Impact of KRAS mutation and PTEN expression on cetuximab-treated colorectal cancer

AIM:To investigate the prognostic value of KRAS mutation,and phosphatase and tensin (PTEN) expression in Chinese metastatic colorectal cancer metastatic colorectal cancer (mCRC) patients treated with cetuximab.METHODS:Ninety Chinese mCRC patients treated with cetuximab were evaluated for KRAS mutation and PTEN protein expression by DNA sequencing of codons 12 and 13 and immunohistochemistry,respectively.We then selected 61 patients treated with cetuximab,either in combination with chemotherapy,or alone as a second-line or third-line regimen to assess whether KRAS mutation or PTEN protein expression is associated with the response and the survival time of mCRC patients treated with cetuximab.RESULTS:KRAS mutation was found in 30 (33.3%) tumor samples from the 90 patients,and positive PTEN expression was detected in 58 (64.4%) of the 90 patients.Among the 61 patients who were treated with cetuximab as a second-line or third-line regimen,the resistance to cetuximab was found in 22 patients with KRAS mutation and in 39 patients without KRAS mutation,with a response rate of 4.5% and 46.1% respectively (P=0.001),a shorter median progression-free survival (PFS) time of 14 ± 1.3 wk and 32 ± 2.5 wk respectively (P < 0.001),a median overall survival (OS) time of 11 ± 1.2 mo and 19 ± 1.8 mo respectively (P < 0.001),as well as in 24 patients with negative PTEN expression and in 37 patients with positive PTEN expression respectively (P < 0.001),with a responsive rate of 4.2% and 48.6% respectively,a shorter median PFS survival time of 17 ± 2.0 wk and 28 ± 1.9 wk respectively (P=0.07),and a median OS time of 11 ± 1.3 mo and 18 ± 1.9 mo respectively (P=0.004).Combined KRAS mutation and PTEN expression analysis showed that the PFS and OS time of patients with two favorable prognostic factors were longer than those of patients with one favorable prognostic factor or no favorable prognostic factor (P < 0.001).CONCLUSION:KRAS mutation and PTEN protein expression are significantly correlated with the response ra     

Standard chemotherapy with cetuximab for treatment of colorectal cancer

AIM: To review and assess the evidence related to cetuximab treatment in metastatic colorectal cancer(mCRC) with regard to KRAS status.METHODS: PubMed, EMBASE, Cochrane database and American Society of Clinical Oncology meeting abstracts were searched for randomized controlled trials(RCTs) reporting the effect of KRAS status on efficacy of chemotherapy regimen with or without cetuximab in mCRC. Baseline information such as sex and age was summarized from the included studies.Hazard ratios of progression-free survival(PFS) and overall survival(OS) as well as objective response based on KRAS status were extracted for analysis.RESULTS: A total of 8 RCTs with 6780 patients were included. The combined analysis showed that cetuximab failed to improve the OS and PFS in patients with mCRC.However, in subgroup analysis, the pooled data showed that addition of cetuximab to irinotecan containing chemotherapy regimen was sufficient to improve OS and PFS in wild-type KRAS mCRC patients, but not in patients with mutant-type KRAS. The addition of cetuximab increased the incidence of adverse events such as diarrhea, rash, skin toxicity/rash, and nausea and vomiting. There was no significant publication bias existing in the included studies.CONCLUSION: The clinical benefit of cetuximab was only confirmed in patients with wild-type KRAS. KRAS status could be considered a biomarker of efficacy of cetuximab.     

Resectability and outcome with anti-EGFR agents in patients with KRAS wild-type colorectal liver-limited metastases: a meta-analysis

Background

Cetuximab (C) and panitumumab (P) increase response rate and survival in KRAS wild-type metastatic colorectal cancer (mCRC). We performed a meta-analysis of randomised controlled trials (RCTs) to assess their effect on overall response rate (ORR), the rate of radical resection (R0) and survival in patients with liver-limited initially unresectable mCRC.

