Prognostic impact of orotate phosphoribosyl transferase among 5-fluorouracil metabolic enzymes in resectable colorectal cancers treated by oral 5-fluorouracil-based adjuvant chemotherapy

Orotate phosphoribosyl transferase (OPRT) is the main enzyme that involves in phosphoribosylation of 5-fluorouracil (5-FU), an essential step that leads to tumor growth inhibition. In our study, the prognostic relevance of OPRT, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in resectable colorectal cancer (CRC) patients treated by oral 5-FU were compared to further clarify the prognostic value of OPRT. Tumor tissue was collected from 90 CRC patients and the patients were followed for 5.2 years (Median). TS, DPD and OPRT activities in the extract of tumor tissue were determined enzymatically. The cut-off value of OPRT (0.147 nmol/(min mg), TS (0.044 pmol/mg) and DPD (72.10 pmol/(min mg) were determined by maximal chi(2) method. Among these 5-FU metabolic enzymes, only high OPRT group demonstrated significantly better disease-free survival (DFS) (p = 0.0152) and better overall survival (p = 0.0078). In Cox regression analysis, node status (p < 0.0005) and OPRT (p = 0.044) were significant factors for DFS. OPRT activity in tumor tissue was a predictor of prognosis in resectable CRC patients treated by oral 5-FU-based adjuvant chemotherapy, and was useful to pick-up high risk patients independent from known prognosis factors.     

Prognostic impact of orotate phosphoribosyl transferase activity in resectable colorectal cancers treated by 5-fluorouracil-based adjuvant chemotherapy

BACKGROUND AND OBJECTIVES: Phosphoribosylation of 5-fluorouracil (5-FU) is an essential step which leads to tumor growth inhibition and orotate phosphoribosyl transferase (OPRT) is the main enzyme that involves in this conversion of 5-FU to 5-fluorouridine monophosphate. This retrospective study was aimed to evaluate the correlation between tumor OPRT activity and the clinical outcome in colorectal cancer (CRC) patients treated by oral 5-FU-based adjuvant chemotherapy. METHODS: Surgical specimen was obtained from resectable 124 CRC patients who were subsequently treated by oral 5-FU-based adjuvant chemotherapy. OPRT activity in the extract of tumor tissue was enzymatically determined. The cut-off value of intratumor OPRT activity against disease free survival was determined by maximal chi2 method. The disease free survival and overall survival in each group were calculated using the Kaplan-Meier method. RESULTS: Patients were divided into two groups by determined cut-off value of intratumor OPRT (0.147 nmol/min/mg protein) (high group: n = 102, low group: n = 22). Five-year DFS (P = 0.035) and OS (P = 0.020) were significantly better for high OPRT group. CONCLUSIONS: This study demonstrated that an assay of tumor OPRT contributes to the determination of 5-FU-based adjuvant chemotherapy outcome and application in clinical practice should be included in tumor analysis prior to 5-FU-based adjuvant chemotherapy.     

Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy

Background:

There have been controversies in prognostic impact of mucinous histology on colorectal cancer, and its implication in patients treated with adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is unclear.

Methods:

Stage II and III colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Patients were grouped according to the mucinous content: >50%, mucinous adenocarcinoma (MAC); <50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, non-MAC (NMA). Clinicopathological features and disease-free survival (DFS) were compared.

Results:

Among a total of 521 patients, 27 patients (5.2%) had MAC, 41 patients (7.9%) had AIM, and 453 patients (86.9%) had NMA. Mucinous adenocarcinoma and AIM had higher frequency of proximal location and microsatellite instability, but lower frequency of angiolymphatic invasion. Disease-free survival was significantly worse in the MAC compared with NMA (3-year DFS 57% and 86%, respectively; P<0.001) and AIM (3-year DFS 87%, P=0.01 vs MAC). Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted hazard ratio 7.96, 95% confidence interval 3.76–16.8).

Conclusion:

Adenocarcinoma with intermediated mucinous component and MAC have distinct clinicopathological features compared with NMA. Mucinous adenocarcinoma has an adverse prognostic impact on stage II or III colorectal cancer treated with adjuvant FOLFOX.     

