Preoperative Neoadjuvant Chemoradiotherapy Research Articles

A single center retrospective study on surgical efficacy of T3NxM0 middle-low rectal cancer without neoadjuvant therapy

To investigate the surgical efficacy and prognostic factors of T3NxM0 middle-low rectal cancer without neoadjuvant therapy. Clinical data of patients with middle-low rectal cancer undergoing TME surgery with T3NxM0 confirmed by postoperative pathology at Colorectal Surgery Department of Changhai Hospital from January 2008 to December 2010 were analyzed retrospectively. (1)no preoperative neoadjuvant chemoradiotherapy (nCRT); (2) complete preoperative evaluation, including medical history, preoperative colonoscopy or digital examination, blood tumor marker examination, and imaging examination; (3) distance between tumor lower margin and anal verge was ≤ 10 cm; (4) negative circumferential resection margin (CRM-). Finally, a total of 331 patients were included in this study. According to the number of metastatic lymph node confirmed by postoperative pathology, the patients were divided into N0 group without regional lymph node metastasis (190 cases) and N+ group with regional lymph node metastasis (141 cases). The perioperative conditions, local recurrence, distant metastasis and prognostic factors were analyzed. Compared to N0 group in the perioperative data, N+ group had higher ratio of tumor deposit [29.8%(42/141) vs. 0, χ²=64.821, P<0.001] and vascular invasion [7.1%(10/141) vs. 0.5%(1/190),χ²=10.860, P<0.001]. There were no significant differences in tumor diameter, number of lymph nodes detected, positive nerve invasion, degree of tumor differentiation, morbidity of postoperative complication and postoperative adjuvant chemotherapy rate between the two groups (all P>0.05). The median follow-up period was 73.4 months. The merged 5-year local recurrence rate was 2.7%(9/331), 5-year distant metastasis rate was 23.3% (77/331), 5-year disease-free survival (DFS) rate was 73.4%, and 5-year overall survival (OS) rate was 77.2%. Multivariate analysis showed that lymph node metastasis (HR=3.120, 95%CI: 1.918 to 5.075, P<0.001), nerve invasion (HR=0.345, 95%CI: 0.156 to 0.760, P=0.008) and vascular invasion (HR=0.428, 95%CI: 0.189 to 0.972, P=0.043) were independent risk factors for DFS in patients with T3NxM0 rectal cancer after operation. Preoperative carcinoembryonic antigen level (HR=1.858, 95%CI:1.121 to 3.079, P=0.016), lymph node metastasis (HR=3.320, 95%CI: 1.985 to 5.553, P<0.001) and nerve invasion (HR=0.339, 95%CI: 0.156 to 0.738, P=0.006) were independent risk factors for OS in patients with T3NxM0 rectal cancer after operation. Optimal local control rate of middle-low rectal cancer patients with T3NxM0 and CRM- can be achieved by standard TME surgery alone. For patients with preoperative elevated blood carcinoembryonic antigen level, regional lymph node metastasis, or neurovascular invasion confirmed by pathology after surgery, adjuvant chemoradiotherapy should be actively applied after surgery to improve prognosis.

Evaluation of The Feasibility and Safety of Laparoscopic Rectal Resection for Rectal Carcinoma After Neoadjuvant Chemoradiation

Purpose: This study aimed to evaluate the technical feasibility and oncological safety of laparoscopic total mesorectal excision (TME) for rectal carcinoma after chemoradiotherapy. Methods: 30 Patients with T3, T4 and⁄ or N1-2 rectal cancer were subjected to a preoperative neoadjuvant chemoradiotherapy (nCRT) protocol in the form of 45-50 Gy of external irradiation over 25-28 weekly fractions to the true pelvis concomitant with oral Capecitabine 825 mg/m2 twice daily. Results: This study included 16 males (53.3%) and 14 females (46.7%) with a mean age of 48.63 ±12.53 years. 19 patients (63.3%) underwent laparoscopic low anterior resection (LLAR) while 11 patients (36.7%) underwent laparoscopic abdominoperineal resection (LAPR). Mean blood loss was 66.05 ± 31.60 cc in LAR group and 241.82 ± 101.37 cc in APR group, the operative time was longer in APR group. The intra-operative adverse events occurred in 7 patients (23.3%). Earlier recovery of bowel function was observed in both groups; with shorter postoperative hospital stay in LLAR vs LAPR groups. Involvement of the circumferential resection margin occurred in two cases (6.7%), the mean number of harvested lymph nodes was 10.57±1.74 lymph node, the distal and proximal resection margins were free from malignant infiltration in all cases. Postoperative morbidity occurred in 8 patients (26.7%) with one case of local recurrence (3.3%). Conclusions: Based on the controllable surgical complications, minimal invasiveness and achieved oncological safety in the current patient series, laparoscopic TME is shown to be technically feasible and oncologically safe and can be recommended for patients with rectal carcinoma requiring preoperative chemoradiotherapy.

