 98.7%, 96.5%, 91.4% and 81.5%, respectively. The total rate of sphincter preservation was 86.25% (138/160) and the rate of patients with low rectal cancer was 73.0% (54/74) without affecting local control rates and survival rates. Both acute adverse reactions to preoperative CRT and postoperative complications were tolerable and controllable. In this retrospective study, preoperative intensive CRT of patients with LARC achieved satisfied disease control and survival outcomes and well acquired the sphincter retention rate in recent years in our institution. On the basis of these findings, a Phase III study to definitively test the intensified preoperative CRT strategy is warranted.

Concurrent/sequential versus sequential immune checkpoint inhibition in inoperable large stage III non-small cell lung cancer patients treated with chemoradiotherapy: a prospective observational study

Purpose/aimThe international standard for patients with large inoperable stage III NSCLC is durvalumab consolidation after concurrent chemoradiotherapy (CRT). In this single centre observational study based on individual data, we prospectively evaluated the role of concurrent/sequential versus sequential immune checkpoint inhibition (ICI).Methods and patientsIn total, 39 stage III NSCLC patients were prospectively enrolled, 11 (28%) patients were treated with simultaneous and consolidation therapy with PD-1 inhibition (nivolumab) (SIM-cohort) and 28 (72%) patients received PD-L1 inhibition (durvalumab) as consolidation treatment up to 12 months after the end of CRT (SEQ-cohort).ResultsFor the entire cohort, median progression-free survival (PFS) was 26.3 months and median survival (OS), locoregional recurrence-free survival and distant metastasis-free survival were not reached. For the SIM-cohort, median OS was not reached and PFS was 22.8 months, respectively. In the SEQ-cohort, neither median PFS nor OS were reached. After propensity score matching, PFS at 12/24 months were 82/44% in the SIM-cohort and 57/57% in the SEQ-cohort (p = 0.714), respectively. In the SIM-cohort, 36.4/18.2% of patients showed grade II/III pneumonitis; in the SEQ-cohort 18.2/13.6% after PSM (p = 0.258, p = 0.55).ConclusionBoth concurrent/sequential and sequential ICI show a favorable side effect profile and promising survival in treated patients with inoperable large stage III NSCLC. Concurrent ICI showed a numerical non-significant improvement regarding 6- and 12-months PFS and distant control compared to sequential approach in this small study. However, concurrent ICI to CRT was associated with a non-significant moderate increase in grade II/III pneumonitis.

Gut Microbiome Is Associated With the Response to Chemoradiotherapy in Patients With Non-small Cell Lung Cancer

To explore the dynamic change of gut microbiota and its predictive role in progression-free survival (PFS) in non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT). Forty-one patients with NSCLC in 2 phase 2 trials (NCT02573506 and NCT03006575) were analyzed. A total of 102 fecal samples were collected at 3 time points (T0, before CCRT; T1, 2 weeks after the initiation of CCRT; and T2, the end of CCRT). Gut microbiota composition and functionality were analyzed by 16S rRNA gene sequencing and shotgun metagenomics, respectively. Alpha diversity, taxonomic composition, and KEGG functional pathways were compared between patients in the long-PFS group (PFS ≥11.0 months) and short-PFS group (PFS <11.0 months). A random forest classifier was constructed to identify microbial signature related to PFS. Clinical and microbial factors potentially predictive of PFS were assessed in the univariate and multivariate Cox regression analysis. The abundance of Bacteroidota and Proteobacteria increased, while the abundance of Firmicutes decreased after CCRT. Shannon index (P=.006) and PD index (P=.022) were significantly higher in the long-PFS group than for those in the short-PFS group at T1. The PFS-prediction microbial signature at T1 included unclassified members of the Lanchospiraceae spp., such as NK4A136 and UCG-003 groups, Dorea sp., various strains from within the Eubacterium hallii and E. siraeum groups, and an unclassified member of the Muribaculaceae, which yielded an area under the ROC curve of 0.87. These discriminatory genera mostly belong to phylum Firmicutes/family Clostridia. Multivariate analysis indicated PD index (HR=8.036, P=.016) and the abundance of Dorea sp. at T1 (HR=4.186, P=.043) were independent predictors of PFS. The KEGG pathways at T1 overrepresented in the long-PFS group included fatty acid metabolism, fatty acid biosynthesis, and arginine biosynthesis. Those overrepresented in the short-PFS group included lipopolysaccharide biosynthesis, ascorbate and aldarate metabolism, and biosynthesis of vancomycin group antibiotics. Gut microbiota composition and functionality at 2 weeks after the initiation of CCRT were associated with PFS in NSCLC. Further research is needed to confirm these results.

