Treatments after progression to first-line FOLFOXIRI and bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies by GONO

Background FOLFOXIRI/bevacizumab (bev) is a first-line regimen of proven activity and efficacy in metastatic colorectal cancer. The upfront exposure to three cytotoxics raises concerns about the efficacy of treatments after progression.Methods We performed a pooled analysis of treatments after progression to upfront FOLFOXIRI/bev in patients enrolled in two randomised Phase 3 studies (TRIBE and TRIBE2) that compared FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev. Response rate, progression-free survival (2nd PFS) and overall survival (2nd OS) during treatments after progression were assessed. The RECIST response in first line and the oxaliplatin and irinotecan-free interval (OIFI) were investigated as potential predictors of benefit from FOLFOXIRI ± bev reintroduction.Results Longer 2nd PFS was reported in patients receiving FOLFOXIRI ± bev reintroduction compared to doublets ± bev or other treatments (6.1 versus 4.4 and 3.9 months, respectively, P = 0.013), and seems limited to patients achieving a response during first line (6.9 versus 4.2 and 4.7 months, respectively, P = 0.005) and an OIFI ≥ 4 months (7.2 versus 6.5 and 4.6 months, respectively, P = 0.045).Conclusions First-line FOLFOXIRI/bev does not impair the administration of effective second-line therapies. First-line response and longer OIFI seem associated with improved response and 2nd PFS from FOLFOXIRI ± bev reintroduction, without impacting 2nd OS.Subject terms: Colorectal cancer, Chemotherapy     

Prognostic role of sarcopenia in metastatic colorectal cancer patients during first-line chemotherapy: A retrospective study

BACKGROUNDSarcopenia is a condition characterized by decreased skeletal muscle mass due to physiological ageing or to a concomitant disease such as neoplasia. In cancer patients, a low lean body mass is suggested to be a negative prognostic factor for survival and for the development of dose-limiting chemotherapy toxicities irrespective of disease stage. AIMTo evaluate the prognostic role of sarcopenia in patients with metastatic colorectal cancer (mCRC) undergoing first-line chemotherapy.METHODSOur retrospective analysis included 56 mCRC patients who received first-line chemotherapy from 2014 to 2017 at the Medical Oncology Unit of our hospital. Computerized scans were performed before starting chemotherapy and at the first disease reassessment. Sarcopenia was assessed using the skeletal mass index = muscle area in cm²/(height in m²) calculated at the L3 vertebra. Overall survival and objective response rate were evaluated. Toxicities were analyzed during the first four cycles of therapy and graded according to Common Terminology Criteria for Adverse Events version 4.0. A loss of skeletal muscle mass ≥ 5% was considered indicative of deterioration in muscle condition.RESULTSMedian age was 67 years and 35.7% of patients were ≥ 70 years old. Fourteen patients (25%) were sarcopenic at baseline computed tomography (CT) scan (7/33 men; 7/23 women); 5/14 sarcopenic patients were ≥ 70 years old. Median follow-up was 26.8 mo (3.8-66.8 mo) and median overall survival was 27.2 mo (95%CI: 23.3-37.3). Sarcopenia was not correlated to overall survival (P = 0.362), to higher toxicities reported during the first 4 cycles of chemotherapy (P = 1.0) or to response to treatment (P = 0.221). At the first disease reassessment, a skeletal muscle loss (SML) ≥ 5% was found in 17 patients (30.3%) 3 of whom were already sarcopenic at baseline CT scan, while 7 patients became sarcopenic. SML was not correlated to overall survival (P = 0.961). No statistically significant correlation was found between baseline sarcopenia and age (P = 1.0), body mass index (P = 0.728), stage at diagnosis (P = 0.355) or neutrophil/lymphocyte ratio (P = 0.751).CONCLUSIONNeither baseline sarcopenia nor SML affected survival. In addition, baseline sarcopenia was not related to worse treatment toxicity. However, these results must be interpreted with caution due to the limited sample size.     

Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO

BackgroundRight-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status.Patients and methodsPatients were randomized to receive upfront 5-fluoruracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or 5-fluoruracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. Tumors were defined as right- or left-sided if they originated from the caecum to the transverse colon or within the splenic flexure and beyond, respectively. Patients with available information about both primary sidedness and RAS and BRAF status were included in the present analysis. Progression-free survival (PFS), overall survival (OS) and RECIST response rate were assessed according to tumor location and RAS and BRAF mutational status.ResultsInformation about primary sidedness and RAS and BRAF status was available for 358 (70.5%) out of 508 randomized patients. Patients with right-sided tumors (N = 173) presented shorter OS [23.7 versus 31.0 months, HR = 1.42 (95% CI 1.09–1.84), P = 0.010] and a trend toward shorter PFS [10.2 versus 11.5 months, HR = 1.24 (95% CI: 0.98–1.56), P = 0.083] than those with left-sided tumors (N = 185), but these associations were no longer evident when adjusting for RAS and BRAF status. Patients with right-sided tumors achieved more relative benefit from the intensification of the chemotherapy backbone in terms of both PFS (HR = 0.59 versus 0.89, P for interaction = 0.099) and OS (HR = 0.56 versus 0.99, P for interaction = 0.030) and this advantage was independent of their RAS and BRAF status.ConclusionsFOLFOXIRI plus bevacizumab may be regarded as a preferred first-line treatment option for clinically selected patients with right-sided metastatic colorectal cancer irrespective of their RAS and BRAF mutational status. Trial registration: clinicaltrials.gov identifier NCT00719797.     

淋巴结转移率对结直肠癌患者预后评估的价值

目的 探讨淋巴结转移率(MLR)在结直肠癌患者预后评估中的临床应用价值.方法 回顾303例手术治疗的结直肠癌患者的临床资料,分析MLR和淋巴结转移数目与清扫淋巴结总数的相关性,以及影响结直肠癌患者预后的因素,探讨MLR预测结直肠癌患者术后5年生存情况的准确性,并与淋巴结转移数目的 预测结果 进行比较.结果 MLR与清扫淋巴结总数无相关性(r=-0.099,P＞0.05),而淋巴结转移数目与清扫淋巴结总数有相关性(r=0.107,P＜0.05).Kaplan-Meier生存分析显示,即使受检淋巴结总数＜12枚,MLR仍影响患者术后生存时间(X2=42.878,P＜0.01).rN0、rN1、rN2和rN3期患者的5年生存率分别为90.9%、68.9%、54.7%和39.4%,差异有统计学意义(P＜0.01).多因素分析显示,肿瘤大小和rN分期是影响结直肠癌患者预后的独立危险因素.通过比较相对危险度,独立危险因素与预后的密切程度依次为rN分期＞肿瘤大小.MLR和淋巴结转移数目预测结直肠癌患者术后5年生存的ROC曲线下面积比较,差异无统计学意义.结论 结直肠癌患者的MLR与清扫淋巴结总数不相关;MLR是结直肠癌患者预后的主要独立危险因素;MLR预测结直肠癌患者术后5年生存情况的准确性与淋巴结转移数目的 预测能力相同.     

Derived neutrophil lymphocyte ratio is predictive of survival from intermittent therapy in advanced colorectal cancer: a post hoc analysis of the MRC COIN study

Background:

The phase III COntinuous or INtermittent (COIN) trial failed to show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in overall survival (OS). The present analysis evaluated whether the derived neutrophil to lymphocyte ratio (dNLR) could predict the effect of intermittent vs continuous chemotherapy on OS in patients with advanced colorectal cancer.

Methods:

A post hoc exploratory analysis of COIN arms A and C was performed. Landmark analysis was conducted on all patients with available WBC and neutrophils data. The dNLR was calculated using a formula which has previously demonstrated predictive power in cancer patients: dNLR=ANC/(WBC−ANC). A high dNLR was defined using a cut-off value of ⩾2.22. Derived neutrophil to lymphocyte ratio was then correlated with clinical outcomes. Survival curves were generated based on dNLR using the Kaplan–Meier method. Comparison between groups was performed using Cox regression.

Results:

A total of 1630 patients were assigned to the continuous (N=815) or intermittent (N=815) arms. There was a strong association between dNLR level and OS. The median survival times in the ITT population were 18.6 months and 12.5 months for patients with low and high dNLR, respectively (HR=1.70; 95% CI=1.52–1.90; P<0.001). The estimate of the hazard ratio did not alter substantially (HR=1.54) after adjusting for treatment, tumour status, number of metastatic sites, alkaline phosphate and platelet count.

Conclusions:

Derived neutrophil to lymphocyte ratio is strongly prognostic for survival in the COIN intermittent vs continuous treatment arms. Derived neutrophil to lymphocyte ratio does not predict for detrimental survival in patients treated with intermittent therapy.     

