Locally Advanced Rectal Carcinoma Research Articles

Performance and Dimensionality of Pretreatment MRI Radiomics in Rectal Carcinoma Chemoradiotherapy Prediction.

(1) Background: This study aimed to develop a machine learning model based on radiomics of pretreatment magnetic resonance imaging (MRI) 3D T2W contrast sequence scans combined with clinical parameters (CP) to predict neoadjuvant chemoradiotherapy (nCRT) response in patients with locally advanced rectal carcinoma (LARC). The study also assessed the impact of radiomics dimensionality on predictive performance. (2) Methods: Seventy-five patients were prospectively enrolled with clinicopathologically confirmed LARC and nCRT before surgery. Tumor properties were assessed by calculating 2141 radiomics features. Least absolute shrinkage selection operator (LASSO) and multivariate regression were used for feature selection. (3) Results: Two predictive models were constructed, one starting from 72 CP and 107 radiomics features, and the other from 72 CP and 1862 radiomics features. The models revealed moderately advantageous impact of increased dimensionality, with their predictive respective AUCs of 0.86 and 0.90 in the entire cohort and 0.84 within validation folds. Both models outperformed the CP-only model (AUC = 0.80) which served as the benchmark for predictive performance without radiomics. (4) Conclusions: Predictive models developed in this study combining pretreatment MRI radiomics and clinicopathological features may potentially provide a routine clinical predictor of chemoradiotherapy responders, enabling clinicians to personalize treatment strategies for rectal carcinoma.

GRECCAR 14 - a multicentric, randomized, phase II-III study evaluating the tailored management of locally advanced rectal carcinoma after a favourable response to induction chemotherapy: Study protocol.

Total neoadjuvant treatment (TNT) is becoming standard in patients with locally advanced rectal carcinoma (LARC). Preoperative chemoradiotherapy (CRT) has proven side effects on bowel and genitourinary function. An early tumoral response to induction chemotherapy demonstrates its high prognostic value. Tailored management could be used as an alternative to systematic CRT. The GRECCAR 14 trial will attempt to personalize treatment strategy according to the patient's early tumour response to intensive chemotherapy with the aim of achieving the best toxicity-efficiency ratio. GRECCAR 14 is a multicentric, randomized, two-arm, phase II-III noninferiority trial. Patients with mid or low LARC with a predictive circumferential resection margin ≤2 mm or T3c-d stage with extramural venous invasion will be included. Evaluation of the tumoral response will be performed after six courses of high-dose FOLFIRINOX chemotherapy. Good responders (GRs) will be defined by a 60% decrease in tumoral volume on magnetic resonance imaging. Patients will be randomized to CRT before surgery. The primary endpoints will be R0 resection for phase II and the 3-year disease-free survival (DFS) for phase III. Tailored management of LARC is becoming an exciting challenge for the modality of neoadjuvant treatment and for the type of surgery or its omission. Neoadjuvant FOLFIRINOX has established efficacy, with a significant increase in the 3-year DFS. Better control of systemic disease must be accompanied by the same locoregional control, with the lowest morbidity. Our previous GRECCAR 4 trial demonstrated the high value of the early tumoral response after induction chemotherapy and the long-term safety of tailored management for GRs. If GRECCAR 14 demonstrates the ability to tailor TNT for LARC, this could lead to changes in clinical practice.

A combination of stromal PD-L1 and tumoral nuclear β-catenin expression as an indicator of colorectal carcinoma progression and resistance to chemoradiotherapy in locally advanced rectal carcinoma.

Programmed cell death‐1 (PD‐1) and its ligand (PD‐L1) are significant mediators of immune suppression in the tumor microenvironment. We focused on the immunological impact of PD‐1/PD‐L1 signaling during tumor progression in colorectal carcinoma (CRC) and its association with resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal carcinoma (LAd‐RC). Histopathological and immunohistochemical analyses of 100 CRC cases (including 34 RC) without NCRT and 109 NCRT‐treated LAd‐RC cases were performed. Membranous tumoral PD‐L1 expression was identified in 9 of 100 (9%) CRC cases, including 1 of 34 (2.9%) RC cases, but PD‐L1 immunopositivity was not associated with any clinicopathological factors, with the exception of deficient mismatch repair (dMMR) status. In contrast, stromal PD‐L1+ immune cells, which frequently exhibited coexpression of PD‐1 and CD8 markers, were significantly correlated with tumor vessel invasion, nuclear β‐catenin+ tumor budding cancer stem cell (CSC)‐like features, and unfavorable prognosis. In the LAd‐RC cases, stromal CD8+ (but not PD‐L1+) immune cell infiltration in pretreatment‐biopsied samples was significantly and positively associated with therapeutic efficacy. After NCRT, tumoral PD‐L1 expression was observed in only 2 of 83 (2.4%) tumors, independent of dMMR status, whereas high stromal PD‐L1+ and tumoral nuclear β‐catenin positivity were significantly linked to a poor response to NCRT and high tumor budding features. In addition, high stromal PD‐L1 immunoreactivity was significantly associated with poorer overall survival. In conclusion, a combination of stromal PD‐L1+ immune cells and nuclear β‐catenin+ tumor budding may contribute to tumor progression in CRC and resistance to NCRT in LAd‐RC, through formation of niche‐like lesions that exhibit immune resistance and CSC properties.

