Post Chemoradiotherapy Research Articles

ASCO 2021 highlights head and neck cancer: nasopharyngeal carcinoma

SummaryDuring the ASCO 2021 virtual meeting, multiple clinically relevant studies were presented addressing open questions regarding the therapy of nasopharyngeal carcinomas (NPC): Is immunotherapy plus chemotherapy the new first line standard of care for patients in the recurrent/metastatic setting? Is adjuvant therapy with capecitabine in high risk NPC patients post chemoradiation (CRT) beneficial? Is there a role for treatment intensification by adjuvant metronomic capecitabine in NPC patients post induction chemotherapy and CRT? This article summarizes the most significant NPC studies presented at the ASCO 2021 virtual meeting and discusses the data in the context of the current literature.

Functional Parotid Sparing: Does Sparing the Parotid Ducts Yield Improvements in Patient Reported Xerostomia?

Literature suggests that salivary gland stem cells, capable of regenerating salivary tissue, may preferentially reside in the large ducts of salivary glands. We conducted a prospective trial in patients receiving definitive chemoradiotherapy (CRT) for oropharyngeal cancer where we preferentially spared the major parotid ducts (localized via MRI sialography) during treatment planning. We hypothesized that (1) this technique would yield improvements in patient reported xerostomia (PRX) at 6- and 12-months post-CRT compared to a prospectively accrued cohort of similar patients, and (2) that parotid duct doses would be predictive for PRX.A total of 38 Patients were prospectively enrolled and underwent MRI sialography guided ductal sparing. 28/38 patients received de-escalated CRT (60Gy). PRX was classified as none/mild versus moderate to very severe. (1) PRX in the 28 de-escalated patients were compared using a fisher exact test to a cohort of 232 patients on the same clinical trials but who did not undergo ductal sparing. (2) Competing nested multivariate logistic models (+/- parotid duct doses) were assessed using dosimetric data from all 38 patients for their ability to predict PRX. Models included contralateral submandibular mean dose, mean parotid gland dose (both) +/- parotid duct mean dose (both). The two nested models were compared using a likelihood ratio test to determine if incorporating mean parotid duct doses significantly improved model fit.(1) Patients reporting moderate to very severe xerostomia was lower in patients with vs without parotid-ductal sparing at 6 months post-CRT (46% vs 67%, P = 0.03), and trended lower at 12 months post-CRT (32% vs 49%, P = 0.11). At 6 months post CRT, the mean parotid duct dose was the only covariate significantly associated with PRX (P = 0.047). At 12 months post CRT, no covariate was significantly associated with PRX but both mean contralateral submandibular dose and mean parotid duct dose approached significance (P = 0.06 and 0.07, respectively). (2) The models +/- parotid duct doses were compared and the addition of parotid ductal mean dose significantly improved model fit at 6- and 12-months post CRT (P = 0.030 and 0.047, respectively).The absolute rates of moderate to very severe patient reported xerostomia were approximately 20% lower for those undergoing MRI sialography guided parotid ductal sparing versus those without ductal sparing at 6- and 12-months post CRT. The significant improvement of model fit upon adding mean parotid ductal dose to the mean major salivary gland doses at 6 and 12 months suggests that the dose received by the parotid ducts relates to patient reported xerostomia severity even when considering traditional metrics such as mean parotid and contralateral submandibular dose.

Incidence and Impact of Lymphopenia Associated With Total Neoadjuvant Therapy for Low-Lying Rectal Tumors

To assess incidence of lymphopenia and its association with outcomes in patients treated with total neoadjuvant therapy (TNT) for low-lying rectal tumors.Patients with Stage II-III, low rectal adenocarcinomas treated from 2015-2018 with TNT were retrospectively reviewed. All patients were candidates for an APR surgical resection, but were treated with intent to omit surgery if they had a clinical complete response. All patients received definitive radiation (median dose 54 Gy, range 50-56 Gy, at 1.8-2 Gy/fx) with concurrent capecitabine, with additional chemotherapy (CT) delivered either prior to or following chemoradiation (CRT). Institutional results on patient outcomes have previously been reported with a clinical complete response rate of 75%; with only 19% of those ultimately requiring surgery for local recurrence. Absolute lymphocyte counts (ALC) were collected prior to initiating CRT and at 3-month intervals following CRT and graded based on severity of lymphopenia (absolute lymphocyte count < 1000/mm3) using CTCAE v5.0. A Cox proportional hazards model was used to identify if degree of lymphopenia was associated with receipt of surgery (as surgery was only performed for either incomplete response or local recurrence).A total of 28 patients with low rectal cancers were treated with TNT during this period, with ALC analyzed for the 26 who had detailed lymphocyte data available. 7 patients were treated with CT followed by CRT, receiving a median of 8 (range 4-8) cycles of CT, and 18 patients were treated with CRT followed by CT, receiving a median of 6 cycles (range 1-9). One patient refused CT after CRT. Prior to initiating CRT, the median ALC was 1,665/mm3 (range, 710-3,060/mm3), with lymphopenia present in only 4 patients (1 neoadjuvant CT and 3 adjuvant CT). The median ALC nadir during CRT was 450/mm3 (range, 230-900/mm3), with all 26 patients experiencing lymphopenia during the course of CRT: 4% Grade 1, 35% Grade 2, 61% Grade 3, and 0% Grade 4. Rates of lymphopenia at 3-, 6-, and 12-months post CRT were 73%, 81%, and 42%, respectively. On Cox regression analysis, increased pre-CRT and 12-month post-CRT lymphocyte counts were associated with a decreased risk of need for surgery (P < 0.05) and remained significant when accounting for the sequencing of CT, while lymphocyte count nadir during CRT and 3-/6-month post-CRT levels were not (P > 0.05).Despite the frequency of lymphopenia during CRT, the degree of lymphopenia during and up to 6 months after CRT did not appear to predict future surgery. However, increased pre-CRT and 12-month post-CRT ALC were associated with decrease need of surgery. CRT produces both oxidative stress and immune response stimulation to kill cancer cells. Patients with higher pre-CRT and 12-month post-CRT ALC may represent a population with more robust immune systems, producing more favorable tumor responses. Additional studies are warranted.

