Yung-Sung Yeh

Detection of KRAS Oncogene in Peripheral Blood as a Predictor of the Response to Cetuximab Plus Chemotherapy in Patients with Metastatic Colorectal Cancer

Purpose: Previously we developed membrane-arrays as a promising tool to detect circulating tumor cells (CTC) with KRAS oncogene in patients with malignancies. This study was conducted to determinate the predictive values of CTCs with KARS mutation by membrane-arrays for metastatic colorectal cancer patients treated with cetuximab plus chemotherapy. Experimental Design: Seventy-six metastatic colorectal cancer patients receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy were enrolled. KRAS mutation status in the peripheral blood of these patients was analyzed using membrane-arrays, and KRAS mutation status in tumors was analyzed by DNA sequencing. Results: Among 76 metastatic colorectal cancer patients, KRAS mutations in tumors and in peripheral blood were identified in 33 (43.4%) and 30 (39.5%) patients, respectively. The detection sensitivity, specificity, and accuracy of membrane-arrays for CTCs with KRAS oncogene were 84.4%, 95.3%, and 90.8%, respectively, and indeed a highly significant correlation to KRAS mutations in tumors (P < 0.0001) was observed. Forty-five (59.2%) patients responded to cetuximab plus chemotherapy, and 41 and 40 were wild-type KRAS in tumors and peripheral blood, respectively (both P < 0.0001). Patients with tumors that harbor wild-type KRAS are more likely to have a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Likewise, patients with CTCs of wild-type KRAS in peripheral blood express a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Conclusions: These findings provide evidence that detection of KRAS mutational status in CTCs, by gene expression array, has potential for clinical application in selecting metastatic colorectal cancer patients most likely to benefit from cetuximab therapy.

The impact on clinical outcome of high prevalence of diabetes mellitus in Taiwanese patients with colorectal cancer

BackgroundBoth colorectal cancer (CRC) and diabetes mellitus (DM) are important public health problems worldwide. As there are controversies about survival impact on CRC patients with preexisting DM, the purpose of the present study is to evaluate the incidence and the survival impact of preexisting DM on the long-term outcomes of patients with CRC in Taiwan.MethodsFrom January 2002 to December 2008, 1,197 consecutive patients with histologically proven primary CRC, who received surgical treatment at a single institution, were enrolled. The clinicopathologic features between these patients with and without DM were retrospectively investigated. Moreover, we intended to analyze the impact of DM on overall survival (OS) and cancer-specific survival (CSS) rates.ResultsOf 1,197 CRC patients, 23.6% of patients had either a reported history of DM or were currently taking one or more diabetes-controlling medications. CRC patients with DM were significantly older than those without DM (P < 0.001), and had a higher incidence of cardiac disease and higher body mass index than those without DM (both P < 0.001). There were no significant differences in gender, tumor size, tumor location, histological type, AJCC/UICC cancer stage, vascular invasion, perineural invasion, comorbidity of pulmonary disease or renal disease, and OS, and CSS between two groups. Additionally, DM patients had a higher incidence of second malignancy than patients without DM (9.54% vs 6.01%, P = 0.040).ConclusionsA considerably high prevalence of DM in CRC patients but no significant impact of DM on survival was observed in the single-institution retrospective study, regardless of cancer stages and tumor locations. Therefore, treatment strategies for CRC patients with DM should be the same as patients without DM.

Co-existence of cyclin D1 and vascular endothelial growth factor protein expression is a poor prognostic factor for UICC stage I-III colorectal cancer patients after curative resection.

Angiogenesis plays an important role in the progression of colorectal cancer (CRC). Studies have indicated vascular endothelial growth factor (VEGF) is the predominant angiogenic factor. Cyclin D1 (CCND1) induces production of VEGF and is required for migration of blood vessels. Our aim was to determine the roles of CCND1 and VEGF overexpression in CRC patients.

A Retrospective Study of the Safety and Efficacy of a First-Line Treatment with Modified FOLFOX-4 in Unresectable Advanced or Recurrent Gastric Cancer Patients