Combined analysis of KRAS mutation and p16INK4a and p14ARF methylation status in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy

Current management of locally advanced rectal carcinoma (LARC) involves preoperative chemoradiotherapy (preCRT) before surgery. Despite improved local control rate, the response to preCRT of individual patients is variable and may reflect heterogeneous biological properties among tumors of the same clinical stage. Identifying novel molecular parameters with predictive and/or prognostic value is of great clinical importance for a personalized therapeutic approach. In this study, KRAS mutation status was analyzed by direct sequencing, while methylation-specific polymerase chain reaction (MSP) was used to examine p16INK4a and p14ARF gene methylation status in pretreatment tumor biopsies of 60 patients with LARC. The examined molecular changes of KRAS, p16INK4a and p14ARF genes were mutually independent (p16INK4a/KRAS, P=0.272; p14ARF/KRAS, P=0.923; p16INK4a/p14ARF, P=0.715). However, the simultaneous presence of p14ARF methylation and KRAS mutation was associated with a more frequent appearance of local recurrences and distant metastasis (P=0.027). Moreover, patients with the simultaneous presence of p16INK4a and p14ARF methylation and KRAS mutation had significantly shorter overall survival (P=0.011). The obtained results strongly suggest that combined analyses of examined genetic and epigenetic molecular alterations could contribute to the identification of LARC patient subgroups with more aggressive tumor behavior and worse disease outcome.

The role of circulating tumor cells and K-ras mutations in patients with locally advanced rectal cancer: a prospective study.

Rectal cancer is a common malignancy with a relatively poor prognosis. We assessed the possible prognostic and predictive role(s) of circulating tumor cells (CTCs) and K-ras mutations in locally advanced rectal carcinoma (LARC) patients. CTCs number and K-ras mutation status were assessed in the Peripheral blood and tumor tissue samples of 60 patients with LARC compared to control group (normal rectal mucosa). Data were correlated to relevant clinico-pathological features, response to treatment, disease free (DFS) and overall survival (OS) rates. K-ras mutations were present in 24/60 (40%) patients. Baseline CTCs (< 5 cells/7ml blood) were detected in 23/60 (38.3%) patients, and 37 (61.7%) had baseline CTCs (≥ 5 cells/7ml) blood (P = 0.071). Serial sampling showed a decrease in CTCs levels in 40 (66.7%) patients and increase in 20 (33.3%) patients (P = 0.01). Patients with K-ras mutations had a significantly poor response to treatment, with reduced DFS and OS rates (P = 0.001, 0.004, and 0.001; respectively). Similarly, decreased CTCs levels during treatment associated significantly with better pathological responses (P = 0.003). Multivariate analysis demonstrated that K-ras mutation and baseline CTCs are independent prognostic factors for DFS (P = 0.014 and 0.045; respectively) and OS (P = 0.002 and 0.045; respectively). The presence of mutant K-ras and baseline CTCs ≥ 5 cells associated significantly with poor pathological response, shorter DFS and OS rates compared to those with either K-ras mutation or CTCs ≥ 5 cells only (P = 0.014, 0.005 and 0.001, respectively). K-ras mutations, baseline and serial CTCs changes represent good prognostic and predictive factors for LARC patients.

Tailored treatment strategy for locally advanced rectal carcinoma: Five-year results of the French phase II, randomized, multicenter GRECCAR4 trial.

4014 Background: Preoperative radiochemotherapy and total mesorectal excision are the standard-of-care for locally-advanced rectal carcinoma, but some patients are over- or undertreated. Our phase II study assessed the feasibility of tailored radiochemotherapy, based on tumor response to induction high-dose chemotherapy (FOLFIRINOX). Methods: We enrolled 206 patients; good responders after chemotherapy (≥75% tumor volume reduction) were randomly assigned to immediate surgery (arm A) or standard radiochemotherapy (Cap 50: 50 Gy and oral capecitabine daily) plus surgery (arm B). Poor responders were randomly assigned to Cap 50 (arm C) or intensive radiochemotherapy (Cap 60 (60 Gy irradiation), arm D) before surgery. Results: After induction treatment, 194 patients were classified as good (n=30, 15%) or poor (n=164, 85%) responders, and included in arms A and B (16 and 14 patients) or C and D (113 and 51 patients). The primary objective was obtained: (90% CI) R0 resection rates in the four arms respectively were 100% (74–100), 100% (85–100), 83% (72–91), and 88% (77–95). At 5 years: overall survival 90% (CI: 47.3-98.5), 93.3% (CI: 61.3-99.0), 84.3% (CI: 71.0-91.8), 86.1% (CI: 71.6-93.5); disease-free survival 80% (CI: 40.9-94.6), 89.5% (CI: 64.1-97.3), 72.9% (CI: 58.5-82.9), 72.8% (CI: 57.7-83.2); local recurrence 0, 0, 2.1% (CI: 0.3-13.9), 9.3% (CI: 3.6-23.0); metastasis 20% (CI: 5.4-59.1), 10.5% (CI: 2.7-35.9), 18% (CI: 31.8-94.6), 18.8% (CI: 10.2-33.0). Late morbidity and quality of life evaluations showed no significant difference between arms. Conclusions: Tailoring preoperative radiochemotherapy based on induction treatment response is safe and promising. Early tumoral response to induction chemotherapy can discriminate tumor prognosis. Clinical trial information: NCT01333709 .

