Challenges and Opportunities With the Use of Hypofractionated Radiation Therapy in Cancer Care: Regional Perspectives From South Korea, Japan, Singapore, and Australia.

Hypofractionated radiotherapy schedules provide higher per-fraction radiation doses delivered in fewer fractions than conventional schedules. This novel delivery method is supported by a large body of clinical trial evidence across various cancer sites in both curative and palliative settings. Hypofractionation is associated with benefits such as lower costs, improved patient access and increased treatment precision, which has led to its inclusion in various treatment guidelines. Despite this, utilization is not uniform across cancer sites and geographic regions due to reasons such as reimbursement models, nuances in healthcare systems, and professional culture. Key factors to ensure patients benefit from access to high quality radiotherapy include publishing clinical evidence, cross-country collaboration to fill knowledge gaps, reviewing reimbursement models, and improving patient advocacy in treatment decision-making.

Post-mastectomy radiation therapy in HER-2 positive breast cancer after primary systemic therapy: Pooled analysis of TRYPHAENA and NeoSphere trials.

PURPOSE: The role of post-mastectomy radiation therapy (PMRT) following primary systemic therapy (PST) in HER-2 positive breast cancer (Her2 + BC) remains poorly understood. The current study evaluates PMRT based on the pathological response to PST in Her2 + BC. METHODS AND MATERIALS: TRYPHAENA and NeoSphere are randomized phase II trials that investigated PST for Her2 + BC. Our study is a pooled analysis of both trials, including 312 node-positive patients treated with HER-2 targeted PST followed by mastectomy with or without PMRT. The primary endpoint is loco-regional recurrence-free survival (LRRFS). RESULTS: Our analysis included 172 (55%) patients who achieved complete nodal pathological response (ypN0) and 140 (45%) patients who did not. Patients with ypN0 had a 5-year LRRFS of 97% in both, the PMRT and no PMRT, groups (p = 0.94). Patients with ypN + had 5-year LRRFS of 89% in the PMRT group and 82% in the no PMRT group (p = 0.17). Patients with ypN1 (n = 62) disease who received PMRT (n = 40) had a 5-year LRRFS of 85% as compared to 89% in those who did not (n = 22); (p = 0.60). A significant LRRFS difference was noted in patients with ypN2-3 (n = 78) disease who received PMRT (n = 53) compared to those who did not (n = 25) (5-year LRRFS 92% vs. 75%; p = 0.019). On multivariate analysis, clinical nodal disease at diagnosis and ypN0 were significantly associated with loco-regional recurrence (LRR). CONCLUSIONS: Her2 + BC patients who achieve ypN0 after PST have excellent locoregional-control which supports de-escalation of PMRT. In contrast, patients with ypN2-3 disease derive significant benefit from PMRT. Clinical nodal stage at presentation and ypN0 status are significantly associated with LRR risk in Her2 + BC.

Urinary 20-HETE: A prospective Non-Invasive prognostic and diagnostic marker for diabetic kidney disease.

INTRODUCTION: The identification and validation of a non-invasive prognostic marker for early detection of diabetic kidney disease (DKD) can lead to substantial improvement in therapeutic decision-making. OBJECTIVES: The main objective of this study is to assess the potential role of the arachidonic acid (AA) metabolite 20-hydroxyeicosatetraenoic (20-HETE) in predicting the incidence and progression of DKD. METHODS: Healthy patients and patients with diabetes were recruited from the Hamad General Hospital in Qatar, and urinary 20-HETE levels were measured. Data analysis was done using the Statistical Package for Social Sciences (SPSS). RESULTS: Our results show that urinary 20-HETE-to-creatinine (20-HETE/Cr) ratios were significantly elevated in patients with DKD when compared to patients with diabetes who did not exhibit clinical signs of kidney injury (p < 0.001). This correlation was preserved in the multivariate linear regression accounting for age, diabetes, family history of kidney disease, hypertension, dyslipidemia, stroke and metabolic syndrome. Urinary 20-HETE/Cr ratios were also positively correlated with the severity of kidney injury as indicated by albuminuria levels (p < 0.001). A urinary 20-HETE/Cr ratio of 4.6 pmol/mg discriminated between the presence and absence of kidney disease with a sensitivity of 82.2 % and a specificity of 67.1%. More importantly, a 10-unit increase in urinary 20-HETE/Cr ratio was tied to a 10-fold increase in the risk of developing DKD, suggesting a 20-HETE prognostic efficiency. CONCLUSION: Taken together, our results suggest that urinary 20-HETE levels can potentially be used as non-invasive diagnostic and prognostic markers for DKD.

