Recurrence and cancer-specific death after adjuvant chemotherapy for Stage III colon cancer.

AIM: The recommended standard of care for patients after resection of Stage III colon cancer is adjuvant 5-fluorouracil based chemotherapy - FOLFOX (fluorouracil, leucovorin with oxaliplatin) - or CAPOX (capecitabine, oxaliplatin). This may be modified in older patients or depending on comorbidity. This has been challenged recently as the apparent benefit of adjuvant chemotherapy may arise from improvements in surgery or preoperative imaging or pathology staging. This study compares recurrence and colon-cancer-specific death between patients who received postoperative adjuvant chemotherapy and those who did not. METHOD: Prospectively recorded data from 363 consecutive patients who had a resection for Stage III colonic adenocarcinoma between 1995 and 2010 inclusive were analysed. Surviving patients were followed for at least 5 years. The suitability of patients for chemotherapy was discussed routinely at multidisciplinary team meetings. The incidence of recurrence and colon-cancer-specific death was evaluated by competing risk methods. RESULTS: After adjustment for the competing risk of non-colorectal cancer death, there was no significant difference in recurrence between the 204 patients who received chemotherapy and the 159 who did not [hazard ratio (HR) 0.94, 95% CI 0.66-1.32, P = 0.700) and no significant difference in colon-cancer-specific death (HR 0.73, 95% CI 0.50-1.04, P = 0.084; HR 0.88, 95% CI 0.57-1.36, P = 0.577 after adjustment for relevant covariates). CONCLUSION: These findings question the routine use of chemotherapy after complete mesocolic excision for Stage III colon cancer. Recurrence and cancer-specific death, assessed by competing risk methods, should be the standard outcomes for evaluating the effectiveness of adjuvant chemotherapy after potentially curative resection.

Overexpression of protein S100A4 is independently associated with overall survival in stage C colonic cancer but only in cytoplasm at the advancing tumour front.

PURPOSE: S100A4, a multifunctional protein, has been linked to the invasive growth and metastases of several human cancers. This study investigated the association between S100A4 and overall survival and other clinicopathological features in patients with stage C colonic cancer. METHODS: Clinical and pathological data were obtained from a prospective hospital registry of 409 patients who had a resection for stage C colonic cancer. Tissue microarrays for immunohistochemistry were constructed from archived tissue. S100A4 staining intensity and percentage of stained cells were assessed in nuclei and cytoplasm for both the central part of the tumour and at the advancing front. Overall survival was analysed by the Kaplan-Meier method and Cox regression. RESULTS: Only a high percentage of cells with S100A4 cytoplasmic staining in frontal tissue was associated with poor survival (hazard ratio, 1.6; 95 % CI 1.1-2.2; p = 0.008) after adjustment for other prognostic variables. There was no association between frontal cytoplasmic S100A4 expression and any of 13 other clinicopathological variables. CONCLUSIONS: High expression of S100A4 in cytoplasm at the advancing front of stage C colonic tumours indicates a poor prognosis. Whether S100A4 can predict response to adjuvant chemotherapy remains to be investigated in a randomised clinical trial.

Identification of distinctive protein expression patterns in colorectal adenoma.

PURPOSE: As a pre-malignant precursor, adenoma provides an ideal tissue for proteome profiling to investigate early colorectal cancer development and provide possible targets for preventive interventions. The aim of this study was to identify patterns of differential protein expression that distinguish colorectal adenoma from normal tissue. EXPERIMENTAL DESIGN: Twenty paired samples of adenoma and normal mucosa were analysed by 2-DE and MALDI-TOF/TOF MS to detect proteins with ≥2-fold differential expression. RESULTS: Four proteins were up-regulated in adenoma (Annexin A3, S100A11, S100P and eIF5A-1) and three were down-regulated (Galectin-1, S100A9 and FABPL). S100P, galectin-1, S100A9 and FABPL expression was localised by immunohistochemistry. CONCLUSIONS AND CLINICAL RELEVANCE: Distinctive patterns of in vivo protein expression in colorectal adenoma were identified for the first time. These proteins have important functions in cell differentiation, proliferation and metabolism, and may play a crucial role in early colorectal carcinogenesis. The ability to recognise premalignant lesions may have important applications in cancer prevention.

Adjuvant chemotherapy for stage C colonic cancer in a multidisciplinary setting.

