Chun-Ming Huang

The prognostic values of EGFR expression and KRAS mutation in patients with synchronous or metachronous metastatic colorectal cancer

BackgroundThe epidermal growth factor receptor (EGFR)/RAS/RAF/MEK/MAPK pathway is an important pathway in the carcinogenesis, invasion and metastasis of colorectal cancers (CRCs). We conducted a retrospective study to determine the prognostic values of EGFR expression and KRAS mutation in patients with metastatic CRC (mCRC) based on synchronous or metachronous status.MethodsFrom October 2002 to March 2012, 205 patients with mCRC were retrospectively analyzed; 98 were found to have metachronous mCRC while 107 were found to have synchronous mCRC. The EGFR expressions were determinate by IHC (immunohistochemistry) analysis and categorized 1+ (weak intensity), 2+ (moderate intensity), and 3+ (strong intensity). Genomic DNA was isolated from frozen primary CRC tissues and direct sequencing of KRAS was performed. The clinicopathological features of these mCRC patients were retrospectively investigated according to EGFR expression and KRAS mutation status. Moreover, we analyzed the prognostic values of EGFR expression and KRAS mutation among these patients.ResultsOf the 205 patients with mCRC, EGFR expression was analyzed in 167 patients, and positive EGFR expression was noted in 140 of those patients (83.8%). KRAS mutation was investigated in 205 patients and mutations were noted in 88 of those patients (42.9%). In patients with metachronous mCRC, positive EGFR expression was significantly correlated with well-and moderately-differentiated tumors (P = 0.028), poorer disease-free survival (DFS) (P < 0.001), and overall survival (OS) (P < 0.001). Furthermore, positive EGFR expression was a significant independent prognostic factor of DFS (P = 0.006, HR: 4.012, 95% CI: 1.130–8.445) and OS (P = 0.028, HR: 3.090, 95% CI: 1.477–10.900) in metachronous mCRC patients. KRAS mutation status was not significantly related to DFS and OS of patients with metachronous mCRC; likewise, KRAS mutation status was not significantly different in the progression-free survival (PFS) and OS of patients with synchronous mCRC (all P > 0.05).ConclusionsThe present study demonstrated that EGFR expression has prognostic value only for patients with metachronous mCRC. However, KRAS mutation did not have prognostic value in patients with metachronous or synchronous mCRC.

Predictive value of ERCC1, ERCC2, and XRCC1 overexpression for stage III colorectal cancer patients receiving FOLFOX-4 adjuvant chemotherapy.

To determine the correlation between expression of three DNA repair genes and early failure/clinical outcome of stage III colorectal cancer (CRC) patients administrated with FOLFOX‐4, including the excision repair cross‐complementation group 1 (ERCC1), the excision repair cross‐complementing 2 (ERCC2), and X‐ray repair cross‐complementing protein 1 (XRCC1).

Prognostic advantage of irinotecan dose escalation according to uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping in patients with metastatic colorectal cancer treated with bevacizumab combined with 5-fluorouracil/leucovorin with irinotecan in a first-line setting

This study compared the clinical responses of patients with metastatic colorectal cancer (mCRC) with 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) plus bevacizumab therapy either with or without uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping and irinotecan dose escalation. Of 107 total patients with mCRC, 79 were classified as the study group and 28 as the control group. The study group received irinotecan dose escalation based on UGT1A1 genotyping whereas the control group did not. Clinicopathologic features, response rates, and survival were compared for the 2 groups. The clinical response rate of patients with mCRC treated with FOLFIRI plus bevacizumab under UGT1A1 genotyping and irinotecan dose escalation was significantly better than that of those without these prospective tests and dose escalation (P = 0.028). Both progression-free survival (PFS) and overall survival were significantly greater in clinical responders than nonresponders (both, P < 0.001), and PFS was significantly greater among the study group patients than among the control group patients, with a median PFS of 12.2 months vs 9.4 months (P = 0.025). Grade 3/4 adverse events were not significantly different between the 2 groups (P = 0.189). Patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan to obtain a better clinical response/outcome with comparable toxicities.

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+.

DPYD, TYMS, TYMP, TK1, and TK2 Genetic Expressions as Response Markers in Locally Advanced Rectal Cancer Patients Treated with Fluoropyrimidine-Based Chemoradiotherapy

This study is to investigate multiple chemotherapeutic agent- and radiation-related genetic biomarkers in locally advanced rectal cancer (LARC) patients following fluoropyrimidine-based concurrent chemoradiotherapy (CCRT) for response prediction. We initially selected 6 fluoropyrimidine metabolism-related genes (DPYD, ORPT, TYMS, TYMP, TK1, and TK2) and 3 radiotherapy response-related genes (GLUT1, HIF-1 α, and HIF-2 α) as targets for gene expression identification in 60 LARC cancer specimens. Subsequently, a high-sensitivity weighted enzymatic chip array was designed and constructed to predict responses following CCRT. After CCRT, 39 of 60 (65%) LARC patients were classified as responders (pathological tumor regression grade 2 ~ 4). Using a panel of multiple genetic biomarkers (chip), including DPYD, TYMS, TYMP, TK1, and TK2, at a cutoff value for 3 positive genes, a sensitivity of 89.7% and a specificity of 81% were obtained (AUC: 0.915; 95% CI: 0.840–0.991). Negative chip results were significantly correlated to poor CCRT responses (TRG 0-1) (P = 0.014, hazard ratio: 22.704, 95% CI: 3.055–235.448 in multivariate analysis). Disease-free survival analysis showed significantly better survival rate in patients with positive chip results (P = 0.0001). We suggest that a chip including DPYD, TYMS, TYMP, TK1, and TK2 genes is a potential tool to predict response in LARC following fluoropyrimidine-based CCRT.