Predictive value of pretreatment lymphocyte count in stage II colorectal cancer and in high-risk patients treated with adjuvant chemotherapy

Pretreatment lymphocyte count (LC) has been associated with prognosis and chemotherapy response in several cancers. The predictive value of LC for stage II colorectal cancer (CRC) and for high-risk patients treated with adjuvant chemotherapy (AC) has not been determined. A retrospective review of prospectively collected data from 1332 consecutive stage II CRC patients who underwent curative tumor resection was conducted. A pretreatment LC value <1.3 Giga/L(28.1%, 373/1332) was defined as low LC. A total of 738 patients (55.4%) were considered high-risk, 459 (62.2%) of whom received AC. Patients with low LCs had significantly worse 5-year OS (74.6% vs. 90.2%, p < 0.001) and DFS (61.3% vs. 84.6%, p < 0.001). High-risk patients with low LCs had the poorest DFS (p < 0.001). Multivariate analysis indicated that low LC value or combined with high-risk status were both independent prognostic factors(p <0.001). High-risk, AC-treated patients with high LCs had significantly longer DFS than untreated patients (HR, 0.594; 95% CI, 0.364–0.970; p = 0.035). There was no difference or trend for DFS or OS in patients with low LCs, regardless of the use of AC (DFS, p = 0.692; OS, p = 0.522). Low LC was also independently associated with poorer DFS in high-risk, AC-treated patients (HR, 1.885; 95% CI, 1.112–3.196; p = 0.019). CONCLUSIONS: Pretreatment LC is an independent prognostic factor for survival in stage II CRC. Furthermore, pretreatment LC reliably predicts chemotherapeutic efficacy in high-risk patients with stage II CRC.     

Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes' B colorectal cancer patients: how much evidence is enough?

The benefit of postoperative adjuvant chemotherapy in patients with Dukes' B colorectal cancer is still uncertain and its routine use is not recommended. Prognostic biomarkers may be useful for identifying high-risk patients with resected, node-negative disease, and this stratification may represent an innovative strategy for designing adjuvant chemotherapy trials. Featured prognostic molecular markers can be divided into the following categories: cell proliferation indices (Ki-67, Mib-1, proliferating cell nuclear antigen); oncogenes/tumor suppressor genes [p53, K-ras, Deleted in Colorectal Cancer (DCC), Bcl-2, c-erbB2]; DNA repair (microsatellite instability); markers of angiogenesis (vascular count, vascular endothelial growth factor); markers of invasion/metastasis (plasminogen-related molecules, matrix metalloproteinases); and biochemical markers (thymidylate synthase). Studies that have investigated their prognostic role in Dukes' B colorectal cancer patients are reviewed here. Current data do not provide sufficient evidence for the incorporation of available prognostic biomarkers into clinical practice. However, a biomarker-based approach could be an effective strategy for improving results of postoperative adjuvant treatments in high-risk Dukes' B colorectal cancer patients. Markers of altered DCC function have shown promising prognostic role and sufficient prevalence in retrospective investigations and they deserve further assessment in prospective studies.     

Dukes'B期结直肠癌术后辅助化疗的Meta分析

背景与目的:Dukes'B期结直肠癌根治性手术后是否需要辅助化疗,各研究报道不一,本研究利用M eta分析探讨Dukes'B期患者术后是否需要辅助化疗。方法:收集国内外1985～2003年间关于Dukes'B期结直肠癌根治性手术后给予辅助化疗的文章,将术后辅助化疗组和单纯手术组5年生存率进行综合比较。结果:符合要求纳入分析的文献共8篇,8个随机对照试验研究,累计病例6518人。比较术后化疗组和单纯手术组的5年死亡率,其合并OR值为0.79(95%CI=0.7～0.9,P<0.01),化疗组可降低术后5年死亡率。结论:Dukes蒺B期结直肠癌术后化疗可提高5年生存率。     

Adjuvant chemotherapy (5-fluorouracil and levamisole) in Dukes' B and C colorectal carcinoma. A cost-effectiveness analysis