Materials and methods

We searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials for RCTs comparing first-line chemotherapy plus or minus C or P and reporting data in patients with KRAS wild-type, unresectable liver-limited mCRC. Relative risks (RRs) with 95% confidence interval were calculated. Meta-analysis of hazard ratios (HRs) for progression-free and overall survival (PFS and OS) was also performed.

Results

Four RCTs involving 484 KRAS wild-type patients were included. Compared to chemotherapy alone, the addition of C or P significantly increased the ORR (RR 1.67, p?=?0.0001), the R0 resection rate from 11% to 18% (RR 1.59, p?=?0.04) and PFS (HR 0.68, p?=?0.002), but not OS (p?=?0.42).

Conclusions

The addition of C and P increased the R0 resection rate by 60% and reduced the risk of progression by 32% in patients with mCRC and unresectable liver-limited disease. This combination represents one of the preferred choices as conversion therapy in KRAS wild-type patients with unresectable liver metastases.     

First-line therapies in metastatic colorectal cancer: integrating clinical benefit with the costs of drugs

Purpose

In light of the relevant expenses of pharmacological interventions, it might be interesting to make a balance between the cost of the new drugs administered and the added value represented by the improvement in progression free survival (PFS) in first-line for metastatic colorectal cancer CRC (mCRC).

Methods

Phase III randomized controlled trials (RCTs) that compared at least two first-line chemotherapy regimens for mCRC patients were evaluated. Differences in PFS between the different arms were compared with the pharmacological costs (at the pharmacy of our hospital). The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above RCTs.

Results

Overall 28 phase III RCTs, including 19,958 patients, were analyzed. The FOLFOX resulted the least expensive (56 € per month of PFS gained) while the addition of irinotecan to FOLFOX (FOLFOXIRI) increased only marginally the costs (90 € per month of PFS gained). Treatments including the monoclonal antibodies showed a cost per month of PFS gained of 2823 € (FOLFIRI with cetuximab in KRAS wild-type patients and liver-only metastases), of € 15,822 (FOLFOX with panitumumab in KRAS wild type), and of 13,383 € (FOLFOX with bevacizumab). According to the ESMO-MCBS, the treatments including an EGFR-inhibitor (cetuximab or panitumumab) were associated with a score of 4, while the inclusion of bevacizumab reached a score of 3.

Conclusions

Our data demonstrate a huge difference in cost per month of PFS gained in modern first-line treatments in mCRC.

     

Anti-EGFR and anti-VEGF agents:Important targeted therapies of colorectal liver metastases

Colorectal liver metastasis(CLM)is common worldwide.Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials,and are now becoming standards for patients with CLM.Thedevelopment and application of anti-epidermal growth factor receptor(anti-EGFR)and anti-vascular endothelial growth factor(anti-VEGF)antibodies represents significant advances in the treatment of this disease.However,new findings continue to emerge casting doubt on the efficacy of this approach.The Kirsten ratsarcoma viral oncogene(KRAS)has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM.Whereas a recent study summarizedseveral randomized controlled trials,and showed thatpatients with the KRAS G13D mutation significantlybenefited from the addition of cetuximab in terms of progress-free survival(PFS,4.0 mo vs 1.9 mo,HR=0.51,P=0.004)and overall survival(OS,7.6 mo vs5.7 mo,HR=0.50,P=0.005).Some other studiesalso reported that the KRAS G13D mutation might notbe absolutely predictive of non-responsiveness to antiEGFR therapy.At the same time,"new"RAS mutations,including mutations in neuroblastoma RAS viral(vras)oncogene homolog(NRAS)and exons 3 and 4 of KRAS,have been suggested to be predictors of a poor treatment response.This finding was first reported by the update of the PRIME trial.The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations,panitumumab-fluorouracil,leucovorin,and oxaliplatin(FOLFOX)4 treatment led to inferior PFS(HR=1.28,95%CI:0.79-2.07)and OS(HR=1.29,95%CI:0.79-2.10),which was consistent with the findings in patients with KRAS mutations in exon 2.Then,the update of the PEAK trial and the FIRE-Ⅲtrial also supported this finding,which would reduce candidates for anti-EGFR therapy but enhance the efficacy.In firstline targeted combination therapy,the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-Ⅶtrial.Also,bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966trial.By the update and further analysis of the COIN trial and the NORDIC-Ⅶtrial,cetuximab plus FOLFOX was reported to be reliable again.But bevacizumab plus oxaliplatin-based chemotherapy was still controversial.In addition,some trials have reported that bevacizumab is not suitable for conversion therapy.The results of the FIRE-Ⅲtrial showed that cetuximab led to a significant advantage over bevacizumab in response rate(72%vs 63%,P=0.017)for evaluable population.With the balanced allocation of second-line treatment,the FIRE-Ⅲtrial was expected to provide evidence for selecting following regimens after first-line progression.There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM,although the combined regimen is often administered based on experience.Combination therapy with more than one targeted agent has been proven to provide no benefit,and even was reported to be harmful as first-line treatment by four large clinical trials.However,recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment.The mechanism of antagonism between different targeted agents deserves further study,and may also provide greater understanding of the development of resistance to targeted agents.     

Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO KRK-0104 trial

Purpose

AIO KRK-0104 investigated first-line therapy of metastatic colorectal cancer (mCRC) with cetuximab, capecitabine and irinotecan versus cetuximab, capecitabine and oxaliplatin. This analysis investigated the impact of primary tumor location on outcome of patients.

Patients and methods

Left-sided primary tumors were defined as tumors from rectum to left flexure, while tumors in the remaining colon were regarded right sided. Overall survival (OS), progression-free survival (PFS) and response rate were correlated with primary tumor location. A Cox regression model was used to evaluate interaction between primary tumor location and KRAS mutation.

Results

Of 146 patients of the AIO KRK-0104 trial, 100 patients presented left-sided (of those 68 KRAS codon 12/13 wild-type) and 46 patients right-sided primary tumors (of those 27 KRAS codon 12/13 wild-type). Left-sided tumors were associated with significantly longer OS (p = 0.016, HR = 0.63) and PFS (p = 0.02, HR = 0.67) as compared to right-sided tumors. These effects were present in the KRAS codon 12/13 wild-type population (HR OS: 0.42; HR PFS: 0.54), while no impact of primary tumor location was evident in patients with KRAS codon 12/13 mutant tumors (HR OS: 1.3; HR PFS: 1.01). A significant interaction of KRAS status and primary tumor location concerning OS and PFS was observed.

Conclusion

Our findings suggest that primary tumor location and KRAS codon 12/13 mutational status interact on the outcome of patients with mCRC receiving cetuximab-based first-line therapy. Left-sided primary tumor location might be a predictor of cetuximab efficacy.     

FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts

AIM: To evaluate the efficacy and safety of the FOLFIRI regimen in patients with metastatic pancreatic adenocarcinoma (PAC) after the failure of gemcitabine and platinum salts.METHODS: All consecutive patients with histologically confirmed, metastatic PAC and World Health Organization performance status (PS) ≤ 2 received FOLFIRI-1 [irinotecan 180 mg/m² on day 1 and leucovorin 400 mg/m² followed by 5-fluorouracil (5-FU) 400 mg/m² bolus, then 5-FU 2400 mg/m² as a 46-h infusion, biweekly] or FOLFIRI-3 (irinotecan 100 mg/m² on day 1 and leucovorin 400 mg/m², then 5-FU 2400 mg/m² as a 46-h infusion and irinotecan 100 mg/m² repeated on day 3, biweekly) after failure of gemcitabine and platinum-based chemotherapies as a systematic policy in two institutions between January 2005 and May 2010. Tumor response, time to progression (TTP), overall survival rate (OS) and grade 3-4 toxicities were retrospectively studied. Subgroup analyses were performed to search for prognostic factors.RESULTS: Sixty-three patients (52.4% male, median age 59 years) were analyzed. Among them, 42.9% were PS 0, 38.1% were PS 1 and 19.0% were PS 2. Fifty one patients (81.0%) had liver metastases. Before the FOLFIRI regimen, patients had received 1 line (n = 19), 2 lines (n = 39) or 3 lines (n = 5) of chemotherapy. Median TTP obtained with the line before FOLFIRI was 3.9 mo (95% CI: 3.4-5.3 mo). A total of 480 cycles was completed (median: 6 cycles, range: 1-51 cycles). The main reason for discontinuing FOLFIRI was tumor progression (90.3%). Tumor control was achieved in 25 patients (39.7%) (partial response: n = 5, stable disease: n = 20) with FOLFIRI. Median TTP was 3.0 mo (95% CI: 2.1-3.9 mo) and median OS was 6.6 mo (95% CI: 5.3-8.1 mo). Dose adaptation was required in 36 patients (57.1%). Fifteen patients (23.8%) had grade 3-4 toxicities, mainly hematological (n = 11) or digestive (n = 4). Febrile neutropenia occurred in 3 patients. There was no toxic death. PS 2 was significantly associated with poor TTP [hazard ratio (HR): 16.036, P < 0.0001] and OS (HR: 4.003, P = 0.004).CONCLUSION: The FOLFIRI regimen had an acceptable toxicity and an interesting efficacy in our study, limited to patients in good condition (PS 0-1).     