Prognostic factors for severe diarrhea in patients with locally advanced rectal carcinoma treated with neoadjuvant chemoradiation with capecitabine: A single-center cohort study.

e15176 Background: Chemoradiation with concomitant capecitabine (CRT) followed by total mesorectal excision is the standard of care for locally advanced rectal carcinoma (LARC). Grade ≥ 3 diarrhea is considered a dose-limiting toxicity of adding capecitabine to radiotherapy. The aim of this study is to describe the risk factors of grade ≥ 3 diarrhea in patients with LARC during CRT. Methods: A single centre retrospective cohort study was conducted in our tertiary center. All patients with LARC treated with CRT from 2009 to 2015 were included. Patients with local recurrence who received CRT for the first time were also included. Univariate logistic regression analyses were used, followed by a multivariate analysis of the significant factors with backward selection at p &lt; 0.05. Results: A total of 738 patients were included: 67% male, median age 64 years (range 17-88), 95% primary presentation. DPYD-testing was not performed upfront. In this cohort 69 patients (9%) developed ≥3 grade diarrhea. In the univariate analysis, factors significantly associated with ≥3 grade diarrhea were; female gender, age ≥65 years, body weight and decreased renal function (defined as MDRD GFR &lt; 60 ml/min/1,73 m2). The following factors remained significantly associated with ≥3 grade diarrhea in the multivariate analysis; female gender (odds ratio (OR) 2.77, 95% confidence interval (CI) 1.54-4.99, p 0.001), age ≥65 years (OR 2.85, 95% CI 1.63-4.98, p &lt; 0.001) and a lower bodyweight (OR 0.98, 95% CI 0.96-1.00, p 0.015). Conclusions: Female gender and age ≥65 years significantly increase the risk of grade ≥ 3 diarrhea caused by neoadjuvant CRT for LARC. So, older female patient must be closely watched during this treatment to intervene on time. The difference in toxicity between females and males might be explained by the pelvic anatomical differences between men and women. The found prognostic factors will be validated in a second cohort of patients with LARC treated with CRT. Besides, sarcopenia will be tested as a prognostic factor as well.

Long-term results of a multicenter phase II study of preoperative chemoradiotherapy with S-1 plus oxaliplatin for locally advanced rectal cancer (JACCRO CC-04: SHOGUN Trial)

PurposeThe study was designed to evaluate the safety and efficacy of adding oxaliplatin to py (CRT) with S-1 in patients with locally advanced rectal carcinoma (LARC). We report here the final results of the study. Patients and methodsPatients with histopathologically confirmed LARC (cT3-T4, any N) were eligible. They received oral S-1 (80 mg/m2/day on days 1–5, 8–12, 22–26, and 29–33) and infusional oxaliplatin (60 mg/m2/day on days 1, 8, 22, 29) plus radiotherapy (1.8 Gy/day, total dose of 50.4 Gy in 28 fractions), with a chemotherapy gap in the third week of radiotherapy. Primary endpoint of the study was pathological complete response (pCR) rate. Secondary endpoints were rates of R0 resection, down-staging, cumulative 3-year local recurrence, 3-year disease-free survival (DFS), and toxicity. ResultsForty-five patients were enrolled at six centers in Japan. All patients received CRT, and 44 underwent operation. The pCR rate was 27.3% (12/44). The R0 resection rate was 95.5% (42/44). T-down-staging rate was 59.1% (26/44), and N-down staging rate was 65.9% (29/44); the combined pathological down-staging rate was 79.5% (35/44). There were no grade 4 adverse events, but 11.1% of the patients had grade 3 adverse events. Cumulative 3-year local recurrence rate was 0%. However, 13 (30.0%) patients suffered from distant metastasis, and one patient suffered from secondary esophageal cancer that was unrelated to rectal cancer. Eight patients had lung metastasis, 4 had liver metastasis, and 3 patients died of the metastatic disease. The 3-year DFS rate of the 44 patients was 67.5% (median follow-up 36.3 months), and the 3-year overall survival (OS) rate was 93.0% (median follow-up 39.6 months). The patients were then divided into the pCR (12 patients) group and non pCR (32 patients) group. The 3-year rate of DFS for each group was 91.7% and 58.1% and that of OS was 100% and 90.3%, respectively. ConclusionsThe study showed a high pCR rate with no severe toxicity, good follow-up results, and good loco-regional control. Therefore, addition of oxaliplatin to preoperative CRT with S-1 in patients with LARC might be feasible and lead to better local control than standard treatment.