The SENECA study: Prognostic role of serum biomarkers in older patients with metastatic colorectal cancer

BackgroundAging induces meaningful changes in the immune system and inflammation response with increase in monocyte-lymphocyte ratio (MLR) and serum lactate dehydrogenase (LDH) levels. Aim of this study was to explore the prognostic role of MLR and LDH levels in older patients (pts) with metastatic colorectal cancer (mCRC).MethodsWe conducted a retrospective analysis of a consecutive cohort of 168 older (>70 years) patients with mCRC. The prognostic impact of MLR and LDH levels on overall survival (OS) was investigated through uni-and multivariate Cox regression analyses. Moreover, we categorized patients into three groups according to MLR and LDH levels (group 1: MLR-low and LDH-low; group 2: MLR-high or LDH-high; group 3: MLR-high and LDH-high).ResultsBy univariate analysis, high LDH level (HR 1.74, 95% CI 1.05–2.90) and high MLR level (HR 2.19, 95% CI 1.48–3.44) were significantly associated with a worse OS. Conversely, primary tumor resection and left-sidedness were significantly associated with a longer OS. By multivariate analysis, high LDH level (HR 2.00, 95% CI 1.13–3.55) and high MLR level (HR 2.99, 95% CI 1.68–5.33) were independent prognostic factors of worse prognosis. Compared to group 1, a shorter survival was reported for patients included in group 2 (HR 1.97, 95% CI 1.21–3.23 in univariate; HR 2.54, 95% CI 1.43–4.51 in multivariate) or in group 3 (HR 2.42, 95% CI 24–4.74, p = .010 in univariate; HR 5.59, 95% CI 2.15-14.54 in multivariate)ConclusionsHigh baseline levels of LDH, MLR or both are independent unfavorable prognostic factors in older patients treated with first-line chemotherapy for mCRC.     

Impact of age and gender on the safety and efficacy of chemotherapy plus bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies

BackgroundThe phase III TRIBE and TRIBE2 studies randomized metastatic colorectal cancer patients to first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI or FOLFOX)/bevacizumab. The studies demonstrated a significant benefit from the triplet at the price of an increased incidence of chemotherapy-related adverse events (AEs). In both trials, males and females aged between 18 and 70 years with ECOG PS ≤2 and between 71 and 75 years with ECOG PS = 0 were eligible. We investigated the effect of FOLFOXIRI/bevacizumab versus doublets/bevacizumab according to age and gender.Patients and methodsSubgroup analyses according to age (<70 versus 70–75 years) and gender were carried out for overall response rate (ORR), progression-free survival (PFS), and AE rates.ResultsOf 1187 patients, 1005 (85%) were aged <70 years and 182 (15%) 70–75 years; 693 (58%) were males and 494 (42%) females. There was no evidence of interaction between age or gender and the benefit provided by the intensification of the upfront chemotherapy in terms of ORR and PFS, or the increased risk of experiencing G3/4 AEs. Elderly patients and females experienced higher rates of overall G3/4 AEs (73% versus 60%, P < 0.01 and 69% versus 57%, P < 0.01, respectively). Notably, in the FOLFOXIRI/bevacizumab subgroup, G3/4 diarrhea and febrile neutropenia occurred in 27% and 16% of elderly patients, respectively, while females reported high incidences of any grade nausea (67%) and vomiting (50%).ConclusionsThe improvements in terms of ORR and PFS of FOLFOXIRI/bevacizumab versus doublets/bevacizumab are independent of gender and age, with a similar relative increase in AEs among elderly patients and females. Initial dose reductions and possibly primary G-CSF prophylaxis should be recommended for patients between 70 and 75 years old treated with FOLFOXIRI/bevacizumab, and a careful management of antiemetic prophylaxis should be considered among females.     

Prognostic significance of neutrophil-to lymphocyte ratio and platelet-to lymphocyte ratio in older patients with metastatic colorectal cancer