Aim: Dismal clinical results in patients with unresectable advanced or recurrent gastric cancer highlight the need for effective systemic chemotherapy. An increase in adverse events associated with systemic chemotherapy is shown in elderly patients, but it remains controversial whether they should receive the same chemotherapy used for younger patients. We retrospectively studied 73 patients with unresectable advanced or recurrent gastric cancer, including 48 nonelderly patients (<65 years old) and 25 elderly patients (≥65 years old) who received a combination of oxaliplatin, 5-fluorouracil and leucovorin (modified FOLFOX-4, mFOLFOX-4 regimen). Patients and Methods: From January 2006 to June 2011, 73 patients with histologically confirmed unresectable advanced or recurrent gastric cancer were enrolled in this study. All patients were treated with an mFOLFOX-4 regimen of 85 mg/m2 of oxaliplatin and 200 mg/m2 of leucovorin on the first day, followed by a 24-hour continuous infusion of 1,000 mg/m2 of 5-fluorouracil in 2 days with a 2-week interval. Treatment continued until disease progression or intolerable adverse events occurred. Results: Overall response rates show clinical efficacy (41.1%, 30/73 patients), stable cancer (26.0%, 19/73 patients) and progressive cancer (32.9%, 24/73 patients). The response rate was 36.0% in the elderly group and 43.8% in the nonelderly group (p = 0.891). In elderly patients, the overall time to progression was 8.1 months and the median overall survival was 11.9 months. On the other hand, in nonelderly patients, the overall time to progression was 7.9 months (p = 0.483) and the median overall survival was 11.2 months (p = 0.953). The results show no statistical differences in efficacy and adverse events between elderly and nonelderly groups (all p > 0.05). Conclusion: The mFOLFOX-4 therapy is an effective and safe first-line treatment for unresectable advanced or recurrent gastric cancer patients. Moreover, mFOLFOX-4 was well tolerated and effective in both nonelderly and elderly patients.

Factors affecting number of lymph nodes harvested and the impact of examining a minimum of 12 lymph nodes in stage I-III colorectal cancer patients: a retrospective single institution cohort study of 1167 consecutive patients.

BackgroundTo identify factors affecting the harvest of lymph nodes (LNs) and to investigate the association between examining a minimum of 12 LNs and clinical outcomes in stage I-III colorectal cancer (CRC) patients.MethodsThe clinicopathologic features and the number of examined LNs for 1167 stage I-III CRC patients were analyzed to identify factors affecting the number of LNs harvested and the correlations between clinical outcomes and high harvests (≧12 LNs) and low harvests (<12 LNs).ResultsA multivariate analysis showed that age (P = 0.007), tumor size (P = 0.030), and higher T stage (P = 0.001) were independent factors affecting the examinations of LNs in colon cancer and that tumor size (P = 0.015) was the only independent factor in rectal cancer. Patients with low harvests had poorer overall survival with stage II and stage III CRC (stage II: P < 0.0001; III: P = 0.001) and poorer disease-free survival for stages I-III (stage I: P = 0.023; II: P < 0.0001; III: P = 0.001).ConclusionsThe factors influencing nodal harvest are multifactorial, and an adequate number of examined LNs (≧12) is associated with a survival benefit. Removal of at least 12 LNs will determine the lymph node status reliably.

Coexistence of perineural invasion and lymph node metastases is a poor prognostic factor in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by radical resection and adjuvant chemotherapy.

Objective: To determine the role of lymph node metastases (ypN) and perineural invasion (PNI) in patients with locally advanced rectal cancer (LARC). Subjects and Methods: Eighty-eight LARC patients receiving preoperative chemoradiotherapy from April 2006 to November 2011 were enrolled in this study. Univariate and multivariate analyses were conducted to determine the association between clinicopathologic features and clinical outcome. Results: The presence of ypN (p = 0.011) and PNI (p = 0.032) was a significant adverse prognostic factor for disease-free survival (DFS). High histologic grade (p = 0.015), PNI+ (p = 0.043) and ypN+ (p = 0.041) were adverse prognostic factors for overall survival (OS). Positive PNI was significantly associated with a higher risk of distant failure (odds ratio = 6.09; 95% CI: 1.57-27.05; p = 0.008). Moreover, patients with a coexistence of ypN+ and PNI+ had the significantly worst DFS (p < 0.001) and OS rates (p < 0.001) compared with other phenotypes. Conclusions: The presence of either PNI or ypN was a significant prognostic factor for predicting poor survival rates in LARC patients, especially those with a coexistence of both factors. Accordingly, we recommend an intensive follow-up and therapeutic programs for LARC patients with simultaneous PNI+ and ypN+.

Helical Tomotherapy Combined with Capecitabine in the Preoperative Treatment of Locally Advanced Rectal Cancer

The aim of this study was to evaluate the efficacy of helical tomotherapy plus capecitabine as a preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Thirty-six LARC patients receiving preoperative CRT were analyzed. Radiotherapy (RT) consisted of 45 Gy to the regional lymph nodes and simultaneous-integrated boost (SIB) 50.4 Gy to the tumor, 5 days/week for 5 weeks. Chemotherapy consisted of capecitabine 850 mg/m2, twice daily, during the RT days. Patients underwent surgery 6–8 weeks after completion of CRT. Information was collected for patient characteristics, treatment response, and acute and late toxicities. Grade 3/4 (G3+) toxicities occurred in 11.1% of patients (4/36). Sphincter preservation rate was 85.2% (23/27). Five patients (14.3%) achieved pathological complete response. Tumor, nodal, and ypT0-2N0 downstaging were noted in 60% (21/35), 69.6% (16/23), and 57.1% (20/35). Tumor regression grade 2~4 was achieved in 28 patients (80%). After a median follow-up time of 35 months, the most common G3+ late morbidity was ileus and fistula (5.7%, 2/35). The study showed that capecitabine plus helical tomotherapy with an SIB is feasible in treatment of LARC. The treatment modality can achieve a very encouraging sphincter preservation rate and a favorable ypT0-2N0 downstaging rate without excessive toxicity.