16. Predicting neoadjuvant therapy response in locally advanced rectal cancer using texture features

Purpose To predict pathological response to neoadjuvant chemo-radiotherapy (CRT) in locally advanced rectal carcinoma (LARC), using a classifier based on texture features derived from MRI and PET acquisitions. Methods 47 patients with: (a) histologically diagnosis of LARC, (b) pre-treatment MRI and PET/CT, (c) neoadjuvant treatment consisting of 46–55 Gy in 23–30 RT fractions alone or in association with either infusional 5-FU or oral Capecitabine, and (d) total mesorectal excision were included in this study. Patients with complete (tumour regression grade, TRG = 1) or near complete (TRG = 2) regression were defined as responders (pR+), while patients with moderate (TRG = 3) to no regression (TRG = 5) were considered as non-responders (pR−) [1] , [2] . Before implementing texture analysis, tumours were semi-automatically segmented on T2-w MRI, ADC maps and PET/CT acquisitions. From the segmented tumours, the following quantitative features were extracted from T2-w, ADC and PET images: (a) first-order parameters: median, mean, percentiles (10th, 25th, and 75th), (b) SUV, metabolic volume and glycolytic volume only for PET images, and (c) 22 s-order texture parameters, derived from Haralick analysis [3] . Multivariate logistic regression was performed to identify features most correlated with TRG. Results Overall, 26 patients were classified as pR−, and 21 as pR+ after total mesorectal excision. Parameters included in the multivariate regression were “10th percentile PET”, “10th percentile T2-w”, “Homogeneity ADC”, “Homogeneity PET”, “Information measure of correlation T2-w” (p = 0.002). The area under the ROC curve was 0.83 (95% confidence interval = 0.69–0.93), sensitivity and specificity were 75% and 76%, respectively, in detecting responders. Conclusions Texture analysis could provide useful information in assessing response to neoadjuvant treatment in LARC patients. These preliminary results, if confirmed on larger dataset, could be useful to personalize the oncological pathway for patients, delaying or advancing surgery, according to the prediction of treatment response.

Neutrophilic Lymphocytic Ratio as Predictive Biomarker in Advanced Rectal Cancer Patients

Background: Preoperative Neutrophil-Lymphocytic ratio has been suggested in many studies in resected colorectal cancer as predictive marker for recurrence and survival. This study investigated impact of pretreatment Neutrophil-Lymphocytic ratio on treatment outcome in rectal cancer patients. Methods: Retrospective analysis of pretreatment Neutrophil-Lymphocytic ratio for one hundred and forty two patients with locally advanced rectal carcinoma (LARC) treated by neoadjuvant concomitant chemo-radiotherapy followed by surgical resection, between June 2006 and June 2011 in Minia University Hospital and Al-Hussein University Hospital. In order to study neutrophil lymphocytic ratio as a predictive factor for disease free survival and overall survival, other factors like age, sex, tumor length, tumor distance from anal verge, number of resected lymph nodes, positive lymph nodes, excision margin, tumor differentiation and circumferential resection margin with their impact on disease free survival and overall survival were also studied. Results: One hundred forty two patients with mean age of 65.1 ± 10.8. 64% were females; more than one third (34.5%) underwent colostomy and 61.3% ≤ 5 cm from anal verge. Pretreatment CEA was above 3 ng/ml in 57.7% of patients. Mean NLR was 4.1 ± 2.87. NLR of 58.4% patients were >3. Regarding disease free survival, In a univariate analysis, only involved excisional margin seen in 8 patients and positive CRM seen in 15 patients show significant impact on DFS (p-value 0,01, 0.001), respectively. On other hand, NLR didn’t show significance on DFS. None of the studied factors showed impact on overall survival in a univariate analysis. However, Neutrophil lymphocytic ratio at cut-off 3 showed significance. Population group with NLR ratio ≥ 3 showed less survival with a mean of 52.5 month compared to those with NLR ratio <3 that showed mean survival of 60.7 (p-value 0.05). Conclusion: Pretreatment NLR is a simple, easily accessible laboratory finding for identifying LARC patients who had poorer prognosis for the standard line of treatment.

