Quality indicators for colonoscopy and the risk of interval cancer.

BACKGROUND: Although rates of detection of adenomatous lesions (tumors or polyps) and cecal intubation are recommended for use as quality indicators for screening colonoscopy, these measurements have not been validated, and their importance remains uncertain. METHODS: We used a multivariate Cox proportional-hazards regression model to evaluate the influence of quality indicators for colonoscopy on the risk of interval cancer. Data were collected from 186 endoscopists who were involved in a colonoscopy-based colorectal-cancer screening program involving 45,026 subjects. Interval cancer was defined as colorectal adenocarcinoma that was diagnosed between the time of screening colonoscopy and the scheduled time of surveillance colonoscopy. We derived data on quality indicators for colonoscopy from the screening program's database and data on interval cancers from cancer registries. The primary aim of the study was to assess the association between quality indicators for colonoscopy and the risk of interval cancer. RESULTS: A total of 42 interval colorectal cancers were identified during a period of 188,788 person-years. The endoscopist's rate of detection of adenomas was significantly associated with the risk of interval colorectal cancer (P=0.008), whereas the rate of cecal intubation was not significantly associated with this risk (P=0.50). The hazard ratios for adenoma detection rates of less than 11.0%, 11.0 to 14.9%, and 15.0 to 19.9%, as compared with a rate of 20.0% or higher, were 10.94 (95% confidence interval [CI], 1.37 to 87.01), 10.75 (95% CI, 1.36 to 85.06), and 12.50 (95% CI, 1.51 to 103.43), respectively (P=0.02 for all comparisons). CONCLUSIONS: The adenoma detection rate is an independent predictor of the risk of interval colorectal cancer after screening colonoscopy.

Colonoscopy in colorectal-cancer screening for detection of advanced neoplasia.

BACKGROUND: Recommendations for colorectal-cancer screening are based solely on age and family history of cancer, not sex. METHODS: We performed a cross-sectional analysis of the data from a large colonoscopy-based screening program that included 50,148 participants who were 40 to 66 years of age. People 40 to 49 years of age were eligible only if they had a family history of cancer of any type. Of the 43,042 participants 50 to 66 years of age, 13.3% reported a family history of colorectal cancer, as did 66.3% of the 7106 participants who were 40 to 49 years of age. We defined advanced neoplasia as cancer or adenoma that was at least 10 mm in diameter, had high-grade dysplasia, or had villous or tubulovillous histologic characteristics, or any combination thereof. We used multivariate logistic regression to identify associations between participants' characteristics and advanced neoplasia in a primary (or derivation) data set, and we confirmed the associations in a secondary (or validation) data set. RESULTS: Advanced neoplasia was detected in 2553 (5.9%) participants 50 to 66 years of age and in 243 (3.4%) participants 40 to 49 years of age. The rate of complications during colonoscopy was 0.1%, and no participants died. In the validation set, a logistic-regression model showed that male sex was independently associated with advanced neoplasia (adjusted odds ratio, 1.73; 95% confidence interval, 1.52 to 1.98; P<0.001). In each age group (40 to 49 years, 50 to 54 years, 55 to 59 years, and 60 to 66 years), the number of persons who would have to undergo colorectal-cancer screening in order to detect one advanced neoplasia was significantly lower in men than in women (23 vs. 36, 17 vs. 28, 12 vs. 22, and 10 vs. 18, respectively). CONCLUSIONS: We detected advanced neoplasia at a significantly higher rate in men than in women, which may warrant refinement of the screening recommendations for colorectal cancer.

Capecitabine as adjuvant treatment for stage III colon cancer.

BACKGROUND: Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting. METHODS: We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines. RESULTS: Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P<0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P=0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P<0.001). CONCLUSIONS: Oral capecitabine is an effective alternative to intravenous fluorouracil plus leucovorin in the adjuvant treatment of colon cancer.

Distal bowel surgical margin shorter than 1 cm after preoperative radiation for rectal cancer: is it safe?

