Immune Score Predicts Outcomes of Gastric Cancer Patients Treated with Adjuvant Chemoradiotherapy.

BACKGROUND: Substantial evidence has demonstrated that tumor-infiltrating lymphocytes (TILs) are correlated with patient prognosis. The TIL-based immune score (IS) affects prognosis in various cancers, but its prognostic impact in gastric cancer (GC) patients treated with adjuvant chemoradiotherapy remains unclear. METHODS: A total of 101 GC patients who received chemoradiotherapy after gastrectomy were retrospectively analyzed in this study. Immunohistochemistry staining for CD3+ and CD8+ T-cell counts in both tumor center (CT) and invasive margin (IM) regions was built into the IS. Patients were then divided into three groups based on their differential IS levels. The correlation between IS and clinical parameters was analyzed. The prognostic impact of IS and clinical parameters was evaluated using Kaplan-Meier analysis and Cox proportional hazard regression analysis. Receiver operating characteristic (ROC) curves were plotted to compare the area under the curve (AUC) of IS with other clinical parameters. Nomograms for disease-free survival (DFS) and overall survival (OS) prediction were constructed based on the identified parameters. RESULTS: Finally, 20 (19.8%), 57 (56.4%), and 24 (23.8%) GC patients were identified with low, intermediate, and high IS levels, respectively. GC patients with higher IS levels exhibited better DFS (p < 0.001) and OS (p < 0.001). IS was an independent prognostic factor for both DFS (p < 0.001) and OS (p < 0.001) in multivariate analysis. IS presented a better predictive ability than the traditional pathological tumor-node-metastasis (pTNM) staging system (AUC: 0.801 vs. 0.677 and 0.800 vs. 0.660, respectively) with respect to both DFS and OS. The C-index of the nomograms for DFS and OS prediction was 0.737 and 0.774, respectively. CONCLUSIONS: IS is a strong predictive factor for both DFS and OS in GC patients treated with adjuvant chemoradiotherapy, which may complement the traditional pTNM staging system.

Adjuvant chemoradiotherapy versus adjuvant chemotherapy for patients with N3 gastric cancer after D2/R0 resection: a retrospective study based on propensity score analyses.

Purpose: N3 gastric cancer (GC) is characterized by a heavy burden of lymph node metastasis and a high postoperative recurrence rate. The role of radiotherapy in this group of patients remains undetermined. The purpose of this study was to compare the effectiveness of adjuvant chemoradiotherapy (CRT) and adjuvant chemotherapy (ChT) for N3 GC after D2/R0 resection. Patients and methods: From January 2004 to December 2015, patients with N3 GC in the database of Fudan University Shanghai Cancer Center were retrospectively reviewed. The eligible patients were enrolled in an adjuvant CRT group and an adjuvant ChT group. Four different methods based on a propensity score model were used to balance the baseline characteristics. Then, survival analyses between the two groups were performed in addition to patterns of recurrence and subgroup analyses. Results: In total, 175 and 365 eligible patients were enrolled into the CRT and ChT groups, respectively. After balancing, the disease-free survival (DFS) of patients in the CRT group was significantly better than that of patients in the ChT group (p=0.021). Subgroup analyses showed that patients with N3a GC benefitted from adjuvant CRT. Conclusion: Compared with adjuvant ChT, adjuvant CRT can further improve the DFS of patients with N3 GC after D2/R0 resection. Patients with lymph node metastases should be further stratified when selecting patients for adjuvant CRT.

Aneuploidy of chromosome 8 and mutation of circulating tumor cells predict pathologic complete response in the treatment of locally advanced rectal cancer.

