Impact of chemotherapy-related prognostic factors on long-term survival in patients with stage III colorectal cancer after curative resection.

BACKGROUND: This retrospective study evaluated the prognostic factors of chemotherapy in stage III colorectal cancer after curative resection. METHODS: From 1996 to 2001, 1,054 patients with primary single colorectal cancer underwent curative resection. Seven hundred sixteen patients received various 5-fluorouracil (FU)-based adjuvant chemotherapy regimens, including oral and intravenous treatments. The chemotherapy-related parameters examined included therapeutic duration, frequency, route of administration, composition of combination therapies, and postoperative time interval from the operation to the start of chemotherapy. RESULTS: The therapeutic duration and postoperative time interval of starting therapy were independent prognostic factors, in addition to clinicopathological factors. The 8-year cancer-specific/overall survival rates in patients who received chemotherapy for >4 months (63.0/58.6%) were significantly higher than the rates in patients who received no chemotherapy (56.7/37.7%, P < 0.01) and those who remained on chemotherapy for 1-4 months (49.4/41.9%, P < 0.05). The 8-year cancer-specific/overall survival rates in patients who waited 1-5 weeks after surgery to receive chemotherapy (62.9/58.5%) were significantly higher versus rates in those who did not receive chemotherapy (56.7/37.7%) and those who did not receive chemotherapy until >5 weeks after surgery (52.3/45.9%) (both P < 0.05). Survival rates did not differ between patients who did not undergo chemotherapy, those for whom chemotherapy lasted 1-4 months, and patients who did not receive chemotherapy until >5 weeks after surgery. CONCLUSIONS: The appropriate duration of therapy and early chemotherapy after surgery were 2 of the most important factors in eradicating occult cancer and effecting long-term survival benefits in patients with stage III colorectal cancer.

Anorectal melanoma: review of 22 consecutive cases.

BACKGROUND/AIMS: To evaluate outcome and prognostic factors of patients with anorectal melanoma. METHODOLOGY: Twenty-two consecutive patients with anorectal melanoma received operation from 1993 through 2011 were reviewed. The definitions of stage I, II and III are local disease, locoregional lymphadenopathy and metastatic disease, respectively. RESULTS: The patients included 8 men and 14 women, aged from 36 to 83 years (mean, 58.4 years). At the end of the follow-up period, 19 patients died of disease and only 3 patients were alive with disease. Only two patients were alive longer than 5 years after operation. For stage I and II tumors that underwent clinical curative resection (n=17), stage II (p=0.04), tumor size >3 cm (p=0.008) and invasion depth to muscle (p=0.021) all showed poorer prognosis in overall survival. Though wide local excision (WLE) were performed in the patients with earlier tumors, there was no statistical difference in overall (p=0.063) and disease-free survival (p=0.333) between WLE and radical surgery. Furthermore, patients with WLE had more chance of local recurrence than radical surgery (6/7 vs. 3/10, p=0.050). Four salvage radical operations could be performed after local recurrence in WLE group. CONCLUSIONS: WLE increases the chance of local recurrence more than radical surgery. Care should be taken to avoid microseeding during performed WLE.

Concurrent chemoradiotherapy in the treatment of locally recurrent rectal cancer.

BACKGROUND/AIMS: Long course concurrent chemoradiotherapy provides potential tumor downstaging. When local recurrent rectal cancer without distant metastases is diagnosed, a potentially curative resection can be performed. The aim of this study was to assess the outcome of concurrent chemoradiotherapy in treating isolated local recurrent rectal cancer. METHODOLOGY: Patients (n=102) with isolated local recurrent rectal cancer within the pelvis were scheduled for concurrent chemoradiotherapy, consisting of pelvic irradiation with a total dose of 50.4 Gy in 28 fractions. Chemotherapy was administered concurrently and included 85 mg/m2 oxaliplatin by venous infusion over 2 h on day 1, followed by 1,200 mg*m-2*day-1 of continuous venous infusion for 2 days. This regimen was repeated every 2 weeks for 6 cycles. The overall survival rate, responses, disease-free interval and toxicities were assessed. RESULTS: A total of 96 patients completed planned concurrent chemoradiation. Complete clinical responses were found in 13 of the 96 patients (14%), partial responses in 59 (61%), stable disease in 21 (22%) and disease progression in 3 (3%). The overall survival and disease-free survival rates in all the 96 patients were 45% and 14%, respectively. CONCLUSIONS: The treatment of locally recurrent rectal cancer is complicated. Concurrent chemoradiation can increase disease-free survival and overall survival by increasing complete resection rate of locally recurrent tumors and even complete response of the tumors. Ongoing treatment strategies aim to enhance response rates and to accurately assess the extent of local recurrent tumor response to concurrent chemoradiation.

