Conventional Chemoradiotherapy Research Articles

Accelerated Fractionation With Concomitant Boost vs. Conventional Radio-chemotherapy for Definitive Treatment of Locally Advanced Squamous Cell Carcinoma of the Head-and-Neck (SCCHN).

Patients with unresectable head-and-neck cancer (SCCHN) unable to tolerate radiochemotherapy may receive unconventionally fractionated radiotherapy. This retrospective study compared both treatments. Eight patients unsuitable for chemotherapy were assigned to accelerated fractionation with concomitant boost (AF-CB, 69.6 Gy/39 fractions) over 5.5 weeks (group A) and 72 patients to cisplatin-based radiochemotherapy (70 Gy/35 fractions) over 7 weeks (group B). Groups were matched (cancer site, gender, age, performance score, T-/N-stage, histologic grade) and compared for loco-regional control (LRC), metastases-free survival (MFS), overall survival (OS) and toxicities. LRC, MFS, OS and radiation-related toxicities were not significantly different between groups A and B. Improved outcomes were associated with favorable cancer site, better performance score and T3-stage. In group B, toxicity led to reduction/discontinuation of chemotherapy in 38.9% and interruptions of radiotherapy >7 days in 19.3% of patients. AF-CB appeared a reasonable alternative for patients who cannot safely receive radio-chemotherapy for unresectable SCCHN.

Hypofractionated short-course preoperative conformal radiotherapy versus long course conventional preoperative chemoradiotherapy in the management of locally advanced rectal cancer – Prospective randomized comparative study

Introduction: Colorectal cancer (CRC) is the primary health problem worldwide. Besides survival, a significant problem in locally advanced rectal cancer is recurrence. Adding radiotherapy to surgery has been shown conclusively to improve local control for rectal cancer. Aim: To compare hypo fractionated short-course preoperative conformal radiotherapy versus long-course conventional preoperative chemoradiotherapy in the management of locally advanced rectal cancer. Materials and Methods: This prospective comparative study was conducted in 44 patients who grouped into ARM A (short course RT) for 22 patients and ARM B (long course Chemoradiotherapy) for 22 patients. Treatment protocol and follow up protocol was followed and the results were statistically analyzed and discussed. Results: Out of 44 patients, 22 patients had short-course radiotherapy (ARM A) and 22 patients had long course radio-chemotherapy (ARM B). In ARM A, 7 patients in stage T3NOMO, 2 patients in stage T3N1MO,9 patients in stage T4N0M0, 4 patients in stageT4N1M0,4patients had an interruption, 18 patients had no interruption, mean duration of diseases free survival is 354.59 125.86 days, 18 patients had a partial response, and 4 patients had stable diseases. In ARM B,5 patients in stage T3NOMO, 5 patients in stage T3N1MO, 7 patients in stages T4N0M0, 5 patients in stage T4N1M0, 14 patients had an interruption, 8 patients had no interruption, mean duration of diseases free survival is 414.27119.97 days, 19 patients had a partial response and 3 patients had stable diseases. Conclusion: Short-course neo-adjuvant radiotherapy using IMRT showed similar response rates and diseases free survival but less acute toxicity and short hospital stay when compared to the conventional long-course chemoradiotherapy. Keywords: Chemoradiotherapy, Preoperative treatment, Rectal cancer.

Letter: The Impact of COVID-19 on the Neurosurgery Department During and After the Lockdown of Wuhan.