KRAS突变对抗EGFR单抗治疗转移性结直肠癌影响的Meta分析

目的评价化疗或联合抗EGFR单抗治疗转移性结直肠癌的临床疗效与KRAS基因突变的关系。方法用"colorectal carcinoma"、"cetuximab"、"Panitumumab"系统检索PubMed、EMBASE、Ovid、CENTRAL(2000年1月-2011年11月)中关于KRAS突变对化疗或联合抗EGFR单抗(包括Cetuximab和Panitumumab)治疗转移性结直肠癌疗效的影响。结果包括无进展期(progressionfree survival,PFS)和总生存期(overall survival,OS)及其相应HR,依据Cochrane Handbook 5.0.2对符合标准的RCT进行Meta分析。结果 PFS的HR在KRAS野生型患者和突变型患者分别为-0.22(95%CI:-0.37~-0.07,P=0.005)和1.07(95%CI:0.88~1.30,P=0.48),OS的HR在KRAS野生型和突变型则为0.83(95%CI:0.82~0.85,P0.00001)、1.04(95%CI:0.95~1.15,P=0.40)。抗EGFR治疗均未见明显延长KRAS突变型mCRC患者的PFS和OS。结论 KRAS状态是预测mCRC患者抗EGFR治疗疗效的有效生物学标志之一。     

Combined Analysis of EGFR and PTEN Status in Patients With KRAS Wild-Type Metastatic Colorectal Cancer

To determine the relationship between the expression of phosphatase and tensin homologue (PTEN) and epidermal growth factor receptor (EGFR) in metastatic colorectal cancer (mCRC) and the clinical outcome of cetuximab-containing chemotherapy.A total of 158 consecutive mCRC patients with wild-type KRAS status who received chemotherapy with or without cetuximab, and for whom tumor tissue was available, were enrolled. The EGFR and PTEN expression was determined by immunohistochemistry (IHC).A total of 158 mCRC patients with wild-type KRAS status were enrolled in the study; 51 patients received chemotherapy combined with cetuximab, 107 patients received chemotherapy alone. Patients who received chemotherapy combined with cetuximab had longer overall survival (OS) compared with patients who received chemotherapy alone. High EGFR expression was detected in 60 patients (38.0%), while normal PTEN expression was detected in 60 patients (59.5%). The PTEN status was significantly related with the histological grade. For patients who received chemotherapy combined with cetuximab the median OS of patients with high-expression of EGFR was longer than the OS of patients with low EGRF expression; 25.0 versus 19.0 months, P = 0.002. For patient with normal PTEN the median OS were longer than the median OS for patients with loss of PTEN; 24.0 versus 19.0 months, P = 0.026. The overall response rate (ORR) had a borderline association with EGFR and PTEN expression (P = 0.055 and 0.048, respectively). In a multivariate analysis, ECOG PS, EGFR status, chemotherapy ± cetuximab, and the interaction of EGFR or PTEN and chemotherapy ± cetuximab were independent prognostic factors for OS.Our findings show that chemotherapy combined with cetuximab demonstrated encouraging antitumor activity for mCRC patients with wild-type KRAS status. Especially, those who have high EGFR expression or normal PTEN expression were more likely to benefit from such a treatment strategy. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.     