Risk factors for lymph node metastasis in pT1 and pT2 rectal cancer: a single-institute experience in 943 patients and literature review.

BACKGROUND: Local excision has become an alternative for radical resection in rectal cancer for selected patients. The purpose of this study was to assess the clinicopathologic factors determining lymph node metastasis (LNM) in patients with T1-2 rectal cancer. METHODS: Between January 1995 and December 2009, a total of 943 patients with pT1 or pT2 rectal adenocarcinoma received radical resection at a single institution. Clinicopathologic factors were evaluated by univariate and multivariate analyses to identify risk factors for LNM. RESULTS: A total of 943 patients (544 men and 399 women) treated for T1-2 rectal cancer were included in this study. LNM was found in 188 patients (19.9%). In multivariate analysis, lymphovascular invasion (LVI; P < 0.001, hazard ratio 11.472), poor differentiation (PD; P = 0.007, hazard ratio 3.218), and depth of invasion (presence of pT2; P = 0.032, hazard ratio 1.694) were significantly related to nodal involvement. The incidence for LNM lesions in the presence of LVI, PD, and pT2 was 68.8, 50.0, and 23.1%, respectively, while that for pT1 carcinomas with no LVI or PD was 7.5%. CONCLUSIONS: LVI, PD, and pT2 are independent risk factors predicting LNM in pT1-2 rectal carcinoma.

Can neutrophil-to-lymphocyte ratio predict the survival of colorectal cancer patients who have received curative surgery electively?

PURPOSE: We evaluated the effect of neutrophil-to-lymphocyte ratio (NLR) on disease-free survival in patients with stages I to III colorectal cancer (CRC). METHODS: There were 3857 patients identified from our database. We used receiver operating characteristic (ROC) analysis to identify the best cutoff value of NLR. A 5-year disease-free survival was used as end point. Survival analysis was used to assess the NLR effect, after stratification by several clinopathologic factors. RESULTS: In the ROC analysis, NLR = 3 had the highest sensitivity and specificity. Elevated NLR (>3) in colon cancer seemed to accompany larger tumor size (~5 cm) and more advanced T stage. By multivariate analysis, elevated NLR in colon cancer was associated with an increased risk of disease progression or cancer death [hazard ratio (HR) 1.377, 95 % confidence interval 1.104-1.717, P = 0.014]. However, elevated NLR in rectal cancer lost its significance in multivariate analysis (HR 1.121, 95 % confidence interval 0.941-1.336, P = 0.200). Patients with elevated NLR had worse outcome, especially for colon cancer. CONCLUSIONS: Preoperative NLR influenced the disease-free survival in patients with stages I to III CRC. Elevated NLR (>3) was associated with worse outcome (5-year disease-free survival 66.3 % vs. 78.9 % in colon cancer, P < 0.001; 60. 5 % vs. 66.2 % in rectal cancer, P = 0.008). The difference was larger in colon cancer than in rectal cancer. NLR should be considered as a prognostic factor for stages I to III CRC patients after curative surgery.

Long-term survival benefits of adjuvant chemotherapy by decreasing incidence of tumor recurrence without delaying relapse in stage III colorectal cancer.