517P - TRUST: Phase II trial of induction chemotherapy (CT) with FOLFOXIRI + bevacizumab (BV) followed by chemo-radiotherapy (CRT) + BV and surgery in locally advanced rectal carcinoma (LARC)

Induction CT followed by CRT is a promising strategy in LARC. FOLFOXIRI + BV is an effective treatment in metastatic colorectal cancer. This is a phase II single-arm trial. Patients (pts) with LARC at <12 cm from the anal verge, staged cN+ or cT4 or high risk cT3 (Magnetic Resonance Imaging criteria), underwent 6 cycles of induction therapy with the GONO FOLFOXIRI + BV regimen, followed by CRT (50.4 Gy + 5FU 225 mg/m2/day or capecitabine 825 mg/m2/bid continuously) + BV (5 mg/kg on days 1, 15, 28). Surgery was planned 8 weeks after CRT. Primary endpoint is 2-year disease-free survival (DFS). We enrolled 48 pts: median age, 53 years (30-74); cT2/T3/T4, 4%/60%/36%; cN0/N +, 4%/96%; distance from anal verge 0-5/5-10/ > 10 cm, 56%/38%/6%. 46 pts completed induction therapy; 2 pts prematurely stopped treatment: 1 bowel perforation and sepsis resulting in death and 1 acute kidney injury recovered without sequelae. Main grade (G) 3/4 toxicities were: neutropenia (42%), febrile neutropenia (4.2%) and diarrhea (12.5%). After induction therapy 45 pts started CRT and 1 underwent surgery. After the first 13 pts, the protocol was amended and the schedule of capecitabine slightly modified (800 mg/m2/bid 5 days/week) due to an excessive rate of G3 hand-foot syndrome (23%) and proctitis (23%). After amendment, all pts completed CRT with acceptable toxicity: no G3-4 toxicities were reported, with the exception of proctitis (6.2%). After CRT 44 pts underwent surgery (1 died due to early progression after CRT): low anterior (89%) or abdomino-perineal (7%) resection. R0 resection was achieved in 98% resected pts. Early post-surgical complication rate was 32%, with a rate of 18% of anastomotic dehiscences (all solved). Pathologic complete response (pCR) rate was 36%. At a median follow up of 25.1 months, 11 pts experienced disease progression (3 local recurrences) and the estimated 2-year DFS is 78.8%. Induction therapy with FOLFOXIRI + BV followed by CRT + BV is feasible, but a careful patient selection is needed because of the overall safety profile. Results in terms of pCR and preliminary DFS data are promising.

D12 - TRUST: phase II trial of induction chemotherapy (CT) with FOLFOXIRI plus bevacizumab (BV) followed by chemo-radiotherapy (CRT) plus BV and surgery in locally advanced rectal carcinoma (LARC)

Background: Induction CT followed by CRT is a promising strategy in LARC. FOLFOXIRI plus BV is an effective treatment in metastatic colorectal cancer. Materials and methods: This is a phase II multicentric single-stage single-arm trial (EUDRACT 2011-003340-45). Patients (pts) with LARC at <12 cm from the anal verge, staged cN+ or cT4 or high risk cT3 (Magnetic Resonance Imaging criteria), underwent 6 cycles of induction therapy with the GONO FOLFOXIRI plus BV regimen (BV 5 mg/kg day 1; irinotecan 165 mg/m2 day 1; oxaliplatin 85 mg/m2 day1; folinate 200 mg/m2 day 1; 5FU 3200 mg/m2 48h continuous infusion starting on day 1), followed by CRT (50.4 Gy + 5FU 225 mg/m2/day or capecitabine 825 mg/m2/bid continuously) plus BV (5 mg/kg on days 1, 15, 28). Surgery was planned 8 weeks after CRT. Primary endpoint was 2-year disease-free survival (DFS). Results: We enrolled 48 pts. Main pts characteristics were: median age, 53 years (30-74); cT2/T3/T4, 4%/60%/36%; cN0/N +, 4%/96%; distance from anal verge 0-5/5-10/ > 10 cm, 56%/38%/6%. 46 pts completed induction therapy; 2 pts prematurely stopped treatment: 1 bowel perforation and sepsis resulting in death and 1 acute kidney injury recovered without sequelae. Main grade (G) 3/4 toxicities were: neutropenia (42%), febrile neutropenia (4.2%) and diarrhea (12.5%). After induction therapy 45 pts started CRT and 1 underwent surgery. After the first 13 pts, the protocol was amended and the schedule of capecitabine slightly modified (800 mg/m2/bid 5 days/week) due to an excessive rate of G3 hand-foot syndrome (23%) and proctitis (23%). After amendment, all pts completed CRT with acceptable toxicity: no G3-4 toxicities were reported, with the exception of proctitis (6.2%). After CRT 44 pts underwent surgery (1 died due to early progression after CRT): low anterior (89%) or abdomino-perineal (7%) resection. R0 resection was achieved in 98% resected pts. Early post-surgical complication rate was 32%, with a rate of 18% of anastomotic dehiscences (all solved). Pathologic complete response (pCR) rate was 36%. At a median follow up of 25.1 months, 11 pts experienced disease progression (3 local recurrences) and the estimated 2-year DFS is 78.8%. Conclusions: Induction therapy with FOLFOXIRI plus BV followed by CRT plus BV is feasible, but a careful patient selection is needed because of the overall safety profile. Results in terms of pCR and preliminary DFS data are promising.