A phase II single arm study of Nivolumab with stereotactic Ablative radiation Therapy after induction chemotherapy in CHOlangiocarcinoma (NATCHO).

BACKGROUND: Intrahepatic cholangiocarcinoma (CCA) is amongst the most common primary liver tumors worldwide. CCA carries a bad prognosis prompting research to establish new treatment modalities other than surgery and the current chemotherapeutic regimens adopted. Hence, this trial explores a new therapeutic approach, to combine stereotactic body radiation therapy (SBRT) and immunotherapy (Nivolumab), and asses its clinical benefit and safety profile after induction chemotherapy in CCA. METHODOLOGY: This is a Phase II open-label, single-arm, multicenter study that investigates Nivolumab (PD-1 inhibitor) treatment at Day 1 followed by SBRT (30 Gy in 3 to 5 fractions) at Day 8, then monthly Nivolumab in 40 patients with non-resectable locally advanced, metastatic or recurrent intrahepatic or extrahepatic CCA. Eligible patients were those above 18 years of age with a pathologically and radiologically confirmed diagnosis of non-resectable locally advanced or metastatic or recurrent intrahepatic or extrahepatic CCA, following 4 cycles of cisplatin-based chemotherapy with an estimated life expectancy of more than 3 months, among other criteria. The primary endpoint is the progression free survival (PFS) rate at 8 months and disease control rate (DCR). The secondary endpoints are overall survival (OS), tumor response rate (TRR), duration of response, evaluation of biomarkers: CD3 + , CD4 + and CD8 + T cell infiltration, as well as any change in the PD-L1 expression through percutaneous core biopsy when compared with the baseline biopsy following 1 cycle of Nivolumab and SBRT. DISCUSSION: SRBT alone showed promising results in the literature by both inducing the immune system locally and having abscopal effects on distant metastases. Moreover, given the prevalence of PD-L1 in solid tumors, targeting it or its receptor has become the mainstay of novel immunotherapeutic drugs use. A combination of both has never been explored in the scope of CCA and that is the aim of this study. TRIAL REGISTRATION: ClinicalTrials.gov NCT04648319 , April 20, 2018.

SMPDL3b modulates radiation-induced DNA damage response in renal podocytes.

The kidneys are radiosensitive and dose-limiting organs for radiotherapy (RT) targeting abdominal and paraspinal tumors. Excessive radiation doses to the kidneys ultimately lead to radiation nephropathy. Our prior work unmasked a novel role for the lipid-modifying enzyme, sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), in regulating the response of renal podocytes to radiation injury. In this study, we investigated the role of SMPDL3b in DNA double-strand breaks (DSBs) repair in vitro and in vivo. We assessed the kinetics of DSBs recognition and repair along with the ATM pathway and nuclear sphingolipid metabolism in wild-type (WT) and SMPDL3b overexpressing (OE) human podocytes. We also assessed the extent of DNA damage repair in SMPDL3b knock-down (KD) human podocytes, and C57BL6 WT and podocyte-specific SMPDL3b-knock out (KO) mice after radiation injury. We found that SMPDL3b overexpression enhanced DSBs recognition and repair through modulating ATM nuclear shuttling. OE podocytes were protected against radiation-induced apoptosis by increasing the phosphorylation of p53 at serine 15 and attenuating subsequent caspase-3 cleavage. SMPDL3b overexpression prevented radiation-induced alterations in nuclear ceramide-1-phosphate (C1P) and ceramide levels. Interestingly, exogenous C1P pretreatment radiosensitized OE podocytes by delaying ATM nuclear foci formation and DSBs repair. On the other hand, SMPDL3b knock-down, in vitro and in vivo, induced a significant delay in DSBs repair. Additionally, increased activation of apoptosis was induced in podocytes of SMPDL3b-KO mice compared to WT mice at 24 h post-irradiation. Together, our results unravel a novel role for SMPDL3b in radiation-induced DNA damage response. The current work suggests that SMPDL3b modulates nuclear sphingolipid metabolism, ATM nuclear shuttling, and DSBs repair.