732 TUMOR INFILTRATING NEUTROPHILS ARE A POOR PROGNOSTIC MARKER FOR ESOPHAGEAL CANCER PATIENTS RECEIVING NEOADJUVANT CHEMORADIOTHERAPY

Abstract Significant advances have been made in our understanding of the tumor immune microenvironment (TIM) and tumor infiltrating lymphocytes (TILs). Nevertheless, there is little understanding of the changes in the TIM in response to neoadjuvant chemoradiotherapy (CRT). Thus, our aim was to investigate the changes in the TIM with neoadjuvant CRT in EC by assessing the immune cell infiltrate, the expression of immune related genes, and their association with treatment response and prognosis. Methods To decipher the effects of neoadjuvant CRT on the TIM, we obtained 58 paired pre-treatment and post neoadjuvant CRT treated EC specimens. TILs and tumor infiltrating neutrophils (TIN) were quantified in pre-treatment biopsies and surgical resection specimens following neoadjuvant CRT. To evaluate the immune transcriptomics, RNA was extracted from these specimens and gene expression was assessed using the Nanostring Platform based on the PanCancer Immune Profiling Panel. Immunohistochemistry (IHC) was performed to validate findings from the immune transcriptomics. Results TIL counts were not prognostic for disease specific survival (DSS). We observed higher expression of immune-suppressive inflammatory chemokines (TGFß-1 and IL-16) in post-neoadjuvant treated samples compared to pre-treatment biopsies. In samples collected after neoadjuvant CRT, low expression of genes related to anti-tumor T cell cytotoxic activity1 was significantly associated with disease recurrence. In patients with residual disease, multivariate analysis revealed a high neutrophil count, but not TIL count, was significantly associated with inferior DSS (HR 3.8 [1.3– 10.8]; p = 0.01). Conclusion In EC, the tumor microenvironment after neoadjuvant CRT remains largely immune-suppressive. We discovered that the presence of TINs in patients with residual disease post neoadjuvant CRT is an independent adverse prognostic factor. Collectively, our results suggest that an inflammatory pro-tumoral microenvironment associated with TINs may contribute to treatment resistance and progressive disease in EC.

Sequential monitoring of PD-L1 on circulating stromal cells in blood predicts PFS in NSCLC patients undergoing immunotherapy after definitive chemoradiation.

8534 Background: Cancer Associated Macrophage-Like cells (CAMLs) are circulating stromal cells in the blood of patients (pts) with solid tumors that are phagocytic macrophages that may represent the inflammatory state of the tumor microenvironment. Previously, we demonstrated CAMLs ≥50µm after chemo-radiation therapy (CRT) in NSCLC is associated with worse progression free survival (PFS) and overall survival (OS). We also showed that PDL1 expression in CAMLs is dynamic &amp; can change with CRT, difficult to assess with repeat biopsies, but possible with liquid biopsy. For this study we evaluated whether CAML properties can predict response to CRT with/without immunotherapy (IMT) agents in unresectable NSCLC. Methods: A single blind multi-year prospective study was undertaken to test the relationship of PDL1 expression and ≥50µm CAML size to PFS/OS in NSCLC, pre and post CRT with (n = 96) and without (n = 72) anti-PDL1/PD1 IMT. This included atezolizumab (prospective single arm NCT02525757) n = 39, durvalumab n = 52 or pembrolizumab n = 5 both after 2018 FDA approval. We recruited 168 pts with pathologically confirmed unresectable NSCLC prior to CRT. Blood samples 15 mL were taken at baseline (BL), CRT completion (T1), and ̃1 month after CRT (T2) (with n = 96 or without n = 72 IMT). Blood was filtered by CellSieve filtration and CAMLs quantified for size ( &lt; 49 µm or ≥50 µm) and PDL1 expression to evaluate PFS and OS hazard ratios (HRs) by censored univariate and multivariate analysis at 24 months. Results: CAMLs were found in 90% of all samples, average 5.8 CAMLs/15mL. At BL, ≥50µm CAMLs did not predict PFS in CRT/IMT pts (HR 1.6, p = 0.220) nor CRT alone (HR 1.3, p = 0.593). However, after completion of CRT (T1) ≥50µm CAMLs predicted PFS in CRT/IMT pts (HR 2.7, p = 0.003) and CRT alone (HR 2.5, p = 0.015). In primary tumor biopsies, PDL1 expression &gt; 1% did not predict CRT/IMT response (PFS HR 1.8, p = 0.262 &amp; OS HR 2.3, p = 0.158). At BL, high CAML PDL1 did not predict PFS in CRT/IMT pts (HR 1.4, p = 0.427) nor CRT alone (HR 1.1, p = 0.982). Further, at CRT completion (T1), high CAML PDL1 only trended for better PFS in CRT/IMT pts (HR 1.7, p = 0.137), but not CRT alone (HR 1.1, p = 0.972). At T2, however, pts with continuously high CAML PDL1 had significantly better PFS with IMT (HR 3.2, p = 0.002) vs CRT alone (HR 1.4, p = 0.616). While ≥50µm CAMLs at BL did not predict 24 month progression, ≥50 µm CAMLs after CRT (with or without 1 cycle of anti-PDL1 IMT) was 84% accurate at predicting progression. Further subtyping and analysis is ongoing to evaluate OS and PDL1 in the CAML populations. Conclusions: Our data suggests that in unresectable NSCLC, ≥50 µm CAMLs after completion of CRT is prognostic regardless of IMT use. PDL1 expression in CAMLs also appears to predict for response to consolidated IMT after CRT. Additional studies are needed to validate these findings.