Efficacy of Thymosin α1 in Management of Radiation Pneumonitis in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiotherapy: A Phase 2 Clinical Trial (GASTO-1043)

To evaluate the efficacy of thymosin α1 in management of radiation pneumonitis (RP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemoradiotherapy (CCRT). This phase 2, single-arm trial enrolled patients with unresectable LANSCLC of 18 to 75 years' old and an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients received definitive CCRT and weekly thymosin α1 from the start of CCRT until 2 months after CCRT. Patients were administered 51 Gy in 17 daily fractions or 40 Gy in 10 daily fractions in the first course followed by a re-evaluation and those patients without disease progression had an adaptive plan of 15 Gy in 5 daily fractions or 24 Gy in 6 daily fractions as a boost. Concurrent chemotherapy consisted of weekly docetaxel (25 mg/m2) and nedaplatin (25 mg/m2) during radiation therapy. The primary endpoint was the incidence of Grade (G) ≥2 RP. Secondary endpoints included the incidence of late pulmonary fibrosis, total lymphocyte count (TLC), serum C-reactive protein (CRP) levels, and the composition of gut microbiota. TLC and CRP data were collected at baseline, 2 to 3 weeks during CCRT, the end of CCRT, 2 and 6 months after CCRT. Fecal samples were collected at baseline and the end of CCRT. Patients treated with CCRT but without thymosin α1 intervention during the same period were selected as the control group by the propensity score matching method. Sixty-nine patients were enrolled in the study, and another 69 patients were selected as the control group. The incidence of G≥2 RP was lower in the study group compared with control cases (36.2% vs 53.6%, P=.040). G1 late pulmonary fibrosis occurred in 2 (3.7%) patients of the control group compared with no event in the study group (P=.243). Compared with the control group, the incidence of G3 to G4 lymphopenia (19.1% vs 62.1%, P < .001) was lower, and the median TLC nadir (0.51 k/µL vs 0.30 k/µL, P < .001) was higher in the study group. The proportion of patients with maximum CRP ≥100 mg/L was lower in the study group (13.8% vs 29.7% P=.029). The diversity and community composition of the gut microbiota were not significantly different between the 2 groups. Administration of thymosin α1 during and after CCRT was associated with significant reductions in G≥2 RP and G3 to G4 lymphopenia in patients with LANSCLC compared with historic controls.

The Treatment Combining Antiangiogenesis with Chemoradiotherapy Impinges on the Peripheral Circulation Vascular Endothelial Cells and Therapeutic Effect in the Patients with Locally Advanced Nasopharyngeal Carcinoma.

