Outcomes of preoperative chemoradiotherapy followed by surgery in patients with unresectable locally advanced sigmoid colon cancer

Background: Complete resection of locally advanced sigmoid colon cancer(LASCC) is sometimes difficult. Patients with LASCC have a dismal prognosis and poor quality of life, which has encouraged the evaluation of alternative multimodality treatments. This prospective study aimed to assess the feasibility and efficacy of neoadjuvant chemora?diotherapy(neo CRT) followed by surgery as treatment of selected patients with unresectable LASCC.Methods: We studied the patients with unresectable LASCC who received neo CRT followed by surgery between October 2010 and December 2012. The neoadjuvant regimen consisted of external?beam radiotherapy to 50 Gy and capecitabine?based chemotherapy every 3 weeks. Surgery was scheduled 6–8 weeks after radiotherapy.Results: Twenty?one patients were included in this study. The median follow?up was 42 months(range, 17–57 months). All patients completed neo CRT and surgery. Resection with microscopically negative margins(R0 resection) was achieved in 20 patients(95.2%). Pathologic complete response was observed in 8 patients(38.1%). Multivisceral resection was necessary in only 7 patients(33.3%). Two patients(9.5%) experienced grade 2 postopera?tive complications. No patients died within 30 days after surgery. For 18 patients with pathologic M0(yp M0) disease, the cumulative probability of 3?year local recurrence?free survival, disease?free survival and overall survival was 100.0%, 88.9% and 100.0%, respectively. For all 21 patients, the cumulative probability of 3?year overall survival was 95.2% and bladder function was well preserved.Conclusion: For patients with unresectable LASCC, preoperative chemoradiotherapy and surgery can be performed safely and may result in an increased survival rate.

Surgery with versus without preoperative concurrent chemoradiotherapy for mid/low rectal cancer: an interim analysis of a prospective, randomized trial

Introduction: Multimodality therapy, including preoperative chemoradiotherapy(CRT) and total mesorectal excision(TME), has effectively reduced local recurrence rates of rectal cancer over the past decade. However, the benefits and risks of the addition of neoadjuvant CRT to surgery need to be evaluated. This study was to compare the efficacy of TME with versus without preoperative concurrent chemoradiotherapy(CCRT) involving XELOX regimen(oxaliplatin plus capecitabine) in Chinese patients with stages II and III mid/low rectal adenocarcinoma.Methods: We randomly assigned patients to the TME group(TME without preoperative CCRT) or CCRT + TME group(TME with preoperative CCRT). The primary endpoint was disease-free survival(DFS); the secondary endpoints were overall survival(OS), local and distant recurrence, tumor response to CRT, toxicity, sphincter preservation, and surgical complications. An interim analysis of the potential inferiority of DFS in the CCRT + TME group was planned when the first 180 patients had been followed up for at least 6 months.Results: A total of 94 patients in the TME group and 90 patients in the CCRT + TME group were able to be evaluated. The 3-year DFS and OS rates were 86.3 % and 91.5 % in the whole cohort, respectively. The 3-year DFS rates of the TME and CCRT + TME groups were 85.7% and 87.9 %(P = 0.766), respectively, and the 3-year OS rates were 90.7 % and 92.3 %(P = 0.855), respectively. The functional sphincter preservation rates of the TME and CCRT +TME groups were 71.3 % and 70.0 %(P = 0.849), respectively. In the TME group, 16(17.0 %) patients were proven to have p TNM stage I disease after surgery. In the CCRT + TME group, 32(35.6 %) patients achieved a pathologic complete response(p CR).Conclusions: Preliminary results indicated no significant differences in the DFS, OS, or functional sphincter preservation rates between the TME and CCRT + TME groups. However, preoperative CCRT with XELOX yielded a high p CR rate. Newer techniques are needed to improve the staging accuracy, and further investigation is warranted.

Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases

Background: Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorecal cancer patients with liver metastases who underwent hepatectomy.However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients.Patients and methods: In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients.The pathologic response was evaluated according to the tumor regression grade(TRG).The prognostic role of pathologic response in recurrence-free survival(RFS) and overall survival(OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests.Results: Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy(median RFS: 9.9 vs.6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors,and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases(all P < 0.05). A decrease in the serum carcinoembryonic antigen(CEA) level after preoperative chemotherapy predicted an increased pathologic response rate(P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens.Conclusions: We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