Quality initiative (QI) in unresectable stage III non-small cell lung cancer (NCSLC): Impact on time-to-treatment (TTT) for immunotherapy post chemoradiation (CRT).

e18780 Background:In August 2019 Integra Connect (IC) partnered on a QI with University of Pittsburgh Medical Center (UPMC) to improve outcomes in patients with stage 3 and 4 NSCLC. This report details the findings and interventions in the unresectable stage 3 cohort of the QI. The addition of durvalumab (D) in the PACIFIC trial (Antonia et al. NEJM 2017) after completion of CRT in stage 3 patients who had not progressed showed significant Progression Free Survival and Overall Survival (OS) benefit with Food and Drug Administration approval on 2/16/2018 in this setting. An update (Gray et al. Thoracic Oncol 2020) on 10/14/2019 noted superior OS in patients in whom randomization to D occurred 1-14 days post CRT vs. those with interval 15-42 days (HR 0.43 vs. 0.79). Data suggest that CRT renders tumors more responsive to immunotherapy (McCall et al. Clin Can Res 2018). As part of the QI, we explored the question whether time from CRT to D (TTT) could be shortened. Methods:From the UPMC and IC real-world-data (RWD) databases, we identified 182 patients with Stage 3 unresectable NSCLC treated with CRT between 2/16/18 (D approval) and 11/16/20 for manual chart abstraction. We calculated the TTT from the latest day of radiation or chemotherapy to the first D dose. Time-to-scan (TTS) used a similar methodology. If post-CRT scan data was not found, those patients were excluded from TTS analysis. We captured caregiver perception with surveys and used RWD to determine the proportion of eligible patients treated with D, categorizing the data into 3 successive time periods: Phase 1 (240 days): 2/16/18 approval of D to Gray update 10/14/19, Phase 2 (321 days): 10/15/19 to physician leadership intervention 8/31/20, Phase 3 (76 days): 9/1/20 to 11/16/20. Patients were excluded in phase 3 who started CRT after 11/16/20 to allow for up to 2 months to start D. Our plan included baseline and ongoing monitoring of metrics complemented with physician leadership intervention to address identified gaps in care. Results: Median age of the 182 patients was 68 (range 46-87) with 60% male. Of eligible patients, 121 (66.5%) received at least 1 dose of D. Median TTS improved 16 days from Phase 1 to Phase 3 while TTT concomitantly improved 17 days (Table ). Conclusions: This QI resulted in simultaneous shortening of TTS and TTT following physician intervention with establishment of TTS as a key potential driver of TTT which ultimately may result in improved OS. To do so required overcoming the traditional paradigm of imaging 4-6 weeks post-CRT to capture maximal response with that of early imaging aimed at assuring no progression had occurred. This, as well as proportion treated with D and its resulting duration, plus any subsequent treatments that might indicate relapse, continue to be monitored in a real-time dashboard.[Table: see text]

Prospective manipulation of the gut microbiome with Microbial Ecosystem Therapeutic 4 (MET4) in locoregionally advanced oropharyngeal squamous cell carcinoma (LA-OPSCC) undergoing primary chemoradiation (ROMA2).