BACKGROUND: In this study of patients undergoing adjuvant chemotherapy for clinicopathological stage C colonic cancer after optimal surgery, the aims were: to describe their immediate experience of chemotherapy, to assess disease-free survival, to compare overall survival with that of a matched untreated historical control group, and to evaluate the associations between previously identified adverse risk factors and survival. METHODS: Data were drawn from a comprehensive, prospective hospital registry of resections for colorectal cancer between 1971 and 2004, with retrospective data on adjuvant chemotherapy. The main end point was overall survival. Statistical analysis employed the chi-squared test, Kaplan-Meier estimation and proportional hazards regression. RESULTS: From May 1992 to December 2004, there were 104 patients who received adjuvant chemotherapy. Duration of treatment, withdrawal from treatment, toxicity and other immediate treatment outcomes were similar to those in other equivalent studies. There were no toxicity-associated deaths. Overall survival was significantly longer in the treated patients than in the control group (3-year rates 81% and 66%, respectively, P = 0.009). A significant protective effect of adjuvant therapy was found (hazard ratio 0.5, 95% confidence interval 0.3-0.8, P = 0.001) after adjustment for histopathology features previously shown to be negatively associated with survival (high grade, venous invasion, apical node metastasis, free serosal surface involvement). CONCLUSIONS: For patients who have had a curative resection for lymph node positive colonic cancer in a specialist colorectal surgical unit and been managed by a multidisciplinary team, post-operative adjuvant chemotherapy is safe and provides the same survival advantage as seen in randomized trials.

Understanding the anatomy of lymphatic drainage and the use of blue-dye mapping to determine the extent of lymphadenectomy in rectal cancer surgery: unresolved issues.

OBJECTIVE: This paper reviews the literature on the pathways of lymphatic drainage of the rectum and their significance in radical cancer surgery. METHOD: This paper reviews some of the seminal works on the lymphatic drainage of the rectum and its surgical implications when operating on patients with rectal cancer. Publications were searched via Medline, sourced from reference lists and by cross referencing with the most widely cited papers. RESULTS: The classical European description of the anatomy of the lymphatic drainage of the rectum is presented. Early lymphatic mapping techniques and the role of newer technologies in lymphatic mapping, including sentinel lymph node mapping are discussed. The differing philosophies between Western practice, of dissection in the plane of the fascia propria and the Japanese wider pelvic lymphadenectomy are discussed. CONCLUSIONS: A clear understanding of the regional lymphatic drainage of the rectum and precise anatomical mobilisation of the rectum is the surgical cornerstone to excellent locoregional control of rectal cancer. The success of the differing Western and Japanese philosophies on the degree of pelvic lymphadenectomy suggests a possible role for 'selective wide pelvic lymphadectomy'. Mapping lateral lymphatic drainage pathways could augment the selection process for radiotherapy.

The importance of tumor stage and relative survival analysis for the association between sex and survival after resection of colorectal cancer.

OBJECTIVE: The aim of this study was to determine whether the previously noted poorer survival of men after resection of colorectal cancer varied among clinicopathological tumor stages. SUMMARY BACKGROUND DATA: The question of whether sex is independently associated with prognosis after resection of colorectal cancer has been examined in numerous studies over the past 2 decades, but with conflicting results. METHODS: Data on 3,301 patients were drawn from a comprehensive, prospective hospital registry of all resections for colorectal cancer performed between January 1971 and December 2005. Statistical analysis employed Kaplan Meier estimation and relative survival analysis to adjust for differential male/female life expectancy in the general population. RESULTS: The relative survival of males was significantly less than that of females (P = 0.004) only in stage B. This was not accounted for by other negative pathology features and cause of death did not differ significantly between males and females. However, men with stage B tumor were more likely than women to experience postoperative morbidity, particularly a respiratory complication or a surgical complication requiring urgent reoperation. The sex difference in relative survival persisted among patients who had either a respiratory complication or an urgent reoperation (P = 0.003) but disappeared among those who had neither (P = 0.193). CONCLUSION: The poorer survival of men with stage B tumor was attributable to their greater postoperative morbidity which led to the earlier death of some due to causes unrelated to their colorectal cancer.

Anastomotic leakage after resection of colorectal cancer generates prodigious use of hospital resources.