Identifying patients who may or may not achieve pathologic complete response (pathCR) allows for treatment with alternative approaches in the preoperative setting. The aim of the current study was to investigate whether aneuploidy of chromosome 8 and mutations of circulating tumor cells (CTCs) could predict the response of patients with rectal cancer to preoperative chemoradiotherapy. A total of 33 patients with locally advanced rectal cancer (cT3-T4 and/or cN+) treated with neoadjuvant chemoradiotherapy between September 2014 and March 2015 were recruited. Blood samples were collected from 33 patients with pre-chemoradiotherapy rectal cancer. It was demonstrated that ≥5 copies of chromosome 8 was associated with pathCR (univariate logistic regression, P=0.042). Of the 6 patients whose CTCs had <5 copies of chromosome 8, 3 achieved pathCR (3/6, 50%), and of the 27 patients whose CTCs had ≥5 copies of chromosome 8 obtained 3 pathCR (3/27, 11.1%; Chi-square test, P=0.0255). Of the 33 patients with mutations assessed, 8 significant nonsynonymous mutations in CTCs were identified as associated with pathCR (Chi-square test, P-values range, 0.0004-0.0298; mutations in ARID1A, HDAC1, APC, ERBB3, TP53, AMER1 and AR). These results suggest that ≥5 copies of chromosome 8 and 8 nonsynonymous mutations in ARID1A, HDAC1, APC, ERBB3, TP53, AMER1 AR in CTCs were associated with pathCR. This conclusion should be validated further in larger prospective studies and the long-term follow-up survival data of this study will also be reported in the future.

Survival outcomes and patterns of failure after D2 dissection and adjuvant chemoradiotherapy for locally advanced gastric cancer: a retrospective study.

OBJECTIVE:   The goal of the study was to analyze the incidence and patterns of failure in patients with gastric cancer who received D2 dissection and adjuvant chemoradiotherapy (CRT). METHODS:   From January 2004 to October 2015, 324 patients with gastric cancer who underwent radical D2 resection followed by postoperative CRT were enrolled. Clinicopathological characteristics and patterns of failure were retrospectively reviewed to identify factors associated with survival and recurrence. RESULTS:   After a median follow-up of 30 months, the 3-year overall survival and 3-year disease-free survival rates of these patients were 60.3 and 51.1%, respectively. 117 patients had recurrence or metastasis, with peritoneal recurrence as the most frequent (20.7%), followed by distant metastasis (14.2%). The most commonly involved distant organs were the liver (5.9%) and bone (4.9%). Locoregional failure occurred in 39 patients (12.0%), with isolated regional failure occurring in only 23 (7.1%). Further multivariate Cox regression analysis revealed N stage to be an independent risk factor for distant failure-free survival (p = 0.012). Independent risk factors for peritoneal metastasis were tumor differentiation (p = 0.022), T stage (p =0.035) and vascular invasion (p = 0.016). CONCLUSION: Postoperative CRT has a potential effect on optimizing locoregional control, resulting in only 12.0% of locoregional failure. In patients after D2 resection and adjuvant CRT, peritoneal metastasis was the leading pattern of failure, followed by distant metastasis. Advances in knowledge: Peritoneal recurrence was the most common pattern of failure after D2 dissection and adjuvant CRT, followed by distant metastasis, whereas locoregional relapse was relatively rare. Selection of patients based on the predicted risk of each recurrence pattern may be a reasonable approach to the optimization of treatment strategies.

Adjuvant chemoradiotherapy versus adjuvant chemotherapy for R1 resected gastric cancer: a retrospective cohort study.

OBJECTIVE: The aim of this study was to compare the effects of adjuvant chemoradiotherapy (CRT) and adjuvant chemotherapy (ChT) on the survival of locally advanced gastric cancer (LAGC) patients treated with R1 resection. METHODS: The patients with LAGC and microscopically positive margins after a potentially curative gastrectomy in Fudan University Shanghai Cancer Centre were retrospectively identified. The patients who were referred to our hospital for adjuvant CRT after an R1 resection elsewhere were also included. The patients were divided into either the CRT group or ChT group according to the treatment strategy. We, then, examined the patient survival results and patterns of recurrence for each group. RESULTS: There were 114 LAGC patients treated with an R1 resection identified (CRT, n = 33; ChT, n = 81). The baseline characteristics between the two groups were not different. The estimated 3 year recurrence-free survival and overall survival in the CRT and ChT groups were 45.1% vs 31.8% (p = 0.09) and 49.6% vs 39.4% (p = 0.20), respectively. The results indicated that only nodal status was an independent prognostic factor (hazard ratio 4.04, 95% confidence interval 2.06-7.93). The risk of locoregional recurrence was increased in the ChT group. The subgroup analysis revealed that patients with pN0-2 GC showed a better recurrence-free survival due to adjuvant CRT (hazard ratio 0.19, 95% confidence interval 0.04-0.90; p = 0.022). CONCLUSION: Adjuvant CRT improves locoregional control and may benefit patients with pN0-2 GC after R1 resection. The nodal status may be the most important predictor for patient selection. Advances in knowledge: Nodal status may be the most important predictor for patient selection. Compared with adjuvant ChT, LAGC patients with pN0-2 disease may further benefit from additional radiotherapy after R1 resection.