BACKGROUNDS AND AIMS: To elucidate the survival benefits of adjuvant chemotherapy by decreasing incidence or by delaying time of tumor recurrence, we reported the long-term results of a nonrandomized prospective study comparing the adjuvant chemotherapy to no chemotherapy in stage III colorectal cancer. PATIENTS: From 1991 to 1995, 463 patients with stage III colorectal cancer were divided to three groups which were no chemotherapy, weekly chemotherapy, and monthly chemotherapy (5-FU plus levamisole). RESULTS: The recurrent incidence was significantly decreased in patients with chemotherapy (47.8% vs. 63.9% of no chemotherapy, P = 0.001), resulting into better survival. The 10-year cancer-specific and overall survival rates of patients with chemotherapy vs. no chemotherapy were 52.1% vs. 37.8% and 46.9% vs. 29.9%, respectively (P < 0.001). Weekly chemotherapy had better survival than monthly chemotherapy (P < 0.05). There was no significant difference in recurrent time or types between the patients with and without chemotherapy. The percentages of patients with recurrence happened within 3 years were 85.2% and 84.6% of those with and without chemotherapy, respectively. Patients with advanced stage of T4b invasion depth, N2, and central node invasion had no significant survival benefits by adjuvant chemotherapy. CONCLUSIONS: Long-term survival benefits achieved by adjuvant chemotherapy is through decreasing recurrent incidence, not through postponing tumor recurrent time. That means adjuvant chemotherapy indeed cures some patients by eradicating occult tumor. In adjuvant setting, more powerful regimen for eradicating occult tumor is the keystone to improve long-term survival of stage III colorectal cancer.

Surgical resection of locally advanced primary transverse colon cancer--not a worse outcome in stage II tumor.

BACKGROUND AND AIMS: In locally advanced primary transverse colon cancer, a tumor may cause perforation or invade adjacent organs. Extensive resection is the best choice of treatment, but such procedures must be weighed against the potential survival benefits. This study was performed to identify the clinicopathological features and treatment outcomes of such tumors. MATERIALS AND METHODS: We retrospectively reviewed the database of the Colorectal Cancer Registry of Chang Gung Memorial Hospital between February 1995 and December 2005. Patients with colon cancer sited between the hepatic and splenic flexure that involved an adjacent organ without distant metastasis were defined as having locally advanced transverse colon cancer. RESULTS: A total of 827 patients who underwent surgery for transverse primary colon cancer were enrolled in the study. Stage II and stage III colon cancer were diagnosed in 548 patients. Thirty-two (5.8%) patients were diagnosed with locally advanced tumors. Multivariate analysis revealed that stage III, preoperative carcinoembryonic antigen ≥5 ng/mL, a tumor with perforation or obstruction, and the presence of a locally advanced tumor were significant prognostic factors for both overall and cancer-specific survival. Postoperative morbidity rates differed significantly between the locally advanced and non-locally advanced tumor groups (22.7% vs. 12.3%, P < 0.01). No significant overall survival difference was observed among the stage II transverse colon tumors (P = 0.21). CONCLUSION: Surgical resection of locally advanced transverse colon tumors resulted in a higher morbidity and mortality than that of non-locally advanced tumors, but the benefit of extensive surgery in the case of locally advanced tumors cannot be underestimated. Furthermore, this benefit is more pronounced in the case of stage II tumors.

Effect of preoperative neutrophil-lymphocyte ratio on the surgical outcomes of stage II colon cancer patients who do not receive adjuvant chemotherapy.

BACKGROUND AND AIMS: Selection of appropriate stage II colon cancer patients for adjuvant chemotherapy is critical for improving survival outcome. With the aim of identifying more high risk factors for stage II colon cancer, this study aimed to determine whether the neutrophil-lymphocyte ratio (NLR) is a predictor of surgical outcomes in patients with stage II colon cancer who do not receive adjuvant chemotherapy. MATERIALS AND METHODS: We enrolled 1,040 stage II colon cancer patients who had undergone colectomy at a single institution between January 1995 and December 2005 and did not receive adjuvant chemotherapy. RESULTS: Of these 1,040 patients, 785 (75.5%) patients had a normal NLR and 255 (24.5%) had an elevated NLR. Those with an elevated NLR included patients ≥65 years, T4b cancer, carcinoembryonic antigen ≥5 ng/mL, and tumor obstruction or perforation. Patients with an elevated NLR had a significantly worse overall survival (OS) and worse disease-free survival (DFS) than did patients with a normal NLR. Cox regression analysis revealed that elevated NLR was an independent predictor of OS (P=0.012) but not DFS (P=0.255). CONCLUSION: An elevated NLR is an independent predictor of OS but not DFS in stage II colon cancer patients who did not receive adjuvant chemotherapy. Preoperative NLR measurement in stage II colon cancer patients may be a simple method for identifying patients with a poor prognosis who can be enrolled in further trials of adjuvant chemotherapy.