Aging is associated with a higher risk of cancer, >70% of cancer-related deaths occur in aged patients; however, this population is underrepresented in clinical trials, therefore, clinical information regarding this age group is rather limited.ObjectivesNeutrophil-to lymphocyte ratio (NLR) and platelet-to lymphocyte ratio (PLR) have been described as biomarkers in cancer, thus, we have assessed their impact in an aged cohort of patients with metastatic colorectal cancer (mCRC).Patients and Methods110 patients with a mean age of 72.2 years at diagnosis were retrospectively reviewed; NLR and PLR were calculated and dichotomized using a cutoff point estimated by a ROC curve. Survival curves and Cox regression analysis were performed to assess the prognostic potential of ratios in terms of progression free survival (PFS) and overall survival (OS).ResultsHigh NLR was associated to worse outcome in terms of PFS (ten vs sixteen months; Log rank <0.001) (HR 2.00 95%CI 1. 29–3.11; p = .002) and OS (20 vs 26 months; Log rank 0.002) (HR 2.28 95%CI 1.40–3.71; p = .001). Similarly it occurs with high PLR and PFS (nine vs fifteen months; Log rank 0.04) (HR 1.55 95%CI 1.01–2.40; p = .04) and OS (nineteen vs 25 months; Log rank <0.001) (HR 2.35 95%CI 1.45–3.80; p < .001).ConclusionThis study confirms the role of NLR and PLR as accessible and noninvasive biomarkers that could be use as a routine tool in the clinical practice in geriatric patients with mCRC.     

CEA increase as a marker of disease progression after first-line induction therapy in metastatic colorectal cancer patients. A pooled analysis of TRIBE and TRIBE2 studies

Background In mCRC, CEA is used to monitor response to systemic therapy together with imaging. After the end of induction, no major improvement in tumour shrinkage is expected, and the availability of a marker able to predict progressive disease (PD) versus no-PD might allow avoiding CT scans.Methods We pooled data from patients with baseline CEA ≥ 10 ng/mL included in TRIBE and TRIBE2 studies with the aim of identifying a threshold for percent increase of CEA from nadir able to predict PD after the end of the induction therapy.Results In total, 1178 paired CEA and radiological assessments from 434 patients were included. According to the optimal cut-off determined by ROC, a CEA increase of at least 120% from nadir differentiated between PD and no-PD with a sensitivity of 74% and a specificity of 78%, excluding PD in the 92% of radiological assessments and allowing to avoid the 67% of CT scans. However, CEA cut-off of 120% was not able to detect radiological PD in 26% of cases. In order to mitigate this issue, a different clinically relevant threshold was evaluated based on the best sensitivity cut-off. Therefore, using any CEA increase from nadir as a threshold, the sensitivity grew to 93% and only in the 7% of cases the radiological PD was not detected.Conclusions In mCRC with baseline CEA ≥ 10 ng/mL, CEA values can accurately predict PD versus no-PD after the end of the first-line induction therapy.Subject terms: Predictive markers, Colorectal cancer     

Prognostic and predictive relevance of microsatellite instability in colorectal cancer

Microsatellite instability (MSI) is the phenotypic hallmark of a deficient DNA mismatch-repair system, observed in 10-20% of sporadic colorectal cancers (CRC). Since the prognostic and predictive value of this genetic alteration has been assessed mainly in non-randomised, uncontrolled studies, we investigated the potential of MSI to predict patient survival and response to adjuvant chemotherapy in tumour specimens from a randomised trial of the Swiss Group for Clinical Cancer Research (SAKK) that tested the value of 5-fluorouracil/mitomycin adjuvant chemotherapy. MSI status was determined in matched normal and tumour tissue samples from 160 patients using a panel of 9 microsatellite markers. There was no correlation between high frequency MSI (MSI-H) and overall (OS) or disease-free survival (DFS) in the untreated control group of patients (HR=1.13, p=0.80; and HR=0.89, p=0.81, respectively). Furthermore, MSI-H phenotype did not predict for a larger benefit of adjuvant chemotherapy on OS or DFS (HR=0.49, p=0.41; HR=0.49, p=0.41, respectively), making a potential value of this molecular marker as a predictive factor in CRC unlikely. Our data do not confirm the prognostic relevance of MSI-H status in colorectal cancer patients found in some other studies. In addition, microsatellite instability did not correlate with the extent of chemotherapy benefit, although we observed a statistically non-significant favourable impact of 5-FU-based treatment in the MSI-H group compared to MSI-L/MSS patients. Larger prospective randomised trials are required to conclusively establish a potential clinical significance of MSI in colorectal cancer.     

KRAS testing of patients with metastatic colorectal cancer in a community-based oncology setting: a retrospective database analysis

Background

In 2009, treatment guidelines were updated to recommend KRAS testing at diagnosis for patients with metastatic colorectal cancer (mCRC). We investigated KRAS testing rates over time and compared characteristics of KRAS-tested and not-tested patients in a community-based oncology setting.