Adjuvant chemotherapy for patients with ypT0-2N0-category after neoadjuvant chemoradiotherapy for rectal cancer.

Locally advanced rectal cancer patients with ypT0-2N0 have good prognosis and may not require as many cycles of adjuvant chemotherapy as patients with a poor (ypT3-4 or N+) response. The aim of the present study was to evaluate the three-year disease-free and overall survival between patients with ypT0-2N0 rectal adenocarcinoma who received 0-3 cycles of 5-fluorouracil-based adjuvant chemotherapy and those who received >3 cycles. A total of 106 patients with locally advanced rectal cancer, classified as ypT0-2N0 after surgery at the Fudan University Shanghai Cancer Center (Shanghai, China) between 2006 and 2012, were identified. The patients were divided into two groups depending on the number of cycles of adjuvant chemotherapy: Group 1 received 0-3 cycles (n=32) and group 2 received ≥4 cycles of adjuvant chemotherapy (n=74). The three-year disease-free survival and overall survival rates were 86.8 and 93.1% for group 1 (P=0.633), and 88.5 and 96.8% for group 2 (P=0.381). No statistically significant difference was observed between the two groups, suggesting that patients with ypT0-2N0 status may not require more than three cycles of post-operative chemotherapy. Further evaluation in prospective studies is urgently recommended.

Validation of the Memorial Sloan Kettering Cancer Center nomogram to predict disease-specific survival in a Chinese gastric cancer population receiving postoperative chemoradiotherapy after an R0 resection.

The widely validated Memorial Sloan Kettering Cancer Center (MSKCC) nomogram for gastric carcinoma (GC) was developed based on patients who received R0 resection only. The purpose of the current study was to assess the performance of this nomogram in Chinese patients who received postoperative chemoradiotherapy (CRT) after an R0 resection for GC. From 2006 to 2015, the clinical data of 150 eligible patients were retrospectively collected from the Fudan University Shanghai Cancer Center (FUSCC) and used for external validation. The nomogram was validated by means of the concordance index (CI) and a calibration plot. The CI for the nomogram was 0.657, which was lower than the CI of the nomogram for patients who received surgery alone (0.80). In the calibration plot, the gap between the observed and the predicted survival gradually increased as the predicted 5-year disease-specific survival (DSS) decreased. Thus the MSKCC nomogram for GC significantly underestimated the survival of patients in the FUSCC cohort, especially the survival of patients whose predicted 5-year DSS was less than 50%. The current study indicates the potential for the nomogram to be developed as an ideal tool to identify target patients for postoperative CRT.

Postoperative chemoradiotherapy versus chemotherapy for R0 resected gastric cancer with D2 lymph node dissection: an up-to-date meta-analysis.

BACKGROUND: This meta-analysis aims to provide more evidence on the role of postoperative chemoradiotherapy (CRT) for gastric cancer (GC) patients in Asian countries where D2 lymphadenectomy is prevalent. METHODS: We conducted a systematic review of randomized controlled trials (RCTs), extracted data of survival and toxicities, and pooled data to evaluate the efficacy and toxicities of CRT compared with chemotherapy (CT) after D2 lymphadenectomy. RESULTS: A total of 960 patients from four RCTs were selected. The results showed that postoperative CRT significantly reduced loco-regional recurrence rate (LRRR: RR = 0.50, 95 % CI = 0.34-0.74, P = 0.0005) and improved disease-free survival (DFS: HR = 0.73, 95 % CI = 0.60-0.89, P = 0.002). However, CRT did not affect distant metastasis rate (DMR: RR = 0.81, 95 % CI = 0.60-1.08, P = 0.15) and overall survival (OS: HR = 0.91, 95 % CI = 0.74-1.11, P = 0.34). The main grade 3-4 toxicities manifested no significant differences between the two groups. CONCLUSIONS: Overall, CRT after D2 lymphadenectomy may reduce LRRR and prolong DFS. The role of postoperative CRT should be further investigated in the population with high risk of loco-regional recurrence.

Sex, Race, and Age Disparities in the Improvement of Survival for Gastrointestinal Cancer over Time.