OBJECTIVE: The aim of this study was to determine the demand for hospital resources generated by anastomotic leakage, including surgical, medical, imaging, pathology, and other allied health consultations or services and length of postoperative hospital stay. METHOD: Data were obtained from a comprehensive, prospective hospital registry of all resections for colorectal cancer from January 1995 to December 2004 and from retrospective review of patients' notes. RESULTS: Forty-one patients with a leak spent 92 days in intensive care, required 129 days of total parenteral nutrition, 69 days of enteric feeding and 41 days on ventilation and had a median postoperative hospital stay of 28 days (range 11-104). These patients required 24 re-operations and 2273 separate medical consultations or allied services. CONCLUSION: Anastomotic leakage generates a very considerable demand for hospital resources and diverts these resources from the hospital population at large.

The significance of involvement of a free serosal surface for recurrence and survival following resection of clinicopathological stage B and C rectal cancer.

OBJECTIVE: To determine whether the presence of tumour at a free serosal surface was independently associated with pelvic recurrence or survival in patients who had a resection for clinicopathological stage B or stage C rectal cancer and who had not received adjuvant therapy. METHOD: Data were drawn from a comprehensive, prospective hospital registry of all resections for rectal cancer from January 1971 to December 1998 with follow up to December 2003. Statistical analysis employed the chi(2) test or Fisher's exact probability, Kaplan-Meier estimation and proportional hazards regression, with a significance level of < or =0.05 and 95% confidence intervals (CI). RESULTS: In 665 patients with stages B or C tumour, 35 (5.3%; CI 3.7-7.2%) had tumour at a free serosal surface. These comprised 6/332 (1.8%; CI 0.8-3.7%) patients with stage B tumour and 29/333 (8.7%; CI 6.1-12.2%) with stage C tumour. After adjustment for other relevant variables, involvement of a free serosal surface was significantly associated with pelvic recurrence [hazard ratio (HR) 2.7; CI 1.3-5.5] and diminished survival (HR 1.6; CI 1.1-2.4) but not with systemic (only) recurrence. CONCLUSION: This study has confirmed that direct tumour spread to a free serosal surface independently predicts pelvic recurrence and diminished survival after resection of clinicopathological stage B and C rectal cancer. This feature should always be sought by the pathologist and reported when present, and noted by the surgeon and oncologist. Serosal involvement should be evaluated further for its utility in selecting patients for adjuvant therapy.

Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer.

The mutated in colorectal cancer (MCC) gene is in close linkage with the adenomatous polyposis coli (APC) gene on chromosome 5, in a region of frequent loss of heterozygosity in colorectal cancer. The role of MCC in carcinogenesis, however, has not been extensively analysed, and functional studies are emerging, which implicate it as a candidate tumor suppressor gene. The aim of this study was to examine loss of MCC expression due to promoter hypermethylation and its clinicopathologic significance in colorectal cancer. Correspondence of MCC methylation with gene silencing was demonstrated using bisulfite sequencing, reverse transcription-polymerase chain reaction and Western blotting. MCC methylation was detected in 45-52% of 187 primary colorectal cancers. There was a striking association with CDKN2A methylation (P<0.0001), the CpG island methylator phenotype (P<0.0001) and the BRAF V600E mutation (P<0.0001). MCC methylation was also more common (P=0.0084) in serrated polyps than in adenomas. In contrast, there was no association with APC methylation or KRAS mutations. This study demonstrates for the first time that MCC methylation is a frequent change during colorectal carcinogenesis. Furthermore, MCC methylation is significantly associated with a distinct spectrum of precursor lesions, which are suggested to give rise to cancers via the serrated neoplasia pathway.

Assessing the evidence for an association between circumferential tumour clearance and local recurrence after resection of rectal cancer.

OBJECTIVE: Circumferential resection margin involvement (CRMI) after resection of rectal cancer is regarded as a risk factor for local recurrence. We have been able to identify only nine peer-reviewed English-language publications which focus primarily on this association, and they report widely differing rates of local recurrence. The aims of this study were to review possible reasons for this variability and to assess the evidence for the micrometrically measured threshold defining CRMI. METHOD: Methodological and statistical evaluation of relevant literature. RESULTS: Several factors which could account for this variability are discussed including the nature of the patient series, surgical technique, curative vs palliative resections, pathology technique, the definition of CRMI, adjuvant therapy, tumour stage, definition and ascertainment of local recurrence, length of follow-up and method of analysis. The objective evidence for the conventional definition of CRMI as tumour 1 mm or less from a circumferential margin is considered along with the evidence supporting a recent proposal that the margin be extended to 2 mm or less. The evidence is numerically weak in both cases and we believe that neither definition should be set in concrete at this stage. CONCLUSION: Pending further research, we recommend that routine pathology reports should record frank tumour transection, if present, or otherwise report the histological width of the margin between the tumour and the nearest circumferential line of resection in millimetres. The definition of CRMI should be simply histological evidence of tumour in a line of resection, that is, a margin of 0 mm. The definition of CRMI as a margin of

Risk factors for tumour present in a circumferential line of resection after excision of rectal cancer.