BACKGROUND: The primary end-point of our randomized trial was sphincter preservation. The secondary aim was to evaluate whether distal bowel clearance < or =1 cm is safe after radiation. METHODS: The study randomized 312 patients with cT3-4 resectable low-lying and mid-rectal cancer to receive either preoperative irradiation (5 x 5 Gy) with immediate total mesorectal excision (TME) or chemoradiation (50.4 Gy, bolus 5-fluorouracil and leucovorin) with delayed TME. After anterior resection, pathologists prospectively measured macroscopic and microscopic distal bowel clearance. RESULTS: Macroscopic and microscopic distal bowel clearance, distal intramural spread, sphincter preservation, local control, disease-free survival, and overall survival did not differ in the two randomized groups. Pooled analysis of the two groups showed that the incidence of local recurrence at 4 years (median follow-up) for patients with macroscopic clearance < or =1 cm (n = 42) and >1 cm (n = 124) was 11.3% and 15.4%, respectively (P = 0.514); the hazard ratio (HR) was 0.70, and the 95% confidence interval (CI) was 0.23-2.07. The corresponding values for patients with microscopic clearance < or =1 cm (n = 51) and >1 cm (n = 101) were 9.6% and 17.6% (P = 0.220; HR 0.51; 95% CI 0.17-1.53). CONCLUSION: After preoperative radiotherapy, distal bowel clearance < or =1 cm did not compromise local control.

Association between pathologic response in metastatic lymph nodes after preoperative chemoradiotherapy and risk of distant metastases in rectal cancer: An analysis of outcomes in a randomized trial.

PURPOSE: To compare 5 x 5 Gy preoperative radiotherapy with immediate surgery vs. preoperative chemoradiotherapy (50.4 Gy, 5-fluorouracil, leucovorin) with delayed surgery in a randomized trial for cT3-T4 low-lying rectal cancer. Despite the downstaging effect of chemoradiotherapy, similar long-term outcomes were observed in both groups. METHODS: The Cox model was used to evaluate the prognostic value of ypTN ("yp" denotes that pathologic classification was performed after initial multimodality therapy) categories and the surgical margin status in 291 patients. RESULTS: Disease-free survival (DFS) (hazard ratio [HR] 1.05, 95% confidence interval [CI], 0.73-1.51), distant metastases (HR, 1.17; 95% CI, 0.77-1.78), and local control (HR, 1.45; 95% CI, 0.74-2.84) were similar in both arms. The ypN status was the only independent prognostic factor for DFS (p < 0.001). An interaction (p = 0.016) between N stage and the assigned treatment was demonstrated. For ypN-negative patients, DFS was similar in both arms (HR, 0.83, 95% CI, 0.47-1.48); however, for ypN-positive patients, DFS was worse in the chemoradiotherapy arm (HR, 1.73; 95% CI, 1.07-2.77). The 4-year (median follow-up) DFS rate in N-positive patients was 51% in the 5 x 5-Gy arm vs. 25% in the chemoradiotherapy arm. The corresponding 4-year rates for the incidence of local recurrence and distant metastases were 14% vs. 27% (HR, 1.95; 95% CI, 0.78-4.86) and 38% vs. 68% (HR, 2.05; 95% CI, 1.21-3.48). CONCLUSION: N-positive disease after chemoradiotherapy indicates radiochemoresistance. N-positive disease after 5 x 5 Gy RT includes both radiosensitive and radioresistant tumors, because the interval between radiotherapy and surgery was too short for radiosensitive cancer to undergo necrosis. Thus, the greater risk of distant metastases recorded in the chemoradiotherapy arm suggests that radiochemoresistance of nodal metastases from rectal cancer is associated with a high potential for developing distant metastases.

Quality of life, anorectal and sexual functions after preoperative radiotherapy for rectal cancer: report of a randomised trial.