Phosphatase and tensin homolog expression related to cetuximab effects in colorectal cancer patients: a meta-analysis

AIM: To investigate the correlation between expression of phosphatase and tensin homolog (PTEN) and cetuximab effects in colorectal cancer.METHODS: We searched PubMed, EMBASE and ASCO to identify eligible studies. Finally, 8 randomized control studies were included in the meta-analysis. STATA 10.0 Software was used to investigate heterogeneity among individual studies and to summarize all the studies. Risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the strength of the association.RESULTS: Compared with 20 of 266 patients with loss of PTEN, 206 of 496 patients with intact PTEN protein expression had a better objective response rate to cetuximab-based therapy (RR, 4.75; 95% CI, 2.59-8.72; P < 0.001). PTEN positivity was associated with better progression-free survival (PFS) (HR, 0.675; 95% CI, 0.473-0.964; P = 0.031) but not with better overall survival (OS) (HR, 0.608; 95% CI, 0.411-0.899; P = 0.013). In patients with KRAS wild-type status, PTEN positivity did not predict a longer PFS or OS (PFS: HR, 0.707; 95% CI, 0.440-1.138; P = 0.154; OS: HR, 0.943; 95% CI, 0.646-1.377; P = 0.761).CONCLUSION: Expression of PTEN is related to the effect of cetuximab in colorectal cancer patients and should be considered in treatment with cetuximab.     

Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma

AIM: To investigate the role of perioperative chemoradiotherapy (CRT) in the treatment of locally advanced thoracic esophageal squamous cell carcinoma (ESCC). METHODS: Using preoperative computed tomography (CT)-based staging criteria, 238 patients with ESCC (stage ⅡⅢ ) were enrolled in this prospective study between January 1997 and June 2004. With informed consent, patients were randomized into 3 groups: preoperative CRT (80 cases), postoperative CRT (78 cases) and surgery alone (S) (80 cases). The 1-, 3-...     

Role of cetuximab in first-line treatment of metastatic colorectal cancer

The treatment of metastatic colorectal cancer(mCRC)has evolved considerably in the last decade,currently allowing most mCRC patients to live more than two years.Monoclonal antibodies targeting the epidermal growth factor receptor(EGFR)and vascular endothelial growth factor play an important role in the current treatment of these patients.However,only antibodies directed against EGFR have a predictive marker of response,which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(KRAS).Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC.The CRYSTAL study showed that adding cetuximab to FOLFIRI(regimen of irinotecan,infusional fluorouracil and leucovorin)significantly improved results in the first-line treatment of KRAS wildtype mCRC.However,results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory.On the other hand,recent advances in the management of colorectal liver metastases have improved survival in these patients.Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients.In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.     