6059 Background: Therapeutic manipulation of the gut microbiome in cancer patients (pts) is an area of active investigation. MET4 (NuBiyota) is an oral alternative to fecal transplant consisting of a mixture of human gut bacteria associated with immunotherapy (IO) response. We previously reported variation in IO-responsive taxa across stages in human papilloma virus related (HPV+) LA-OPSCC pts treated with chemoradiotherapy (CRT) (Oliva et al., ASCO 2020). ROMA-2 is the first interventional study evaluating the safety, feasibility and ecological effect of MET4, in combination with definitive CRT in HPV+ LA-OPSCC (NCT03838601). Methods: This is an investigator-initiated study of pts with HPV+ LA-OPSCC treated with standard of care CRT. MET4 is administered daily until week 4 of CRT or unacceptable toxicity. Stool samples are collected at baseline, week 4, week 8-10, and 2-months post CRT. Bacterial V4 16S rDNA was extracted from stool and sequenced. Microbiome analyses were conducted in R using DADA2, phyloseq and DESeq2. Results: As of February 11 2021, 25 pts have been enrolled. A total of 50 stool samples from the first 14 pts were collected (98% adherence) and analyzed. Baseline cohort characteristics: median age = 62.5 (range, 48-69); Stage I/II/III = 5/1/8; use of antibiotics = 1pt. 3 pts did not complete the 3-week course of MET4 treatment due to non-compliance (n = 1), withdrawal of consent (n = 1) and grade 2 diarrhea (n = 1). Other reported MET4-related adverse events (all grade 1) included bloating (n = 2), flatulence (n = 1) and belching (n = 1). No longitudinal changes in alpha-diversity were seen from baseline through follow up. Administration of MET4 resulted in a transient trend towards increased cumulative MET4 taxa relative abundance (RA) by week 4. Stage III patients demonstrated the lowest MET4 taxa RA at baseline, and the greatest increase in MET4 taxa RA from baseline to week 4. By week 4 the following taxa in all pts were increased compared to baseline: Eubacterium hallii (21.71 Log2Fold change[L2FC], padj &lt; 0.001) and Parabacteroides johnsonii (23.67 L2FC, padj &lt; 0.001). An increase in the following taxa was observed by weeks 8-10 compared to baseline: Akkermansia muciniphilla (3.75 L2FC, padj = 0.027), Bacteroides fragilis (6.73 L2FC, padj = 0.010), Alistipes onderdonkii (3.30 L2FC, padj = 0.049) and Parabacteroides distasonis (24.43 L2FC, padj &lt; 0.001). Conclusions: Manipulation of the gut microbiota in these pts was feasible and safe. MET4-induced ecological changes are heterogenous and vary by taxa. MET4 taxa implicated in IO-response were increased by week 4 and week 8-10. This increase was higher in pts with stage III disease. These data suggest that specific subgroups may benefit from combination IO therapy and may guide pt selection for further interventional clinical trial design. Clinical trial information: NCT03838601.

Impact of three-dimensional chemoradiation on pelvic bone mineral density, low back pain, and disability in cervical cancer: a prospective study

ObjectiveTo prospectively analyze the effect of three-dimensional chemoradiation on the bone mineral density of pelvic bones and its association with low back pain and disability in patients with locally advanced...

The Correlation Between Tnm and Yy1 and P53 Mrna Expression in Nasopharyngeal Cancer

Nasopharyngeal cancer is the fifth most severe malignant disease in the head and neck in the human body. The main treatment is chemoradio therapy. The protein gene 53 (p53) is a tumor suppressor gene. YinYang1 (YY1) is a transcription factor having an important role in cell cycle control. YY1 can function as an activator, suppressor or initiator of the gene transcription process. This research aims to see the relationship between p53 mRNA gene expression and YY1 mRNA gene expression on the NPC TNM Stage. Materials andmethods cross-sectional research at 20 WHO type 3 NPC in which 3 samples after chemoradiotherapy, 17 non-chemoradio therapy samples consisted of 8 stage two samples, 7 stage three samples and 2 stage four samples. With RT-PCR, YY1 mRNA gene expression and p53 mRNA gene expression were measured, then the T-test was independent of the average chemoradio therapy group. It was concluded, at a higher NPC stage, the level of YY1 mRNA gene expression was relatively higher while p53 expression was lower. Post-chemoradio therapy levels of p53 mRNA gene expression were higher and YY1 expression was lower than in the non-chemoradio therapy group.

Outcomes of Definitive Chemoradiotherapy for Stage IVa (T4b vs. N4) Esophageal Squamous Cell Carcinoma Based on the Japanese Classification System: A Retrospective Single-Center Study.

Simple SummaryDefinitive chemoradiotherapy is a standard treatment for stage IVa esophageal cancer, although it is unclear whether T/N factors affect treatment outcomes and whether we should modify chemoradiotherapy regimens based on T/N factors. This single-center retrospective study aimed to determine whether T/N factors affected progression patterns and overall survival after chemoradiotherapy for stage IVa esophageal squamous cell carcinoma. There were no significant differences between the T/N groups in terms of overall survival, progression-free survival, or progression patterns. Therefore, it may not be useful to modify chemoradiotherapy regimens based on T/N factors for patients with stage IVa squamous cell carcinoma.The differences in prognoses or progression patterns between T4b non-N4 and non-T4b N4 esophageal squamous cell carcinoma post chemoradiotherapy (CRT) is unclear. This study compared the outcomes of CRT for stage IVa esophageal squamous cell carcinoma according to T/N factors. We retrospectively identified 66 patients with stage IVa esophageal squamous cell carcinoma who underwent definitive CRT at our center between January 2009 and March 2013. The treatment outcomes, i.e., progression patterns, prognostic factors, and toxicities based on version 5.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events, were studied. The patients (56 men and 10 women) had a median age of 67 (range: 37–87) years. The T/N classifications were T4b non-N4 (28/66), non-T4b N4 (24/66), and T4b N4 (14/66). Objective response was achieved in 57 patients (86.4%, (95% confidence interval, 74.6–94.1%)). There were no significant differences between the T/N groups in terms of overall survival, progression-free survival, and progression pattern. We found no significant differences in prognoses or progression patterns among patients with T4b non-N4, non-T4b N4, and T4b N4 esophageal squamous cell carcinoma. Thus, it seems impractical to modify CRT regimens based on T/N factors.