To the Editor: When the 2019 novel coronavirus (COVID-19) was first reported in Wuhan (China) last December, and as warned by the World Health Organization (WHO),1 the Chinese government decided to seal Wuhan city on January 23 to prevent the spread of the virus across the world. On April 8, 2020, China lifted the lockdown of the first Chinese city of Wuhan and Hubei Province, and Wuhan's borders were reopened based on the basically stable epidemic trend and no local infection. It is common knowledge that blockade measures cause delays in seeking medical attention for most patients. In this study, we retrospectively analyzed the attendance conditions in the neurosurgery department of our hospital during and after the lockdown of the city. In terms of the number of hospitalized patients, we have treated 864 patients who mainly presented with cerebrovascular diseases and brain tumors over the past 6 mo. From the information given in Figure 1, we can see a dramatic change in the number of patients newly admitted from February to July. During the period, there was a dramatic increase from 13 operations in February to 176 operations in July. During this period, the largest number of patients were admitted in June, which might be due to the influx of patients from the surrounding areas or provinces of Wuhan. There are at least 2 fundamental causes accounting for these changes. On one hand, the epidemic situation in Wuhan was worst in February. Since most of the medical resources were reserved for patients with COVID-19, many patients with serious diseases failed to receive timely and effective treatment during the endemic, whereas hospitals in Wuhan accepted only emergency patients. On the other hand, after February, with the remission of the epidemic situation, the number of patients admitted to the hospital increased significantly.FIGURE 1.: Number of newly admitted patients (February-July).Figure 2 clearly reveals the statistics of comparison in the number of newly admitted patients between preclosure and postclosure of Wuhan. According to the column chart, there was a significant increase in all kinds of diseases. Among them, cerebrovascular disease and brain tumor accounted for 54.6% and 25.5% of the total number of cases, ranking first and second, respectively. During the period of the blockade, we received and cured only emergency cases, including cerebral hemorrhage and life-threatening brain tumors, to reduce the chances of cross-infection. We speculated that the main cause was that the number of patients who could not be hospitalized for treatment during the epidemic period increased continuously, and most of them demanded to be hospitalized for active treatment after the healthcare work had returned to normal.FIGURE 2.: Comparison in the number of newly admitted patients between preclosure and postclosure of Wuhan.For operation volume, the line chart (Figure 3) illustrates the growth in surgical operations in our department from February to July. There were a least number of patients in our department in February and March, with only 8 patients undergoing surgery. Among them, most of the surgery cases were related to cerebrovascular disease and brain tumor as cerebral vascular hemorrhage and stroke of brain tumors are emergency cases, which need immediate surgical treatment. With the effective control of the epidemic situation in Wuhan after March, the number of operations in our department has increased significantly, among which most of the operations were related cerebrovascular diseases and brain tumors. Because these patients could not get medical treatment during the epidemic period, they needed immediate treatment after the epidemic situation had become stable.FIGURE 3.: Comparison of operation volume of different neurosurgical diseases during the first half of the year.According to the above data collected by our department, we found that the number of patients admitted to the neurosurgical department increased significantly during and after the epidemic period, and the number of operations also increased. This also led to an increase in the workload of surgeons. Similarly, for patients, the recurrence rate of some malignant brain tumors with resection before the epidemic situation increased due to no access to conventional chemoradiotherapy. In conclusion, neurosurgery departments across the world should be prepared for the expected increase in operation volume with the improvement in the epidemic situation and should reasonably prepare the operation schedule and arrange medical resources, so as to seamlessly carry out normal diagnosis and treatment processes after the epidemic situation. Funding This study did not receive any funding or financial support. Disclosures The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

Angiopoietin-2 Combined with Radiochemotherapy Impedes Glioblastoma Recurrence by Acting in an Autocrine and Paracrine Manner: A Preclinical Study.

Simple SummaryGlioblastoma (GB) is a highly aggressive brain tumor characterized by poor prognosis and high rate of recurrence in response to conventional treatments consisting of tumor resection and radiochemotherapy (RCT). The reasons for this therapeutic failure are mainly due to the complexity of GB biology and its environment. GB progression is highly dependent on its vascularization and inflammatory status. Besides, evidence showed that RCT also induces vascular change and inflammation. In GB patients, Angiopoietin-2 (Ang2), biomarker of poor prognosis is a crucial angiogenic factor also involved in inflammation. Our aim was to clarify the role of Ang2 in RCT-induced changes in the GB environment. To this end, we generated Ang2-overexpressing GL261 cells and characterized tumor progression, as well as inflammation and vascularization, in response to RCT. We showed that Ang2 delays tumor recurrence and makes a lasting improvement in animal survival when combined with conventional RCT.(1) We wanted to assess the impact of Ang2 in RCT-induced changes in the environment of glioblastoma. (2) The effect of Ang2 overexpression in tumor cells was studied in the GL261 syngeneic immunocompetent model of GB in response to fractionated RCT. (3) We showed that RCT combined with Ang2 led to tumor clearance for the GL261-Ang2 group by acting on the tumor cells as well as on both vascular and immune compartments. (4) In vitro, Ang2 overexpression in GL261 cells exposed to RCT promoted senescence and induced robust genomic instability, leading to mitotic death. (5) Coculture experiments of GL261-Ang2 cells with RAW 264.7 cells resulted in a significant increase in macrophage migration, which was abrogated by the addition of soluble Tie2 receptor. (6) Together, these preclinical results showed that, combined with RCT, Ang2 acted in an autocrine manner by increasing GB cell senescence and in a paracrine manner by acting on the innate immune system while modulating the vascular tumor compartment. On this preclinical model, we found that an ectopic expression of Ang2 combined with RCT impedes tumor recurrence.