Is breast conservation superior to mastectomy in early stage triple negative breast cancer?

PURPOSE: Compare overall survival (OS) and breast cancer-specific survival (BCSS) outcomes of breast conservative therapy (BCT) and mastectomy in a large cohort of patients with early-stage triple negative breast cancer (TNBC), using a propensity score-based matching approach. METHODS: Surveillance, Epidemiology, and End Results (SEER) database was used to study the role of RT in early stage TNBC. Primary end points were OS and BCSS. Cox proportional hazard regression models and Kaplan-Meier plots were used to generate the desired outcomes. Propensity score matching was done to minimize bias. RESULTS: 12,761 patients with T1-2N0M0 TNBC as their first malignancy were retrieved. Of these 7237 had lumpectomy with RT, and 5524 had mastectomy only. Age, race, marital status, tumor laterality, grade and stage, and receipt of chemotherapy were prognostic variables for OS and BCSS. Among 4848 matched subjects, the 5-year OS was significantly higher in patients with lumpectomy and RT (89%) compared to mastectomy alone (84.5%) (p-value <0.001). Similarly, BCSS was significantly higher in patients with lumpectomy and RT (93%) compared to mastectomy alone (91%) (p-value <0.001). On subgroup analysis, patients who are younger than 40 had similar survival outcomes after either mastectomy alone or lumpectomy with RT. However, those who are older than 60, have any grade or T stage had better survival outcomes with lumpectomy and RT. CONCLUSIONS: Overall, lumpectomy followed by RT is associated with better OS and BCSS compared to mastectomy in T1-2N0M0 TNBC patients. Further research is needed to determine the optimal treatment strategy for specific patient subgroups.

Evaluation of Cardiotoxicity in HER-2-Positive Breast Cancer Patients Treated With Radiation Therapy and Trastuzumab.

PURPOSE: Trastuzumab is associated with cardiac dysfunction in patients with human epidermal growth factor receptor 2 (HER-2)-positive breast cancer. The current study examines the effect of radiation therapy (RT) on cardiotoxicity in this patient population. METHODS AND MATERIALS: The Herceptin Adjuvant (HERA) trial is a phase 3 prospective, randomized clinical trial that established the efficacy of trastuzumab in HER-2-positive breast cancer. The current study is a retrospective analysis of 3321 trial patients treated with trastuzumab, with or without RT. Cardiac function was closely monitored over a median follow-up period of 11 years. The primary endpoint of the current study was to determine the effect of RT on left ventricular ejection fraction (LVEF) and the occurrence of cardiovascular events. RESULTS: Patients were divided into 3 groups: 1270 patients received trastuzumab and left-sided RT (group 1); 1271 patients received trastuzumab and right-sided RT (group 2); and 780 patients received trastuzumab with no RT (group 3). The incidence of decline in LVEF documented by echocardiography was 9.18%, 8.99%, and 8.80%, respectively, with no significant differences among the 3 groups (P = .073). The incidence of cardiovascular events was low in all groups, with the lowest incidence noted in group 3 (0.62%) followed by group 2 (0.92%) and group 1 (1.08%) (P = .619). Univariate and multivariate competing-risks regression showed that left-sided and right-sided RT delivery did not significantly increase the risk of LVEF decline or cardiovascular events. CONCLUSIONS: Our analysis of the HERA trial suggests that RT does not significantly increase the risk of cardiotoxicity in HER-2-positive breast cancer patients treated with trastuzumab. Continued monitoring of patients is needed to investigate late effects of contemporary treatments for breast cancer patients.

Post-mastectomy Radiation Therapy in Triple-Negative Breast Cancer Patients: Analysis of the BEATRICE Trial.