Short-term efficacy and safety of the synchronous neoadjuvant chemoradiotherapy with paclitaxel plus carboplatin in stage III adenocarcinoma of esophagogastric junction

To evaluate the short-term efficacy and safety of neoadjuvant synchronous chemoradiotherapy (paclitaxel plus carboplatin regimen) in stage III adenocarcinoma of esophagogastric junction (AEG). Forty cases clinically diagnosed as stage III AEG were prospectively enrolled at the Department of Gastrointestinal Oncology Surgery, the First Affiliated Hospital of Hebei North University from December 2014 to November 2017 and then were randomly divided into paclitaxel plus carboplatin combined with synchronous radiotherapy group(neoadjuvant group) and direct operation group. Inclusion criteria was as follows:(1) AEG was diagnosed by gastroscopic biopsy and III stage was confirmed by ultrasound endoscopy and spiral CT;(2) physical strength score ≥70, and age ≤75 years old; (3) no contraindications of chemoradiotherapy and operation. Exclusion criteria was as follows:(1) patients voluntarily withdrew or refused the treatment;(2) occurrence of severe anaphylaxis; (3) uncontrollable events happened during treatment and treatment was unable to continue;(4) tumor developed obviously during treatment. Preoperative neoadjuvant synchronous chemoradiotherapy used TP regimen: paclitaxel 80 mg/m², drug concentration-time area under curve of carboplatin= 1.5 mg×ml⁻¹×min⁻¹, once per week for 9 weeks; radiotherapy began at the second week, 40 Gy/20 F, completed within 4 weeks. Operative procedure of both groups was radical resection of cardiac cancer(D2). Postoperative chemotherapy regimen was oral Tegafur(Gimeracil and Oteracil potassium). The side effects, diet situation, change of gastroscopic image after treatment in patients of neoadjuvant group were observed and efficacy evaluation of chemotherapy was performed according to solid tumor efficacy evaluation criteria of US National Cancer Institute. Operation-associated parameters, including R0 resection rate, lymph node metastasis, operative mortality and postoperative complications, were compared between two groups. There were no significant differences in baseline information between the two group (all P>0.05). One case in neoadjuvant group was excluded because of perforation at lesion site 7 weeks after chemotherapy. The side effects of 19 cases in neoadjuvant group were mainly alopecia (100%) and marrow inhibition (68.4%), while 3-4 degree side effects were alopecia(8/19,42.1%), leukopenia (3/19, 15.8%) and neutropenia(3/19, 15.8%). Complete remission was observed in 4 cases; partial remission was observed in 13 cases and stable disease in 2 cases, with an objective response rate of 89.5% and a disease control rate of 100%. Before neoadjuvant chemotherapy, 16 cases were difficult to take liquid diet and 3 cases received liquid diet only, while after 12 weeks of neoadjuvant chemotherapy, all the 19 cases received normal diet. Besides, after neoadjuvant chemotherapy, gastroscopic examination showed close healing of cardiac ulcer, disappearance of swelling, and renewal of normal mucosa. Compared to direct operation group, neoadjuvant group had less number of positive lymph node (4.9±3.6 vs. 8.8±2.8, P<0.05) and higher R0 resection rate (94.7% vs. 50.0%, P<0.05). Total number of harvested lymph node was not significantly different between two groups (19.1±2.5 vs. 18.6±7.0, t=0.326, P=0.746). There was no surgical death in either group. One case in direct operation group developed postoperative inflammatory obstruction. No associated complication was found in neoadjuvant group. Paclitaxel plus carboplatin combined with synchronous radiotherapy can elevate the R0 resection rate of patients with stage III esophagogastric junction adenocarcinoma, without increasing operative mortality and postoperative complications.

Feasibility and application value of autonomic nerve-preserving D3 radical resection for right-sided colon cancer under laparoscope

To explore the feasibility and application value of the preservation of vegetative nervous functions in radical resection for right-sided colon cancer. Clinical data of 55 cases with right-sided colon cancer undergoing laparoscopic D3+ complete mesocolic excision (CME) radical resection from January 2016 to July 2017 at Department of Gastrointestinal Surgery of Guangdong Province Hospital of Traditional Chinese Medicine were retrospectively analyzed. Exclusion criteria included emergency surgery for various reasons, intestinal obstruction or perforation, distant metastasis or locally advanced cancer, previous history of abdominal surgery and preoperative neoadjuvant chemoradiotherapy. Twenty-nine cases underwent lymphadenectomy with intrathecal dissection of superior mesenteric artery (SMA) and part of superior mesenteric plexus was resected (nerve partial resection group, NPR group). Twenty-six cases received lymphadenectomy with the clearance of lymphatic adipose tissue on the right side of SMA by sharp or obtuse method outside the sheath; the sheath of superior mesenteric vein (SMV) was entered at the junction of SMA and SMV; the SMV was naked in the sheath; the third station lymph node dissection was completed with preservation of superior mesenteric plexus (nerve preserved group, NP group). Intra-operative and postoperative complications were compared between two groups. The baseline data were not significantly different between two groups (all P>0.05). The operation time in NP group was significantly shorter than that in NPR group [(164.0±19.8) minutes vs. (176.0±19.7) minutes, t=2.249, P=0.029]. No significant differences in operative blood loss, operative vessel damage, postoperative time to flatus, postoperative hospital stay and abdominal pain were observed between two groups(all P>0.05). The number of harvested lymph node in two groups was 28.5±7.8 and 27.6±6.5 respectively without significant difference(P>0.05). As compared to NPR group, NP group had lower incidence of chylous leakage[3.8%(1/26) vs. 37.9%(11/29), χ²=9.337, P=0.002] and postoperative diarrhea [15.4%(4/26) vs. 41.4%(12/29), χ²=4.491, P=0.034]. Autonomic nerve-preserving D3+ CME radical resection for right-sided colon cancer is safe and feasible, and can prevent the postoperative gastrointestinal dysfunction caused by nerve injury and decrease the risk of chylous leakage.