NCOG-33. HEMATOLOGIC PREDICTORS OF OUTCOMES IN GLIOBLASTOMA TREATED WITH SURGERY AND CHEMORADIATION

Abstract BACKGROUND There are conflicting reports regarding the prognostic value of platelet and other blood counts in glioblastoma. However, few series have looked at all hematologic parameters simultaneously. METHODS We performed a retrospective chart review of patients diagnosed with supratentorial glioblastoma from 2014-2019 who started conventional chemoradiation following initial surgical biopsy and/or resection. Hematologic parameters were collected at baseline, in the preoperative and postoperative periods and at the initiation and completion of chemoradiation. This included platelet counts, hemoglobin levels, white blood cell counts (WBC), neutrophil and lymphocyte counts with neutrophil:lymphocyte (NLR) and platelet:lymphocyte ratios (PLR) calculated at each time point. Cox regression was performed to assess the association between each hematologic parameter and both overall survival (OS) and progression free survival (PFS). A multivariate Cox proportional hazards model adjusted for all hematologic parameters, age, sex, race and KPS was generated for each time point. All hematologic parameters were modeled as continuous variables. RESULTS A total of 58 patients met inclusion criteria. 18 were female and 40 male. The median age was 59.5 (range 43-82). Median follow up for all patients was 15.3 months. A total of 52 patients completed radiation therapy and 18 completed 6 cycles of adjuvant chemotherapy. Hemoglobin and neutrophil counts at the conclusion of chemoradiation were associated with OS and PFS on univariate and multivariate analyses. The HR for OS were 0.74 (95% CI 0.5807-0.9313) and 1.28 (1.143-1.441) respectively. The HR for PFS were 0.70 (0.5531-0.8881) and 1.16 (1.05-1.271) respectively. Postoperative lymphocyte and platelet counts at initiation of chemoradiation were both associated with OS with unadjusted HR of 3.2 (1.037-9.960) and HR of 0.99 (0.9898-0.9999) respectively, which remained significant on multivariate analysis. However, neither were associated with PFS. CONCLUSION Several hematologic parameters are associated with glioblastoma outcomes in these initial analyses. Further analyses with additional patients are ongoing.

Immune checkpoint expression in HNSCC patients before and after definitive chemoradiotherapy.

Primary platinum-based chemoradiotherapy (CRT) remains the treatment of choice for nonresectable squamous cell carcinoma of the head and neck (HNSCC). Immune-checkpoint modulators are used as palliative therapy and studied in combination with definitive CRT. However, the immunological changes by CRT need yet to be understood. A cohort consisting of 67 paired tissue biopsies (N = 134) of HNSCC patients before and after CRT was created. The expression of PD-1, PD-L1, and CD27 of tumor and immune cells by immunohistochemistry was evaluated. PD-L1 expression on immune cells of non-responders was significantly lower before CRT (P = .008). CD27 was expressed only on immune cells and not on cancer cells. A significant lower CD27-expression score was observed following CRT (P = .019). Conventional CRT changes the expression of CD27 in the tumor microenvironment. Whether this is due to a loss of expression or a reduction of CD27+ cells must be evaluated in further analyses.

English

BACKGROUND As most cases of head and neck cancer are locally advanced, i.e., stage III and IV, it may be useful to compare induction chemotherapy policies accompanied by simultaneous chemoradiation with concomitant chemoradiation alone, in terms of tumour response and toxicity profile in these cases. That's why this study was undertaken. We wanted to evaluate induction chemotherapy accompanied by chemoradiation in terms of local regulation as opposed to chemoradiation alone in locally advanced Head and Neck Cancers. METHODS This is a prospective comparative study. Study was done between July 2017 and July 2019, with Arm A (Test Group) & Arm B (Control group). Forty patients of locally advanced Head and Neck cancer from the outpatient department, selected for treatment, were included in the study, with 20 in each arm. RESULTS Reduction in tumour size after treatment was compared in both the groups with RECIST (Response Evaluation Criteria in Solid Tumours) 1.1. Induction chemotherapy caused significant reduction in tumour size but had more toxicities which were manageable. When compared to conventional chemoradiation, the induction chemo group did not show statistically significant benefit. Response was better in patients with high nodal volume as some of the cases showed good response in the nodal volume irrespective of response of the primary. CONCLUSIONS This study emphasizes the role of induction chemotherapy in select patients with advanced disease, especially in high volume, where majority of cases (more than 80 %) are stage III or IV and above. Hence, patient selection is the key to outweigh the risk involved. KEYWORDS Cancer Undergoing Radiation Therapy

Real-World Analysis of Clinical Characters, Prognosis, And Recurrence Pattern: A Retrospective Multicenter Study of 429 Patients with Epidermal Growth Factor Receptor (EGFR) Mutant Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC)