Prognostic value of pigment epithelium-derived factor for neoadjuvant radiation therapy in patients with locally advanced rectal carcinoma.

The aim of the study was to investigate the prognostic value of pigment epithelium-derived factor (PEDF) in locally advanced rectal carcinoma (LARC) treated with neoadjuvant radiation therapy (nRT). The level of PEDF expressing was examined in LARC tissues treated with nRT by immunohistochemistry and the prognostic significance of PEDF was analysed by univariate and multivariate survival analyses. We forced expression of PEDF in highly metastatic LoVo cells. The clonogenic survival assay was used to test the cellular sensitivity to radiation. Wound healing and Boyden chamber assays were used to detect cell migration and invasion. To assess the contribution of PEDF in vivo, we established tumor xenografts. The mechanisms of PEDF on cancer cells was analysed by bioinformatics. Our immunohistochemical staining of tissue samples revealed that prolonged DFS (77.1 vs 49.0%) and OS (87.1 vs 56.3%) was observed in PEDF-positive cases (P<0.001) following nRT. PEDF could be an independent factor for DFS [P=0.001; HR, 0.422 (95%CI, 0.249-0.717)] and OS [P=0.003; HR, 0.418 (95%CI, 0.234-0.749)]. Positive-expression of PEDF was negatively correlated with tumor differentiation (P<0.016), ypT stage (P<0.037), ypTNM stage (P<0.033), and ypN stage (P=0.006). Overexpression of PEDF in high metastatic cells enhanced radiosensitivity and, suppressed migration and invasion invitro. In tumor xenografts, PEDF significantly suppressed tumor growth. Furthermore, by bioinformatics analysis, we found PEDF performs functions via activating P53 to regulate double-strand break repair pathway and activate the Gprotein activation pathway. Our findings indicate that PEDF was identified as a predictive candidate for nRT responsiveness. These findings may be used to stratify LARC patients and make alternative strategies for adjuvant treatment.

Short-term efficacy comparison between preoperative three dimensional conformal radiotherapy and volumetric modulated arc therapy concurrently combined with chemotherapy in the treatment of locally advanced rectal carcinoma

To compare the short-term efficacy and treatment-related adverse reaction between preoperative three dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT) concurrently combined with chemotherapy in the treatment of locally advanced rectal carcinoma (LARC). Clinical data of 334 patients with LARC undergoing preoperative 3D-CRT(172 cases) or VMAT(162 cases) with concurrent Xelox chemotherapy (main protocol: capecitabine plus oxaliplatin) and surgery in Sun Yat-sen University Cancer Center from May 2007 to April 2013 were retrospectively analyzed. The total radiation dose of VMAT group was: 50 Gy/2.0 Gy per fraction ×23 fractions for planning target volume 1(PTV1) and 46 Gy/1.84 Gy per fraction ×25 fractions for PTV2; the total radiation dose of 3D-CRT group was: 46 Gy/2.0 Gy per fraction ×23 fractions for PTV. The treatment-related adverse reaction of both groups during chemoradiotherapy was measured according to the criteria of Common Terminology Criteria for Adverse Events v3.0 (CTCAE 3.0). Rate of adverse reaction and short-term efficacy between 3D-CRT and VMAT group were compared, in terms of radiotherapy break, hematological and non-hematological toxicity, average duration of surgery and perioperative hospitalization, intraoperative blood loss, surgical procedures, R0 excision, sphincter preservation, postoperative complications, pathological complete response (pCR), and postoperative pathological staging. There were no significant differences in baseline clinical parameters between 3D-CRT and VMAT group (all P>0.05), except for the distance from lower tumor margin to anal verge (P=0.009). The median radiation dose for all the patients was 46 (45 to 70) Gy. There was no significant difference in the rate of radiotherapy cessation between 3D-CRT and VMAT group [1.7%(3/172) vs. 1.2%(2/162), P=1.000]. During concurrent chemotherapy, incidences of grade 2 to 3 hematological toxicities, grade 2 diarrhea, and grade 3 non-hematological toxicities were not significantly different(all P>0.05), while in grade 2 non-hematological toxicities, ratio of radiodermatitis and hand-foot syndrome was higher in VMAT group as compared to 3D-CRT group [25.9%(42/162) vs. 10.5%(18/172), P=0.000; 3.7%(6/162) vs. 0, P=0.012]. There was no grade 4 adverse event in both groups. Surgical procedure, average duration of surgery, R0 excision, anus preservation, postoperative complications, pCR, and postoperative pathological staging were not significantly different(all P>0.05). As compared to 3D-CRT group, VMAT group had less intraoperative blood loss [(114.6±100) ml vs. (169±143.9) ml, P<0.001] and shorter perioperative hospitalization [16(8 to 84) d vs. 20(10 to 47) d, P<0.001]. There was no death case in two groups within 30 days after operation. Compared with 3D-CRT technique, preoperative VMAT technique can not significantly reduce the incidence of treatment-related adverse reaction and improve the short-term efficacy in the treatment of LARC.