This study was implemented for the evaluation on the circulating endothelial cells' (CECs) clinical significance in the locally advanced nasopharyngeal carcinoma treatment with endostatin-combined chemoradiotherapy. This study enrolled 47 patients with locally advanced nasopharyngeal carcinoma who were hospitalized from May 9, 2012 to March 10, 2013. These patients were split up into the observation group (25 patients) and control group (22 patients). Patients in the observation group received the endostatin combined with induction chemotherapy and subsequently with concurrent chemoradiotherapy with endostatin. Patients in the control group were treated with inductive chemotherapy followed by concurrent chemoradiotherapy. CECs in peripheral blood were conducted separately before or after inductive chemotherapy and additionally in the end of concurrent chemoradiotherapy. The CEC values of the observation group showed significant statistical differences (p < 0.05) before or after different therapies, whereas those data in the control group were not statistically different. And, the mostly importantly, the CEC values in the observation group and control group turned out a statistical difference. The combination of endostatin and chemoradiotherapy significantly reduced parameters of peripheral blood CECs in these patients. According to the CEC parameters' variety that we observed in the combined therapies, this study demonstrated that the CECs might be a clinical clue to evaluate this antiangiogenic chemoradiotherapy. And the clinical value of CECs will be further determined along with increasing comparative studies and clinical long-term efficacy observation.

Propensity-matched analysis of concurrent/sequential versus sequential immune checkpoint inhibition in inoperable stage III NSCLC patients treated with chemoradiotherapy.

e20589 Background: Durvalumab maintenance treatment after completion of concurrent chemoradiotherapy (CRT) in patients with inoperable stage III NSCLC is the international standard. In this propensity-matched analysis, we prospectively evaluated the role of concurrent/sequential versus sequential immune checkpoint inhibition. Methods: Between 10/1/2016 and 12/31/2020, 39 NSCLC patients in stage IIIA/B/C were analyzed. 11 (28%) patients received concurrent/sequential PD-1 inhibition (nivolumab) and 28 (72%) patients received sequential PD-L1 inhibition (durvalumab) up to one year after the end of CRT. A 1:2 propensity score matching (PSM) using age, gender, T category and histology was performed to reduce selection bias and address for confounding factors (n = 33, 11 patients receiving nivolumab (SIM-cohort), 22 patients receiving durvalumab (SEQ-cohort). Treatment-related adverse events were assessed weekly during the CRT and at 6 weeks, 3,6,9, and 12 months after the end of CRT. Results: The median follow-up time of the overall cohort, SIM-I cohort, and SEQ-I cohort was 27.6, 33.3, and 26.5 months after CRT, respectively. For the entire cohort median survival (OS) was not reached; median progression-free survival (PFS) achieved 26.3 months. In the SIM-cohort, median PFS was 22.8 months and median OS was not reached. In the SEQ-cohort, neither median PFS nor OS was reached. PFS at 12/24 months was 82/44% in the SIM-cohort and 57/57% in the SEQ-cohort (p = 0.714), respectively. In the SIM-cohort, 18.2% of patients showed grade III pneumonitis; in the SEQ-cohort 13.6% (p = 0.735). Grade 4 and 5 toxicities were not observed. Conclusions: Both concurrent/sequential and sequential immune checkpoint inhibition shows a favorable side effect profile and promising survival in terated patients. Concurrent immunotherapy did not result in an improved outcome (PFS, OS) compared to sequential approach. However, our propensity-matched analysis found that concurrent immunotherapy was associated with a non-significant moderate increase in grade III pneumonitis.

Durvalumab treatment initiation delays in patients with unresectable stage III non–small cell lung cancer treated at Veterans Health Administration facilities.