Advanced NSCLC with EGFR mutations is a distinct subgroup which has unique biology and a high response rate towards target therapy of EGFR-tyrosine kinase inhibitors (TKIs). However, for EGFR-mutant unresectable LA-NSCLC who treated with conventional chemoradiotherapy (CRT), limited data are available about the relationship between clinical characteristics, prognosis, and subsequent failure patterns. Here we summarized these clinical data using a joint academic center database. We retrospectively collected data for patients with unresectable stage III NSCLC harboring EGFR mutations from nine major academic cancer institutions in China from Jan 2012 to December 2018. Patients with concurrent ALK rearrangements were excluded. Tumor or ctDNA genotyping was performed using polymerase chain reaction amplification or next-generation sequencing method. OS, PFS, local-regional failure free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated from the date of diagnosis. A total of 429 patients met selection criteria were included in the study, among whom 209 (48.7%) patients had exon 19 deletion, 165 (38.5%) had L858R exon, 26 (6.1%) had uncommon mutations, and 29 (6.8%) had multiple mutations. 298 patients (69.5%) were smoker, and 227 (61.9%) were female. The median age was 58 (30-89) years and 230 (53.6%) was younger than 60 years. 296 (69.0%) patients had stage IIIB disease and 285patients (66.4%) with smaller primary lesions (T1/2). Of the 367 patients with survival information, the median follow-up time was 40.8 months. the median OS were 55.5 month (95%CI 43.4-67.5). The 1-, 2-, 3-, and 5-years OS rates are 94%, 79%, 63%, and 47%, respectively. The median PFS was 16.6 months (95%CI 14.9-18.2). The 1-, 2-, 3-, and 5-years PFS rates are 64%, 34%, 22%, and 14%, respectively. There was no difference in OS or PFS by different genotypes. In multivariable analysis, use of EGFR-TKIs (yes v not: HR = 0.56, 95%CI 0.43-0.74, P<0.001) and stage (IIIA v IIIB: HR = 0.67, 95% CI 0.51-0.87, P = 0.003) were independently associated with PFS; and age was independently associated with OS (≥60 v <60 years: HR = 1.45, 95% CI 1.03-2.03, P = 0.035). As for relapse pattern after initial treatment of thoracic radiotherapy (RT) and chemotherapy, 46.5% of patients developed DM, 31.0% developed LRR, and 22.5% developed simultaneous DM and LRR. The incidence of brain metastasis was 24.8% (91 patients). By multivariable analysis, EGFR-TKIs independently increased the DMFS (yes v not: HR 0.51,95%CI 0.37-0.70, P<0.001). To our knowledge this is the largest retrospective analysis of EGFR-mutant LA-NSCLC, aiming to provide a reliable baseline and prognosis estimate. Multivariable analysis demonstrated EGFR-TKIs might independently prolong DMFS. The combined treatment modality of RT and EGFR-TKIs may be promising.

Augmentation of Radiotherapy Using a Novel Loco-regional Hydrogel Based Radiosensitizer Delivery Platform for Head and Neck Squamous Cell Carcinoma

Head and neck cancers are one of the major causes of morbidity and mortality globally. Concurrent chemoradiation is a definitive treatment for majority of locoregionally advanced head and neck squamous cell carcinomas (HNSCC). However, it is associated with dose dependent side effects on normal tissues due to systemic absorption. Though numerous radiosensitizers are being used clinically to lower the therapeutic dose of radiotherapy, their dose associated toxicities, low circulation half-life and bioaccumulation at target site limits the use. Hence, we developed a novel low cost mucoadhesive nanoparticle-in-hydrogel platform for the loco-regional delivery of synergistically acting dual radiosensitizers for the treatment of HNSCC. Dual nanoparticles containing hydrogel (DN-H) was characterized in terms of size, surface charge, encapsulation efficiency, release profile and visco-elastic behavior. Biocompatibility and immunogenicity studies were performed on mouse fibroblast L929 and human THP-1 cells respectively. In vitro efficacy of the formulation was evaluated on malignant AW8507 sublingual squamous cells using cell viability assay, Annexin-V apoptosis assay, Gamma H2AX assay and cell cycle analysis. In vivo biodistribution, efficacy and survival studies were performed on subcutaneous oral cancer xenograft bearing NOD-SCID mice. Dual nanoparticles of size 150-220 nm exhibiting sustained release profile of respectively loaded radiosensitizers were encapsulated into an injectable, viscoelastic and sheer thinning hydrogel. Blank DN-H was found to be biocompatible and non-immunogenic with no elicitation of IFN-ɣ and IL-6 cytokine. In vitro efficacy study showed ∼57-fold reduction in the IC50 when cells were treated with DN-H along with radiation as compared to free drug combination. Effect of DN-H on AW8507 cell cycle revealed the enhanced progression of cells previously arrested in S-G2 phase into early and late apoptotic phase due to increased generation of double stranded DNA nicks upon irradiation as compared to single radiosensitizer containing formulation and non-irradiated controls. In vivo biodistribution of both the radiosensitizers showed a preferential accumulation at the tumor site over a period of 72 hours as compared to other organs reflecting the improvement in mice survival. In vivo efficacy study revealed ∼11-fold, ∼5-fold, and ∼3-fold enhanced tumor inhibition in mice treated with DN-H along with radiation as compared to untreated control, only radiation treated control, and marketed systemic formulation treated controls respectively. Based on profound preclinical evaluations, developed nanoparticle-in-hydrogel system exhibits a promising and efficacious strategy over conventional chemoradiotherapy of HNSCC.