Carcinoembryonic antigen in monitoring of response to cetuximab plus FOLFIRI or FOLFOX-4 in patients with metastatic colorectal cancer.

First-line treatment of metastatic colorectal cancer with combinations of cetuximab and irinotecan-based or oxaliplatin-based chemotherapy has shown promising efficacy. The clinical response to such treatment is generally assessed by tumor measurement through imaging. This study was performed to evaluate the correlation between serial changes in imaging results and carcinoembryonic antigen (CEA) levels. In 64 patients with metastatic colorectal cancer receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy we retrospectively analyzed the relationship between changes in serum CEA and changes in imaging results throughout the treatment course. Response in terms of serum CEA change was defined as a >/=50% drop in CEA level for more than 4 weeks. The sensitivity and specificity of serum CEA changes after targeted chemotherapy in relation to imaging results were 80.5% (33/41) and 73.9% (17/23), respectively, with a diagnostic accuracy of 78.1% (50/64). The progression-free survival time of responders assessed by serum CEA change was significantly longer than that of nonresponders (p=0.0091). Our results highlight the importance of serum CEA monitoring in assessing the response to targeted chemotherapy and in predicting the prognosis of patients with metastatic colorectal cancer.

Prospective analysis of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab plus FOLFIRI as the first-line setting: study protocol for a randomized controlled trial

BackgroundIrinotecan is approved and widely administered to metastatic colorectal cancer (mCRC) patients; however, it can cause severe toxicities including neutropenia and diarrhea. The polymorphisms of genes encoding drug-metabolizing enzymes can play a crucial role in the increased susceptibility of cancer patients to chemotherapy toxicity. Therefore, we plan to explore the effect of the genetic polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) for irinotecan detoxification in mCRC patients. This trial will compare the clinical outcomes and side effects observed in mCRC patients treated with bevacizumab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with and without UGT1A1 genotyping and irinotecan dose escalation. A total of 400 mCRC patients were randomized into a study group and a control group.Methods/DesignThis trial is a prospective, multicenter, randomized clinical trial comparing UGT1A1 promoter polymorphism for irinotecan dose escalation in mCRC patients administered with bevacizumab plus FOLFIRI as the first-line setting. The enrolled patients were randomly assigned to one of two groups, a study group and a control group, on the basis of receiving UGT1A1 genotyping or not. The study group receive a biweekly FOLFIRI regimen, with irinotecan dose escalation based on UGT1A1 genotyping; whereas the control group receive the conventional biweekly FOLFIRI regimen without UGT1A1 genotyping. The clinicopathological features, response rates, toxicity, and progression-free survival or overall survival will be compared between the two groups.DiscussionPatients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan for a potentially more favorable clinical response and outcome, in addition to comparable toxicities. Such personalized medicine based on genotyping may be feasible for clinical practice.Trial registrationNCT02256800. Date of registration: 3 October 2014. Date of first patient randomized: 16 January 2015

An observational study of extending FOLFOX chemotherapy, lengthening the interval between radiotherapy and surgery, and enhancing pathological complete response rates in rectal cancer patients following preoperative chemoradiotherapy

Introduction: Patients with rectal cancer who exhibit a pathologic complete response to preoperative concurrent chemoradiotherapy have excellent oncologic outcomes. In this study, we evaluated the potential advantages of adding oxaliplatin to preoperative fluoropyrimidine-based chemoradiotherapy administered in rectal cancer patients. Methods: A total of 78 patients with rectal cancer were enrolled. Patients were administered chemoradiotherapy, which comprised radiotherapy and chemotherapy involving a 5-fluorouracil, leucovorin, and oxaliplatin regimen every 2 weeks. Surgery was performed 10–12 weeks after radiotherapy completion. Tumor regression, adverse events, surgical complications, and short-term clinical outcomes were recorded. Results: Two patients were excluded because of incomplete radiotherapy treatment or refusal of surgery. Eventually, 76 patients underwent total mesorectal excision and no perioperative mortality was observed. Of these, 20 patients (25.6%) developed grade 3 or 4 toxicity during concurrent chemoradiotherapy. Among the 76 patients who underwent surgery, 24 (31.6%) patients achieved a pathologic complete response. The sphincter preservation rate was 96.1% (73/76) in all patients and 92.2% (39/42) in patients with tumors located less than 5 cm from the anal verge. The 2-year overall and disease-free survivals were 94% and 87.4%, respectively. Conclusion: The intensified multimodality therapy was well tolerated in our cohort and resulted in a considerably high pathologic complete response rate. Regardless of favorable short-term clinical outcomes, long-term oncologic outcomes will be closely monitored among the patients with a pathologic complete response.