Survival analysis of preoperative involved-field irradiation with concurrent chemotherapy for patients with Siewert′s type II and III adenocarcinoma of esophagogastric junction

Objective To analyze the clinical efficacy, toxicity and survival prognosis of patients diagnosed with Siewert type Ⅱ and Ⅲ locally advanced adenocarcinoma of esophagogastric junction (AEG) undergoing preoperative involved-field irradiation with concurrent chemotherapy. Methods A total of 45 cases were recruited in this prospective clinical trial. Prior to surgery, patients received 2 cycles of chemotherapy with XELOX and concurrent radiotherapy (a total of 45 Gy in 25 fractions, 5 times weekly). After 6-8 weeks, they underwent surgical resection. After the surgery, patients received 6 cycles of adjuvant chemotherapy. The completion of preoperative neoadjuvant chemoradiotherapy, postoperative pathological status, TNM down-staging effect and adverse reactions were observed. Kaplan-Meier method was applied to estimate survival analysis. Results All 45 patients completed preoperative neoadjuvant chemoradiotherapy. Among them, 39 patients completed 2 cycles of chemotherapy, and 6 patients completed 1 cycle of chemotherapy. The median time of surgical interval was 6 weeks. The R0 resection rate was 96%.The pathological complete response (pCR) rate was 22%. The TNM down-staging rate was 69%.The incidence of acute radiation-induced esophagitis or gastritis was 44% and the incidence of radiation-induced pneumonitis was 7%. The incidence of grade 1-3 leukocytopenia, thrombocytopenia and neutropenia was 78%, 47% and 44%, respectively. In terms of gastrointestinal reactions, the incidence of nausea, vomiting and loss of appetite was 62%, 24% and 71%, respectively. No hematologic or nonhematologic adverse effects was observed at grade 4 or 5.The median follow-up time was 30 months. 11 patients died of cancer, 1 patient was treatment-related death in the perioperative period and 1 patient died of pneumonia. The 1-, 2-and 3-year progression-free survival (PFS) rates were 90%, 70% and 67%, respectively. The 1-, 2-and 3-year overall survival rates were 95%, 80% and 75%, respectively. The 1-, 2-and 3-year local control rates were 95%, 84% and 84%, respectively. The 1-, 2-and 3-year distant metastasis rates were 7%, 25% and 25%, respectively. Conclusions Preoperative involved-field irradiation with concurrent chemotherapy yields relatively high clinical efficacy and is well tolerated by patients with Siewert type Ⅱ and Ⅲ locally advanced AEG.Patients are recommended to receive 4 cycles of adjuvant chemotherapy following neoadjuvant chemoradiotherapy and surgery. Key words: Adenocarcinoma of esophagogastric junction/radiotherapy; Adenocarcinoma of esophagogastric junction/chemotherapy; Prognosis; Drug tolerance

Abstract 5360: Mutational profile and genomic instability according to response to therapy in rectal carcinomas