8556 Background: Durvalumab is an FDA-approved immunotherapy for the treatment of adults with UnResectable stage III non-small cell lung cancer (UR-NSCLC) without disease progression following concurrent chemoradiotherapy (CRT). There are limited real-world data regarding Durvalumab treatment initiation delays (TIDs) and reasons for them in the UR-NSCLC population. Methods: Patients with stage III UR-NSCLC receiving consolidation Durvalumab at the Veterans Health Administration (VHA) between January 1, 2017 and June 30, 2020 were selected from the VHA database using ICD-10, HCPCS, and J codes. All had the opportunity to be treated for 12 months and were followed from Durvalumab initiation through the earliest of their last VHA visit, loss to follow up, death, or the study’s end (and excluded if Durvalumab therapy was ongoing at the study’s end). Trained data abstractors determined the occurrence and reasons for TIDs (&gt; 6 weeks from end of CRT to initiation of Durvalumab as in the PACIFIC trial) by chart review. Results: 935 patients were eligible for analysis (median age = 69 years; 95% males; 16% with ECOG performance status &gt;1). TIDs occurred in 39% of the patients (Table). Durvalumab was initiated 61 days (median) from the end of CRT in TID patients vs. 31 days for those without TIDs. There were no significant (α&lt;0.05) differences in age, race, smoking status, histology, or ECOG performance status and no comorbidity differences (except in patients with a history of cerebrovascular accident, for whom TIDs were more likely) between the TID/No-TID patients. Patients without timely post-CRT scans were more likely to have a TID. Of the 367 patients who experienced TIDs, 200 had documented reasons for the delay, consisting of other (not categorized) (28.5%), physician preference (20%), toxicity (11%), patient preference (10.5%), decline in performance status (10%), system issues (9.5%), social reasons (9%), and progression (0.5%). Conclusions: This is one of the largest retrospective cohort studies reporting real-world data in patients with UR-NSCLC receiving Durvalumab. TIDs were associated with increased time to post-CRT scans. This potential issue can be improved with care coordination and involvement of cancer navigators. Additional studies are needed to assess the impact of TIDs on survival outcomes.[Table: see text]

Long-term follow-up results of the effects of chronotherapy and conventional chemotherapy combined with intensity modulated radiotherapy on dendritic cells and lymphocyte subsets in nasopharyngeal carcinoma.

e18066 Background: In this study, we compared the effects of chronotherapy with conventional chemotherapy plus intensity modulated radiotherapy (IMRT)on dendritic cells and lymphocyte subsets in locoregionally advanced NPC. Methods: Analysis of 136 patients with treatment locoregionally advanced nasopharyngeal carcinoma enrolled, 68 patients were randomly assigned to the chronotherapy group and 68 patients to the conventional chemotherapy group, and all patients received 2-3 cycles of TPF induction chemotherapy plus 2-3 cycles of cisplatin concurrent chemoradiotherapy with the following schedules: docetaxel (DOC): 60mg / m2, ivgtt, D1 (03:30-04:30); Cisplatin (DDP): 60mg / m2, civ, d1-d5 (10:00-22:00); 5-fluorouracil (5-FU): 600mg / m2 / D 1, civ, d1-d5 (22:00-10:00); Synchronized DDP 100mg / m2, civ, D1 (10:00-22:00). Conventional group: Doc 60 mg / m2, ivgtt, D1; DDP 60mg/m2, ivgtt, d1; 5-FU 600mg/m2 /d 1, civ, d1-d5(120h); Synchronized DDP 100mg / m2, IVGTT, D1. Both groups were treated with IMRT at the same dose。 Lymphocyte and lymphocyte subsets were measured by flow cytometry before induction chemotherapy and 1 year versus 3 years after the end of concurrent chemoradiotherapy in patients, and changes in immune parameters, survival, and long-term toxicities were compared between the two groups. Results: One year after induction chemotherapy and concurrent chemoradiotherapy, the chronotherapy group showed higher plasma dendritic cells (PDC) than the conventional group (P &lt; 0.05). At 1 year after induction chemotherapy and concurrent chemoradiotherapy, CD4 +, activated CD4 +, activated CD8 +, CD3-CD16 +, PDC, and MDC were significantly higher (P &lt; 0.05) in both pre - and post-treatment groups, and at 1 year after induction chemotherapy and concurrent chemoradiotherapy in the conventional group (P &lt; 0.05). At 3 years after induction chemotherapy and concurrent chemoradiotherapy, CD4 +, activated CD4 +, activated CD8 +, CD4 + CD25 +, cd3-cd19 +, and CD3-CD16 + were significantly increased in the chronic group (P &lt; 0.05), and CD4 +, activated CD4 +, activated CD8 +, and CD4 + CD25 + were significantly increased in the conventional group (P &lt; 0.05). In the comparison of toxic effects between the two groups, the incidences of xerostomia and dysphagia in the group at 3 years after treatment were significantly lower than those in the conventional group (P &lt; 0.05). There were no significant differences in PFS, OS, DMFS, LRRFS between the two groups at 3 years (P &gt; 0.05). Conclusions: Chronotherapy with intensity-modulated radiotherapy for locoregionally advanced nasopharyngeal carcinoma more than conventional chemoradiotherapy reduces damage to dendritic cells and lymphocytes and alleviates toxic effects such as xerostomia and dysphagia at the same survival rate.