Methods

Adult patients with a diagnosis of mCRC from 2008–2011 were selected from the ACORN Data Warehouse (ACORN Research LLC, Memphis, TN). Text mining of physician progress notes and full chart reviews identified KRAS-tested patients, test dates, and test results (KRAS status). The overall proportion of eligible patients KRAS-tested in each calendar year was calculated. Among KRAS-tested patients, the proportion tested at diagnosis (within 60 days) was calculated by year. Univariate and multivariate analyses were used to compare patient characteristics at diagnosis between tested and not-tested cohorts, and to identify factors associated with KRAS testing.

Results

Among 1,363 mCRC patients seen from 2008–2011, 648 (47.5%) were KRAS-tested. Among newly diagnosed mCRC patients, the rate of KRAS testing increased from 5.9% prior to 2008, to 13.9% in 2008, and then jumped dramatically to 32.3% in 2009, after which a modest yearly increase continued. The proportions of KRAS-tested patients who had been diagnosed in previous years but not tested previously increased from 17.7% in 2008 to 27.0% in 2009, then decreased to 19.0% in 2010 and 17.6% in 2011. Among patients who were KRAS-tested, the proportions tested at the time of diagnosis increased annually (to 78.4% in 2011). Patients more likely to have been tested included those with lung metastases, poor performance status, more comorbidities, and mCRC diagnosis in 2009 or later.

Conclusions

The frequency of KRAS testing increased over time, corresponding to changes in treatment guidelines and epidermal growth factor receptor inhibitor product labels; however, approximately 50% of eligible patients were untested during the study period.     

Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer

Background:

We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC).

Methods:

We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively.

Results:

KRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1–7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2–7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy.

Conclusions:

These results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials.     

Prognostic and predictive value of tumor-infiltrating lymphocytes in breast cancer: a systematic review and meta-analysis

Background

Breast cancer is the most common invasive cancer to affect women in the world. Studies showed tumor-infiltrating lymphocytes can exhibit both beneficial and harmful effects on the biology and clinical outcome of breast cancer, the conclusion still remains incomplete. Here, we conducted a meta-analysis to evaluate the relationship between tumor-infiltrating lymphocytes and breast cancer.

Methods

A comprehensive search strategy was used to search relevant literatures in PubMed and the ISI Web of Science. The correlation among TILs and breast cancer clinicopathological features and prognosis was analyzed by using Review Manager 5.3 and Stata 12.0.

Result

Seventeen eligible studies consisting of 12,968 participants were included. We found that higher value of tumor-infiltrating lymphocytes had no relationship with breast cancer clinicopathological variables. Interestingly, it was correlated with response to neoadjuvant chemotherapy in majority (pooled RR 2.43, 95 % CI 1.99–2.97). Moreover, higher value of total tumor-infiltrating lymphocytes (both intraepithelial and stromal) was associated with better prognosis (pooled HR 0.88, 95 % CI 0.83–0.94), whereas some subtypes predicted a worse prognosis.

Conclusion

This meta-analysis indicated that high value of total TILs is not associated with breast cancer clinicopathological features, but can predict a favorable outcome for neoadjuvant chemotherapy in majority except for hormone receptor (?) subtype. And higher total TILs (both intraepithelial TILs and stromal TILs) may be the potential better prognostic indicators, while some subtypes like PD-1⁺ TILs and Foxp3⁺ TILs show a worse prognosis.

     

改良FOLFOXIRI方案作为三线或三线后方案治疗晚期结直肠癌的回顾性研究

  目的  标准治疗失败后,评估改良FOLFOXIRI方案后线治疗不可切除的晚期转移性结直肠癌患者的安全性及疗效。  方法  回顾性分析杭州市第一人民医院和杭州市肿瘤医院2011年1月至2016年12月收治的晚期结直肠癌患者。共13例患者在标准疗失败后应用了改良FOLFOXIRI方案(5-氟尿嘧啶或卡培他滨、亚叶酸钙联合伊立替康、奥沙利铂)治疗,并接受了随访。  结果  13例患者中位年龄为54(41~68)岁,接受了中位化疗周期为4(1~8)个周期的改良FOLFOXIRI方案治疗,并进行了疗效和不良反应的评估。其中10例(76.9%)患者接受了超过4个周期的方案,中位无进展生存期(median progression-free survival,mPFS)为4.5(95% CI:2.5~6.5)个月。由于观察时间较短,4例未达到观察终点,中位总生存期(median overall survival,mOS)为14(95% CI:5.7~22.3)个月,客观缓解率(objective remission rate,ORR)为30%,临床获益率(clinical benefit rate,CBR)为90%。最常出现的3~4级不良发应事件为贫血、白细胞减少、血小板减少和周围神经病变。未发生治疗相关性死亡。  结论  本研究中,患者体力状况允许的前提下,标准治疗失败后应用改良FOLFOXIRI方案的晚期结直肠癌患者可获得mPFS与mOS的获益。不良反应均在可控范围内。      