Abstract Rectal cancer (ReCa) patients with locally advanced disease present a high risk of locoregional recurrence and death by the disease. Preoperative neoadjuvant chemoradiotherapy (nCRT) and total mesorectal surgery have been used to reduce these events. However, nCRT has resulted in significant morbidity and up to 30% of patients present pathologic incomplete response (pIR) and ~20% develop distant metastasis or minimal regression to stable disease. These findings reinforce the relevance of identifying predictive markers of response to therapy. Genomic instability (GI) is one of the cancer hallmarks. Patterns of genomic alterations (gains, losses, and cnLOH) and the mutational profile have resulted in prognostic and predictive signatures in several cancer types. Targeted next-generation sequencing (105 cancer-related genes panel, including 13 genes involved in the homologous recombination-HR and, 5 in the mismatch repair-MMR pathways) was performed in 31/33 pretreatment ReCa biopsies. 33 samples were evaluated by SNP array to identify the GI index and the HR deficiency (HRD) scores (LST: large-scale transitions, tAI: telomeric allele imbalance, HRD-LOH: loss of heterozygosity). The GI index represents the fraction of the altered genome and the HRD scores (LST, tAI, HRD-LOH) are reported as markers of deficiency in DNA repair by HR pathway. We found 161 mutations in 51 genes; TP53 (84%), APC (81%) and KRAS (45%) were more frequently mutated. No survival differences were observed among the subgroups studied according to the presence of two APC mutations, KRAS, and TP53 mutations or lacking APC mutations. Overall, a high burden of genomic alterations was observed in ReCa samples. The median GI index was 0.358, much higher than those observed in breast cancer. Patients with complete pathologic response (pCR) presented higher GI index (0.475) compared to pIR (0.294). A significant difference was observed grouping responders (TRG 0+1) and nonresponders (TRG 2+3) (p = 0.043). The GI index of chromosome 12 was higher in pCR (p=0.019). Deficient mismatch repair indicates ineffectiveness of 5-FU used in the nCRT. Three tumors presented mutations in MLH3 or MSH6. An additional analysis performed in HR pathway genes revealed that 7/31 cases presented mutations. Three of these seven ReCa showed high tAI scores, indicating sensitivity to platinum-based therapy. HR-defective tumors have been associated with better platinum response rates. In addition, five cases presented PTEN loss; five, PIK3CA mutations; and one case, BRAF mutation. These alterations have been reported as promising predictors for treatment response in colorectal cancer. The involvement of HR pathway or other driver mutations in the response to therapy in rectal cancers remains unclear. Comprehensive studies in a large set of cases are required to confirm the predictive value of these alterations in rectal cancer. Citation Format: Luisa Matos do Canto, Simon J. Larsen, Bruna E. Catin Kupper, Maria D. Ferreira de Souza Begnami, Cristovam Scapulatempo Neto, Jan Baumbach, Annabeth Høgh Petersen, Mads Malik Aagaard Jørgensen, Samuel Aguiar, Silvia R. Rogatto. Mutational profile and genomic instability according to response to therapy in rectal carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5360.

Loop ostomy following laparoscopic low anterior resection for rectal cancer after neoadjuvant chemoradiotherapy

BackgroundBoth loop ileostomy (LI) and loop transverse colostomy (LTC) could achieve absolute fecal diversion and have several advantages. This study compared LI and LTC following laparoscopic low anterior resection for rectal cancer after neoadjuvant chemoradiotherapy.MethodsBetween January 2009 and December 2016, 186 patients who underwent laparoscopic low anterior resection for rectal cancer and loop ostomy were included. All patients received preoperative neoadjuvant chemoradiotherapy. Of these, 77 underwent LI and 109 underwent LTC. Demographic characteristics, operative details, and complications were analyzed.ResultsIn the fecal diversion period, the LTC group showed significantly less dermatitis (p = 0.001) and electrolyte disturbance (p = 0.002), while LI group showed significantly shorter time to first defecation (p = 0.006) and lower incidence of parastomal hernia (p = 0.014). In the stoma closure period, a significantly higher incidence of wound infection was found in LTC group (p = 0.001).ConclusionsBoth LI and LTC have advantages and disadvantages. For its lower wound infection rate, lower incidence of parastomal hernia, and shorter time to first defecation, LI is recommended for all patients except those with potential electrolyte disturbance and sensitive skin.

Prognostic significance of miR-21 and PDCD4 in patients with stage II esophageal carcinoma after surgical resection.

Many studies have shown that randomized clinical trial with long-term follow-up found no improvement in stage II esophageal carcinoma (EC) patients receiving preoperative neoadjuvant chemoradiotherapy or chemotherapy treatment, this limitation underscored the urgent need for novel and reliable biomarkers for prognosis and prediction in stage II EC. miR-21 is frequently over-expressed while programmed cell death 4 (PDCD4) is often down-regulated in solid tumors. This study aimed to investigate the clinicopathological and prognostic significance of miR-21 and PDCD4 expression and to elucidate any correlation between miR-21 and PDCD4 expression in stage II EC patients. The expression level of miR-21 was up-regulated while the PDCD4 protein was down-regulated in stage II EC tissues compared with the adjacent non-cancerous tissues. Analyses of the clinicopathological parameters indicated that miR-21 expression was associated with differentiation grade, T stage, and N stage. PDCD4 protein expression was associated with T stage, N stage, and tumor size. The univariate linear regression analysis suggested a significant negative correlation between miR-21 and PDCD4 expression. The Kaplan-Meier curve showed that high miR-21 expression or low PDCD4 expression predicted poor progression-free survival (PFS) and overall survival (OS) of patients with stag II EC. In conclusion, both up-regulated miR-21 and down-regulated PDCD4 expression were associated with the aggressive progression and poor prognosis of stage II EC. miR-21 and PDCD4 might be potential biomarkers of tumor progression and indicators of prognosis of stag II EC.