Background: Adjuvant chemotherapy (5-fluorouracil, levamisole) is nowstandard practice in the treatment of Dukes' B and C coloretal carcinoma(CRC), and this has increased the financial burden on health care systemsworld-wide.Patients and methods: Between 1993 and 1996, 95 patients in northernNorway were included in a national randomised CRC study, and assigned tosurgery plus adjuvant chemotherapy or surgery alone. In April 1996, 94 of thepatients were evaluable and 82 were still alive. The total treatment costs(hospital stay, surgery, chemotherapy, administrative and travelling costs)were calculated. A questionnaire was mailed to all survivors for assessmentof the quality of their lives (QoL) (EuroQol questionnaire, a simpleQoL-scale, global QoL-measure of the EORTC QLQ-C30), and 62 of them(76%) responded.Results: Adjuvant chemotherapy in Dukes' B and C CRC raised the totaltreatment costs by £3,360. The median QoL was 0.83 (0–1 scale) in botharms. Employing a 5% discount rate and an improved survival of adjuvanttherapy ranging from 5% to 15%, we calculated the cost of onegained quality-adjusted life-year (QALY) to be between £4,800 and £16,800.Conclusion: Using a cut-off point level of £20,000 per QALY, adjuvantchemotherapy in CRC appears to be cost-effective only when the improvement in5-year survival is 5%. Adjuvant chemotherapy does not affectshort-term QoL.     

Predictors of short-term survival and progression to chemotherapy in patients with advanced colorectal cancer treated with 5-fluorouracil-based regimens

The aim of this study was to assess in patients with advanced colorectal cancer which factors were associated with short-term survival (6 months or less) and progression to first-line 5-fluorouracil (5-FU) chemotherapy. Three hundred twenty-one consecutive nonselected patients with advanced colorectal cancer were treated with conventional 5-FU-based regimens as first-line treatment from 1988 to 1999. Factors related to patient, tumor, or treatment were analyzed by univariate and multivariate logistic regression analysis by comparing short survivors (SS, those who survived or= 2) (p = 0.015), elevated (>or=5 microg/l) serum carcinoembryonic antigen (CEA) (p = 0.015), and more than one site of metastatic disease (p < 0.001). Progression to first-line chemotherapy (p < 0.001) was also a strong factor associated with short survival in multivariate analysis; factors predictive of progression were elevated CEA (p = 0.027) and diffuse metastatic disease (p = 0.029). Our data indicate the relevance of some clinical prognostic factors (younger age, poor performance status, elevated CEA, site of primary, number of metastatic sites, resistance to chemotherapy) as independent factors associated with poor survival and progression to first-line chemotherapy in patients with metastatic colorectal cancer treated with conventional 5-FU regimens. Patients identified by these factors as having a poor prognosis and low probability of response to treatment should be considered either for more aggressive regimens or supportive care only: conventional 5-FU treatments do not impact on response or survival.     

Pretherapeutic uracil and dihydrouracil levels in saliva of colorectal cancer patients are associated with toxicity during adjuvant 5-fluorouracil-based chemotherapy

Purpose

5-fluorouracil (5-FU) competes with uracil (Ura) as a substrate for dihydropyrimidine dehydrogenase (DPD). Low DPD activity impairs breakdown of Ura to dihydrouracil (UH₂) and is associated with toxicity during 5-FU-based chemotherapy. Calculation of the 5-FU dose is based on body surface area, and new tools are needed to individualize treatment. The aim of study was to measure Ura and UH₂ in saliva of patients with colorectal cancer and relate levels to treatment-induced toxicity.

Methods

Saliva was collected from 73 patients with stage III colorectal cancer prior to adjuvant 5-FU-based treatment. Ura and UH₂ were analyzed by a column-switching HPLC method. Toxicity was evaluated before each treatment cycle and the highest grade was noted at end of treatment.

Results

Toxicity was more common and severe among women compared with men. The Ura and UH₂ concentrations in saliva were 5.0 ± 6.8 and 5.0 ± 4.0 nmol/ml, respectively. The UH₂/Ura ratio was lower in women compared with men (1.2 ± 1.0 and 2.2 ± 2.5, respectively, p = 0.0026). Patients who needed to reduce the drug dose during treatment (or terminate treatment) due to toxicity had a lower ratio (1.3 ± 0.85) compared to patients who completed treatment without dose reduction (4.1 ± 4.3, p < 0.0001).