O-021 Tailored strategy for locally-advanced rectal carcinoma: preliminary results of a phase II multicenter trial (GRECCAR 4)

O-021 Tailored strategy for locally-advanced rectal carcinoma: preliminary results of a phase II multicenter trial (GRECCAR 4)

Results of the phase II TRUST trial of induction treatment with FOLFOXIRI + bevacizumab (BV) followed by chemo-radiotherapy (CRT) plus BV and surgery in locally advanced rectal carcinoma (LARC).

3615Background: Induction chemotherapy (CT) is a promising option in LARC. FOLFOXIRI + BV is an effective treatment in metastatic colorectal cancer. Methods: This is a phase II multicentric single-...

Induction treatment with FOLFOXIRI + bevacizumab (BV) followed by chemo-radiotherapy (CRT) + BV and surgery in locally advanced rectal carcinoma (LARC): The phase II TRUST trial.

673 Background: Induction chemotherapy (CT) is a promising option in LARC. FOLFOXIRI + BV is an effective treatment in metastatic colorectal cancer. Methods: Patients (pts) with LARC at &lt; 12 cm from the anal verge, N+ or cT4 or high risk cT3 (MRI criteria) underwent 6 cycles of FOLFOXIRI + BV followed by CRT (50.4 Gy + 5FU 225 mg/m2/day or capecitabine 800 mg/m2/bid 5 days/week + BV 5 mg/kg on days 1, 15, 28). Surgery was planned 8 weeks after CRT. Primary endpoint is 2-year disease-free survival (DFS). Results: From April 2012 to April 2015 48 pts were enrolled. At now, 46 pts completed induction CT, 43 completed CRT and 39 underwent surgery (5 pts ongoing). Pts characteristics were: median age, 53 years (range 30-74); cT2/cT3/cT4, 4%/60%/36%; cN0/N+, 4%/96%. Main grade (G) 3/4 toxicities during induction were neutropenia (42%), febrile neutropenia (4.2%), diarrhea (12.5. Two pts did not complete induction: one died due to bowel perforation and sepsis and one discontinued CT after acute kidney injury. Response rate (RR) after induction was 77%. Forty-five pts started CRT (1 pts underwent surgery after induction because of SAE). After the first 13 patients, protocol was amended and schedule of capecitabine modified due to an excessive rate of G3 toxicities during CRT: hand-foot syndrome (23%), proctalgia (23%), proctitis (23%) and diarrhea (15%). After amendment all pts completed CRT with acceptable toxicity: G3 proctitis 6.7% and proctalgia 3.3%. One pts died due to early progressive disease (PD) after CRT. RR after CRT was 88%. Surgery was low anterior resection 87%, abdomino-perineal resection 8%, other 5%. Radical resection was achieved in 95% of pts. Early post-surgical complication rate was 31%. Pathologic complete response was reached in 33% and pathological downstaging in 44% of pts. At a median follow up of 17 months, 8 pts had PD and estimated 2y-DFS is 72%. Conclusions: Induction CT with FOLFOXIRI + BV is feasible and highly active. A protocol amendment was needed due to toxicities during CRT. The rate of early post-surgical complications is not negligible. A longer follow up is needed for DFS. Clinical trial information: 2011-003340-45.

Micro-RNAs as positive biomarkers of pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal carcinoma.