A Murine Model Of Kidney Injury: The role of SMPDL3b In Radiation And Cisplatin-Induced Nephrotoxicity

Cisplatin is widely used as a chemotherapeutic agent and a known radiosensitizer. The current study aimed to investigate the role of lipid-modulating enzyme sphingomyelin phosphodiesterase acid-like 3B (SMPDL3b) in cisplatin toxicity. Nephrotoxicity is dose-limiting toxicity. Cultured oocytes were treated with rituximab mAb (100 μg/ml) or IgG (100 μg/ml) 30 minutes before irradiation with 0-8 Gy, with or without Cisplatin (2μM). In other experiments, 10–14-week old C57BL/6 male and female mice were given bilateral kidney X-irradiation (4Gyx1, 6 Gyx5, and 2Gyx24) with or without Cisplatin (6mg/kg, IP). Animals received rituximab mAb (RTX) or IgG (50mg/kg; IV) 30 minutes before radiation treatment. Functional kidney parameters (serum BUN, hematocrit, and creatinine), histopathological assessments (oil red staining, H&E, Periodic Acid-Schiff, and TEM) and biochemical changes were studied at baseline, 10- and 20-weeks post-chemo-radiotherapy. Glomerular filtration rate (GFR) was estimated at 10- and 20-weeks post-radiation using FITC-sinistrin based transdermal monitor and iSMAART dynamic contrast-enhanced (DCE) imaging. RT and concurrent Cisplatin (2 μM) produced time-dependent apoptosis in wild-type human podocytes, causing an 85% increase in caspase 3 activity 2h post-RT (8Gy). Different doses of RT, 1x4Gy, 1x10Gy, and 1x14Gy increased glomerular base membrane (GBM) thickness in irradiated mice significantly (100%, 150%, and 200% respectively). Cisplatin and RT (1x4Gy) increased GBM thickness from 225nm to 425nm, respectively (p = 0.01). The eGFR values changed significantly from 1010±214 to 718±205, 687±175, 508±56, 596±180, and 639±221 mL/min after x4Gy, 1x10Gy, 1x14Gy, 5x6Gy, and 24x2Gy, respectively. RTX pretreatment improved eGFR and other functional parameters (serum BUN, hematocrit, serum creatinine, and urine albumin/creatinine ratio (ACR) significantly post chemoradiotherapy. RTX pretreatment protected podocytes cytoskeletal remodeling in vitro and foot process effacement in vivo. SMPDL3b expression and podocytes count significantly decreased post chemoradiotherapy. RTX ameliorated SMPDL3b down-regulation, and improved podocytes count significantly. This study shows that RTX pretreatment protects podocytopathy in vitro and chemoradiation induced kidney injury in vivo. SMPDL3b may be an important therapeutic target for radiation-induced kidney injuries in cancer patients.

Results of a Randomized, Open Label, Multicenter Trial Assessing the Safety, Dose and Schedule of RRx-001 (R001) in Reducing Severe Oral Mucositis (SOM) in Patients Receiving Chemoradiation (CRT) for Oral Cavity/oropharynx Squamous Cell Carcinoma (OSCC)

Severe oral mucositis (SOM, assessed WHO grade 3 or 4) occurs in up to 70% of patients receiving CRT for OSCC, many of whom require enteral nutrition or experience treatment interruption. Pharmacological targeting of nuclear factor erythroid related factor (Nrf2) represents an opportunity to mitigate radiation-associated toxicities mediated by oxidative species (OS). Preclinical studies demonstrate R001 activates Nrf2, a key regulator of gene expression encoding antioxidant, phase II detoxifying enzymes, and downstream Antioxidant Response Element signaling pathways. Activation of Nrf2 increases the threshold and buffering capacity of OS generated by CRT, and its multi-target activity provides a counterbalance to oxidative stress resulting in focal and systemic radioprotection. This proof of concept Phase 2a randomized clinical trial examined the safety, efficacy and schedule-dependent effects of R001 in reducing the incidence, severity and duration of SOM. Patients with OSCC treated with definitive or postoperative CRT were randomized to one of 4 treatment arms: 2 doses/week for 2 weeks before (pre) CRT (Arm 1); pre-CRT plus 2 doses or pre-CRT plus 6 weekly doses during CRT (Arm 2, 3 respectively); or standard of care (SOC) (Arm 4). The primary endpoint was duration of SOM through resolution < grade 2. Secondary endpoints included safety, time to onset, incidence, and duration of SOM and grade 4 mucositis through 60 and 70 Gy. Between June 2018 and July 2019 across 11 institutions, 53 patients were randomized, with 45 evaluable. Short 15-minute infusions of R001 were well tolerated with no associated serious adverse events (SAE). Side effects were comparable to SOC. Trends in treatment benefits for all endpoints were consistent across the 3 treatment arms, with the greatest effect size in Arm 1. R001 delayed time to onset (38 vs. 26 days) and duration of SOM (22 vs. 40 days), with 83% having resolution vs 60% with SOC, respectively. No patients developed grade 4 mucositis vs 30% SOC arm. A 95% decrease in duration of SOM (1 vs 17 days) through 60 Gy was also observed. Gastrostomy requirement was reduced by 45% (33% vs 60%). In this small open-label trial, R001 demonstrated a favorable benefit-risk profile with a markedly decreased incidence and duration of SOM through 60 Gy, 70 Gy and follow-up post CRT. Treatment effect was greatest in Arm 1 suggesting short periods of Nrf2 activation prior to generation of OS by CRT may be sufficient to increase the threshold and buffering capacity of antioxidants. Larger, blinded trials, confirming the observed dose, schedule and treatment effect are planned.