Conclusion

Sampling of saliva is a quick, noninvasive, safe and painless process that gives information about patients Ura and UH₂ levels prior to chemotherapeutical treatment. This information may be useful in order to predict and prevent occurrence of treatment-related toxicities which otherwise may limit drug administration.     

Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy

Background: Low tumour expression levels of thymidylate synthase(TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase(TP) have been linked with improved outcome for colorectal cancer(CRC) patients treated with 5-fluorouracil (5-FU). It is unclearwhether this occurs because such tumours have better prognosisor they are more sensitive to 5-FU treatment. Patients and methods: Associations between TS, DPD and TP levels,determined by tissue microarrays and immunohistochemistry, andsurvival was evaluated in 945 CRC patients according to treatmentstatus. Results: Low TS and DPD expression associated with worse prognosisin stage II [hazard ratio (HR) = 1.69, 95% confidence interval(CI) (1.09–2.63) and HR = 1.92 (95% CI 1.23–2.94),respectively] and stage III CRC patients treated by surgeryalone [HR = 1.39 (95% CI 0.92–2.13) and HR = 1.49 (95%CI 1.02–2.17), respectively]. Low TS, DPD and TP associatedwith trends for better outcome in stage III patients treatedwith 5-FU [HR = 0.81 (95% CI 0.49–1.33), HR = 0.70 (95%CI 0.42–1.15) and HR = 0.66 (95% CI 0.39–1.12),respectively]. Conclusion: Low TS and DPD expression are prognostic for worseoutcome in CRC patients treated by surgery alone, whereas lowTS, DPD and TP expression are prognostic for better outcomein patients treated with 5-FU chemotherapy. These results provideindirect evidence that low TS, DPD and TP protein expressionare predictive of good response to 5-FU chemotherapy. Key words: colorectal cancer, fluorouracil, predictive, prognostic, thymidylate synthase Received for publication July 12, 2007. Revision received December 10, 2007. Accepted for publication December 17, 2007.     

Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapy

Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Genetic variations and expression alterations in genes involved in 5-FU metabolism and effect have been shown to modulate 5-FU sensitivity in vitro, however these alterations do not fully explain clinical resistance to 5-FU-based chemotherapy. To determine if alterations of DNA copy number in genes involved in 5-FU metabolism-impacted clinical resistance to 5-FU-based chemotherapy, we assessed thymidylate synthetase (TYMS) and thymidine phosphorylase (TYMP) copy number in colorectal liver metastases. DNA copy number of TYMS and TYMP was evaluated using real time quantitative PCR in frozen colorectal liver metastases procured from 62 patients who were pretreated with 5-FU-based chemotherapy prior to surgical resection (5-FU exposed) and from 51 patients who received no pretreatment (unexposed). Gain of TYMS DNA copy number was observed in 18% of the 5-FU exposed metastases, while only 4% of the unexposed metastases exhibited TYMS copy gain (p = 0.036). No significant differences were noted in TYMP copy number alterations between 5-FU-exposed and -unexposed metastases. Median survival time was similar in 5-FU-exposed patients with metastases containing TYMS amplification and those with no amplification. However, TYMS amplification was associated with shorter median survival in patients receiving post-resection chemotherapy (hazard ratio = 2.7, 95% confidence interval = 1.1–6.6; p = 0.027). These results suggest amplification of TYMS amplification as a putative mechanism for clinical resistance to 5-FU-based chemotherapy and may have important ramifications for the post-resection chemotherapy choices for metastatic colorectal cancer.     

