Comparing pathological complete response rate using oral capecitabine versus infusional 5-fluorouracil with preoperative radiotherapy in rectal cancer treatment.

BACKGROUND: Infusional 5-fluorouracil (5-FU) has been the standard radiation sensitizer in patients undergoing preoperative long-course chemoradiotherapy (CRT) for locally advanced rectal cancer in Australia. Capecitabine (Xeloda) is an oral 5-FU prodrug of comparable pharmacodynamic activity, currently preferred in place of 5-FU infusion, its established counterpart in neoadjuvant CRT for rectal cancer. The few studies quantifying pathological complete response (pCR) of Xeloda versus 5-FU have produced inconsistent results. We reviewed our own data to determine if the rates of pCR of oral capecitabine were non-inferior to intravenous 5-FU in patients undergoing neoadjuvant CRT for rectal cancer. METHODS: A retrospective study was performed from a prospectively kept database. Four hundred and fifty-two patients received preoperative CRT from January 2006 to January 2016. Pelvic radiotherapy was delivered concurrently with capecitabine (n = 42) or infusional 5-FU (n = 341). The remaining received different chemotherapy regimens. Surgery was performed 6-12 weeks of CRT completion. Pathological responses were assessed using Dworak regression grading score (0-4). Clinical outcomes were evaluated in terms of local control and recurrence-free survival. RESULTS: The proportion of patients who had a tumour regression score of 4 (pCR) after CRT was 4/42 (9.5%) in the capecitabine group and 71/341 (20%) in the infusional 5-FU group (P = 0.082). pCR was an independent predictor for survival in this group of patients (hazard ratio: 0.002, P = 0.0001, 95% confidence interval: 0.0001-0.027). CONCLUSION: The use of capecitabine as neoadjuvant chemotherapy in patients with rectal cancer was associated with a reduced rate of pCR. However this difference did not achieve statistical significance.

Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil­based chemotherapy.

BACKGROUND & AIMS: Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil­based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T(17) intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin.We investigated whether HSP110 T(17) could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. METHODS: We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T(17) affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II­III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T(17). RESULTS: HSP110 and HSP110DE9 interacted in a1:1 ratio. Tumor cells with large deletions in T(17) had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T(17) were mostly biallelic in primary tumor samples with MSI. Patients with stage II­III cancer who received chemotherapy and had large HSP110 T(17) deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012­0.8; P = .03). We found a significant interaction between chemotherapy and T17 deletion (P =.009). CONCLUSIONS: About 25% of patients with stages II­III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T(17) intron repeat of HSP110 in tumor DNA.

Changing management and survival in patients with stage IV colorectal cancer.

BACKGROUND: Patients with metastatic colorectal cancers have poor outcomes. Yet recent developments in the use of chemotherapy and surgery have promised improvements in survival. The aim of this study was to compare the treatment and survival for all patients presenting with stage IV colorectal cancer managed over the last 20 years at a tertiary referral center and to define independent predictors for survival. METHODS: A cohort of patients with stage IV colorectal cancer treated from 1989 through 1995 served as a historical control for comparison with prospective cohorts treated from 1996 through 2002 or from 2003 through 2009. The Kaplan Meier technique was used to calculate overall survival. The Cox proportional hazards model was used to determine independent predictors of survival. RESULTS: A total of 313 patients with stage IV colorectal cancer were analyzed. Two-year overall survival was significantly higher in the 2003 to 2009 cohort (40.3%; 95%CI, 28.6-51.8%) than in either the 1989 to 1995 cohort (20.6%, 95%CI, 13.5- 28.6%) or the 1996 to 2002 cohort (19.3%; 95%CI, 12.8-26.9%). Significant independent predictors for overall survival included surgical resection with anastomosis (hazard ratio, 0.507; 95%CI, 0.371-0.692), surgical resection with stoma (0.578; 0.401-0.833), ASA score 3 (1.493; 1.150-1.941) or score 4 (2.532; 1.505-4.258), receiving palliative chemotherapy (0.64; 0.457-0.885), and receiving palliative radiotherapy (0.543; 0.352-0.835). CONCLUSIONS: In this analysis of overall survival for patients with stage IV colorectal cancer treated from 1989 through 2009, significant improvements were noted only in the last 7 years. Improvements may be related to more widespread use of palliative chemotherapy, newer chemotherapy agents, surgical excision of the primary tumor, and lower postoperative mortality.

Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy.

PURPOSE: The major pathologic markers of prognosis in colorectal cancer include vascular invasion by tumor cells, invasion of adjacent lymph nodes, and perforation of the serosal wall. Recent work suggests that a high density of tumor-infiltrating lymphocytes (TIL) is associated with good outcome independently of these established prognostic markers. The aim of the present study was to investigate the prognostic significance of TILs and other routinely reported pathologic features in colon cancer, particularly in relation to the use of adjuvant chemotherapy. EXPERIMENTAL DESIGN: Pathologic markers, disease-specific survival, and the use of adjuvant chemotherapy were recorded in a retrospective, population-based series of 1,156 stage III colon cancer patients with a median follow-up time of 52 months. RESULTS: In patients treated by surgery alone (n = 851), markers with significant prognostic value included poor histologic grade, T4 stage, N2 nodal status, vascular invasion, and perforation, but not the presence of TILs. In patients treated with 5-fluorouracil-based chemotherapy (n = 305), TILs were associated with significantly improved survival [hazard ratio (HR), 0.52; 95% confidence interval, 0.30-0.91; P = 0.02] and perforation with a trend for improved survival (HR, 0.67; 95% confidence interval, 0.27-1.05; P = 0.16). Patients with TILs or perforation seemed to gain more survival benefit from chemotherapy (HR, 0.22 and 0.21, respectively) than patients without these features (HR, 0.84 and 0.82, respectively). CONCLUSION: The apparent survival advantage from 5-fluorouracil associated with TILs and perforation requires confirmation in prospective studies. Because the presence of TILs reflects an adaptive immune response and perforation is associated with inflammatory response, these results suggest that there may be interactions between the immune system and chemotherapy leading to improved survival of colon cancer patients.

Survival rates for stage II colon cancer patients treated with or without chemotherapy in a population-based setting.

BACKGROUND AND AIMS: There is considerable uncertainty as to whether adjuvant 5-fluorouracil-based chemotherapy provides survival benefit for colon cancer patients with stage II disease. Consequently, the current rates of chemotherapy use for this disease are low despite 5-year survival rates of only 70-80%. The aim of the present study is to compare the survival rate of stage II colon cancer patients treated by surgery alone with that of patients also treated by chemotherapy. PATIENTS AND METHODS: A population-based observational study was conducted on the survival of stage II colon cancer patients (n = 812) diagnosed in Western Australia from 1993 to 2003. The study was restricted to patients aged < or =75 years, of whom 18% (n = 142) were treated with chemotherapy. Only 0.9% of patients older than 75 years received chemotherapy. RESULTS: Patients who received chemotherapy were significantly younger (mean age 6 years) than those treated by surgery alone (65 years, P < 0.001), and their tumors were more often positive for vascular invasion (P = 0.007). Multivariate analysis that included all prognostic factors revealed adjuvant chemotherapy was associated with improved survival (HR = 0.62, 95% CI [0.39-0.98], P = 0.043), with women gaining more benefit (HR = 0.48, 95% CI [0.20-1.22], P = 0.09) than men (HR = 0.94, 95% CI [0.54-1.64], P = 0.8). CONCLUSIONS: In view of the apparent survival benefit from chemotherapy for stage II colon cancer, the present study raises concerns about the current low rates of adjuvant treatment for this disease in the community, particularly for female patients.