Accuracy of MRI for nodal restaging in rectal cancer: a retrospective study of 166 cases.

Assessing metastatic mesorectal nodal involvement is a challenge in rectal cancer, especially in the post chemoradiation setting. We aim to assess the accuracy of MRI for nodal restaging and the validity of SAR criteria (≥ 5mm size being metastatic). This was an IRB-approved retrospective study of 166 patients with locally advanced rectal cancers, operated after neoadjuvant treatment. Two dedicated oncoradiologists reviewed the 166 post-chemoradiation presurgical MRIs in consensus. Nodal size and morphology (shape, margins, and signal intensity) were noted. The most accurate cut-off for size for predicting positive pN status was determined using the Youden index. MRI understaged 30/166 (18%) and overstaged 40/166 (24%) patients using the SAR criteria. The most accurate cut-off for node size was 5.5mm, with a sensitivity of 75%, specificity of 60.2%, PPV of 40.7%, NPV of 86.9% (95% CI:78-92.5%), accuracy of 64.2%, and area under the curve (AUC) 0.657 (95% CI-0.524-0.79). Morphological characteristics were not significant to determine involvement, with positive nodes including 42% of round and 31% of oval nodes, 40% of heterogeneous and 45% of homogeneous nodes, and 31% irregularly marginated and 46% nodes with regular margins beingpositiveon pathology. MRI was accurate in predicting pathology for mucinous nodes in 9/29 (31%) cases. Seven cases which were yN2 on MRI and yN0 on pathology demonstrated mucinous changes on MRI and had acellular mucin on histopathology. MRI has good negative predictive value, poor positive predictive value and moderate accuracy in nodal restaging. The cut-off of 5.5mm demonstrated in our study is close to the SAR cut-off of 5mm in the post-treatment setting. MRI accuracy is lower in patients with mucinous nodes.

Induction chemotherapy for locally advanced laryngeal and hypopharyngeal cancer: Single institution experience.

The role of induction chemotherapy (IC) in locally-advanced head and neck squamous cell carcinoma (LAHNSCC) is unclear. A retrospective study of 104 patients with LAHNSCC of the larynx and hypopharynx, treated with IC or up-front chemoradiotherapy (CRT). Eighty patients received CRT and 24 IC followed by CRT; median follow up was 51.33 months. IC significantly improved median overall survival (OS) in the hypopharyngeal cancer group (64.7 vs 21 months, P = .003); with significant difference in the proportion of complete response at first imaging assessment post definitive CRT; no significant difference in disease free survival (DFS), loco-regional or distant failure in the hypopharyngeal cancer group; or OS and DFS in the laryngeal cancer group. Patients with laryngeal cancer had significantly better median OS than those with hypopharyngeal cancer. IC significantly improved complete response rates after CRT, and improved outcomes for patients with locally advanced hypopharyngeal, not laryngeal, cancers.

Prevention of diffuse, minimal lymphatic "retention" with Robuvit®: a concept, supplement registry study.

The aim of this study was to evaluate the effects of the standardized supplement Robuvit® (oak wood extract) in defined diffuse, minimal lymphatic "retention" (DMLR). Robuvit® has already been investigated in both primary and secondary (post-surgical, post chemo-radiotherapy) lymphatic insufficiency. This registry included subjects with diffuse, minimal lymphatic "retention" (DMLR). The registry management groups included women with mild-moderate limb swelling using standard management (SM) as controls. A second, comparable group used prevention with Robuvit® at the dosage of 3 cp/day (300 mg/day) for 4 weeks. No tolerability problems or side effects were observed with the preventive supplementation. The management groups (34 women in total), including 18 women in Robuvit® and 16 in SM were comparable in age and baseline evaluations. After 4 weeks, in the Robuvit® group, edema scale values derived from ultrasound observations decreased significantly (P<0.05) at all measurement's sites, from the proximal (inguinal) level to the more distal (ankle-foot) level. No significant changes in edema were observed in control subjects. Generally, in areas with higher level of edema (distal areas at the foot and ankle), the edema decrease was larger than in more proximal, ultrasound measurement sites. Preventive Robuvit® supplementation appears to be safe and effective in controlling DMLR in subjects without significant or apparent clinical conditions. This preventive, concept study should be extended to a larger population for more meaningful observations.