Avasopasem Manganese Protects Against Radiation Induced Oral Mucositis and Enhances the Response of Squamous Cell Carcinoma of the Head and Neck to Ionizing Radiation and Radioimmune Therapy

Locoregional recurrence (LRR) is the major cause of morbidity and mortality in patients with squamous cell carcinoma of the head and neck (HNSCC). For those patients that experience surgically unresectable LRR, median overall survival (OS) is less than one year. Approaches utilizing stereotactic ablative radiotherapy (SabR) and immuno-oncology agents such as Nivolumab (α-PD-1 inhibitor) in the salvage setting have become alternatives to conventional chemoradiation therapy. Despite improvements in OS, rates of acute oral mucositis (OM) and late toxicities (skin fibrosis) remain concerns with SabR in the context of re-irradiation. Here we present pre-clinical evidence that avasopasem manganese (GC4419), a highly selective superoxide dismutase mimetic that has received FDA Breakthrough Therapy Designation and is currently in a Phase III trial for reducing severe OM in patients undergoing chemoradiotherapy for locally advanced HNSCC (NCT03689712) also enhances the anti-tumor radiation response of HNSCC tumors. We demonstrate in pre-clinical animal models that avasopasem protects the normal mucosa of the mouse tongue from primary irradiation toxicity. We will also report the results of ongoing studies examining whether avasopasem protects murine mucosa from reirradiation as with SabR as a salvage therapy. Utilizing clonogenic survival assays, we demonstrate that avasopasem at physiologically achievable concentrations exhibits single agent anti-cancer activity and also enhances the response of HNSCC lines to irradiation. In tumor growth delay (TGD) experiments utilizing the syngeneic HNSCC tumor model, AT-84, when avasopasem is delivered in combination with biologically equivalent fractionation schedules of 17 Gy x 1 fxn, 10.24 Gy x 2 fxn, or 5 Gy x 5 fxn, an enhancement of the radiation response is achieved. This potentiation of the anti-tumor response with GC4419 is more pronounced at fraction doses exceeding the threshold considered for intensity modulated radiation therapy. In addition, when avasopasem is combined with radiation and an α-PD-1 inhibitor, a further enhancement of the radiation response is observed, indicating that it compliments radiotherapy combined with immunotherapy. The pre-clinical data strongly suggest that avasopasem should be combined with radio-immune therapy to not only enhance local tumor control, but also to provide normal tissue protection with SabR which may allow dose escalation and further improve treatment outcomes. Whether radiation combined with avasopasem and checkpoint inhibitor has an effect on metastasis is under examination.

Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: long-term update of a randomised phase 3 trial

BackgroundTo report the long-term outcomes of a phase III trial designed to test two hypotheses: (1) elective nodal irradiation (ENI) is superior to conventional field irradiation (CFI), and (2) chemoradiotherapy plus erlotinib is superior to chemoradiotherapy in locally advanced oesophageal squamous cell cancer (ESCC).MethodsPatients with locally advanced ESCC were randomly assigned (1:1:1:1 ratio) to one of the four groups: A: radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel and cisplatin) plus erlotinib; B: radiotherapy adoption of ENI with two cycles of concurrent TP; C: radiotherapy adoption of CFI with two cycles of concurrent TP plus erlotinib and D: radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 60 Gy of radiation doses was delivered over 30 fractions. We explored the impact of epidermal growth factor receptor (EGFR) expression on the efficacy of erlotinib plus chemoradiotherapy.ResultsA total of 352 patients (88 assigned to each treatment group) were enrolled. The 5-year survival rates were 44.9%, 34.8%, 33.8% and 19.6% in groups A, B, C and D, respectively (P = 0.013). ENI significantly improved OS compared with standard CFI (median, 38.5 vs 22.6 months; HR, 0.74; P = 0.018). The addition of erlotinib significantly improved OS (median, 39.4 vs 27.4 months; HR, 0.75; P = 0.025). Patients with overexpressing EGFR treated with erlotinib had a better OS and PFS than those without erlotinib.ConclusionsConcurrent chemoradiotherapy with ENI and/or erlotinib improved long-term survival in locally advanced ESCC.Clinical trial registrationTrial registration: NCT00686114.

Advances in the treatment of gastric cancer.

To provide an up-to-date review on the management of cancers of the stomach and esophagogastric junction (EGJ). Microsatellite instable (MSI) high status in gastric cancer may portend a relatively good prognosis and indicate that adjuvant chemotherapy is of no added benefit to primary surgical management. In the preoperative treatment of HER2 (ErbB2)-positive EGJ adenocarcinoma with chemoradiotherapy, the addition of trastuzumab, a recombinant humanized mAb directed against the extracellular domain of Her2, failed to improve outcome over conventional chemoradiotherapy alone. Escalating the dose of radiation in combined chemoradiotherapy regimens did not improve survival over conventional dose radiotherapy in the nonoperative management of EGJ cancer. The use of proton vs. conventional external beam radiation therapy, although potentially less toxic, did not improve therapy outcome with preoperative or definitive chemoradiotherapy in EGJ cancer. In metastatic HER2-positive gastric cancer, after disease progression on trastuzumab, continuation of trastuzumab did not improve progression free or overall survival compared with second-line chemotherapy alone. However, in the setting or prior trastuzumab therapy in metastatic HER2-positive gastric cancer, the new agent trastuzumab deruxtecan achieved significant rates of response, progression free and overall survival compared with standard chemotherapy. After initial chemotherapy for metastatic esophagogastric cancer, maintenance therapy with the anti PDL-1 agent avelumab was no better than chemotherapy alone. MSI high gastric cancer has a better prognosis and may not require adjuvant chemotherapy. Trastuzumab, added to preoperative chemoradiotherapy in HER2-positive esophageal adenocarcinoma, does not improve outcome. Dose escalation of radiotherapy in the nonoperative management of EGJ cancer does not improve local control or survival, and proton therapy may not achieve superior outcomes compared with external beam radiotherapy. In metastatic HER2-positive gastric cancer, continuing trastuzumab into second-line chemotherapy does not add benefit; however, the novel agent trastuzumab deruxtecan has substantial activity after prior trastuzumab-based therapy.