5-氟尿嘧啶为基础的联合化疗对结直肠癌患者血糖代谢的影响

目的:观察结直肠癌患者接受以5-氟尿嘧啶(5-fluorouracil, 5-FU)为基础的联合化疗前和化疗期间血糖水平的变化,探讨5-FU与患者发生糖尿病(diabetes mellitus, DM)之间的关系.方法:采用回顾性方法分析97例接受含5-FU方案化疗的结直肠癌患者在化疗前和化疗期间空腹血糖的变化.结果: 剔除化疗前罹患DM的3例患者、空腹血糖受损的3例患者以及糖耐量异常的1例患者,对剩余的化疗前空腹血糖正常的90例患者进行分析.其中,化疗期间继发DM者5例(5/90,5.56%),继发空腹血糖损伤者16例(16/90,17.78%),继发糖耐量损伤者1例(1/90,1.11%).5例继发DM的患者在化疗前以及化疗期间出现继发DM时的平均空腹血糖分别为(4.95±0.31)和(12.20±6.23) mmol/L,化疗后空腹血糖水平明显高于化疗前空腹血糖水平(P＜0.01);继发DM时的中位5-FU累积剂量为7 500 mg/m2,至DM时的中位化疗周期数为2个;其中4例患者有糖皮质激素注射史,继发DM时的中位地塞米松累积剂量为25 mg;继发DM患者中有1例死于DM酮症酸中毒.16例继发空腹血糖损伤的患者中,12例患者在化疗结束2～7个月后空腹血糖恢复至正常,其余4例仍维持空腹血糖损伤状态,短期随访无一例演变为DM.结论:以5-FU为基础的化疗可诱使结直肠癌患者继发DM,甚至可引起DM酮症酸中毒.部分患者出现一过性空腹血糖受损.     

DCR3 locus is a predictive marker for 5-fluorouracil-based adjuvant chemotherapy in colorectal cancer

Adjuvant chemotherapy reduces the incidence of distant metastasis and increases survival of patients with colorectal cancer. However, predictive markers are needed to define subsets of patients with stage II and III disease that may benefit from adjuvant treatment. A secreted member of the TNF receptor superfamily, the decoy receptor 3 (DcR3), was reported to be amplified in colorectal cancer as a negative regulator of Fas-mediated apoptosis. We analyzed DcR3 gene copy number and protein expression in a large series of tumors from a randomized multicenter trial of 5-fluorouracil/mitomycin C (FU/MMC) adjuvant chemotherapy of the Swiss Group for Clinical Cancer Research (SAKK 40/81), using real-time quantitative PCR and immunohistochemistry on tumor microarrays. Results of gene status and protein expression of DcR3 were correlated with disease-free and overall survival of patients. We observed amplification of the DcR3 gene in 185/294 (63%) and overexpression of the DcR3 protein in 163/223 (73%) of colorectal tumors. Multivariate analysis showed no prognostic effect of DcR3 gene amplification and protein overexpression. However, adjuvant chemotherapy was significantly more beneficial in patients with normal DcR3 gene copy number than in patients with amplification (DFS: HR 2.84, 95% CI 1.16-6.98, p = 0.02; OS: HR 3.15, 95% CI 1.19-8.32, p = 0.02), whereas DcR3 protein overexpression did not influence the effect of adjuvant chemotherapy (DFS: HR 1.02, 95% CI 0.65-1.60, p = 0.95; OS: HR 0.95, 95% CI 0.61-1.49, p = 0.83). We conclude that amplification of the 20q13 locus is a predictive marker for adjuvant chemotherapy in colorectal cancer.     

Prognostic factors in patients with colorectal cancer receiving adjuvant chemotherapy or chemoradiotherapy

Background. Although the TNM system is useful in predicting survival in resected colorectal cancer, heterogeneity within the same stages regarding prognosis exists. We are presenting a pooled analysis of prognostic factors from two randomized studies of adjuvant treatment conducted by the Hellenic Cooperative Oncology Group. Patients and Methods. Patients with stage II or III colon (n=279) or rectal (n=220) cancer were included in this analysis. Following surgery, patients received: 5-fluorouracil/leucovorin (5-FU/LV) (n=135), 5-FU/LV and interferon Alfa-2a (IFNA-2a) (n=138), 5-FU/LV and pelvic chemoradiotherapy (n=106), and pelvic chemoradiotherapy alone (n=108). Results. Median follow up was 92 mo. The number of involved lymph nodes (LNs), tumor differentiation, and the presence of regional implants were independent prognostic factors for both OS and TTP, while nerve invasion was only significant for TTP. Patients were stratified into three prognostic groups (low-risk: no LNs and grade 1/2; high-risk: >3 LNs and grade 3/4; intermediate-risk: remaining patients) with distinct differences in 5-yr survival (84.7% vs 57.6% vs 32.4%) and 5-yr TTP (81.2% vs 54.5% vs 28.6%). Conclusion. The combination of clinicopathological prognostic factors can be more informative than the traditional TNM staging system. Such stratification may be necessary in randomized trials and could be useful in deciding the most appropriate adjuvant treatment strategies.     