Immunohistochemical study of vascular endothelial growth factor (VEGF) and matrilysin (MMP-7) in T1 adenocarcinoma of the colon and rectum to predict lymph node metastases or distant metastases.

BACKGROUND/AIMS: Predicting the lymph node metastatic or distant metastatic potential of T1 adenocarcinoma of the colon and rectum remains a major challenge. We investigated the role of the expressions of tumor matrilysin (MMP-7), VEGF-C and VEGF-A in predicting these metastatic potentials. METHODOLOGY: Single T1 adenocarcinomas were examined and pathological tumor factors were reviewed. Immunohistochemical staining of VEGF and MMP-7 was performed and the metastatic potential was defined on the basis of the presence of lymph nodes in the specimen or the identification of other distant metastasis during follow-up examinations. RESULTS: There was little correlation between the IHC staining results of VEGF-A, VEGF-C and MMP-7 in the same specimen (kappa<0.1). After a 61-month median follow-up (2-131 months), 17 (11.8%) tumors showed metastatic potential, including 14 lymph node metastases and 3 distant metastases. The tumors showing high levels of MMP-7 expression had higher metastatic potentials than those with low expression (19.1% vs. 8.2%, respectively; p=0.057). Overexpression of MMP-7 generally indicated an inferior overall survival (p=0.09). In analysis of the traditional pathological tumor factors, only lymphovascular invasion showed significance in predicting metastatic potential (p=0.04). CONCLUSIONS: Overexpression of MMP-7 generally indicated a higher metastatic potential and inferior overall survival. Lymphovascular invasion was a significant risk factor for lymph node metastasis.

Pathological examination of 12 regional lymph nodes and long-term survival in stages I-III colon cancer patients: an analysis of 2,056 consecutive patients in two branches of same institution.

PURPOSE: Pathologic examination of at least 12 lymph nodes (LNs) is widely accepted as a standard for colon cancer surgery. We sought to address its association with patient source, other clinicopathological factors, and survival by comparing information from two branches in a large single institution. METHODS: Patients with stages I-III adenocarcinoma of the colon between 1998 and 2003 were identified from the Chang Gung Colorectal Tumor Registry in two branches (Linkou and Kaohsiung branches) of same institution. We used multivariate analysis to adjust for variables with P < 0.1 in univariate analyses. RESULTS: A minimum of 12 examined nodes were observed in 80% of patients in Linkou branch versus 25% in Kaohsiung branch (P < 0.0001). Younger age, right hemicolectomy, larger tumor, higher tumor stage, higher caseload of surgeons, and patients at Linkou branch with an odds ratio (OR) as high as 23 (95% CI, 17-31) were independently associated with a higher frequency of ≥12 examined nodes. Patients with examined node number of <12 had a greater risk of recurrence within stages II and III (stage II: adjusted OR 1.88, 95% CI 1.27-2.79; stage III: adjusted OR 1.58, 95% CI 1.15-2.17) but not within stage I (OR 0.73, 95% CI 0.23-2.24). CONCLUSIONS: The results confirm that factors influencing nodal harvest are multifactorial and the examined LN number of 12 or more is associated with an increased long-term survival in stages II-III colon cancer. It is possible to adequately sample and examine a sufficient number of nodes in the majority of colon cancer specimens by standardized conventional methods.

Carcinoma obstruction of the proximal colon cancer and long-term prognosis--obstruction is a predictor of worse outcome in TNM stage II tumor.