Conventional chemoradiation vs. induction chemotherapy followed by conventional chemoradiation for locally advanced head and neck cancer: A prospective, randomized study

The standard‑of‑care in locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) remains concurrent chemoradiotherapy. The present study compared the disease response and safety profile of induction chemotherapy followed by concomitant chemoradiotherapy (CRT) vs. CRT alone in patients with LA SCCHN. The present prospective randomized study was conducted between July, 2014 and July, 2015 on 52&nbsp;patients with SCCHN of the oropharynx, hypopharynx and larynx. Patients were randomly divided into the induction chemotherapy [docetaxel, cisplatin and 5‑FU (TPF)] followed by CRT arm (TPF&nbsp;+&nbsp;CRT arm, n=25) or the CRT alone arm (CRT arm, n=27). The disease response, and acute and late toxicities were assessed. At the first follow‑up (6&nbsp;weeks), the overall response rate (ORR) was 82.6% for the TPF&nbsp;+&nbsp;CRT arm and 72% for the CRT arm; the difference was not significant. In addition, no statistically significant differences were observed in the nodal response between the treatment arms. Acute toxicities were significantly higher in the TPF&nbsp;+&nbsp;CRT arm, with respect to mucositis and hematological toxicities. No differences were observed in late‑onset toxicities observed following 3&nbsp;months of radiotherapy. Triple drug‑based sequential therapy was tolerable in the population in the present study and may thus hold promise for the treatment of SCCHN; however, larger prospective studies are required to confirm these results.

Abstract 1067: Proteogenomic discovery of novel tumor proteins as neoantigens for personalized T cell immunotherapy in pediatric medulloblastoma

Abstract Medulloblastoma is a common childhood brain tumor for which current therapies fail to cure high-risk subgroups, including metastatic and recurrent disease. Toxicity limits further intensification of conventional chemo-radiation therapy and most survivors endure significant lifelong sequelae from treatment. There is an urgent need to develop new tools to combat this cancer without increasing the late effects burden. Neoantigens exclusively expressed on tumor cells, are one of the main targets of an effective antitumor T-cell response. The ideal target antigen is abundantly expressed by tumor cells but not by normal tissues, in order to limit off-target effects. Tumors translate a host of unique transcripts that are the result of aberrations in tumor DNA and the unmasking of alternative or novel exons. We used a novel proteogenomic approach to identify tumor-restricted peptides and used them to select and expand T cells capable of mounting a tumor-specific cytotoxic immune response, with no off-target effects for patients with MB. Using RNA-seq and WGS data, we created personalized custom searchable databases containing predicted novel proteins from somatic mutations, novel isoforms and fusion proteins from 46 medulloblastoma tumors. By searching this database with raw mass spectrometry data from the paired medulloblastoma tumor, we have identified tens of peptides arising from the translation of tumor-specific transcripts; these peptides are potential neoantigens. Our data indicates that in cases of tumors with low mutation rates, such as pediatric brain tumors, novel isoforms are the main source of neoantigens. In a pilot study, we tested these peptides for their ability to select and expand polyclonal populations of T cells from a patient whose tumor was the source of the peptides. The immunogenicity of each individual peptide was then determined. Flow cytometry cellular characterization reveals populations of both CD4+ and CD8+ cells with an activation profile marked by IFN-γ and TNF-α production. Inhibitory co-receptor profiles were also characterized for these cells. Using cytotoxicity assays, we demonstrated that tumor specific T cells can eliminate neoantigen bearing tumor cells. These findings demonstrate an initial proof of principle that proteogenomics can be used to identify immunogenic tumor specific peptides and lay the groundwork for a personalized, targeted T cell therapy for children with high risk medulloblastoma. Citation Format: Samuel Rivero-Hinojosa, Melanie Grant, Aswini Panigrahi, Huizhen Zhang, Veronika Caisova, Catherine M. Bollard, Brian R. Rood. Proteogenomic discovery of novel tumor proteins as neoantigens for personalized T cell immunotherapy in pediatric medulloblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1067.