A retrospective analysis of periodontitis during bevacizumab treatment in metastatic colorectal cancer patients

Background

Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has showed clinical benefits in patients with metastatic colorectal cancer. Periodontitis has been observed infrequently in bevacizumab-containing chemotherapy in clinical practice. The purpose of this study was to retrospectively investigate bevacizumab-related periodontitis in metastatic colorectal cancer patients.

Methods

From January 2008 to March 2010, 274 patients received bevacizumab-containing chemotherapy at the National Cancer Center Hospital in Tokyo. Patients who had consulted the dentist for periodontitis were included in the study. We examined the interval between the initiation of the first bevacizumab administration and the day of the consultation with the dentist. Periodontitis was evaluated before and after conservative therapy.

Results

Twenty-six patients (9.5 % of the 274 metastatic colorectal cancer patients) were included in this study. The median age was 60 years (range 30–79 years). Nineteen (73 %) patients had a good performance status of 0. The combination regimens used with bevacizumab were infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX, 53 %); infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI, 27 %); capecitabine + oxaliplatin (CapeOX, 8 %); S-1 + oxaliplatin (8 %); and S-1 + irinotecan (4 %). The median time from bevacizumab administration to the consultation with a dentist for periodontitis was 69 days (range 12–390 days), and the median number of bevacizumab administrations was 3.5 (range 1–25). After conservative therapy, 22 (85 %) patients with periodontitis showed an improvement.

Conclusions

Periodontitis occurred frequently in patients receiving bevacizumab. The conservative therapy for periodontitis was very effective, and the prophylaxitic treatment was important.     

中性粒细胞/淋巴细胞比值与结直肠癌病理因素及预后相关性

目的研究中性粒细胞/淋巴细胞比值（NLR）与结直肠癌病理因素及预后的关系,为临床预测结直肠癌预后提供依据。方法回顾性分析2013年1月至2016年1月中国医科大学附属第四医院收治的120例可手术结直肠癌患者的临床资料,收集患者入院2 d的血常规资料,计算NLR。对患者进行随访,随访截至2019年3月30日,采用受试者工作特征（ROC）曲线分析术前NLR对可手术结直肠癌患者死亡率的预测价值。分析NLR与结直肠癌病理特征及预后的关系,采用Cox分析影响结直肠癌患者全因死亡的危险因素。结果截至随访结束,本组120例患者中有10例失访,随访成功率91.7%（110/120）。中位随访时间为55个月。110例中死亡37例,存活73例。ROC曲线显示,NLR预测死亡的最佳临界点为3.1,此时的灵敏度为65.2%,特异度为74.4%。将3.1作为NLR的临界值,将110例患者分为NLR升高组（NLR>3.1）40例和NLR降低组（NLR≤3.1）70例。NLR升高组的年龄、恶性肿瘤家族史比例、肿瘤部位在结肠者及TNM分期为Ⅲ期的比例高于NLR降低组,差异有统计学意义。logistic回归分析显示肿瘤部位为结肠（OR=1.325,95%CI=1.104～2.654,P=0.042）、TNM分期高（OR=1.674,95%CI=1.233～5.987,P=0.032）是术前NLR升高的独立危险因素。NLR升高组的生存率较NLR降低组显著降低,差异有统计学意义（P＜0.05）。Cox多因素回归分析显示,术前NLR（OR=1.725,95%CI=1124～6.674）、TNM分期（OR=1.835,95%CI=1.324～8.417）、年龄（OR=1.129,95%CI=1.054～2.215）、肿瘤分化程度（OR=1.378,95%CI=1.114～3.699）、脉管侵犯（OR=1.341,95%CI=1.097～3.241）是结直肠癌患者死亡率的独立影响因素（P＜0.05）。结论术前NLR是结直肠癌死亡率的独立影响因素,可用于预测结直肠癌患者预后,NLR升高患者的预后不良。     

Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients

Background:

Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy.

Methods:

Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status.

Results:

In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (p<0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P=0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P=0.01).

Conclusions:

TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30–40% of CRC patients, may represent a new avenue of investigation for targeted therapy.