PURPOSE: Colon obstruction is suggested to be a predictor of poor outcome in colon cancer. However, the effect of obstruction on outcome in patients with different tumor-nodes-metastases (TNM) stage cancer has not been fully addressed. The aim of this study is to determine whether colon obstruction predicts surgical and long-term oncologic outcomes in patients with proximal colon cancer. METHODS: A total of 1,492 consecutive patients underwent open resection of primary adenocarcinoma of right colon in a single institution between January 1995 and December 2005. Clinical and follow-up data were extracted from a prospective colorectal cancer database. Univariate and multivariate analyses were performed to identify colon obstruction and other predictors of surgical and oncologic outcomes. RESULTS: Among 1,492 patients, 306 (20.5%) patients presented with colon obstruction. The rates of surgical morbidity and mortality were greater in patients with an obstruction as compared to patients without an obstruction (22.2% and 3.9% vs. 14.1% and 1.9%; p = 0.0005 and 0.041, respectively). Obstruction predicted a worse long-term disease-free survival (DFS) among patients with stage II-III disease (log-rank test, p = 0.0003). The data were stratified by TNM stage. Obstruction predicted a worse DFS among patients with TNM stage II cancer (598 patients; log-rank test, p = 0.001; Cox regression, p = 0.012), but it was not a predictor in TNM stage III cancer patients (424 patients; p = 0.116; p = 0.108). CONCLUSIONS: Colon obstruction was an independent predictor of long-term outcome only in TNM stage II but not in stage III proximal colon cancer. Patients with TNM stage II obstructive colon cancer could be included in future trials of adjuvant therapies.

Lead time of carcinoembryonic antigen elevation in the postoperative follow-up of colorectal cancer did not affect the survival rate after recurrence.

BACKGROUND AND AIMS: The role of carcinoembryonic antigen (CEA) in the early detection of recurrence during the postoperative follow-up of colorectal cancer remains unclear. We hypothesize that the tumor with longer lead time of CEA elevation to the definite recurrence may have a better prognosis because of its slower growth rate and closer observation. MATERIALS AND METHODS: From 1995 to 2003, 4,841 consecutive patients who received curative resection of localized colorectal adenocarcinoma were enrolled from a prospective database. The patients with persisting CEA elevation after operation had been already excluded. Postoperative follow-up, including physical examination, imaging, and CEA test, were performed according to a surveillance program. A CEA >/=5 ng/mL was defined as elevated. The definition of the CEA lead time was the period between CEA elevation and detection of recurrence. All statistical analyses were performed by SPSS package for Windows (Microsoft, Redmond, WA, USA). RESULTS: The postoperative median follow-up time for the 4,841 patients was 68 months. A total of 999 patients (20.6%) had CEA elevation and recurrence. Among these patients, recurrence was confirmed in 727 patients (72.8%)before, at the same time, or within 3 months of CEA elevation and thus had a short lead time of CEA elevation (SLT group). In 272 patients (27.2%), recurrence was confirmed after more than 3 months of CEA elevation and thus had a longer lead time of CEA elevation (LLT group). The recurrence pattern showed similarities in these two groups. A total of 193 patients (193/999, 19.3%) received a second radical operation, and 806 patients (80.7%) were inoperable. The re-resection rate between the SLT group (146 patients, 20.1%) and the LLT group (47 patients, 17.3%) was not significantly different. The overall survival rate after recurrence showed no difference between these two groups (P = 0.123). CONCLUSION: Most cases of recurrence were detected at nearly the same time when the CEA level was elevated. Therefore, a more sensitive test is needed for early detection. The relationship between the lead time of CEA and the clinical outcome was not statistically significant. A more aggressive approach to the patient who has CEA elevation and is highly suspect of recurrence may be needed.

Effect of body mass index on the outcome of patients with rectal cancer receiving curative anterior resection: disparity between the upper and lower rectum.