113P Proton-therapy and concurrent chemotherapy in stage III NSCLC: Effects on durvalumab eligibility and safety profile

Concurrent chemo-radiotherapy (CCRT) followed by adjuvant Durvalumab (D) represents standard of care for patients (pts) with unresectable stage III NSCLC. The RT can be delivered with both protons and photons. An earlier start of adjuvant D after CCRT may lead to better outcome. Little is known about the effects of protons on adjuvant D efficacy and safety. We assessed whether intensity modulated proton therapy (IMPT), compared to intensity modulated photon therapy (IMRT) affects eligibility for D (primary endpoint) and immune related adverse events (IRAEs) (secondary endpoint) in pts with stage III NSCLC treated with CCRT and adjuvant D. Retrospective data completion and analysis of a 2-center prospectively collected series of pts with stage III NSCLC, receiving CCRT between 06.16 and 02.21, staged with FDG-PET and brain imaging. Main exclusion criteria were previous cancer diagnosis-within 2 years- and thoracic RT. A list of 226 pts was collected, 67 pts received adjuvant D and were included (IMPT: n=28, IMRT: n=39). Median age was 66 years, 52% were male, 33% had a squamous NSCLC and 42% had a WHO Performance Status (PS) of 0 before CCRT. All pts received 60-64 Gy of RT. Programmed death-ligand 1 (PDL-1) level was available for 76% of pts and 39% had a PDL-1 ≥ 50% (no significant differences between IMPT and IMRT). At day 21 after CCRT, 93% (IMPT) vs 72% (IMRT) treated pts had a PS≤1 (Odds Ratio 0.8, 95% CI: 0.67-0.95, p=0.03). The median time from the end of CCRT and start of D was 32 vs 38 days respectively (Not Significant (NS)). IRAEs of any grade were reported in 21% versus 31% of pts treated with IMPT versus IMRT, respectively (NS). Hypothyroidism accounted for 44% of IRAEs. Any grade (grade 3) pneumonitis during D was reported in 25% (7%) of IMPT and 23% (5%) of IMRT (NS). Median follow-up was 19.5 months and 9.5 months for IMRT and IMPT, respectively. 90% of pts were still alive and 73% were disease free. IMPT vs IMRT treated pts received a significantly lower RT dose to bone marrow, heart and lungs. PS at day 21 after CCRT was better in IMPT treated pts, potentially increasing eligibility for adjuvant D. The lower RT dose delivered with IMPT might explain our findings. IMPT appears to be as safe as IMRT regarding IRAEs during D.

Lymphocyte dynamics during and after chemo-radiation correlate to dose and outcome in stage III NSCLC patients undergoing maintenance immunotherapy