BACKGROUND: Transected tumour in a circumferential line of resection after excision of rectal cancer carries a high likelihood of local recurrence. The aim of this study was to identify independent risk factors for transected tumour and to examine their temporal variability. METHODS: Data were drawn from a comprehensive, prospective hospital registry of all resections for rectal cancer from January 1971 to July 2004. Transected tumour was defined as tumour present histologically in a line of resection and was assessed in all specimens. RESULTS: Transection occurred in 129 of 1613 patients (8.0 (95 per cent confidence interval 6.7 to 9.4) per cent). The following variables were independently associated with transected tumour: tumour perforation, a non-restorative operation, tumour adherence, non-standardized operative technique, preoperative radiotherapy, male sex, histological involvement of an adjacent organ or tissue, high-grade tumour and venous invasion. The mean number of risk factors per patient per year and the annual percentage of patients with transection varied distinctly over the history of the database. CONCLUSION: The varying prevalence of risk factors, both within and between hospitals and patient series, should be taken into account if the rate of transection is to be regarded as an index of the quality of surgery.

Outcomes after admission on the day of elective resection for colorectal cancer.

BACKGROUND: When a policy encouraging day of surgery admission (DOSA) was introduced in public hospitals in New South Wales, Australia, there were concerns that patient outcomes would be compromised. The aim of the present study was to compare patients having an elective resection for colorectal cancer (CRC) on a DOSA and a non-DOSA basis in respect of postoperative complications, operative mortality and 2-year survival. METHODS: A comprehensive prospective computerized database is maintained for all patients undergoing a resection for CRC at Concord Hospital, Sydney, Australia. The present study is based on patients who had an elective resection during the transition to DOSA between January 2000 and December 2003. Background characteristics, comorbidity, perioperative factors, tumour pathology, postoperative morbidity and mortality, and overall survival were compared between 274 DOSA and 103 non-DOSA patients. RESULTS: Of the 24 postoperative complications considered there was a significant difference in only four: DOSA patients were less likely than non-DOSA patients to have a respiratory complication (16.1% vs 29.1%, P = 0.004), a prolonged organic confusional state (5.5% vs 23.3%, P < 0.001), acute drug withdrawal (0.4% vs 3.9%, P = 0.021) or multisystem failure (0.4% vs 3.9%, P = 0.021). There was no difference in operative mortality or 2-year survival. CONCLUSION: The present study shows that DOSA did not adversely affect a wide range of outcomes for patients having a resection for CRC. In fact the results suggest that DOSA may protect against respiratory complications and prolonged postoperative confusion.

Local recurrence after curative resection for rectal cancer is associated with anterior position of the tumour.

BACKGROUND: Mobilization of rectal cancer can be difficult if the tumour is located anteriorly and may result in a higher incidence of local recurrence. The aim of this study was to determine whether local recurrence and survival following curative resection of rectal cancer were associated with the position of the tumour. METHODS: Data were drawn from a comprehensive, prospective hospital registry of all resections for rectal cancer from January 1990 to December 1998, with follow-up to December 2003. RESULTS: The 5-year local recurrence rate was 15.9 (95 per cent confidence interval (c.i.) 11.0 to 22.8) per cent in 176 patients with tumours that had an anterior component compared with 5.8 (95 per cent c.i. 2.8 to 11.9) per cent in 132 patients with tumours without an anterior component (P = 0.009). This association persisted after adjustment for other factors linked to local recurrence (hazard ratio (HR) 2.4 (95 per cent c.i. 1.1 to 5.4)). Similarly, anterior position had a significant negative independent association with survival (HR 1.4 (95 per cent c.i. 1.0 to 2.00)). CONCLUSION: Anterior position is an independent negative prognostic factor for both local recurrence and survival after curative resection of rectal cancer.

Effect of supervised surgical training on outcomes after resection of colorectal cancer.