OBJECTIVE: The aim of this study was to investigate the effect of body mass index (BMI) on local recurrence of primary rectal cancer after open curative sphincter-saving resection. BACKGROUND: Increasing BMI was reported to be associated with a higher likelihood of local recurrence in male patients with rectal cancer. However, it remained unclear whether BMI exerts the same effects on local recurrence of rectal cancer in the upper and lower rectum. METHODS: Between January 1995 and December 2002, we investigated 1873 patients with well-documented body height and body weight who underwent curative anterior resection for primary rectal cancer in a single institution. The patients were assigned to 4 groups according to their BMI: underweight, normal, overweight, and obese. RESULTS: The frequency of local recurrence increased with an increase in the BMI in patients with lower rectal cancer. The local recurrence rates were 2.5% (2 of 79), 6.1% (48 of 782), 9.2% (39 of 424), and 13.8% (9 of 65) in underweight, normal, overweight, and obese patients with lower rectal cancer, respectively. These results were different from those of patients with upper rectal cancer. Independent risk factors for local recurrence in the lower rectal cancer group were BMI, resection margin, histologic grade of differentiation, depth of tumor invasion, and status of lymph node metastases. In the upper rectal cancer group, the depth of tumor invasion and histologic grade of differentiation reached statistical significance. CONCLUSIONS: BMI exerted different effects on local recurrence of rectal cancer in the upper and lower rectum. Further, more aggressive adjuvant and/or neoadjuvant treatments should be considered for patients with tumor in the lower rectum and with higher BMI.

Serum p53 antibody as tumor marker for follow-up of colorectal cancer after curative resection.

BACKGROUND: No large-scale studies have examined the use of serial measurements of serum p53 antibodies (s-p53Abs) combined with carcinoembryonic antigen (CEA) measurements during the follow-up of colorectal cancer (CRC) patients after curative resection. METHODS: A highly specific enzyme-linked immunosorbent assay was used to analyze s-p53Abs levels in 305 CRC patients before and after curative resection at a single institution. Agreement between recurrence and serial s-p53Ab and CEA measurements was evaluated by diagnostic accuracy odds ratio (DOR), kappa, and area under receiver operating characteristic curve (AUC). RESULTS: Among 305 patients, 76 (25%) patients had disease recurrence during follow-up. None of the 168 s-p53Ab seronegative patients (s-p53Ab < 10 U/microL) without recurrence had an abnormal s-p53Ab test during follow-up. Among the remaining low-level (10 U/microL 76 U/microL, n = 34) seropositive patients, recurrence defined by s-p53Ab tests resulted in a DOR of 4.3 and infinity, a kappa of 0.35 and 1.00, and an AUC of 0.633 [95% confidence interval (CI), 0.495 to 0.772; P = 0.047], and 1.0 (95% CI, 1.000 to 1.000; P < 0.0001), respectively. Recurrence defined by CEA tests had an AUC of 0.781 (95% CI, 0.654 to 0.909) for low-level and 0.796 (95% CI, 0.611 to 0.982) for high-level seropositive patients. CONCLUSIONS: Agreement between clinical recurrence and serial s-p53Ab test was dependent upon preoperative s-p53Ab level. Serial s-p53Ab testing outperformed CEA testing when predicting clinical recurrence in colorectal cancer patients with an abnormal preoperative s-p53Ab level.

Postoperative fever and survival in patients after open resection for colorectal cancer: a long-term follow-up study of 2,311 prospectively enrolled patients.

PURPOSE: Two reports on the impact of postoperative fever on survival after surgery in patients with colorectal cancer yielded contradictory results. Our study examined possible associations between postoperative fever and long-term survival of patients who underwent resection of colorectal cancer. METHODS: We investigated 2,311 consecutive patients who underwent elective open colorectal resection for primary colorectal cancer at a single institution between 1995 and 1998. The primary end points were cancer-specific and overall survival. Multiple covariate impact of risk factors on survival rates was assessed by Cox regression analysis. RESULTS: A total of 252 patients (12.2 percent) developed postoperative fever. The most important independent risk factor for postoperative fever was postoperative morbidity (odds ratio, 4.9; 95 percent confidence interval, 3.7-6.6) followed by blood transfusion (1.7; 1.2-2.2), Stage IV disease (1.6; 1.1-2.2), male gender (1.4; 1.0-1.9), and rectal cancer (1.4; 1.0-1.8). Cox regression modeling indicated that stage, histology, tumor location, and blood transfusion were statistically significant covariate predictors for cancer-specific survival. Postoperative fever was not independently associated with cancer-specific or overall survival. CONCLUSIONS: This study did not support the hypothesis that postoperative fever is an independent prognostic factor after colorectal resection for primary colorectal cancer.