BACKGROUND AND PURPOSE: Patients (N=316) with resectable cT3-4 low-lying and mid-rectal cancer were randomised to receive either preoperative 5x5Gy irradiation with subsequent surgery performed within 7 days or chemoradiation (50.4, 1.8Gy per fraction plus boluses of 5-fluorouracil and leucovorin) followed by surgery after 4-6 weeks. No differences were found in sphincter preservation, survival, local control and late complications. Early complications were less frequent in the short-course group. The aim of this report is to find out whether large doses per fraction of short-course schedule result in more severe anorectal and sexual dysfunction and quality of life (QoL) impairment. MATERIALS AND METHOD: Patients who were free of disease were asked to answer the QLQ-C30 and those without stoma were, additionally, asked to fill in a questionnaire of anorectal (19 items) and sexual function (1 item). RESULTS: Two hundred and twenty-two patients (86% response rate) completed the QLQ-C30 and 118 (86% response rate) the anorectal-sexual function questionnaire. The median time from surgery to filling in the QLQ-C30 questionnaire was 12 months, and to filling in the anorectal-sexual function questionnaire - 13 months. We did not find significant differences between the randomised groups regarding QoL and the anorectal and sexual functions. Approximately two-thirds of patients had anorectal function impairment. Approximately 20% of patients stated that this considerably influenced their QoL. CONCLUSIONS: QoL and the anorectal and sexual functioning did not differ in patients receiving short-course radiotherapy, as compared to those receiving chemoradiation.

Distal intramural spread of rectal cancer after preoperative radiotherapy: the results of a multicenter randomized clinical study.

PURPOSE: To evaluate the extent of distal intramural spread (DIS) after preoperative radiotherapy for rectal cancer. METHODS AND MATERIALS: A total of 316 patients with T(3-4) primary resectable rectal cancer were randomized to receive either preoperative 5x5 Gy radiation with immediate surgery or chemoradiation (50.4 Gy, 1.8 Gy per fraction plus boluses of 5-fluorouracil and leucovorin) with delayed surgery. The slides of the 106 patients who received short-course radiation and of the 86 who received chemoradiation were available for central microscopic evaluation of DIS. RESULTS: The length of DIS did not differ significantly (p = 0.64) between the short-course group and the chemoradiation group and was 0 in 47% vs. 49%; 1 to 5 mm in 41% vs. 42%; 6 to 10 mm in 8% vs. 9%, and greater than 10 mm in 4% vs. 0, respectively. Among the 11 clinically complete responders, DIS was found 1 to 5 mm from the microscopically detected ulceration of the mucosa in 5 patients. The discontinuous DIS was more frequent in the chemoradiation group as compared with the short-course group (i.e., 57% vs. 16% of cases, p < 0.001). CONCLUSIONS: Approximately 1 out of 10 advanced rectal cancers after preoperative radiotherapy or radiochemotherapy was characterized by DIS of over 5 mm. No significant difference was seen in the length of DIS between the 2 groups.

Does rectal cancer shrinkage induced by preoperative radio(chemo)therapy increase the likelihood of anterior resection? A systematic review of randomised trials.

BACKGROUND AND PURPOSE: According to common conviction rectal tumour shrinkage after preoperative radio(chemo)therapy increases the likelihood of anterior resection (AR). In order to verify this belief, we performed a systematic review of randomised trials. PATIENTS AND METHODS: We identified 10 randomised trials encompassing altogether 4596 patients in whom preoperative radio(chemo)therapy resulted in tumour shrinkage in the experimental arm as compared to the control arm. RESULTS: Tumour shrinkage observed in the experimental groups did not result in a statistically significant higher ARs rate in any study when we performed an analysis of all the randomised cases. Subgroups of patients considered to be candidates for abdominoperineal resection before randomisation were identified in three trials. A statistically significantly higher rate of ARs was demonstrated in the experimental arm of the CAO/ARO/AIO 94 study. However, in that study, sphincter preservation was a secondary endpoint and some features of the trial may bias the estimation of the effect. The benefit of sphincter preservation was not confirmed by subgroup analyses performed in the Lyon R90-01 study and in the Polish study, which were originally designed to evaluate the sphincter preservation issue. CONCLUSION: The body of evidence gathered from randomised trials does not support the concept of a beneficial effect of preoperative radiotherapy on the ARs rate.

Prediction of mesorectal nodal metastases after chemoradiation for rectal cancer: results of a randomised trial: implication for subsequent local excision.