PURPOSE: Post-mastectomy radiation therapy (PMRT) improves locoregional control and overall survival in patients with breast cancer. With the evolution of systemic therapy, the benefit of PMRT in patients with triple-negative disease requires further evaluation. PATIENTS AND METHODS: BEATRICE is a phase III randomized clinical trial that examined the efficacy of bevacizumab in patients with triple-negative breast cancer (TNBC). The current study is a retrospective analysis of data on patients enrolled and treated with mastectomy and systemic therapy. The primary endpoint was determining the effect of PMRT on locoregional recurrence rates (LRR). Hazard ratios were estimated using Cox regression, and LRR curves were generated by the Kaplan-Meier method. RESULTS: In total, 940 patients were included in our analysis, of whom 359 (38.2%) received PMRT while 581 (61.8%) did not. At median follow-up of 5 years, no significant difference in LRR was noted between the PMRT and no PMRT groups in node-negative patients (HR = 1.09). Patients with N1 disease had 5-year LRR-free survival of 96% for PMRT versus 91% for no PMRT (HR = 0.46). Most N2 patients received PMRT and had 5-year LRR-free survival of 76%. CONCLUSION: PMRT benefit in TNBC patients treated with modern systemic therapy is lower than historical reports. Delivery of PMRT in patients with N1 disease enrolled in the BEATRICE trial was not shown to improve local control. As this might be due to patient selection for PMRT, future randomized controlled trials are required to assess the role of PMRT in this patient population.

Crosstalk Between SMPDL3b and NADPH Oxidases Mediates Radiation-Induced Damage of Renal Podocytes.

Patients undergoing radiotherapy (RT) for various tumors localized in the abdomen or pelvis often suffer from radiation nephrotoxicity as collateral damage. Renal podocytes are vulnerable targets for ionizing radiation and contribute to radiation-induced nephropathies. Our prior work previously highlighted the importance of the lipid-modifying enzyme sphingomyelinase acid phosphodiesterase like 3b (SMPDL3b) in modulating the radiation response in podocytes and glomerular endothelial cells. Hereby, we investigated the interplay between SMPDL3b and oxidative stress in mediating radiation injury in podocytes. We demonstrated that the overexpression of SMPDL3b in cultured podocytes (OE) reduced superoxide anion generation and NADPH oxidase activity compared to wild-type cells (WT) post-irradiation. Furthermore, OE podocytes showed downregulated levels of NOX1 and NOX4 after RT. On the other hand, treatment with the NOX inhibitor GKT improved WTs' survival post-RT and restored SMPDL3b to basal levels. in vivo, the administration of GKT restored glomerular morphology and decreased proteinuria in 26-weeks irradiated mice. Taken together, these results suggest a novel role for NOX-derived reactive oxygen species (ROS) upstream of SMPDL3b in modulating the response of renal podocytes to radiation.

Oligometastatic breast cancer: Are we there yet?

Patients with metastatic breast cancer are usually considered incurable. Recent advances have resulted in significant improvements in survival for patients with metastatic breast cancer. Due to the lack of randomised trials and heterogeneous disease biology, treatment decisions for patients with oligometastatic breast cancer vary widely. Some patients are treated similar to those with widespread disease while others are treated more aggressively. We conducted a review of the evidence for treatment options in oligometastatic breast cancer and consulted ClinicalTrials.gov to explore currently accruing or studies in development aimed at investigating oligometastatic disease in breast cancer. Surgery to the primary tumour in patients with metastatic breast cancer has failed to show any advantage over systemic therapy. However, there may be a benefit in women with controlled systemic disease who are hormone receptor positive with bone-predominant metastasis. Stereotactic radiotherapy has gained increased interest in this setting due to its excellent efficacy and lower rates of associated toxicity. A significant challenge remains in identifying the patient population who would benefit from such an approach, and to do so, we need to understand the distinct biology of oligometastatic breast cancer. Unique miRNA expression and low levels of tumour infiltrating lymphocytes in the immune micro-environment have been described in tumour tissues in patients with oligometastatic breast cancer. There is ongoing research aimed to better characterise these tumours, thus, allowing the selection of patients who would truly benefit from multi-modality treatment in an attempt for long-term survival and cure.

Post-lumpectomy radiation therapy boost in breast cancer patients: evidence revisited.

PURPOSE: Radiation therapy is an integral part in the management of breast cancer after breast conservative surgery. In selected patients at high risk for local recurrence (LR), a boost radiation dose is commonly applied to the tumour bed. METHODS: We performed a review of the English literature using PubMed, Medline and Google Scholar for published manuscripts addressing the effect of boost radiation in breast cancer patients, focusing mainly on LR and overall survival (OS). RESULTS: A total of seven studies were included in our review. Most studies (6/7, 85.7%) showed a significant improvement in local control independent of age (hazard ratios ranging between 0.34 and 0.73), with the largest absolute benefit in younger patients. None of the studies, however, was able to demonstrate an improvement in OS. CONCLUSIONS: With lack of sufficient studies addressing the role of boost radiation, individualised treatment decisions are recommended, taking into account the risk factors for LR, including tumour biology. Real-life data are sorely needed to better assess the role of tumour bed boost in the contemporary era.