There have been notable improvements in survival over the past 2 decades for gastrointestinal (GI) cancer. However, the degree of improvement by age, race, and sex remains unclear. We analyzed data from 9 population-based cancer registries included in the SEER program of the National Cancer Institute (SEER 9) in 1990 to 2009 (n = 288,337). The degree of survival improvement over time by age, race, and sex was longitudinally measured. From 1990 to 2009, improvements in survival were greater for younger age groups. For patients aged 20 to 49 years and diagnosed from 2005 to 2009, adjusted HRs (95% CIs) were 0.74 (95% CI, 0.66-0.83), 0.49 (95% CI, 0.37-0.64), 0.69 (95% CI, 0.65-0.76), 0.62 (95% CI, 0.54-0.69), and 0.56 (95% CI, 0.42-0.76), for cancer of the stomach, small intestine, colon, rectum and anus, respectively, compared with the same age groups of patients diagnosed during 1990 to 1994. Compared with African Americans, whites experienced greater improvement in small intestinal and anal cancer survival. Female anal cancer and regional anal cancer patients experienced no improvement. Our data suggest that different improvement in survival in age, sex and race exists.

Variations in CT determination of target volume with active breath co-ordinate in radiotherapy for post-operative gastric cancer.

OBJECTIVE: To investigate interobserver and inter-CT variations in using the active breath co-ordinate technique in the determination of clinical tumour volume (CTV) and normal organs in post-operative gastric cancer radiotherapy. METHODS: Ten gastric cancer patients were enrolled in our study, and four radiation oncologists independently determined the CTVs and organs at risk based on the CT simulation data. To determine interobserver and inter-CT variation, we evaluated the maximum dimensions, derived volume and distance between the centres of mass (CMs) of the CTVs. We assessed the reliability in CTV determination among the observers by conformity index (CI). RESULTS: The average volumes ± standard deviation (cm(3)) of the CTV, liver, left kidney and right kidney were 674 ± 138 (range, 332-969), 1000 ± 138 (range, 714-1320), 149 ± 13 (range, 104-183) and 141 ± 21 (range, 110-186) cm(3), respectively. The average inter-CT distances between the CMs of the CTV, liver, left kidney and right kidney were 0.40, 0.56, 0.65 and 0.6 cm, respectively; the interobserver values were 0.98, 0.53, 0.16 and 0.15 cm, respectively. CONCLUSIONS: In the volume size of CTV for post-operative gastric cancer, there were significant variations among multiple observers, whereas there was no variation between different CTs. The slices in which variations more likely occur were the slices of the lower verge of the hilum of the spleen and porta hepatis, then the paraoesophageal lymph nodes region and abdominal aorta, and the inferior vena cava, and the variation in the craniocaudal orientation from the interobserver was more predominant than that from inter-CT. ADVANCES IN KNOWLEDGE: First, this is the first study to evaluate the interobserver and inter-CT variations in the determination of the CTV and normal organs in gastric cancer with the use of the active breath co-ordinate technique. Second, we analysed the region where variations most likely occur. Third, we investigated the influence of interobserver variation on the dose distribution.

YpT1-2N0 rectal cancer after neoadjuvant chemoradiation has lower survival compared with pT1-2N0 rectal cancer.

Pathologic T1-2N0 rectal cancer shows an excellent prognosis without preoperative or postoperative chemoradiation. However, oncologic outcome of ypT1-2N0 remains unclear and undetermined. Thus, the aim of this study was to compare the survival of ypT1-2 and pT1-2 rectal cancer patients after radical resection and identify risk factors of ypT1-2 rectal cancer in Surveillance, Epidemiology, and End Results Program (SEER)-registered rectal cancer patients. The results showed that ypT1-2N0 rectal cancer after neoadjuvant chemoradiation has lower survival compared with pT1-2N0 rectal cancer and mucinous/signet-ring cancer and less than 12 lymph nodes retrieval were two risk factors in ypT1-2 patients. These results suggest that ypT1-2 patients with one or two risk factors may benefit from postoperative adjuvant chemotherapy.

Implications for determining the optimal treatment for locally advanced rectal cancer in elderly patients aged 75 years and older.