Neoadjuvant therapy of bevacizumab in combination with oxaliplatin and capecitabine (XELOX) for patients with metastatic colorectal cancer with unresectable liver metastases: a phase II, open-label, single-arm, noncomparative trial.

AIM: This phase II, open-label study evaluated the efficacy and safety of neoadjuvant therapy with bevacizumab plus XELOX (capecitabine and oxaliplatin) for untreated metastatic colorectal cancer with unresectable liver metastases and assessed conversion of unresectable to resectable metastases after neoadjuvant treatment. METHODS: Patients received bevacizumab 5 mg/kg and oxaliplatin 85 mg/m2 on day 1, and capecitabine 1000 mg/m2 twice daily on days 1-5 followed by 2 days of rest in a 14-day cycle for 12 cycles; bevacizumab was excluded in cycles 6 and 7. Patients were later divided into resected and unresected groups, depending upon whether they underwent curative resection after chemotherapy. Efficacy and safety were evaluated. RESULTS: Of 45 patients enrolled, 17.8% completed the study. The resection rate of liver metastases after neoadjuvant therapy was 42.2%. The median time to disease progression was 10.1 and 8.7 months in the resected and unresected groups, respectively (P = 0.1341). Response rate was significantly higher in the resected (47.4%) versus the unresected group (34.6%; P = 0.0010), and seven patients achieved complete response (resected group). Overall, 94.3% of adverse events were of mild or moderate severity, and grade ≥3 adverse events occurred in 4.3% and 7.3% of patients in the resected and unresected groups, respectively. The most common adverse events in both groups were palmar-plantar erythrodysesthesia syndrome, decreased appetite, thrombocytopenia, peripheral neuropathy, fatigue, diarrhea, vomiting, proteinuria and nausea. CONCLUSION: Neoadjuvant therapy with bevacizumab plus XELOX was well tolerated and effective in previously untreated metastatic colorectal cancer patients with initially unresectable liver metastases.

Inverse effects of mucin on survival of matched hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer patients.

PURPOSE: To compare survival and histologic features of hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome) cases to well-matched sporadic colon cancers from the same patient population. EXPERIMENTAL DESIGN: Between January 1995 and March 2002, a total of 5,138 consecutive patients underwent resection of primary colorectal adenocarcinoma in a single institution. According to the Amsterdam criteria, 56 HNPCC patients were matched to 147 sporadic colorectal cancer (SCRC) with no family history of cancer and with the same gender, tumor location, and age within 3 years. Immunohistochemical analyses were done for MUC1, MUC2, MUC3, and MUC5AC. RESULTS: The HNPCC group had a marginally significantly better long-term outcome than the SCRC group (P = 0.058). The trend disappeared after adjustment by tumor-node-metastasis stage in a Cox model (P = 0.774). We noted a difference of >50% in the 5-year cancer-specific survival rates of HNPCC- and SCRC-mucinous groups (92% versus 31%, P = 0.0003). Interaction between mucin and HNPCC and its effects on survival were further confirmed by comparing the Cox models with and without interaction terms (hazard ratio, 0.1; P = 0.034 with adjusting stage). Patients with tumors showing dual expression of mucin and MUC1, which appeared in 11% of those with HNPCC and 50% of those with SCRC, had a lower 5-year cancer-specific survival rate than patients without (30% versus 60%; P = 0.004 by log-rank test; P = 0.039 with adjustment for tumor-node-metastasis stage). CONCLUSIONS: These results suggest that mucin has an inverse effect on survival in patients with HNPCC and SCRC, which might be partly explained by a lower prevalence of MUC1 expression in the mucinous HNPCC group than in the SCRC groups.