Predictive role of REG IV and YKL-40 in locally advanced rectal cancer patients receiving neoadjuvant chemoradiotherapy

Abstract Objective: Patients with locally advanced rectal cancer (LARC) need extensive surgical interference. Preoperative neoadjuvant chemoradiotherapy (CRT) shifts this extensive surgical procedure to another sphincter saving one as well as lowers patient's morbidity and mortality. Till now, there is no definite method to predict patients' response to neoadjuvant CRT. Methods: REG IV and YKL-40 immunohistochemistry was evaluated in pre-treatment endoscopic biopsies from 42 LARC cases who received neoadjuvant CRT followed by surgical interference. The findings were correlated with the clinico-pathological features, tumor response and tumor regression grade of the post-operative specimens. Results: REG IV high expression was associated with advanced post-treatment pathological tumor status, post -treatment pathological nodal status and presence of lympho-vascular invasion with statistical significance. Furthermore, it was correlated with a lower extent of tumor regression after neoadjuvant CRT. All patients with pCR exhibited negative/low REG IV expression and only 13.6% of the responders showed high REG IV expression with statistical significance. YKL-40 immunohistochemical expression was highly associated with the tumor regression rate where 85% of LARC patients with poor neoadjuvant CRT response highly expressed YKL-40 and 66.6% of patients with complete regression showed negative\low expression of YKL-40. Conclusion: Our findings implicate REG IV and YKL-40 as important predictors of neoadjuvant CRT response in locally advanced rectal cancer.

Predictive factors for pathologic complete response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Objective To evaluate the predictive factors associated with pathological complete response (pCR) after preoperative neoadjuvant chemoradiotherapy for rectal cancer. Methods A retrospective analysis was performed on the clinical data of 84 patients with rectal cancer, who underwent neoadjuvant chemoradiotherapy followed by radical surgery from January 2010 to December 2016. Univariate analysis and multivariate Logistic regression analysis were performed to analyze associated factors of pCR. Results In 84 patients, 18 (21.4%) achieved pCR after neoadjuvant chemoradiotherapy. The univariate analysis showed that circumferential extent of the tumor (≤1/2 cycle) (P=0.008), pre-chemoradiotherapy serum carcino embryonie antigen (CEA) level (≤5 μg/L) (P=0.001), pre-chemoradiotherapy T stage (cT1-3) (P=0.001), pre-chemoradiotherapy N stage (N0) (P=0.049), distance between tumor and the anal verge (≤5 cm) (P=0.023) were associated with pCR or non-pCR after neoadjuvant chemoradiotherapy for rectal cancer. The multivariate Logistic analysis revealed that circumferential extent of the tumor (≤1/2 cycle) (P=0.041), pre-chemoradiotherapy serum CEA level (P=0.012), and T stage (P=0.003) were predictive factors for pCR or non-pCR after neoadjuvant chemoradiotherapy for rectal cancer. Conclusion Patients with circumferential extent of the tumor (≤1/2 cycle), low CEA level, and early T stage before treatment are more likely to achieve pCR after neoadjuvant chemoradiotherapy for rectal cancer. Key words: Rectal cancer; Neoadjuvant chemoradiotherapy; Pathological features

Mid-term outcomes of a prospective phase II trial of preoperative sandwich-like neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Objective To evaluate the mid-to long-term survival benefits of preoperative sandwich-like neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Methods A total of 45 LARC patients who underwent neoadjuvant sandwich CRT in the form of XELOX regimen prior to, concurrently with, and following volumetric modulated arc radiotherapy (VMAT) in 2012 were enrolled in this study. VMAT was given at a gross tumor volume dose of 50 Gy in 25 fractions, and a clinical target volume dose of 45-46 Gy in 25 fractions. Total mesorectal excision was performed 6 to 8 weeks after completion of VMAT.The overall survival (OS) and disease-free survival (DFS) were determined by the Kaplan-Meier method, and survival comparison and univariate prognostic analysis were performed using the log-rank test. Results The median follow-up time was 46.7 months. There was no local recurrence detected among the patients. The 3-year distant metastasis (DM) rate was 18%, and the 3-year OS and DFS were 96% and 84%, respectively. Univariate analysis indicated that perineural invasion, N1-N2 pathology (pathological stage Ⅲ), and Ca-199>35 U/ml before treatment were risk factors for DM (P=0.000, 0.000, and 0.013, respectively). Conclusions The significant short-term efficacy of preoperative sandwich-like neoadjuvant CRT can be extended to a positive mid-term survival in LARC patients. However, further phase Ⅲ clinical studies will be needed to confirm this finding. Key words: Rectal neoplasms/chemoradiotherapy; Chemoradiotherapy, neoadjuvant; Prognosis

Immunoscore in mismatch repair-proficient and -deficient colon cancer.