BACKGROUND AND PURPOSE: For patients with rectal cancer treated with full thickness local excision the risk of mesorectal nodal metastases has to be very low. The aim was to assess this risk after preoperative radiotherapy in relation to pathological T-category. PATIENTS AND METHODS: Three hundred sixteen patients with resectable cT3-4 low rectal carcinoma were randomised to receive either pre-operative 5 x 5 Gy irradiation with subsequent surgery performed within 7 days or chemoradiation (50.4, 1.8 Gy per fraction plus bolus 5-fluorouracil and leucovorin) followed by surgery after 4-6 weeks. The pathological reports of patients who fulfilled entry criteria and had preoperative irradiation followed by transabdominal surgery were analysed. RESULTS: Significant downstaging of primary tumour (P<0.001) and of nodal disease (P=0.007) was observed after chemoradiation in comparison with short-course irradiation. In chemoradiation group, for patients with complete pathological response and for ypT1 category, the rate of nodal metastases was low - 5% (95% confidence interval [CI] 0-14%) and 8% (95% CI 0-24%), respectively. The rate of ypN-positive disease in chemoradiation group was similar to that recorded in short-course irradiation group for ypT2 category 26% (95% CI 14-38%) vs. 28% (95% CI 16-40%), P=0.83 and for ypT3-4 category 55% (95% CI 41-69%) vs. 64% (95% CI 54-74%), respectively, P=0.37. For ypT2 category after chemoradiation, the rate of nodal disease remained high even in subgroup with low residual cancer cells density (20%, 95% CI 4-36%). CONCLUSIONS: For patients with tumours downstaged by chemoradiation to ypT0 and ypT1 full thickness local excision may be considered as an acceptable approach, because the risk of mesorectal lymph nodes metastases is low. The selection criteria for preoperative radio(chemo)therapy and local excision are discussed.

Risk of permanent stoma after resection of rectal cancer depending on the distance between the tumour lower edge and anal verge.

The distance between the anal verge and lower edge of rectal cancer is one of the most important factors affecting the feasibility of sphincter-preserving resection.The aim of the study was to assess the risk of permanent stoma after resection of rectal tumour depending on the distance between the tumour and the anal verge.Material and methods. The retrospective analysis covered 884 patients after resection of rectal cancer. The distance between the anal verge and the lowest edge of the tumour was measured during endoscopic examination. Surgical technique was similar in all cases. For statistical analysis, the chi-square test and Fisher exact test were used.Results. The overall rate of sphincter-preserving procedures was 71.8%, 90.1% of which were anterior resections. The greatest differences between the rate of anterior resections were noted for the segment between the 4th and the 5th centimetres: 30.1% for 4 cm vs 66.7% for 5 cm, p = 0.005. Overall, in 328 patients (37.1%) surgical treatment resulted in a permanent stoma. The number included: 246 (75.0%) patients after abdominosacral resection, 44 (13.4%) patients after the Hartmann procedure, three (0.9%) patients after proctocolectomy, and 28 (8.5%) patients after anterior resection, with a permanent stoma as a result of anastomotic leak. The overall rate of anastomotic leak was 11.7%. Formation of a defunctioning stoma in patients with a low-lying (6 cm from the anal verge) tumour reduced the risk of symptomatic anastomotic leak: 6.3% vs 20.5%; p = 0.049.Conclusions. Anterior resection of tumours located 6 cm from the anal verge is feasible in 90%. Anastomotic leak that requires reoperation increases the risk of permanent colostomy. In selected cases, formation of a defunctioning stoma after resection of low-lying rectal cancer can reduce the risk of permanent colostomy.

Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.

PURPOSE: The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. RESULTS: The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. CONCLUSION: The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

Preoperative radiotherapy and local excision of rectal cancer with immediate radical re-operation for poor responders.

BACKGROUND AND PURPOSE: To report an early analysis of prospective study exploring preoperative radiotherapy and local excision in rectal cancer. MATERIALS AND METHODS: Mucosa at tumour edges was tattooed. Patients with cT1-3N0 tumour <3-4 cm were treated with either 5x5Gy+4Gy boost (N=31) or chemoradiation (50.4Gy+5.4Gy boost, 1.8Gy per fraction+5-fluorouracyl and leucovorin; N=13). Thirteen patients from the short-course group were unfit for chemotherapy. The interval from radiation to full-thickness local excision was 6 weeks. The protocol called for conversion to a transabdominal surgery in case of ypT2-3 disease or positive margin. RESULTS: The postoperative complications requiring hospitalization were recorded in 9% of patients. The rate of pathological complete response was 41%. The rate of patients requiring conversion was 34%; however, 18% actually underwent conversion and the remaining 16% refused or were unfit. During the 14 months of median follow-up, local recurrence was detected in 7% of patients and all underwent salvage surgery. Of 19 patients in whom initially anterior resection was likely, 16% had abdominoperineal resection performed for a conversion or as a rescue procedure. CONCLUSION: Our study suggests that the short-course radiation prior to local excision is a treatment option for high-risk patients.

Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients.

PURPOSE: To report the results of a planned safety analysis from a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus fluorouracil/leucovorin (FU/LV) as adjuvant therapy for stage III colon cancer. PATIENTS AND METHODS: Patients with stage III colon carcinoma were randomly assigned to receive either XELOX (intravenous oxaliplatin plus oral capecitabine; 3-week cycle for eight cycles) or standard intravenous bolus FU/LV administered as the Mayo Clinic (Mayo; Rochester, MN) or Roswell Park (RP; Buffalo, NY) regimen for a similar length of time. A total of 1,886 patients were randomly assigned. RESULTS: The safety population comprised 1,864 patients, of whom 938 received XELOX and 926 received FU/LV. Most treatment-related adverse events (AEs) occurred at similar rates in both treatment arms. However, patients receiving XELOX experienced less all-grade diarrhea, alopecia, and more neurosensory toxicity, vomiting, and hand-foot syndrome than those patients receiving FU/LV. Compared with Mayo, XELOX showed fewer grade 3/4 hematologic AE and more grade 3/4 gastrointestinal AE. Compared with RP, XELOX showed less grade 3/4 gastrointestinal AE and more grade 3/4 hematologic AE. As expected grade 3/4 neurosensory toxicity and grade 3 hand-foot syndrome were higher with XELOX. Treatment-related mortality within 28 days from the last study dose was 0.6% in the XELOX group and 0.6% in the FU/LV group. CONCLUSION: XELOX has a manageable tolerability profile in the adjuvant setting. Efficacy data will be available within the next 24 months.

Prospective, randomized trial examining the role of gentamycin-containing collagen sponge in the reduction of postoperative morbidity in rectal cancer patients: early results and surprising outcome at 3-year follow-up.

OBJECTIVE: The study was carried out to evaluate the efficacy of the gentamycin collagen sponge placed in the pelvic cavity after excision of rectal cancer in view of postoperative complications and the risk of cancer recurrence. METHODS: A total of 229 patients were recruited into the study and randomized into two groups: GRM(+), in which a gentamycin collagen sponge was used, and GRM(-), without the sponge. Tumors were resected using a TME technique. In the GRM(+) group, the sponge was placed into the tumor bed. RESULTS: Analysis covered 218 patients for whom all follow-up data were available. There were fewer early postoperative complications in the GRM(+) group: 20.7 vs. 37.5%; p=0.044. This effect was found mainly in patients with surgery lasting longer than 3 h. After 36 months' follow-up, the overall survival after R0 resection for the GRM(+) and GRM(-) groups was: 88.66 vs. 73.96%. There was significant reduction in the distant metastasis rate in favor of the GRM(+) group. CONCLUSION: The use of the gentamycin collagen sponge after excision of rectal cancer is safe and reduces the rate of early postoperative complications. The reasons for the lower rate of distant metastasis in the GRM(+) group are not clear, but the patients enjoy significant survival benefits.

Total cystectomies in the surgical treatment of rectal cancer with prior chemoradiation: analysis of postoperative morbidity and survival.

BACKGROUND AND AIMS: Curative surgery for rectal cancer seldom requires urinary tract resections. The study investigated morbidity and survival following resection of rectum with total cystectomy following chemoradiation for primary rectal cancer. PATIENTS AND METHODS: 19 consecutive patients with primary nonresectable rectal cancer undergoing preoperative chemoradiation and operated on by a multidisciplinary team of surgeons. RESULTS: Morbidity was moderately low, and only five cases required surgical reintervention. No postoperative deaths were observed. Long-term survival in this group of patients compares well with the survival of patients with primarily nonresectable rectal cancer without the involvement of urinary bladder. CONCLUSION: Extended pelvic exenteration due to rectal cancer is relatively safe and in selected patients offers long-term survival and a chance of a cure. Involvement of the urinary bladder does not adversely affect outcome of rectal cancer treatment.