624 Background: Neoadjuvant chemoradiotherapy (nCRT) follow by surgery, as treatment for locally advanced rectal carcinoma (LARC), has improve local disease control, increase of complete pathological response (cPR) and preserve anal sphincter. cPR is associated with better prognosis. CRT act mainly through induction of DNA damage. MicroRNAs (miRNAs) are small non-coding RNAs able to regulate gene expression at post-transcriptional level. miRNAs are involved in the regulation of DNA damage/repair mechanism. Our goal was to measure expression of miRNAs involved in DNA damage/repair genes and correlated with cPR. Methods: Retrospectively, we analyzed the initial paraffin embedded tissue block of 20 Mexican patients with LARC treated with nCRT at National Cancer Institute of Mexico between 2010-2013. Treatment response was evaluated with Ryan Classification. Ten patients had cPR (Ryan Grade 0) meanwhile other 10 poor response (Ryan Grade 3). RNA extraction was done with RNeasy FFPE (Qiagen) Kit. RNA concentration and purity was assessed using NanoDrop 2000 Spectrophotometer. miRNAs expression were evaluated by real-time polymerase chain reaction (PCR) analysis with TaqMan Probes from Applied Biosystems. Statistical analysis was carried out with IBM SPSS Statistics 22.0. Differential expression between the two groups was performed with Chi square test. Results: There wasn’tsignificant difference betweenclinical/demographic features between the 2 groups. All patients received CRT at a total dose of 4500 cGy of pelvic irradiation, concomitantly with fluoropyrimidine. Surgical treatment was performed 14 weeks after completion of nCRT. The 2 miRNAs (188-5p and 590-5p) was overexpressed in the cPR group vs poor response group (p = 0.011 and p = 0.057, respectively). Conclusions: We evaluated the expression of miR590-5p and miR188-5p because they are related to DNA repair genes such as: MSH2, ERCC3, BRCC3 and XRCC5. We found overexpression in both miRNAs. Even though miR590 5p didn't reach statistical significance this maybe because of simple size.Our results now are been analyzed with a biological and functional genes network platform: Ingenuity Pathway Analysis.

A multicenter phase II study of preoperative chemoradiotherapy with S-1 plus oxaliplatin for locally advanced rectal cancer (SHOGUN trial)

PurposeThis study was designed to evaluate the safety and efficacy of adding oxaliplatin to preoperative chemoradiotherapy (CRT) with S-1 in patients with locally advanced rectal carcinoma (LARC). Patients and methodsThis was a multicenter phase II study in patients with histologically proven clinical stage T3 or T4 (any N, M0) LARC. Patients preoperatively received oral S-1 (80mg/m2/day on days 1–5, 8–12, 22–27, and 29–33) and infusional oxaliplatin (60mg/m2 days on 1, 8, 22, and 29) plus radiotherapy (50.4Gy), with a chemotherapy gap in the third week of radiotherapy. Pathological complete response (pCR) was the primary endpoint. Secondary endpoints included toxicity, compliance, R0 resection rate, and downstaging rate. ResultsA total of 45 patients were enrolled at six centers in Japan. All 45 patients received CRT, and 44 underwent operation. A pCR was achieved in 12 (27.3%) of the 44 patients who underwent surgery. Near-total tumor regression was confirmed in 47.7%. There were no grade 4 adverse events, and 11.1% of the patients had grade 3 adverse events. R0 resection was achieved in 95.5% of the patients. ConclusionPreoperative CRT with S-1 plus oxaliplatin had a high pCR rate and a favorable toxicity profile.

A phase I/II study of S-1 plus oxaliplatin combined with radiation (SOX/RT) for preoperative locally advanced rectal carcinoma (JACCRO CC-04: SHOGUN trial).

602 Background: Previous western trials of preoperative chemoradiation (CRT) in patients with locally advanced rectal carcinoma (LARC) have been shown to increase the chance of sphincter preservation and local control, and has become the standard of care in western countries. In Japan, preoperative CRT has not been utilized in LARC and its value is unconfirmed. Thus, we conducted a phase I/II study of preoperative CRT with S-1, which is widely used oral fluoropyrimidine in Japan to treat gastrointestinal cancer, plus oxaliplatin in patients with LARC. Methods: Patients with histopathologically confirmed LARC (cT3-T4, any N) were eligible. A total radiation dose of 50.4 Gy was delivered in 28 fractions over 5 weeks, and S-1 was orally administered 40mg/m2 twice a day for 5 days a week at 1st, 2nd, 4th and 5th week. Oxaliplatin was administered at a dose of 40 mg/m2 (level 1), 50 mg/m2 (level 2) or 60 mg/m2(level 3) on day 1, 8, 22 and 29. Surgery was performed within 6-10 weeks after CRT. The primary endpoint of phase I part was to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of oxaliplatin. Primary endpoint of phase II was evaluated pathologic complete response (pCR) rate at RD. Results: 13 patients were enrolled in the phase I part, 2 dose-limiting toxicities (DLTs, skipping oxaliplatin due to the grade 2 neutropenia) occurred in the dose level 3, and the MTD was not reached. In phase II, 45 patients were treated at the RD of oxaliplatin (60 mg/m2) and 44 patients (97.8%) underwent surgery. A pCR was observed in 12 patients (27.3%). The relative dose intensity of radiation, S-1, oxaliplatin was 98.4%, 94.0%, and 94.3%, respectively. The incidence of grade 3-4 diarrhea and neutropenia was 8.9% and 2.2%, respectively. Postoperative complications of any grade occurred in 27.3% of patients. Conclusions: Preoperative CRT with S-1 plus oxaliplatin showed promising results in pathological responses and favorable toxicities profiles. Clinical trial information: NCT01227239.