The aim of this study was to investigate immune response and its prognostic significance in colon carcinomas using the previously described Immunoscore (IS). A population‐based series of 779 colorectal cancers, operated on between 2000 and 2010, were classified according to tumour, node, metastasis (TNM) status, mismatch repair (MMR), and BRAF mutation status. Rectal cancer cases (n = 203) were excluded as a high proportion of these patients received preoperative neoadjuvant chemoradiotherapy. Tissue microarray (TMA) samples collected from the tumour centre and invasive front were immunostained for CD3 and CD8. Lymphocytes were then digitally calculated to categorize IS from grade 0 to 4. Samples adequate for IS were available from 510 tumours. IS was significantly associated with AJCC/UICC stage, T stage, lymph node and distant metastases, perineural and lymphovascular invasion, MMR status, and BRAF mutation status. For IS0, IS1, IS2, IS3 and IS4, respectively, the 5‐year disease‐free survival (DFS) rates were 59, 68, 78, 83 and 94% (p < 0.001); 5‐year disease‐specific survival (DSS) rates were 47, 55, 75, 80, and 89% (p < 0.001); and 5‐year overall survival (OS) rates were 40, 44, 66, 61, and 76% (p < 0.001). IS was also prognostic for DFS, DSS, and OS within subsets of microsatellite‐stable (MSS) and microsatellite‐instable (MSI) disease. Multivariable analysis showed that IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS. Age was an independent prognostic factor for DSS and OS. Gender and BRAF mutation were independent prognostic factors for OS. In conclusion, IS differentiated patients with poor versus improved prognosis in MSS and MSI disease and across AJCC/UICC stages. IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS.

Accuracy of MRI in Rectal Cancer After Preoperative Neoadjuvant Chemoradiotherapy

Background: About 1/4 colorectal cancers are related to the rectum. There 40.000 patients with the mean age of 50 years diagnosed with rectal cancer in USA. The symptoms are in a wide spectrum such as rectal bleeding, changing of defecation habits, pain, incontinenecy in the case of esphincter invasion. The diagnosis depends on getting a detailed history and a physical examination. For years the main treatment of rectal cancer was abdominoperineal resection with permanent clostomy. Todays treatment plan includes less invasive surgical techniques combined with neoadjuvant chemoradiotherapy which results in less recurrent rates. MRI is a reliable modality in staging primary tumors but there has been conflicts about its accuracy for restaging after neoadjuvant chemoradiotherapy. In this study, accuracy, sensitivity and specifity of MRI will be discussed. Methods: Study on 34 patients diagnosed with rectal adenocarcinoma referred to oncology clinic was conducted. The treatment plan included 4050 cGY radiotherapy and 5FU, Xeloda chemotherapy. All patients were assessed with 1/5 T MRI 6 to 8 weeks after treatment. T1 and T2 images with sagittal, cronal and axial planes with and without contrast agent were obtained and interpreted by two radiologists and compared with pathologic specimens as a gold standard. Results: The demographic information was: mean age of 65/26 years, 19 men (55/9%), 15 women (44/1%). Accuracy of MRI at T and N staging were 38/2 % and 61/8% with the highest sensitivity of T3NM0 and specifity of T1N2. Conclusions: MRI can be used for assessing rectal tumors and restaging after preoperative chemoradiotherapy.

Identification of protein clusters predictive of tumor response in rectal cancer patients receiving neoadjuvant chemo-radiotherapy.

Preoperative neoadjuvant chemoradiotherapy (nCRT) is the gold standard in locally advanced rectal cancer, only 10–30% of patients achieving benefits. Currently, there is a need of a reliable selection of markers for the identification of poor or non-responders prior to therapy. In this work, we compared protein profiles before therapy of patients differing in their responses to nCRT to find novel predictive markers of response to therapy. Patients were grouped into 3 groups according to their tumor regression grading (TRG) after surgery: 'TRG 1–2′, good responders, 'TRG 3′ and 'TRG 4′, poor responders. Paired surgical specimens of rectal cancer and healthy (histologically confirmed) rectal tissues from 15 patients were analysed before nCRT by two dimensional difference in gel electrophoresis followed by mass spectrometry. Thirty spots were found as differentially expressed (p < 0.05). Among them, 3 spots (spots 471, 683 and 684) showed an increased amount of protein in poor responders compared with good responders, and they were more tumor associated compared with healthy tissues. Proteins of these spots were identified as fibrinogen ß chain fragment D, actin isoforms, B9 and B5 serpins, cathepsin D isoforms and peroxiredoxin-4. In an independent validation set of 20 rectal carcinomas we validated the increased fibrinogen ß chain abundance before nCRT in poor responders by immunoblotting. In conclusion, we propose a risk-stratification tool in predicting the response to nCRT treatment in rectal cancer based on the quantity of these proteins.

Risk factors for perineal wound infection after abdominoperineal resection of advanced lower rectal cancer.