Frequency and spectrum of K-RAS codons 12 and 13 mutations in colorectal adenocarcinomas from Taiwan.

Mutations in codons 12 and 13 of the K-RAS oncogene are detected at a remarkably high frequency in colorectal adenocarcinoma and are believed to be a critical event in oncogenesis. In the present study, we evaluated colorectal tumor specimens from Taiwan for mutations in K-RAS codons 12 and 13 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and direct DNA sequencing. Mutations were found in 48 of 181 (26.5%) tumors, 30 mutations were G-->A transitions (62.5% of all mutations), 14 were G-->T transversions (29.2%), and only 4 were G-->C transversions (8.3%). Similar relative mutation frequencies and spectra were found regardless of the sex of the patient, the tumor grade, or the tumor stage. The high frequency of transitions among K-RAS mutation suggests that G/T mismatches play an important role in the oncogenesis of colorectal adenocarcinoma, implying that alkylating carcinogens may be involved in the colorectal carcinogenesis. Although the frequency of mutation (26.5%) appears to be lower than those reported in the United States (40%), France (49%), and the Netherlands (34%), the spectrum of point mutations in codons 12 and 13 of the K-RAS gene in the Taiwan Chinese population appears to be similar. The reason for these results may be that diet and ethnicity are not rate limit factors in controlling the spectra of mutations but influence on the frequency of K-RAS mutations in human colorectal adenocarcinomas.

S100P, a calcium-binding protein, is preferentially associated with the growth of polypoid tumors in colorectal cancer.

Colorectal cancer (CRC) is a genetically heterogeneous disease with distinct morphological patterns. It has been shown that polypoid and ulcerative CRC displays different genetic alterations. In the present study, we aimed to investigate genes with differential expression patterns between ulcerative and polypoid CRC. cDNA microarray analysis was performed to compare the gene expression profiles in samples of ulcerative and polypoid CRC with paired normal mucosa samples. Potential candidate genes were further validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunohistochemistry. The epigenetic regulation of gene expression was investigated using methylation-specific PCR (MSP). cDNA microarray analysis identified 11 upregulated and 14 downregulated genes which were differentially expressed in samples from both tumor types compared to the matched normal mucosa samples. Among these, S100P was the only upregulated gene preferentially associated with polypoid CRC (P=0.032). The samples of polypoid CRC displayed significantly higher S100P protein and mRNA expression levels than the samples of ulcerative CRC (P<0.05, respectively). Using semi-quantitative immunohistochemical analyses, S100P overexpression was found to be preferentially associated with polypoid CRC (24/30 vs. 14/40, P<0.001). The relative methylation level determined by MSP did not differ significantly between the samples of polypoid and ulcerative CRC (43.36 vs. 49.10%, P=0.168), indicating that promoter hypomethylation was not directly related to the upregulation of S100P mRNA. Our results demonstrate that the upregulation of S100P mRNA and protein expression is a predominant characteristic in polypoid CRC, whereas ulcerative CRC presents with a wide range of expression levels, indicating that S100P overexpression is not a key determinant in conferring invasion properties. The clinicopathological significance of S100P in CRC requires further investigation in well-controlled studies.

p53 is an independent pre-treatment markers for long-term survival in stage II and III colorectal cancers: an analysis of interaction between genetic markers and fluorouracil-based adjuvant therapy.

One hundred and thirty-eight stage II and III colorectal cancer patients were included to evaluate the prognostic significance of genetic markers (including mutations of the p53, K-ras genes, and microsatellite instability) on the response to 5-fluorouracil (FU)-based post-operative adjuvant therapies (PAT). When stratified by PAT and adjusting for other prognostic variables, presence of p53 mutation was associated with a poor outcome (hazard ratio (HR)=3.1, 95% confidence interval (CI), 0.9-11.0) among patients without PAT. Our data confirmed that p53 mutation is an independent pre-treatment factor in stage II and III colorectal cancer after curative resection.