Abstract 6284: GC4419 protects again radiation induced oral mucositis, enhances the response of squamous cell carcinoma of the head and neck tumors to ionizing radiation, and enhances radioimmune therapy

Abstract Locoregional recurrence (LRR) is the major cause of morbidity and mortality in patients with squamous cell carcinoma of the head and neck (HNSCC). For those patients that experience surgically unresectable LRR, median overall survival (OS) is less than one year. Approaches utilizing stereotactic ablative radiotherapy (SAbR) and immune oncology agents such as Nivolumab (α-PD-1 agonist) in the salvage setting have become alternatives to conventional chemoradiation therapy. Despite improvements in OS, rates of acute oral mucositis (OM) and late toxicities (skin fibrosis) remain a concern with SAbR, particularly in the context of re-irradiation. Here we present pre-clinical evidence that GC4419 (Galera Therapeutics), a highly selective superoxide dismutase mimetic that recently received FDA Breakthrough therapy status following a Phase II, randomized, placebo controlled trial for reducing the duration and incidence of severe OM in patients undergoing chemoradiation therapy for locally advanced HNSCC (NCT02508389) also enhances the anti-tumor radiation response of HNSCC tumors to irradiation. We demonstrate in pre-clinical animal models that GC4419 protects the normal mucosa of the mouse tongue from radiation exposure. Utilizing clonogenic survival assays, GC4419 demonstrates single agent anti-cancer activity at physiologically achievable concentrations, while also enhancing the response of HNSCC lines to irradiation. In tumor growth delay (TGD) experiments utilizing the syngeneic HNSCC tumor model, AT-84, when GC4419 is delivered 30-60 minutes pre-irradiation with biologically equivalent fractionation schedules of 17 Gy x 1 fxn, 10.24 Gy x 2 fxn, or 5 Gy x 5 fxn, an enhancement of the radiation response is achieved. In tumor cure rate (TCD50) studies, GC4419 enhanced radiation exposure with a DEF of 1.25. Furthermore, when GC4419 is combined with radiation and an α-PD-1 inhibitor, a further enhancement of the radiation response is observed, indicating that GC4419 compliments radiotherapy combined with immune oncology. We will also report the results of ongoing studies examining the potency of GC4419 in protecting normal murine mucosa in the setting of reirradiation relevant to SAbR as a salvage therapy. This potentiation of the anti-tumor response with GC4419 is more pronounced at doses exceeding the threshold to be considered for intensity modulated radiation therapy (IMRT). The accompanying pre-clinical data strongly suggest that GC4419 should be combined with radio-immune therapy to not only enhance local tumor control, but that the potential for normal tissue protection with SAbR also creates the opportunity for dose escalation and may further improvement in treatment outcome. Citation Format: Brock James Sishc, Elizabeth Polsdofer, Debabrata Saha, Michael Story. GC4419 protects again radiation induced oral mucositis, enhances the response of squamous cell carcinoma of the head and neck tumors to ionizing radiation, and enhances radioimmune therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6284.

Effects of Surgery Combined with Chemoradiotherapy on Short- and Long-Term Outcomes of Early-Stage Nasopharyngeal Carcinoma.

ObjectiveThe efficacy of surgery as the primary treatment modality for nasopharyngeal carcinoma (NPC) is yet to be clarified. Therefore, we aimed to explore the short- and long-term efficacy of surgery for early-stage NPC.MethodsWe retrospectively evaluated 341 patients diagnosed with early-stage NPC between September 2010 and December 2015. Among them, 58 patients underwent endoscopic nasopharyngectomy combined with chemoradiotherapy, whereas 283 patients underwent conventional chemoradiotherapy. The patients who underwent concurrent chemoradiotherapy or radiotherapy alone were matched to patients who underwent surgery in a 1:2 ratio using propensity score matching to analyze the clinical efficacy of each therapeutic modality. The primary endpoint was survival, and the secondary endpoints were tumor regression rate and reduction in Epstein–Barr virus (EBV)-DNA levels.ResultsAfter matching, 156 patients were enrolled (58 patients in the surgery group; 98 patients in the non-surgery group). The baseline data of the matched patients had good inter-group comparability (All P>0.05). The surgery group had significantly higher 5-year overall survival (98.30% vs. 91.70%), disease-free survival (98.30% vs. 81.40%), and recurrence-free survival (100.00% vs. 90.10%) rates than did the non-surgery group (All P<0.05). In total, 0 and 14 patients in the surgery and non-surgery groups, respectively, had residual cancer at the end of treatment (P=0.001). All patients in the surgery group tested negative for EBV-DNA, whereas two patients in the non-surgery group tested positive. The incidence of hematologic toxicity during treatment was similar between the two groups (All P>0.05). Still, the incidence of severe oral mucositis was lower in the surgery group than in the non-surgery group (37.9% vs. 54.08%, P=0.051).ConclusionSurgery can improve the clearance rate of EB virus and reduce tumor residue. Surgery may be a safe and effective treatment for early NPC.