PurposeAbdominoperineal resection (APR) of advanced lower rectal cancer carries a high incidence of perineal wound infection. The aim of this study was to retrospectively evaluate risk factors for perineal wound infection after APR.MethodsThe study group comprised 154 patients who underwent APR for advanced lower rectal cancer in our department from January 1990 through December 2012. The following 15 variables were studied as potential risk factors for perineal wound infection: sex, age, body-mass index, American Society of Anesthesiologists score, diabetes mellitus, preoperative albumin level, preoperative hemoglobin level, neoadjuvant chemoradiotherapy(NCRT), surgical procedure (open surgery vs. laparoscopic surgery), operation time, bleeding volume, intraoperative transfusion, tumor diameter, invasion depth, and histopathological stage.ResultsAmong the 154 patients, 30 (19%) had perineal wound infection. Univariate analysis showed that a hemoglobin level of ≤11 g/dL (p = 0.001) and NCRT (p = 0.001) were significantly related to perineal wound infection. On multivariate analysis including the preoperative albumin level (≤3.5 g/dL) in addition to the above 2 variables, neoadjuvant chemoradiotherapy (NCRT) was the only independent risk factor for perineal wound infection. Perineal wound infection developed in 31% of patients who received NCRT, as compared with 10% of patients who did not receive NCRT. The relative risk of perineal infection in the former group was 4.092 as compared with the latter group (p = 0.0002).ConclusionsNCRT is a risk factor for perineal wound infection after APR in patients with advanced lower rectal cancer.

Adjuvant Second-Dose Chemotherapy before Surgery for Patients with Locally Advanced Rectal Malignancy Is Not Beneficial: A Systematic Review and Meta-Analysis.

Background Preoperative chemoradiotherapy is the standard treatment for patients with locally advanced rectal cancer, although tumor responses vary widely; some patients may achieve a pathologic complete response rate (pCR) after chemoradiotherapy. Controversy exists with regard to the efficacy of different preoperative combination chemotherapy regimens and neoadjuvant chemoradiotherapy, compared with chemoradiotherapy alone. Methods PubMed, the Cochrane Library, and Embase databases were searched for comparative studies of patients with locally advanced rectal cancer that were published between January 1991 and January 2016. Efficacies of different preoperative combination chemotherapy regimens and neoadjuvant chemoradiotherapy (group A) were compared with chemoradiotherapy alone (group B) in a meta-analysis using Review Manager v5.2. Results Three prospective randomized controlled trials and two prospective nonrandomized controlled trials comprising 444 cases were eligible for analysis. No significant difference was detected in the rate of pCR (50/223, 22.4% versus 35/223, 15.7%; relative risk, RR: 1.42 [95% confidence interval, CI: 0.97–2.09], p = 0.07) between the two groups. The rate of tumor regression was similar for both groups (122/203, 60.1% versus 111/203, 54.7%; RR: 1.11 [95% CI: 0.94–1.29], p = 0.22). Conclusions Adjuvant chemotherapy with preoperative chemoradiotherapy did not significantly improve the rate of pCR nor the rate of T and N downstaging.

Abstract A135: Novel immunotherapy for intractable pancreatic cancer focusing on the myeloid derived suppressor cells in the tumor microenvironment

Abstract Pancreatic cancer is one of malignant diseases with poor prognosis. Despite the recent progress for preoperative neoadjuvant chemoradiotherapy, the long term prognosis is still poor to make forward new treatment strategy. We have recently reported novel mechanism of anticancer reagents to impact patients' prognosis improving tumor microenvironment other than its direct cytotoxic effects (Ann Surg Oncol 2013, Cancer Sci 2014). The underlying mechanism include inhibition of HLA class I down regulation and Treg infiltration, increase of CD4 and CD8 T cell infiltration (Int J Clin Oncol 2015, Cancer Res 2015). Here we report that GM-CSF production was significantly enhanced in various PDAC cell lines after treatment with chemotherapy including gemcitabine or 5-FU, which induced the differentiation of CD14 positive monocytes into myeloid-derived suppressor cells (MDSC). This differentiation was promoted through MAPK signal pathway or NFkB pathway. Furthermore, blockade of GM-CSF with monoclonal antibodies helped to restore T-cell proliferation when co-cultured with monocytes stimulated with tumor supernatants. GM-CSF expression was also observed in primary tumors and correlated with poor prognosis in 68 PDAC patients analyzed by immunohistochemistry. We expect that postoperative prognosis of pancreatic cancer would be more improved by multidisciplinary strategy targeting MDSC and GM-CSF followed by curative surgical intervention. Citation Format: Takahiro Tsuchikawa, Shintaro Takeuchi, Toru Nakamura, Mizuna Takahashi, kazuho Inoko, Toshihiro Kushibiki, Koji Hontani, Masato Ono, Shota Kuwabara, Toshiaki Shichinohe, Satoshi Hirano. Novel immunotherapy for intractable pancreatic cancer focusing on the myeloid derived suppressor cells in the tumor microenvironment [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A135.