Clinicopathological correlation of serum vascular endothelial growth factor and tissue carbonic anhydrase factor IX in stage IA to IIA carcinoma cervix.

e18012 Background: VEGF initiates endothelial cell proliferation and angiogenesis in tumour cells while CA IX has an important role in pH regulation and elimination of hypoxia generated acid load during glycolysis.The present study was designed to identify these biomarkers and their correlation with tissue spread and behavior and eventually could lead to development of novel target therapies. The objective of this study was to correlate serum VEGF levels and tissue CA IX expression with clinicopathological features of carcinoma cervix stage IA to IIA. Methods: This exploratory case-control study included 19 cases with carcinoma cervix FIGO 2009 stage IA to IIA and 19 age matched controls. Out of the 19 cases, 12 underwent surgery and 7 received chemoradiation. Pre-therapy blood samples were collected for serum VEGF estimation from both cases and controls. For CA IX expression estimation, cervical tissue was taken for analysis. For cases, post-operative / post chemoradiation blood samples were taken for VEGF level estimation after 6 weeks. Results: The difference in mean serum VEGF levels between cases 1235.84 pg/ml (SD± 433.67) and controls 153.74 pg/ml (SD± 108.11) was statistically significant (p = 0.001). Mean serum VEGF level between pre and post-operative cases was 1108 pg/ml (SD± 407.62) and 391.42 pg/ml (SD± 270.71) while in pre and post chemoradiation cases it was 1455 pg/ml (SD± 413.38) and 623 pg/ml (SD± 238.41). This decrease was statistically significant (p = 0.00 &amp; p = 0.018). VEGF positively correlated with histopathologic type (p = 0.016), grade (p = 0.012), and lymphovascular space invasion (p = 0.042).CA IX expression was seen in all cases while in controls no expression was seen. CA IX expression had a positive association with lymphnode metastasis (p = 0.041). Conclusions: Elevated pre-therapeutic serum VEGF suggests spread of tumor and can be used as a prognostic marker for cancer cervix. CA IX immunostaining in cervical biopsy samples can be used as a surrogate marker for tumor aggressiveness and distant spread.

Consolidation nivolumab/ipilimumab versus nivolumab following concurrent chemoradiation in patients with unresectable stage III NSCLC: A planned interim safety analysis from the BTCRC LUN 16-081 trial.

9010 Background: Consolidation PD-1/PD-L1 inhibition after chemoradiation (CRT) for unresectable stage III NSCLC improves overall survival. In stage IV NSCLC, the combination of nivolumab/ipilimumab improved overall survival compared to chemotherapy in patients with PD-L1 &gt; 1% and performed favorably in patients with PD-L1 &lt; 1%. The safety of consolidation nivolumab/ipilimumab after CRT has not been previously assessed. Methods: In this randomized, multi-center, phase II study, a total of 105 planned pts with unresectable stage IIIA/IIIB NSCLC will receive chemoradiation, then randomize 1:1 to either nivolumab 480mg IV q4 wks (Arm A) or nivolumab 3mg/kg IV q2 wks + ipilimumab 1mg/kg IV q6 wks (Arm B), for up to 24 wks. In this planned interim analysis, the safety of the first 50 patients, with 25 patients treated on each arm, is assessed. Results: From 9/2017 to 6/2019, the first 50 patients were accrued and analyzed for this planned safety analysis. Baseline characteristics for Arm A/B: median age 64/62, stage IIIA 17/16, stage IIIB 8/9, non-squamous 14/13, squamous 11/12. The median number of cycles completed in Arm A was 6 (range 1-6, cycle length q4 wks) and in Arm B was 4 (range 1-4, cycle length q6 wks). The rate of treatment-related adverse events leading to discontinuation of therapy was 16% in Arm A and 40% in Arm B. The percentage of patients with any &gt; grade 3 adverse event (AE) was 32% in Arm A and 44% in Arm B. With respect to immune-related AE (irAEs), the percentage of patients with any ≥grade 2 was 44% in Arm A and 60% in Arm B; any ≥ grade 3 irAEs was 16% in Arm A and 32% in Arm B. The incidence of &gt; grade 2 pneumonitis was 16% in Arm A and 36% in Arm B. The percentage of patients with &gt; grade 3 pneumonitis was 4% in Arm A and 20% in Arm B. No treatment-related deaths were reported on either arm. Conclusions: In the post chemoradiation setting, the incidence of &gt; grade 3 toxicity was greater in the consolidative nivolumab/ipilimumab arm, which resulted in a higher rate of treatment discontinuation than nivolumab alone. The Data and Safety Monitoring Board recommended continued enrollment without modification to the trial and the study currently remains open to accrual (66 of 105 patients have been enrolled as of 1/17/2020). Clinical trial information: NCT03285321.