PurposeWe investigated the dynamics of lymphocyte depletion and recovery during and after definitive concurrent chemoradiotherapy (CCRT), dose to which structures is correlated to them, and how they affect the prognosis of stage III non-small cell lung cancer (NSCLC) patients undergoing maintenance immunotherapy. Methods and materialsIn this retrospective study, absolute lymphocyte counts (ALC) of 66 patients were obtained before, during, and after CCRT. Persistent lymphopenia was defined as ALC < 500/μL at 3 months after CCRT. The impact of regional dose on lymphocyte depletion and recovery was investigated using voxel-based analysis (VBA). ResultsMost patients (n = 65) experienced lymphopenia during CCRT: 39 patients (59.0%) had grade (G) 3+ lymphopenia. Fifty-nine patients (89.3%) recovered from treatment-related lymphopenia at 3 months after CCRT, whereas 7 (10.6%) showed persistent lymphopenia. Patient characteristics associated with persistent lymphopenia were older age and ALC before and during treatment. In multivariable Cox regression analysis, recovery from lymphopenia was identified as a significant prognostic factor for Progression Free Survival (HR 0.35, 95% CI 0.13–0.93, p = 0.034) and Overall Survival (HR 0.24, 95% CI 0.08–0.68, p = 0.007). Voxel-based analysis showed strong correlation of dose to the upper mediastinum with lymphopenia at the end of CCRT, but not at 3 months after CCRT. ConclusionRecovery from lymphopenia is strongly correlated to improved survival of patients undergoing CCRT and adjuvant immunotherapy, and is correlated to lymphocyte counts pre- and post-CCRT. VBA reveals high correlation of dose to large vessels to lymphopenia at the end of CCRT. Therefore, efforts should be made not only for preventing lymphocyte depletion during CCRT but also for helping lymphocyte recovery after CCRT.

Dynamic changes in practical inflammation and immunity markers in cancer patients receiving immune-enhancing nutritional supplementation during concurrent chemoradiotherapy.

BACKGROUND: Immune-enhancing nutrition (IMN) strengthens the systematic inflammatory response and the immune system. Neutrophil to lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) are affected during cancer therapies.OBJECTIVE: We carried out an analysis of the dynamic changes in NLR and ALC over time in cancer patients with or without IMN supplementation.METHODS: 88 cancer patients receiving concurrent chemoradiotherapy (CCRT) were randomized into regular diet group, and regular diet and IMN group.Generalized estimation equation models were used to assess associations between patient’s characteristics, IMN, and dynamic changes in NLR and ALC over time.RESULTS: NLR and ALC at pre-CCRT were significantly associated with dynamic changes in NLR (adjusted 1.08, 95% confidence interval [CI]: 0.64–1.52) and ALC (adjusted 0.41, 95% CI: 0.36–0.46). The magnitudes of the NLR and ALC changes through CCRT were lower in patients receiving IMN, although the differences were not statistically significant except ALC at the end of CCRT in head and neck cancer patients ( 0.023).CONCLUSION: Dynamic negative changes in both markers were demonstrated throughout CCRT. There were non-significant trend in promising changes in both NLR and ALC values in the whole group in IMN supplementation.

Diagnostic Signatures for Lung Cancer by Gut Microbiome and Urine Metabolomics Profiling

<h3>Purpose/Objective(s)</h3> To develop the diagnostic signatures for lung cancer (LC) by gut microbiome and urine metabolomics profiling with multi-omics approach. Additionally, to investigate the predictive role of gut microbiome on the prognosis of locally advanced non-small cell lung cancer (LANSCLC) patients after concurrent chemoradiotherapy (CCRT). <h3>Materials/Methods</h3> Fecal and urine samples were collected in LC patients and healthy individuals. The total cohort had been divided into the training set (47 patients and 20 healthy individuals) and the validation set (48 patients and 30 healthy individuals) for multi-omics analysis. Gut microbiota was analyzed through the 16S ribosomal RNA gene sequencing and shotgun metagenomics. Urine untargeted metabolomics was analyzed by liquid chromatography-mass spectrometry. Multi-omics diagnostic model incorporating features from fecal microbiome and urine metabolites was developed in the training set, and then validated in the validation set. Among them, 36 patients with LANSCLC were selected for prognosis analysis, with fecal samples collected at three longitudinal time points (baseline, 2 weeks after the start of CCRT and the end of CCRT). These patients were divided into 2 groups according to progression-free survival (PFS) (PFS > = 12 months [LP], n = 14; PFS < 12 months [SP], n = 22). The microbiome profiling of LP and SP were compared using Wilcoxon rank-sum test. <h3>Results</h3> LC patients had a significant shift of microbiota composition and functional genes distribution compared with healthy individuals. Diagnostic model for LC had been achieved by combining gut microbiome and urine metabolomics profiling, the area under curve (AUC) of the training set was 0.9997, and 0.9769 for the validation set. We also found a significant decrease of Prevotella in LC patients and it was negatively correlated with multiple functions in KEGG level 2. For the 36 patients with LANSCLC who had underwent CCRT, the alpha diversity was significantly increased in LP group compared with SP group at 2 weeks after CCRT (Chao1: <b>P</b> = 0.013, PD: <b>P</b> = 0.037, Shannon: <b>P</b> = 0.011). Further analysis of microbiota composition identified 21 differentially abundant species (<b>P</b> < 0.05). 19 and 2 species were LP-enriched and SP-enriched, respectively. 5 Lachnospiraceae genus, 3 Eubacterium genus were significantly enriched in LP group, while Prevotellaceae and Lactobacillus were significantly enriched in SP group. <h3>Conclusion</h3> The current study employed a multi-omics approach, analyzed the fecal microbiome and urine metabolites from LC patients using a standardized pipeline, and identified disease-associated microbiome shifts across datasets using statistical analysis. We inferred a microbiome-metabolite catalog and its molecular pathway and functional link to host targets, which could be further utilized to aid lung cancer diagnosis and treatment decision. Furthermore, gut microbiota at 2 weeks after the start of CCRT might have a predictive role on the prognosis of NSCLC after CCRT.