S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer: A meta-analysis

AIM: To assess the efficacy and tolerability of S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer (AGC).METHODS: We extracted reported endpoints, including overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), objective response rate (ORR) and adverse effects, from randomized controlled trials identified in PubMed, the Cochrane library, Science Direct, EMBASE and American Society of Clinical Oncology meetings. Stata software was used to calculate the pooled values.RESULTS: Seven randomized controlled trials involving 2176 patients were included in this meta-analysis. Compared to non-S-1-based regimens, the use of S-1-based regimens were associated with an increase in ORR (RR = 1.300; 95%CI: 1.028-1.645); OS (HR = 0.89; 95%CI: 0.81-0.99; P = 0.025), TTF (HR = 0.83; 95%CI: 0.75-0.92; P = 0.000), and a lower risk of febrile neutropenia (RR = 0.225; P = 0.000) and stomatitis (RR = 0.230; P = 0.032). OS, PFS and TTF were prolonged, especially in the Asian population. In subgroup analysis, statistically significant increases in ORR (RR = 1.454; P = 0.029), OS (HR = 0.895; P = 0.041) and TTF (HR = 0.832; P = 0.000) were found when S-1-based chemotherapy was compared to 5-fluorouracil (5-FU)-based chemotherapy. The incidence of leukopenia (RR = 0.584; P = 0.002) and stomatitis (RR = 0.230; P = 0.032) was higher in the 5-FU-based arm. S-1-based regimens had no advantage in ORR, OS, PFS, TTF and grade 3 or 4 adverse events over capecitabine-based regimens.CONCLUSION: S-1-based chemotherapy may be a good choice for AGC because of longer survival times, better tolerance and more convenient use.     

Skeletal muscle loss during chemotherapy and its association with survival and systemic treatment toxicity in metastatic colorectal cancer: An AGEO prospective multicenter study

PurposeWe showed in a previous study that the PG-SGA score is associated with survival and chemotherapy-related toxicities in metastatic colorectal cancer (mCRC) patients. The objective was to evaluate the association between pretherapeutic sarcopenia and variation in skeletal muscle index (SMI) during treatment with these outcomes in the same population.MethodsThis prospective, multicenter, observational study enrolled non-pretreated mCRC patients. SMI was measured on routine CT scan at day 0 (D0) and day 60 (D60). Nutritional factors were collected at D0. Progression-free survival (PFS) and overall survival (OS) were calculated from treatment start.Results149 patients were included from 7/2013 to 11/2016. Pretherapeutic sarcopenia was not significantly associated with survival or chemotherapy-related toxicities. The decrease in SMI > 14% was significantly associated with shorter PFS (6 vs 9 mo; HR 1.8, 95% CI 1.1?3.1, p = 0.02) and OS (8.5 vs 26 mo; HR 2.6, 95% CI 1.4?4.8, p = 0.002), independently of hypoalbuminemia and malnutrition defined by PG-SGA. Patients with a SMI decrease > 14% had a higher rate of grade ≥ 2 clinical toxicities (40% vs 22%, OR 3.0, 95% CI 1.2?7.7, p = 0.02), but the difference was not statistically significant in multivariable analysis.ConclusionTo our knowledge, this is the first study to assess prospectively the association of skeletal muscle loss with survival and treatment toxicities in non-pretreated patients with mCRC. Pretherapeutic sarcopenia was not associated with poor outcomes, but the loss of skeletal muscle mass within 60 days from treatment start was highly prognostic, independently of other prognostic and nutritional factors.     

Efficacy of adjuvant XELOX and FOLFOX6 chemotherapy after D2 dissection for gastric cancer

AIM: To compare the efficacy of capecitabine and oxaliplatin (XELOX) with 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX6) in gastric cancer patients after D2 dissection. METHODS: Between May 2004 and June 2010, patients in our gastric cancer database who underwent D2 dissection for gastric cancer at the First Affiliated Hospital of Sun Yat-Sen University were retrospectively analyzed. A total of 896 patients were enrolled into this study according to the established inclusion and exclusion criteria. Of these patients, 214 received the XELOX regimen, 48 received FOLFOX6 therapy and 634 patients underwent surgery only without chemotherapy. Overall survival was compared among the three groups using Cox regression and propensity score matchedpair analyses. RESULTS: Patients in the XELOX and FOLFOX6 groups were younger at the time of treatment (median age 55.2 years; 51.2 years vs 58.9 years), had more undifferentiated tumors (70.1%; 70.8% vs 61.4%), and more lymph node metastases (80.8%; 83.3% vs 57.7%), respectively. Overall 5-year survival was 57.3% in the XELOX group which was higher than that (47.5%) in the surgery only group (P = 0.062) and that (34.5%) in the FOLFOX6 group (P = 0.022). Multivariate analysis showed that XELOX therapy was an independent prognostic factor (hazard ratio = 0.564, P < 0.001). After propensity score adjustment, XELOX significantly increased overall 5-year survival compared to surgery only (58.2% vs 44.2%, P = 0.025) but not compared to FOLFOX6 therapy (48.5% vs 42.7%, P = 0.685). The incidence of grade 3/4 adverse reactions was similar between the XELOX and FOLFOX6 groups, and more patients suffered from hand-foot syndrome in the XELOX group (P = 0.018). CONCLUSION: Adjuvant XELOX therapy is associated with better survival in patients after D2 dissection, but does not result in a greater survival benefit compared with FOLFOX6 therapy.     