Patients were excluded if they were older than 75 years of age in most clinical trials. Thus, the optimal treatment strategies in elderly patients with locally advanced rectal cancer (LARC) are still controversial. We designed our study to specifically evaluate the cancer specific survival of four subgroups of patients according to four different treatment modalities: surgery only, radiation (RT) only, neoadjuvant RT and adjuvant RT by analyzing the Surveillance, Epidemiology, and End Results (SEER)-registered database. The results showed that the 5-year cancer specific survival (CSS) was 52.1% in surgery only, 27.7% in RT only, 70.4% in neoadjuvant RT and 60.4% in adjuvant RT, which had significant difference in univariate log-rank test (P < 0.001) and multivariate Cox regression (P < 0.001). Thus, the neoadjuvant RT and surgery may be the optimal treatment pattern in elderly patients, especially for patients who are medically fit for the operation.

[Association of nutrition with treatment compliance and toxicities in patients undergoing chemoradiation after gastrectomy].

OBJECTIVE: To investigate the association of nutritional status with treatment compliance and toxicities in patients undergoing chemoradiation therapy (CRT) after gastrectomy. METHODS: From September 2010 to May 2012, 40 patients with gastric cancer received adjuvant CRT in the Department of Radiation, Shanghai Cancer Center. Data including clinical data, weight loss of perioperative period, dynamic changes of weight, NRS 2002 score, PG-SGA score, lymph cell count and serum albumin during CRT, toxic effects and nutritional interventions were collected. Treatment compliance of CRT and adjuvant chemotherapy was recorded. Associations among nutrition, toxicities and treatment compliance were statistically studied. RESULTS: Weight loss percentage from pre-operation to pre-CRT(T1-T2) was 10.0%, which was significantly higher than that of 4.3% during CRT(T3) (P<0.05). Adverse reaction incidence of digestive tract during T3 was 95.0% (38/40). Patients with weight loss >5% during T3 had higher ratio of >II degree digestive tract adverse reaction [91.3% (21/23) vs. 76.5% (13/17), P<0.01] and higher ratio of >3 symptoms of digestive tract[82.4% (14/17) vs. 39.1% (9/23), P<0.05] as compared to those with weight loss ≤5% during T3. Fourteen patients (35.0%) did not complete the synchronous CRT. Factors related to incompletion of CRT were weight loss >7% after surgery (T1) or >10% during T1-T2, malnourishment before CRT, dependence on nutritional support during CRT. Factors related to incompletion of adjuvant chemotherapy were weight loss >5% during CRT(T3), requirement for nutritional support and NRS 2002 score ≥5 at the end of radiation (all P<0.05). CONCLUSIONS: Nutritional deterioration before CRT may aggravate the toxicities and reduce compliance of CRT in patients with radical resection of gastric cancer. Malnutrition during CRT may impair compliance to adjuvant chemotherapy. Therefore, early and persistent nutritional interventions are crucial considerations of strategies of multidisciplinary treatment for patients with gastric cancer.

Are biomarkers correlated with recurrence patterns in patients with resectable gastric adenocarcinoma.

The aims of this study are to analyze the failure patterns in radical resected gastric adenocarcinoma, and to evaluate the correlation between recurrence patterns and potentially prognostic factors, including clinical pathological characteristic and biomarkers. Between Jan 2004 and Jun 2006, 84 patients were enrolled into the database analysis, including 8 with clinical stage I, 20 with clinical stage II, 21 with clinical stage IIIA, 22 with clinical stage IIIB and 13 with clinical stage IV, male 61 and female 23. The collected biomarkers including: preoperative tumor markers: CEA, AFP, CA199, CA50, CA72-4 and CA24-2; postoperative immunohistochemical (IHC) markers: Bax, Bcl-2, P27, CyclinD1, TOPO2, MDR, GST-π, Ki67, epidermal growth factor receptor (EGFR), P21, P53, proliferating cell nuclear antigen (PCNA), C-myc and Neu. Three-year local control rate (LCR), disease-free survival (DFS) and over-all survival (OS) were 66, 61 and 64% respectively. Logistic regression analysis showed cyclinD1 and CEA were correlated with prognosis; cyclinD1, CEA were correlated with loco-regional recurrence; PCNA was correlated with remote metastasis; bcl-2, ki67, c-myc2 and Neu were correlated with lymph node metastasis. The present study indicate that patterns of recurrence are variable and may be associated with specific biomarkers, in addition, high level of CEA and low-expressed of cyclinD1 resulted in poor prognosis.