Phytol Down-Regulates Expression of Some Cancer Stem Cell Markers and Decreases Side Population Proportion in Human Embryonic Carcinoma NCCIT Cells

Cancer stem cells (CSCs), a subgroup of cancer cells, have self-renewal capacity and differentiation potential and drive tumor growth. CSCs are highly-resistant to conventional chemo-radio therapy. Phytochemicals were shown to be able to eliminate CSCs. Phytol is a diterpene alcohol with demonstrated anticancer effects. The current study compared the effect of phytol with retinoic acid (RA) as a well-known inducers of CSC differentiation and cisplatin, a common chemotherapy drug, on CSC markers in human embryonic carcinoma NCCIT cells. NCCIT cells were exposed to 10 mM RA for 14 day to induce differentiation. Moreover, NCCIT cells were treated with IC50 dose of cisplatin (12 µM) and phytol (40 µM) for 7 day. Real-time PCR showed that phytol was more effective that RA and cisplatin in down-regulating the CSC markers OCT4, NANOG, SOX2, ALDH1, ABCB1, CD44 and CD133. Percentage of SP (13%) and ABCB1+ (0.34%) in NCCIT cells decreased to 7% and 0.1% respectively after treatment with phytol. A very small proportion of NCCIT cells were positive for CD44 (0.2%) and CD133 (0.48%) and this fraction did not change significantly after treatment with three agents. In conclusion, phytol has the greatest inhibitory effect on CSC population and markers than RA and cisplatin.

Delayed coloanal anastomosis: an alternative option for restorative rectal cancer surgery after high-dose pelvic radiotherapy for prostate cancer.

Restorative total mesorectal excision (TME) for rectal cancer after high-dose pelvic radiotherapy for prostate cancer has been reported to provide an unacceptable rate of pelvic sepsis. In a previous publication we proposed that delayed coloanal anastomosis (DCAA) should be performed in this situation. The present study aimed to assess the feasibility and outcomes of this strategy. Between 2000 and 2018, 1094 men were operated on for rectal cancer in our institution. All men with T2/T3 mid and low rectal cancer with preoperative radiotherapy and restorative TME were considered for this study (n=416). Patients with external-beam high-dose radiotherapy (EBHRT) for prostate cancer (70-78Gy) were identified and compared with patients with conventional long-course chemoradiotherapy (CRT) followed by TME. We compared our already published historical cohort (2000-2012), including arm A (CRT+TME; n=236) and arm B (EBHRT+TME; n=12), with our early cohort (2013-2018), including arm C (CRT+TME; n=158) and arm D (EBHRT+TME-DCAA; n=10). The end-points were morbidity, pelvic sepsis, reoperation rate and quality of the specimen. Overall morbidity was not significantly different between groups. Pelvic sepsis decreased from 50% (arm B) to 10% (arm D) with the use of DCAA (P=0.074), and was similar between arms A, C and D. Quality of the specimen was not significantly different between the four groups. Our results suggest that TME with DCAA in patients with previous EBHRT is feasible, with the same postoperative pelvic sepsis rate as conventional CRT.

A Prospective Observational Study Comparing Long-Course Conventional Neoadjuvant Chemoradiotherapy with Short-Course Radiotherapy Followed by Consolidation Chemotherapy with Delayed Surgery in Locally Advanced Rectal Cancer.

Background Polish and Australian randomized studies compared short-course radiotherapy (RT) with immediate surgery and long-course chemoradiotherapy (CRT) with delayed surgery. In these studies, similar long-term survival and local control have been reported for both these approaches, but pathological complete response (pCR) is not better with short-course RT. Moreover, studies have shown better tumor downstaging with delayed surgery. In this context, the use of short-course RT with delayed surgery may have some advantages and needs to be tested in clinical trials. Patients and Methods This was a two-arm, prospective, observational study, in which preoperative short-course RT followed by two cycles of chemotherapy was compared with the conventional neoadjuvant CRT in locally advanced rectal cancer. The primary end points were the rate of complete response and toxicity profile. The secondary end points were the rate of R0 resection, overall survival, and progression-free survival. The data obtained from the two arms were analyzed using Pearson’s chi-square test to determine the statistical significance between the two treatment arms. Results The pCR rate was 6.7% in the study arm and 0 in the control arm ( p = 0.343). The RO resection rates were 92.8 and 92.3% in the study and control arms, respectively. The rates of grade 3and 4 acute toxicity in the study and control arms were 14.2 and 61.5%, respectively ( p = 0.011). The rates of grade 3 and 4 late toxicity in the study and control arms were 21.4 and 15.3%, respectively ( p = 0.686). Conclusions The pCR rates and the late toxicities in both arms are comparable. The major advantages of the 5 × 5 Gy regimen with chemotherapy in a neoadjuvant setting are a significant reduction in acute toxicities and better patient compliance along with similar efficacy as that of the standard regimen.

Tumor Immunity as Well as Its Treatment Methods

in the passing years, tumor immunotherapy has become a major research topic and up till now, some remarkable progress has been achieved. It has come up with a new oncotherapy method different from surgery, conventional chemoradiotherapy. Tumor immunotherapy aims to kill or inhibit tumor growth by activating the immune system of the human body itself or enhancing the functions of the immune system. This thesis reviews the research and development of oncolytic virus therapy, CAR-T therapy and phytochemical drug therapy.