P82.04 Adaptive Radiation Therapy with Consolidation Sintilimab in Stage III NSCLC: Challenges in Recruiting Patients for Adjuvant Immunotherapy

The PACIFIC reported a significantly improved overall survival for consolidative durvalumab after chemoradiotherapy in unresectable stage III non-small cell lung cancer (NSCLC) in 2018. However, the details in the exclusion of patient enrollment were not reported. It is unclear what proportion of patients after chemoradiotherapy would be eligible to receive immunotherapy. In this study, we aimed to recruit all for consolidation sintilimab, an anti-PD-1 antibody, after definitive chemoradiotherapy using adaptive radiotherapy which can target to the shrunk tumor to reduce the dose to surrounding normal tissues and decrease the toxicities. This was a single-arm prospective phase II trial (CARTAI; NCT03732430). Patients with histologically confirmed NSCLC, unresectable stage III medically fit for concurrent chemoradiotherapy were eligible. Radiation therapy was delivered using mid-treatment CT guided adaptive IMRT. Sintilimab was given within 45 days after completion of RT, when patients had grade 1 or less acute toxicity, with ECOG PS 0 or 1, adequate hematologic, liver and kidney function. Any patients who had unresolved grade 2 or higher toxicity were excluded from enrollment. The prescription doses of radiotherapy were 64-66Gy to the GTV and 54Gy to the PTV in 30 fractions, unless exceeding the dose constraints. The patents were intravenously given sintilimab, an anti-PD-1 antibody, 200mg q3w. We initially screened potential patients before the radiotherapy and all interested patients were treated consistently with adaptive RT. Final written consent was obtained, and eligibility was confirmed after completion of radiotherapy. From November 2018 to December 2019, after the initial screening, 107 consecutive patients potentially eligible received concurrent chemoradiation received adaptive IMRT. Eight-eight patients failed for enrollment of consolidation sintilimab. In which, seventy (80%) patients refused to participate the study at the last minutes. Eighteen of 88 (20%) did not meet the inclusion criteria after the end of radiotherapy. main ineligible reasons were grade 2 or higher toxicities, including radiation-induced pneumonitis in 7 patients, unresolved esophagitis in 5, 2 developed both, and 2 with unresolved leukopenia. A total of 19 patients (17.8%) consented to participate in the adjuvant immunotherapy. Four of them (21.5%) were found ineligible, including 2 patients with grade 2 radiation pneumonitis, 1 with esophagitis, and 1 with leukopenia. There were finally 15 patients (78.9%) enrolled in this study. This study found approximately twenty percent of all consented and refused patients were ineligible to receive consolidative immunotherapy after the end of concurrent chemoradiotherapy. The main barrier for eligibility was the radiation-induced acute toxicities, especially pneumonitis and esophagitis.