A prognostic analysis of patients with pathologic complete response after preoperative neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Objective To analyze the clinical factors for pathologic complete response (pCR) after preoperative neoadjuvant chemoradiotherapy (neo-CRT) for locally advanced rectal cancer. Methods From 2005 to 2012, 297 patients with locally advanced rectal cancer and complete clinical data were enrolled as subjects. Those patients were diagnosed with biopsy and treated with neo-CRT (radiotherapy by 3-dimonsional conformal radiotherapy or volumetric-modulated arc therapy) followed by radical surgery. The logistic regression model was used for the multivariate analyses of the correlation of pCR with age, gender, distance between tumor and the anal verge, serum level of carcinoembryonic antigen (CEA) before treatment, hemoglobin level before treatment, cT staging, and cN staging. Results In all patients, 78(26.7%) patients had pCR after treatment. The numbers of patients with pCR were 42(34.4%) in patients with stage T1-T3 disease and 37(21.1%) in patients with stage T4 disease. In the patients with serum CEA levels no higher than 5.33 ng/ml, 55(36.4%) had pCR after treatment, while in the patients with serum CEA levels higher than 5.33 ng/ml, only 24(16.4%) had pCR. The univariate analysis revealed that age, gender, distance between tumor and the anal verge, anemia before treatment, or cN staging were not related to pCR. The multivariate analysis showed that stage cT1-T3 and a serum CEA level no higher than 5.33 ng/ml before treatment were influencing factors for pCR after neo-CRT for locally advanced rectal cancer (P=0.031, P=0.000). Conclusions The clinical staging and the serum CEA level before treatment are influencing factors for pCR after neo-CRT for locally advanced rectal cancer. The serum CEA level before treatment can be considered as a predictor of pCR after neo-CRT for locally advanced rectal cancer. Key words: Rectum neoplasms/neoadjuvant chemoradiotherapy; TN staging; Pathologic complete response

IMRT-based preoperative neoadjuvant chemoradiotherapy for thoracic esophageal squamous cell carcinoma (ESCC): an analysis of outcome and prognosis

To analyze the outcome and prognostic factors of IMRT-based preoperative neoadjuvant chemoradiotherapy in patients with thoracic esophageal squamous cell carcinoma (ESCC). Clinical data of 62 patients with thoracic ESCC who received IMRT-based neoajuvant chemoradiotherapy from January 2009 to January 2015 were retrospectively analyzed. The radiation therapy was given 1.8-2 Gy/fraction per day over 5 days per week with 6 MV X-rays, and then all patients underwent esophagectomy and lymphadenectomy. Among the 62 patients, the R0 resection rate was 96.8%. Twenty (32.3%) patients achieved pCR and 56 (90.3%) cases got down-staging. Grade Ⅲ marrow suppression and esophagitis were seen in 8 (12.9%) and 2 (3.2%) patients, respectively. Eleven (17.7%) patients experienced postoperative complications and three died. The median follow-up was 27 months. The 1-, 3- and 5-year overall survival rates were 88.0%, 63.3% and 44.2%, respectively, with a corresponding disease-free survival rate of 68.1%, 54.8%, and 43.9%, respectively.The univariate analysis showed that pre-treatment stage Ⅱ, down-staging, T/N pCR, good tumor response to neoadjuvant chemoradiotherapy, pN0 and R0 resection were favorable prognostic factors (P<0.05). The multivariate analyses indicated that pre-treatment stage was an independent prognostic factor. For patients with thoracic ESCC, IMRT-based neoadjuvant chemoradiotherapy followed by surgery can achieve a higher R0 resection rate, down-staging rate, higher pCR rate, and a better tolerance. The incidence of postoperative complications is low. Pre-treatment stage, down-staging, pathological tumor response, lymph node status and R0 resection results are prognostic factors, and the pre-treatment stage is an independent prognostic factor.

Clinical study on locally advanced rectal cancer patients with pathological complete response after neoadjuvant chemoradiotherapy

To explore the efficacy prediction of the locally advanced rectal cancer patients, especially those with pathological complete response(pCR), receiving neoadjuvant chemoradiotherapy in order to execute precise preoperative neoadjuvant chemoradiotherapy. From January 2000 to January 2011, 125 patients diagnosed as locally advanced rectal cancer receiving preoperative neoadjuvant chemoradiotherapy in our department with complete data were enrolled in this study, including 85 males and 40 females with mean age of 54(15 to 77) years old. All the patients received radiotherapy with 46 Gy(23 times) and administered XELOX regimen (oxaliplatin 100 mg/m(2) plus capecitabine 2 000 mg/m(2)) for 2 courses simultaneously, and underwent radical operation 6 to 8 weeks after chemoradiotherapy. The data of these patients were analyzed retrospectively. Pathological remission was divided into 4 grades. Patients achieving grade 4 were defined as pCR, and those achieving above grade 2 were defined as better response. Logistic regression analysis was used to identify significant predictors of pCR. Among 125 patients, 16(12.8%) achieved pCR status, and 90(72.0%) had better response to the neoadjuvant chemoradiotherapy. Logistic regression analysis showed that age(OR:1.060, P=0.037) and preoperative positive lymph nodes detected by endorectal ultrasonography (OR:0.059, P=0.006) were independent predictors of pCR after neoadjuvant chemoradiotherapy. Preoperative existence of lymph node metastasis around bowel indicates the poor response to neoadjuvant chemoradiotherapy. Age is associated with pCR in patients receiving neoadjuvant chemoradiotherapy.