Outcome of locally advanced carcinoma of oesophagus: A single institution experience.

e16507 Background: Oesophageal cancer is the twelfth most common cancer worldwide and seventh leading cause of cancer related death. Neoadjuvant treatment in addition to surgery has shown improved overall survival compared to surgery alone in resectable oesophageal cancer. We aimed to analyse the survival outcome among locally advanced oesophageal carcinoma patients in neoadjuvant setting. Methods: We analysed 37 patients with locally advanced carcinoma of oesophagus from 2015 to 2019 who underwent neoadjuvant chemoradiotherapy followed by surgical excision of tumour. Descriptive analysis was used for demographic data. overall survival and disease free survival was analysed using Kaplan-Meier survival analysis. Results: Our study includes 20 males (54%) and 17 females (45%). Over all consumption of Tobacco and alcohol consumption was found to be 64% and 18% respectively. The most common tumour site in this study was middle oesophagus (56%) followed by lower (37%) and upper (5%). Histopathologically, moderately differentiated squamous cell carcinoma constituted the highest (62%), followed by well differentiated squamous cell carcinoma (21%) and poorly differentiated carcinoma (16%). The pathological stage post chemoradiotherapy was 80%, 50% and 57% for stage I, II and III respectively. Median over all survival is 60 months and no statistical difference in stage I and stage II. Median over all survival for poorly differentiated squamous cell carcinoma is 16 months and lower one third of squamous cell carcinoma is 37 months. Complete pathological response is 42 %. Conclusions: Our study concluded that patients with tobacco and alcohol consumption have poorer survival. Prognosis was worst for patients with lower end oesophagus and poorly differentiated type. Disease free survival was better for patients who achieved complete pathological response when compared to partial responders.

Predictive Value of Early Post-Treatment Diffusion-Weighted MRI for Recurrence or Tumor Progression of Head and Neck Squamous Cell Carcinoma Treated with Chemo-Radiotherapy

Aims: To investigate the predictive capacity of early post-treatment diffusion-weighted magnetic resonance imaging (MRI) for recurrence or tumor progression in patients with no tumor residue after chemo-radiotherapy (CRT) for head and neck squamous cell carcinoma, and, to assess the predictive capacity of pre-treatment diffusion-weighted MRI for persistent tumor residue post-CRT. Materials and Method: A single center cohort study was performed in one French hospital. All patients with squamous cell carcinoma receiving CRT (no surgical indication) were included. Two diffusion-weighted MRI were performed: one within 8 days before CRT and one 3 months after completing CRT with determination of median tumor apparent diffusion coefficient (ADC). Main outcome: The primary endpoint was progression-free survival. Results: 59 patients were included prior to CRT and 46 (78.0%) completed CRT. A post-CRT tumor residue was found in 19/46 (41.3%) patients. In univariate analysis, initial ADC was significantly lower in patients with residue post CRT (0.56 ± 0.11 versus 0.79 ± 0.13; p < 0.001). When initial ADC was dichotomized at the median, initial ADC lower than 0.7 was significantly more frequent in patients with residue post CRT (73.7% versus 11.1%, p < 0.0001). In multivariate analysis, only initial ADC lower than 0.7 was significantly associated with tumor residue (OR = 22.6; IC [4.9–103.6], p < 0.0001). Among 26 patients without tumor residue after CRT and followed up until 12 months, 6 (23.1%) presented recurrence or progression. Only univariate analysis was performed due to a small number of events. The only factor significantly associated with disease progression or early recurrence was the delta ADC (p = 0.0009). When ADC variation was dichotomized at the median, patients with ADC variation greater than 0.7 had time of disease-free survival significantly longer than patients with ADC variation lower than 0.7 (377.5 [286–402] days versus 253 [198–370], p < 0.0001). Conclusion and relevance: Diffusion-weighted MRI could be a technique that enables differentiation of patients with high potential for early recurrence for whom intensive post-CRT monitoring is mandatory. Prospective studies with more inclusions would be necessary to validate our results.

Long-term defects of nasal epithelium barrier functions in patients with nasopharyngeal carcinoma post chemo-radiotherapy

Background and purposeChronic and recurrent upper respiratory tract infection and inflammation is common in patients with nasopharyngeal carcinoma (NPC) post chemo-radiotherapy (CRT). Whether it is due to intrinsic (e.g., host-defense mechanisms of the epithelium), epigenetic or extrinsic factors is not fully understood. Materials and methodsTissue biopsies of the middle turbinate (MT) and inferior turbinate (IT) from NPC patients after CRT (mean of 3 years, n = 39) were compared with the IT biopsies from healthy subjects (n = 44). The epithelial ultrastructure was examined by transmission electron microscope (TEM). mRNA and protein expressions of epithelial stem/progenitor cells markers, as well markers of cell proliferation and differentiation markers was analyzed. ResultsAbnormal epithelial architecture was observed in all tissue samples of NPC patients. Significantly decreased expression levels of mRNA and protein levels for p63 (basal cells), Ki67 (cell proliferation), p63+/KRT5+ (epithelial stem/progenitor cells), MUC5AC and MUC5B (secretary proteins from goblet cells), alpha-tubulin, beta-tubulin and TAp73 (ciliated cells), DNAH5 and DNAI1 and RSPH4A (microtubule assemblies of motile cilia), FOXJ1 and CP110 (ciliogenesis-associated markers) were evident in MT and IT biopsies from NPC patients when compared to healthy controls. ConclusionCRT causes long-term defects of epithelial barrier functions and increases the susceptibility of these patients to upper respiratory tract infection and inflammation.