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.

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.

A retrospective comparison of outcome and toxicity of preoperative image-guided intensity-modulated radiotherapy versus conventional pelvic radiotherapy for locally advanced rectal carcinoma

Abstract The aim of the study was to compare clinical outcomes and toxicity between 3D conformal radiotherapy (3DCRT) and image-guided intensity-modulated radiotherapy (IG-IMRT) administered through helical tomotherapy in locally advanced rectal cancer (LARC) patients receiving preoperative chemoradiotherapy. We reviewed 144 patients with Stage II–III rectal cancer receiving preoperative fluoropyrimidine-based chemoradiotherapy followed by radical resection. Tumor responses following chemoradiotherapy were evaluated using the Dworak tumor regression grade (TRG). Of the 144 patients, 45 received IG-IMRT and 99 received 3DCRT. A significant reduction in Grade 3 or 4 acute gastrointestinal toxicity (IG-IMRT, 6.7%; 3DCRT, 15.1%; P = 0.039) was observed by IG-IMRT. The pathologic complete response (pCR) rate did not differ between the IG-IMRT and the 3DCRT group (17.8% vs 15.1%, P = 0.52). Patients in the IG-IMRT group had the trend of favorable tumor regressions (TRG 3 or 4) compared with those in the 3DCRT group (66.7% vs 43.5%, P = 0.071). The median follow-up was 53 months (range, 18–95 months) in the 3DCRT group and 43 months (range, 17–69 months) in the IG-IMRT group. Four-year overall, disease-free, and local failure–free survival rates of the IG-IMRT and 3DCRT groups were 81.6% and 67.9% (P = 0.12), 53.8% and 51.8% (P = 0.51), and 88% and 75.1% (P = 0.031), respectively. LARC patients treated with preoperative IG-IMRT achieved lower acute gastrointestinal adverse effects and a higher local control rate than those treated with 3DCRT, but there was no prominent difference in distant metastasis rate and overall survival between two treatment modalities.

Feasibility and efficacy of helical tomotherapy in cirrhotic patients with unresectable hepatocellular carcinoma

BackgroundThis study is to evaluate the toxicity and outcomes of helical tomotherapy (HT) in patients treated for unresectable hepatocellular carcinoma (HCC).MethodsFrom March 2008 to September 2010, 38 patients with unresectable HCC were treated with HT. The median patient age was 67 years (range, 45–85). The median follow-up period was 17.2 months (range, 7–46). All patients had liver cirrhosis. Median radiation dose was 54 Gy (range, 46–71.8) delivered in 1.8 to 2.4-Gy fractions. The planning target volumes were 241.2 ± 153.1 cm3 (range, 45.8–722.4). Treatment responses were assessed in 3–6 months after HT.ResultsThere was a complete response in 2 patients (5.2 %), partial response in 18 patients (47.4 %), stable disease in 13 patients (34.2 %), and progressive disease in 5 patients (13.2 %). The median overall survival was 12.6 months, and 1- and 2-year overall survival rates were 56.2 and 31.7 %, respectively. Eastern Cooperative Oncology Group (ECOG score, p = 0.008), Child-Pugh classification (p = 0.012), albumin (p = 0.046), and hemoglobin (p = 0.028) were significant parameters that predicted primary tumor response to radiotherapy in multivariate analysis. ECOG score (p = 0.012), Child-Pugh class (p = 0.026), and response to radiotherapy (p = 0.016) were independent prognostic factors for overall survival in multivariate analysis. Responders had better overall survival than non-responders (23.6 vs. 5.8 months, p < 0.001). The 1- and 2-year overall survival rates for responders were 68.3 and 57 %, respectively, while for non-responders, they were 0 %. The 1- and 2-year local control rates were 88.2 and 82.3 %, respectively. Five patients (13.2 %) had grade 3 or greater liver toxicity, and one patient (2.6 %) had a grade 3 gastric ulcer. No treatment-related liver failure or death was documented in this study.ConclusionsRadiotherapy using HT seems to be a safe and effective treatment option for unresectable HCC patients. This study indicates that HT is a feasible treatment even in patients without good performance status and hepatic function reservation.

Comparison of adjuvant FOLFOX4 chemotherapy and oral UFUR/LV following adjuvant FOLFOX4 chemotherapy in patients with stage III colon cancer subsequent to radical resection

The present study aimed to demonstrate the potential advantage of oral uracil-tegafur (UFUR)/leucovorin (LV) as the subsequent therapy in patients with stage III colon cancer following adjuvant LV, 5-fluorouracil and oxaliplatin (FOLFOX4) chemotherapy. Of a total 143 patients, 62 patients received only FOLFOX adjuvant chemotherapy (FOLFOX4 biweekly × 12 cycles for 6 months), and 81 patients received FOLFOXU adjuvant treatment (which consisted of FOLFOX4 biweekly × 12 cycles for 6 months followed by oral UFUR/LV for an additional 6 months). The 3-year disease-free survival (DFS) rate of the FOLFOXU group was 74.3%; which was superior to that of the FOLFOX4 group (59.9%). The average DFS time of the FOLFOXU group was superior to that of the FOLFOX4 group (P=0.003). The 5-year overall survival (OS) rate of the FOLFOXU group was 76.9%, which was also superior to that of the FOLFOX4 group (63.8%). The average OS time of patients in the FOLFOXU group was longer than that of the patients in the FOLFOX4 group (hazard ratio, 0.155; 95% confidence interval, 0.054-0.450; P=0.001). In comparison to the FOLFOX regimen, the FOLFOXU regimen achieved a more favorable response and survival time without a significant increase of toxicities in patients with stage III colon cancer as the adjuvant chemotherapy.