FOLFOX和FOLFIRI方案用于大肠黏液腺癌辅助化疗的比较

目的探讨FOLFOX及FOLFIRI方案在大肠黏液腺癌术后辅助化疗中的疗效差异。 方法将40例术后病理证实为大肠黏液腺癌患者随机分为2组,实验组应用FOLFIRI方案化疗,对照组应用FOLFOX方案化疗。比较两组的无进展生存时间（progression free survival,PFS）,并应用Kaplan-Meier法进行生存率统计分析。 结果FOLFOX组的中位PFS为13个月,FOLFIRI组的中位PFS为18个月。FOLFIRI方案组PFS比FOLFOX方案组PFS长5个月,差异有统计学意义（χ²=4.294,P=0.038）。 结论对于大肠黏液腺癌,术后应用FOLFIRI方案化疗比FOLFOX方案可延长PFS。     

Cetuximab plus irinotecan in pretreated metastatic colorectal cancer patients: the ELSIE study

AIM:To evaluate the efficacy and safety of cetuxim-ab plus irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients from South-East Asia and Australia. METHODS:In this open-label,phase Ⅱ study,the main eligibility criteria were epidermal growth factor receptor-positive mCRC with progressive disease within 3 mo of an irinotecan-based regimen as the most recent chemotherapy. Patients received cetuximab 400 mg/m2 initially,then 250 mg/m2 every week,with the same regimen of irinotecan on...     

免疫治疗相关性甲状腺功能异常与不可切除/晚期肝细胞癌患者预后改善相关

摘要 目的：探讨免疫治疗相关性甲状腺功能异常与不可切除/晚期肝细胞癌（HCC）患者预后改善的相关性。方法：回顾性分析45例接受免疫检查点抑制剂（ICIs）治疗的不可切除/晚期HCC患者。根据ICIs治疗过程中是否出现免疫相关性甲状腺功能异常分为甲状腺功能正常组（28例）和异常组（17例）,比较2组患者的预后和免疫应答情况,主要终点指标为中位总生存期（OS）、无进展生存期（PFS）,次要终点指标为疾病控制率（DCR）。结果：所有患者的中位OS、PFS分别为10.8个月（95% CI ：3.0~18.6）和5.0个月（95% CI ：3.0~12.2）。正常组中位OS为5.8个月（95% CI ：3.7~7.9）,异常组中位OS尚未达到（ P =0.026）。异常组中位PFS长于正常组（8.2个月 vs. 3.1个月, P =0.011）,DCR高于正常组（52.9% vs. 21.5%,P =0.030）。多因素Cox回归分析显示,甲状腺功能异常是达到6个月OS（ HR=0.213,95%CI ：0.048~0.944, P =0.042）和PFS（ HR=0.383,95%CI：0.151~0.967,P =0.042）的独立影响因素;甲状腺功能异常（ HR=0.403 ,95%CI：0.185~0.877,P =0.022）、基线无大血管侵犯（MVI）（ HR=2.848,95%CI：1.406~5.768,P =0.004）、Child-Pugh A级（ HR=2.404,95%：1.099~5.255,P =0.028）与12个月PFS相关。结论：免疫治疗相关性甲状腺功能异常的不可切除/晚期HCC患者预期生存和免疫应答效果更佳。治疗期间出现甲状腺功能异常、基线无MVI、Child-Pugh A级与患者预后改善相关。     