奥沙利铂和卡培他滨联合贝伐单抗加放疗的新辅助方案治疗局部晚期直肠癌:单中心Ⅱ期研究结果

背景与目的新辅助放化疗后手术被推荐为局部晚期直肠癌的标准治疗方案,可降低局部复发但对远处转移无效。所以加强系统治疗是降低远处转移风险的必要措施。本研究旨在评价奥沙利铂和卡培他滨(XELOX)联合贝伐单抗加放疗的新辅助方案治疗局部晚期直肠癌的安全性和有效性。方法Ⅱ至Ⅲ期直肠癌患者接受1个疗程的诱导化疗及XELOX加贝伐单抗的同步放化疗。放疗结束后6–8周行手术治疗,并进行3个疗程XELOX和2个疗程卡培他滨的术后化疗。本研究的主要终点是病理学完全缓解(pathologic complete response,pCR)率和安全性,次要终点为3年总生存和无进展生存。结果 2013年2月至2015年4月间招募了45例患者。所有患者均完成了新辅助治疗。7例患者(15.6%)因个人原因拒绝了后续手术治疗,其余38例患者接受了根治性切除术,括约肌保留率为84.2%,pCR率为39.5%。毒性是可接受的,分别在6例和2例患者中观察到3–4级血液学毒性和腹泻。需要手术干预的吻合口瘘的发生率为13.3%。中位随访37个月后,5例患者出现疾病进展,2例患者因癌症死亡。3年总生存率和3年无进展生存率分别为95.3%和88.6%。结论增加贝伐单抗至新辅助放化疗中获得了令人满意的pCR率和3年生存率,但也增加了吻合口瘘的风险,因此该方案不宜作为局部晚期直肠癌的常规推荐方案。

Temporal Change in Treatment Patterns of Metastatic Colorectal Cancer and Its Association with Patient Survival:A Retrospective Cohort Study Based on an Intelligent Big-Data Platform

There is a lack of high-quality,large-scale,real-world evidence from patients with metastatic colorectal cancer(mCRC),especially in China.It remains unclear whether efforts to improve the quality of care for mCRC would improve patient survival outcomes in real-world practice.On the basis of an intelligent bigdata platform,we established a large-scale retrospective cohort of mCRC patients.We investigated the temporal changes in the systemic and local treatment(resection,ablation,or radiation to liver,lung,or extrahepatic and/or extrapulmonary metastases)patterns of mCRC,and whether these changes were associated with improved overall survival(OS)over time.Between July 2012 and December 2018,3403 eligible patients were included in this research.The median OS was 42.8 months(95%confidence interval(CI),40.7–46.6)for the entire cohort,25.6 months(95%CI,24.7–26.9)for those treated with systemic therapy only,and not reached(95%CI,78.6 months–not reached)for those receiving local therapy.The utility rate of local therapy increased continuously from 37.9%in 2012–2014 to 46.9%in 2017–2018.A dramatic increase in the utility rate of either cetuximab or bevacizumab was observed since 2017(39.9%,43.2%,and 60.3%in 2012–2014,2015–2016,and 2017–2018,respectively).Compared with 2012–2014,the OS of the entire population significantly improved in 2015–2016(hazard ratio(HR)=0.87(95%CI,0.78–0.99);P=0.034),but not for patients receiving systemic therapy only(HR=0.99(95%CI,0.86–1.14);P=0.889),whereas an improved OS was found in 2015–2018 for both the entire population(HR=0.75(95%CI,0.70–0.81);P<0.001)and for patients receiving systemic therapy only(HR=0.83(95%CI,0.77–0.91);P<0.001).In summary,the quality of care for mCRC,as indicated by the utility rate of targeted and local therapies,has been continuously improving over time in this study cohort,which is associated with continuously improving survival outcomes for these patients.

Neoadjuvant oxaliplatin and capecitabine combined with bevacizumab plus radiotherapy for locally advanced rectal cancer: results of a single-institute phase II study

Background:Neoadjuvant chemoradiotherapy followed by surgery is recommended as the standard of care for locally advanced rectal cancer,reducing local recurrence but not distant metastasis.Intensified systemic therapy is warranted to reduce the risk of distant metastasis.The present study aimed to evaluate the safety and efficacy of neo-adjuvant oxaliplatin and capecitabine(XELOX)combined with bevacizumab plus radiotherapy for locally advanced rectal cancer.Methods:Patients with stages II to III rectal cancer received one cycle of induction chemotherapy and concurrent chemoradiotherapy with XELOX plus bevacizumab.Surgery was performed 6-8 weeks after completion of radiotherapy,and postoperative chemotherapy with three cycles of XELOX and two cycles of capecitabine were given.The primary endpoints were pathologic complete response(pCR)rate and safety,and the secondary endpoints were 3-year overall survival and progression-free survival.Results:Forty-five patients were enrolled between February 2013 and April 2015.All completed the neoadjuvant therapy.Seven patients(15.6%)refused subsequent surgical therapy for personal reasons,and the other 38 patients received radical resection,with a sphincter preservation rate of 84.2%and a pCR rate of 39.5%.Toxicity was acceptable,with grades 3-4 hematological toxicity and diarrhea observed in six and two patients,respectively.Incidence of anastomotic leak that required surgical intervention was 13.3%.After a median follow-up period of 37 months,five patients developed disease progression and two died of cancer.The 3-year overall survival rate and 3-year progres-sion-free survival rate were 95.3%and 88.6%,respectively.Conclusions:The addition of bevacizumab to neoadjuvant chemoradiotherapy resulted in a satisfying pCR rate and 3-year survival,but also may increase the risk of anastomotic leak,thus this regimen is not suitable to be considered for regular recommendation for locally advanced rectal cancer.