Concurrent Chemoradiotherapy Increases the Levels of Soluble Immune Checkpoint Proteins in Patients with Locally Advanced Cervical Cancer

Concurrent chemoradiotherapy (CCRT) could influence systematic immunity in cancer patients, but its impact on soluble immune checkpoint molecules remain largely unknown. Here, we investigated the dynamic alterations of 16 soluble immune checkpoint molecules in locally advanced cervical cancer (LACC) patients treated with CCRT. Sixty LACC patients treated with CCRT were prospectively enrolled and patients’ blood was collected before, during, and at the end of CCRT. Sixteen soluble immune checkpoint molecules were tested by Luminex platform. Tumor response was evaluated based on RECIST 1.1 guidelines at one month after CCRT. One-way analysis of variance with Bonferroni's post-test or paired t tests were used to evaluate the change of the levels of soluble immune checkpoint molecules. Forty-five (75%) patients experienced complete response (CR), 12 (20%) patients experienced partial response (PR), and 3 (5%) patients experienced stable disease after CCRT. Levels of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) increased both during and at the end of CCRT (P = .015 and .003, respectively), while inducible T-cell costimulator (ICOS), B7-2, glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) increased at the end of CCRT (P = .032, .048, and .050, respectively). The other soluble immune checkpoint molecules including CD40 showed no significant change throughout CCRT (all P >0.05). Interestingly, we found that these changes were more significant in patients with CR than patients with PR/SD. Specifically, for patients with CR, levels of TIM-3 were significantly elevated both during and at the end of CCRT (P = .008 and < .001, respectively), while ICOS, B7-2, GITRL were significantly elevated at the end of CCRT (P = .023, .039, and .042, respectively). Meanwhile, CD40 was significantly elevated at the end of CCRT in patients with CR (P = .040). However, patients with PR/SD, no soluble immune checkpoint molecules were significantly changed (all P > 0.05). Our study reveals that CCRT could induce the elevation of the levels of soluble TIM-3, ICOS, B7-2, and GITRL in the blood of patients with LACC. This phenomenon was more obvious in patients with good response to CCRT.

Impact of early nutrition counseling in head and neck cancer patients with normal nutritional status.

Nutritional counseling is frequently overlooked in cancer patients with normal nutritional status. This study aimed to evaluate the impact of nutritional counseling in head and neck cancer (HNC) patients with normal nutritional status prior to concurrent chemoradiotherapy (CCRT). A total of 243 patients with pretreatment normal nutritional status and locally advanced HNC receiving concurrent chemoradiotherapy (CCRT) at three medical centers were enrolled. All patients were retrospectively allocated into the early (≤ 2 weeks, n = 105, 43.2%), late (> 2 weeks, n = 102, 42.0%), and no nutritional counseling groups (n = 36, 14.8%) according to the time interval between the date of CCRT initiation and the first date of nutritional counseling for comparison. The 1-year overall survival rates were 95.0%, 87.5%, and 81.3% in the early, late, and no nutritional counseling groups (p = 0.035), respectively. The median body weight changes at end of CCRT were - 4.8% (range, - 13.3 to 8.7%), - 5.6% (range, - 21.9 to 5.6%), and - 8.6% (range, - 20.3 to 2.4%) in patients in the early, late, and no nutritional counseling groups, respectively. The early termination of chemotherapy rates and the incompletion rates of planned radiotherapy were 1.9% and 1.9%, 2.9%, and 2.0%, 13.9%, and 19.4% in patients in the early, late, and no nutritional counseling groups, respectively. Our findings strongly suggest that while some HNC patients may have pretreatment normal nutritional status, early nutritional counseling is nevertheless essential for the improvement of treatment tolerance and survival outcome.