Combined endovascular brachytherapy,sorafenib, and transarterial chemobolization therapy for hepatocellular carcinoma patients with portal vein tumor thrombus

AIM To evaluate the safety and efficacy of combined endovascular brachytherapy(EVBT),transarterial chemoembolization(TACE),and sorafenib to treat hepatocellular carcinoma(HCC) patients with main portal vein tumor thrombus(MPVTT).METHODS This single-center retrospective study involved 68 patients with unresectable HCC or those who were unfit for liver transplantation and percutaneous frequency ablation according to the BCLC classification. All patients had Child-Pugh classification grade A or B,Eastern Cooperative Oncology Group(ECOG)performance status of 0-2,and MPVTT. The patients received either EVBT with stent placement,TACE,and sorafenib(group A,n = 37),or TACE with sorafenib(group B,n = 31). The time to progression(TTP) and overall survival(OS) were evaluated by propensity score analysis.RESULTS In the entire cohort,the 6-,12-,and 24-mo survival rates were 88.9%,54.3%,and 14.1% in group A,and 45.8%,0%,and 0% in group B,respectively(P 0.001). The median TTP and OS were significantly longer in group A than group B(TTP: 9.0 mo vs 3.4 mo,P 0.001; OS: 12.3 mo vs 5.2 mo,P 0.001). In the propensity score-matched cohort,the median OS was longer in group A than in group B(10.3 mo vs 6.0 mo,P 0.001). Similarly,the median TTP was longer in group A than in group B(9.0 mo vs 3.4 mo,P 0.001). Multivariate Cox analysis revealed that the EVBT combined with stent placement,TACE,and sorafenib strategy was an independent predictor of favorable OS(HR = 0.18,P 0.001). CONCLUSION EVBT combined with stent placement,TACE,and sorafenib might be a safe and effective palliative treatment option for MPVTT.     

Advances in chemotherapy against advanced or metastatic colorectal cancer

In the early 1990s, some prospective controlled trials revealed the superiority of chemotherapy for survival compared with best supportive care for advanced or metastatic colorectal carcinoma. Until recently, 5-fluorouracil (5-FU) and leucovorin (LV) were the standard therapies against advanced or metastatic colorectal cancer. Theoretically, LV should increase the antitumor activity of 5-FU, although this effect of LV addition has been controversial. A meta-analysis which analyzed 21 randomized controlled trials revealed that a combination of 5-FU and LV doubled the response rate compared with 5-FU alone (from 11 to 21%) and prolonged the median survival time by about 1 month (from 10.5 to 11.7 months). Chemotherapy against advanced or metastatic colorectal cancer has steadily advanced after the introduction of triplet regimens containing 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) and (trans-R,R-1,2-diamine cyclohexane)oxalatoplatinum(II) (L-OHP). For LV/5-FU/CPT-11, the regimen in which 5-FU is administered with continuous infusion (FOLFIRI) is preferred compared with the 5-FU bolus infusion. According to the results of the randomized controlled trial comparing FOLFIRI followed by FOLFOX6 and the reverse sequence, FOLFOX6 followed by FOFIRI, in the treatment of advanced colorectal cancer, FOLFIRI and FOLFOX are now considered to have almost the same efficacy in the treatment of advanced or metastatic colorectal cancer. FOLFIRI followed by FOLFOX or FOLFOX followed by FOLFIRI provide a median survival time of about 21 months in advanced or metastatic colorectal cancer. Both an anti-vascular endothelial growth factor monoclonal antibody, bevacizumab, and an anti- epidermal growth factor receptor monoclonal antibody, cetuximab, should prolong the survival of advanced or metastatic colorectal cancer by 2-3 months in combination with FOLFIRI or FOLFOX. However, from the viewpoint of medical economics, because of the high acquisition costs in relation to clinical benefits, antibodies are unlikely to represent a cost-utility solution. New agents, including macromolecule agents, small-molecule agents and vaccines, will be introduced alongside chemotherapy against colorectal cancer. Subsequently, clinical researchers will have to consider the cost-utility of these agents.