5-fluorouracil pharmacokinetics predicts disease-free survival in patients administered adjuvant chemotherapy for colorectal cancer.

PURPOSE: To evaluate 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU) pharmacokinetics and disease-free survival (DFS) in colorectal cancer patients given 5-FU-based adjuvant chemotherapy within a nonrandomized, retrospective, pharmacokinetic study. EXPERIMENTAL DESIGN: One hundred fifteen patients including 72 men (median age, 63 years; range, 36-79 years) and 43 women (median age, 60 years; range, 36-73 years) received 6 cycles of l-leucovorin 100 mg/m(2)/day and 5-FU 370 mg/m(2)/day i.v. boluses (5 days every 4 weeks). Individual plasma concentrations of 5-FU and 5-FDHU were determined on day 1 of the first cycle with a validated high performance liquid chromatography method, and the main pharmacokinetic variables were determined. Follow-up of all patients was extended up to 5 years after the end of adjuvant chemotherapy, and DFS was recorded. Univariate and multivariate analyses were conducted to evaluate any correlation among 5-FU pharmacokinetics, clinical and pathologic variables, and DFS. RESULTS: The area under the time/concentration curve (AUC) of 5-FU was significantly lower in 58 subjects who recurred (7.5 +/- 2.9 h x mg/L) with respect to other patients (9.3 +/- 4.1 h x mg/L). Furthermore, AUC values lower than 8.4 h x mg/L together with lymph node involvement and the interruption of treatment or reduction of doses were identified as risk factors at univariate analysis. The completion of 6 cycles of adjuvant treatment without dosage modifications was the only independent risk factor at multivariate analysis, despite a trend toward significance for 5-FU AUC values (cutoff value, 8.4 hxmg/L) was observed (P = 0.06). CONCLUSIONS: Pharmacokinetics of 5-FU should be regarded as an important factor for predicting disease recurrence in colorectal cancers.     

Prognostic value of mismatch repair deficiency in patients with advanced gastric cancer,treated by surgery and adjuvant 5-fluorouracil and leucovorin chemoradiotherapy

ObjectiveThe predictive value of mismatch repair protein deficiency (MMRD) for chemoradiotherapeutic outcome has rarely been reported in gastric cancer. This study investigated the clinical significance of MMRD as a prognostic factor for tumor recurrence, and as a predictor of response to adjuvant chemoradiotherapy in advanced gastric cancer patients.MethodsBetween 1995 and 2008, tissue specimens of 881 patients who underwent radical gastrectomy for stage II and III gastric cancer were analyzed. MMRD was assessed using immunohistochemical stains for MLH1, PMS2, MSH2, and MSH6. Patients were divided into two groups according to adjuvant treatment: a 5-fluorouracil/leucovorin (FL) adjuvant chemoradiotherapy group and a surgery alone group. Disease-free survival (DFS) was compared between the two groups correlated to MMRD. Risk factors for tumor recurrence were analyzed using multivariate analysis.ResultsOf the 881 gastric cancer patients, 88 (10.0%) exhibited MMRD and 398 (45.2%) patients received adjuvant FL chemoradiotherapy. The multivariate analysis revealed that MMRD was a good independent prognostic factor (hazard ratio, 0.572; 95% confidence interval, 0.370–0.883; P = 0.012). For stage III gastric cancer displaying mismatch repair protein proficiency (MMRP), adjuvant FL chemoradiotherapy after surgery resulted in better DFS than surgery alone (P = 0.001). Among the stage II gastric cancer patients, adjuvant FL chemoradiotherapy did not show survival benefit, regardless of MMRD.ConclusionMMRD is a good independent prognostic factor in advanced gastric cancer. Adjuvant FL chemoradiotherapy was beneficial in patients with stage III gastric cancer with MMRP but not in those with MMRD.