Noninvasive assessment of radiation-induced renal injury in mice.

PURPOSE: The kidney is a radiosensitive late-responding normal tissue. Injury is characterized by radiation nephropathy and decline of glomerular filtration rate (GFR). The current study aimed to compare two rapid and cost-effective methodologies of assessing GFR against more conventional biomarker measurements. METHODS: C57BL/6 mice were treated with bilateral focal X-irradiation (1x14Gy or 5x6Gy). Functional measurements of kidney injury were assessed 20 weeks post-treatment. GFR was estimated using a transcutaneous measurement of fluorescein-isothiocyanate conjugated (FITC)-sinistrin renal excretion and also dynamic contrast-enhanced CT imaging with a contrast agent (ISOVUE-300 Iopamidol). RESULTS: Hematoxylin and eosin (H&E) and Periodic acid-Schiff staining identified comparable radiation-induced glomerular atrophy and mesangial matrix accumulation after both radiation schedules, respectively, although the fractionated regimen resulted in less diffuse tubulointerstitial fibrosis. Albumin-to-creatinine ratios (ACR) increased after irradiation (1x14Gy: 100.4 ± 12.2 µg/mg; 6x5Gy: 80.4 ± 3.02 µg/mg) and were double that of nontreated controls (44.9 ± 3.64 µg/mg). GFR defined by both techniques was negatively correlated with BUN, mesangial expansion score, and serum creatinine. The FITC-sinistrin transcutaneous method was more rapid and can be used to assess GFR in conscious animals, dynamic contrast-enhanced CT imaging technique was equally safe and effective. CONCLUSION: This study demonstrated that GFR measured by dynamic contrast-enhanced CT imaging is safe and effective compared to transcutaneous methodology to estimate kidney function.

Radiation-induced neuropathies in head and neck cancer: prevention and treatment modalities.

Head and neck cancer (HNC) is the sixth most common human malignancy with a global incidence of 650,000 cases per year. Radiotherapy (RT) is commonly used as an effective therapy to treat tumours as a definitive or adjuvant treatment. Despite the substantial advances in RT contouring and dosage delivery, patients suffer from various radiation-induced complications, among which are toxicities to the nervous tissues in the head and neck area. Radiation-mediated neuropathies manifest as a result of increased oxidative stress-mediated apoptosis, neuroinflammation and altered cellular function in the nervous tissues. Eventually, molecular damage results in the formation of fibrotic tissues leading to susceptible loss of function of numerous neuronal substructures. Neuropathic sequelae following irradiation in the head and neck area include sensorineural hearing loss, alterations in taste and smell functions along with brachial plexopathy, and cranial nerves palsies. Numerous management options are available to relieve radiation-associated neurotoxicities notwithstanding treatment alternatives that remain restricted with limited benefits. In the scope of this review, we discuss the use of variable management and therapeutic modalities to palliate common radiation-induced neuropathies in head and neck cancers.

Proton Therapy as a Bridging Treatment in CAR T-Cell Therapy for Relapsed and Refractory Large B-Cell Lymphoma: Is There a Role?

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Since the relapse rate of DLBCL to frontline chemoimmunotherapy and salvage autologous hematopoietic cell transplant is high, CD19-directed chimeric antigen receptor (CAR) T-cell therapy was adopted. Given the time interval needed for CAR T cells to be manufactured (3-5 weeks) and the aggressiveness of these relapsed/refractory lymphomas, some patients do not make it to the CAR T-cell infusion phase. This calls for a bridging therapy to control, debulk, and sensitize the disease during this period. Radiation therapy can serve this purpose and has shown promising results in some studies. Proton therapy, compared to standard radiation therapy, in some locations, can reduce the radiation dose to the organs at risk, which may lead to fewer side effects for patients with lymphomas. Thus, we hypothesize that proton therapy may serve as a promising bridging strategy to CAR T-cell therapy for some patients.

Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy and short-course radiotherapy followed by resection has been gaining recognition in the treatment of rectal cancer. Avelumab is a fully human immunoglobulin that binds Programmed Death-Ligand 1 (PD-L1) and prevents the suppression of the cytotoxic T cell immune response. This phase II trial evaluates the safety and pathologic response rate of short-course radiation followed by 6 cycles of mFOLFOX6 with avelumab in patients with locally advanced rectal cancer (LARC). METHODS: This study is prospective single-arm, multicenter phase II trial adopting Simon's two-stage. Short-course radiation is given over 5 fractions to a total dose of 25 Gy. mFOLFOX6 plus avelumab (10 mg/kg) are given every 2 weeks for 6 cycles. Total mesorectal excision is performed 3-4 weeks after the last cycle of avelumab. Follow up after surgery is done every 3 months to a total of 36 months. Adverse event data collection is recorded at every visit. RESULTS: 13 out of 44 patients with LARC were enrolled in the first stage of the study (30% from total sample size). All patients met the inclusion criteria and received the full short-course radiation course followed by 6 cycles of mFOLFOX6 plus avelumab. 12 out of the 13 patients completed TME while one patient had progression of disease and was dropped out of the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33-73) years. The first interim analysis revealed that 3 (25%) patients achieved pathologic complete response (pCR) (tumor regression grade, TRG 0) out of 12. While 3 (25%) patients had near pCR with TRG 1. In total, 6 out of 12 patients (50%) had a major pathologic response. All patients were found to be MMR proficient. The protocol regimen was well tolerated with no serious adverse events of grade 4 reported. CONCLUSION: In patients with LARC, neoadjuvant radiation followed by mFOLFOX6 with avelumab is safe with a promising pathologic response rate. Trial Registration Number and Date of Registration ClinicalTrials.gov NCT03503630, April 20, 2018. https://clinicaltrials.gov/ct2/show/NCT03503630?term=NCT03503630&draw=2&rank=1 .

Short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma.

BACKGROUND: Current standard practice for locally advanced rectal cancer (LARC) entails a multidisciplinary approach that includes preoperative chemoradiotherapy, followed by total mesorectal excision, and then adjuvant chemotherapy. The latter has been accompanied by low compliance rates and no survival benefit in phase III randomized trials, so the strategy of administering neoadjuvant, rather than adjuvant, chemotherapy has been adapted by many trials, with improvement in pathologic complete response. Induction chemotherapy with oxaliplatin has been shown to have increased efficacy in rectal cancer, while short-course radiation therapy with consolidation chemotherapy increased short-term overall survival rate and decreased toxicity levels, making it cheaper and more convenient than long-course radiation therapy. This led to recognition of total neoadjuvant therapy as a valid treatment approach in many guidelines despite limited available survival data. With the upregulation (PDL-1) expression in rectal tumors after radiotherapy and the increased use of in malignant melanoma, the novel approach of combining immunotherapy with chemotherapy after radiation may have a role in further increasing pCR and improving overall outcomes in rectal cancer. METHODS: The study is an open label single arm multi- center phase II trial. Forty-four recruited LARC patients will receive 5Gy x 5fractions of SCRT, followed by 6 cycles of mFOLFOX-6 plus avelumab, before TME is performed. The hypothesis is that the addition of avelumab to mFOLFOX-6, administered following SCRT, will improve pCR and overall outcomes. The primary outcome measure is the proportion of patients who achieve a pCR, defined as no viable tumor cells on the excised specimen. Secondary objectives are to evaluate 3-year progression-free survival, tumor response to treatment (tumor regression grades 0 & 1), density of tumor-infiltrating lymphocytes, correlation of baseline Immunoscore with pCR rates and changes in PD-L1 expression. DISCUSSION: Recent studies show an increase in PD-L1 expression and density of CD8+ TILs after CRT in rectal cancer patients, implying a potential role for combinatory strategies using PD-L1- and programmed-death- 1 inhibiting drugs. We aim through this study to evaluate pCR following SCRT, followed by mFOLFOX-6 with avelumab, and then TME procedure in patients with LARC. TRIAL REGISTRATION: Trial Registration Number and Date of Registration: ClinicalTrials.gov NCT03503630, April 20, 2018.