Germline mutational profile of Chinese patients under 70 years old with colorectal cancer

Background:Inherited susceptibility accounts for nearly one-third of colorectal cancer(CRC)predispositions and has an 80%-100%lifetime risk of this disease.However,there are few data about germline mutations of hereditary CRC-related genes in Chinese patients with CRC.This study aimed to assess the prevalence of gene mutations related to cancer susceptibility among Chinese patients with CRC,differences between Chinese and Western patients,and the phenotypegenotype correlation.Methods:We retrospectively collected tumor samples from 526 patients with CRC under 70 years old who underwent hereditary CRC genetic testing.A series of bioinformatic analyses,as well as statistical comparisons,were performed.Results:We found that 77 patients(14.6%)harbored functional variants of the 12 genes.The mutation frequencies of the top 5 mutated genes were 6.5%for MutL homolog 1(MLH1),5.1%for MutS homolog 2(MSH2),1.0%for MSH6,0.8%for PMS1 homolog 2(PMS2),and 0.8%for APC regulator of the WNT signaling pathway(APC).Our data showed much higher rates of mutations of MSH6 and PMS2 genes among all mismatch repair(MMR)genes as compared with those in Western populations.Mutations in MLH1,MSH2,and MSH6 were found to be mutually exclusive.Patients with MLH1 or MSH2 mutations had higher frequencies of personal history of cancer(MLH1:20.6%vs.8.7%;MSH2:25.9%vs.8.6%)and family history of cancer than those without these mutations(MLH1:73.5%vs.48.4%;MSH2:70.4%vs.48.9%),and the lesions were more prone to occur on the right side of the colon than on the left side(MLH1:73.5%vs.29.3%;MSH2:56.0%vs.31.0%).The proportion of stage I/II disease was higher in patients with MLH1 mutations than in those without MLH1 mutations(70.6%vs.50.7%),and the rate of polyps was higher in patients withAPC mutations than in those with wild-type APC(75.0%vs.17.4%).Conclusion:These results provide a full-scale landscape of hereditary susceptibility over 12 related genes in CRC patients and suggest that a comprehensive multi-gene panel testing for hereditary CRC predisposition could be a helpful analysis in clinical practice.

A frameshift mutation in exon 19 of MLH1 in a Chinese Lynch syndrome family: a pedigree study

Lynch syndrome (LS),an autosomal dominantly inherited disease previously known as hereditary non-polyposis coloreetal cancer (HNPCC),leads to a high risk of colorectal cancer (CRC)as well as malignancy at certain sites including endometrium,ovary,stomach,and small bowel (Hampel et al.,2008;Lynch et al.,2009).Clinically,LS is considered the most common hereditary CRC-predisposing syndrome, accounting for about 3% of all CRC cases (Popat et al., 2005).LS is associated with mutations of DNA mismatch repair (MMR)genes such as MLH1,MSH2, MSH6,PMS2,and EPCAM (Ligtenberg et al.,2009;Lynch et al.,2009),which can trigger a high frequency of replication errors in both microsatellite regions and repetitive sequences in the coding regions of various cancer-related genes.

Low prevalence of mismatch repair deficiency in Chinese colorectal cancers:a multicenter study

Background:Although universal testing for mismatch repair deficiency(dMMR)has been recommended to all colorectal cancer(CRC)patients,related evidence for the Chinese population is lacking.Here,we investigated the prevalence and clinicopathological features of dMMR patients in a large Chinese CRC cohort.Methods:We included 7,373 CRC patients treated at four Chinese medical centers between August 2010 and September 2016.Patients’baseline characteristics and pathological features were recorded.The clinicopathological features were compared between patients with MLH1/PMS2 deficiency(dMLH1/PMS2)and MSH2/MSH6 deficiency(dMSH2/MSH6).Results:Among the investigated patients,654(8.9%)were identified with dMMR CRCs and,of them,401(61.3%)were males,with a median age of 55 years(range,22-87 years);355(54.3%)had stage II CRC based on American Joint Committee on Cancer 8th edition.The prevalence of the dMLH1/PMS2 group and the dMSH2/MSH6 group were 51.5%(337/654)and 25.1%(164/654),respectively.Compared with dMSH2/MSH6 patients,those with dMLH1/PMS2 were older(57 vs 52 years,P<0.001),more likely to be female(45.7%vs 31.5%,P=0.004),prone to having tumors located in the right-hand side of the colon(59.0%vs 47.6%,P=0.015),and less likely to have a family history of tumors(29.7%vs 43.3%,P=0.003).Conclusions:The prevalence of dMMR in Chinese CRC patients was low,especially in the dMLH1/PMS2 group.The clinicopathological features were different between dMMR subgroups.