BACKGROUND: The process of training surgeons in technique for resection of colorectal cancer should not compromise patient care or outcomes. The aim of this study was to compare morbidity, mortality and survival rates after resection performed by trainees with those for a consultant surgeon. METHODS: Outcomes for 150 patients operated on by a single colorectal surgeon at a private hospital were compared with those of 344 patients admitted under the same surgeon and operated on by closely supervised trainee surgeons in a public teaching hospital between 1995 and 2002. RESULTS: Co-morbidity was significantly more common in patients operated on by trainees; their American Society of Anesthesiologists grades were higher and tumours were more advanced. Of 16 postoperative complications evaluated, only respiratory and cardiac problems were significantly more common in patients operated on by trainees. There was no difference in operative mortality, local recurrence or 2-year survival rate after adjustment for age and tumour stage. CONCLUSION: Outcomes after resection for colorectal cancer did not differ between the consultant and trainees in the context of a closely supervised training programme.

Low microsatellite instability is associated with poor prognosis in stage C colon cancer.

PURPOSE: The significance of low microsatellite instability (MSI-L) in colorectal cancer is poorly understood. No clear biologic distinction has been found between MSI-L and microsatellite stable (MSS) colorectal cancer, and these two phenotypes are usually combined when analyzed against the well-defined high MSI (MSI-H) phenotype. Evidence is emerging that an O(6)-methylguanine DNA methyltransferase (MGMT) gene defect is associated with MSI-L. Therefore, to further define this phenotype, we undertook a detailed analysis of the prognostic significance of MSI-L and loss of MGMT expression in colon cancer. PATIENTS AND METHODS: The study cohort was 183 patients with clinicopathologic stage C colon cancer who had not received adjuvant therapy. We analyzed MSI status, MGMT, and mismatch repair protein expression, as well as MGMT and p16 promoter hypermethylation. RESULTS: We showed that MSI-L defines a group of patients with poorer survival (P = .026) than MSS patients, and that MSI-L was an independent prognostic indicator (P = .005) in stage C colon cancer. Loss of MGMT protein expression was associated with the MSI-L phenotype but was not a prognostic factor for overall survival in colon cancer. p16 methylation was significantly less frequent in MSI-L than in MSI-H and MSS tumors and was not associated with survival. CONCLUSION: MSI-L characterizes a distinct subgroup of stage C colon cancer patients, including the MSI-L subset of proximal colon cancer, who have a poorer outcome. Neither the MGMT defect nor p16 methylation are likely to contribute to the worse prognosis of the MSI-L phenotype.

What factors influence survival in patients with unresected synchronous liver metastases after resection of colorectal cancer?

OBJECTIVE: The aim of this study was to determine whether the survival of patients with untreated synchronous liver metastases after resection of a colorectal cancer was associated with any features of the primary tumour. METHODS: Information for 398 consecutive patients with unresected liver metastases in the period 1971-2001 was examined by multivariate survival analysis. RESULTS: Of 19 clinical and pathological variables considered, survival was independently associated only with residual tumour in a line of resection (hazard ratio (HR) 1.95), venous invasion (HR 1.87), right colonic tumour (HR 1.68), lymph node metastasis (HR 1.54), and extra-hepatic metastasis (HR 1.16); 8.3% of patients had none of these adverse features. Their 2-year overall survival rate was 39.2%, compared with only 16.5% (P < 0.001) in those with one or more adverse features. CONCLUSIONS: These findings may assist in selecting patients most likely to benefit from treatment of hepatic metastases and in counselling patients and their relatives.

Low level microsatellite instability may be associated with reduced cancer specific survival in sporadic stage C colorectal carcinoma.

BACKGROUND: Colorectal cancers (CRCs) may be categorised according to the degree of microsatellite instability (MSI) exhibited, as MSI-high (MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS). MSI-H status confers a survival advantage to patients with sporadic CRC. AIMS: To determine if low levels of MSI are related to the clinicopathological features and prognosis of sporadic stage C CRC. PATIENTS: A total of 255 patients who underwent resection for sporadic stage C CRC were studied. No patient received chemotherapy. Minimum follow up was five years. METHODS: DNA extracted from archival malignant and non-malignant tissue was amplified by polymerase chain reaction using a panel of 11 microsatellites. MSI-H was defined as instability at > or =40% of markers, MSS as no instability, and MSI-L as instability at >0% but <40% of markers. Patients with MSI-H CRC were excluded from analysis as they have previously been shown to have better survival. RESULTS: Thirty three MSI-L and 176 MSS CRCs were identified. There was no difference in biological characteristics or overall survival of MSI-L compared with MSS CRC but MSI-L was associated with poorer cancer specific survival (hazard ratio 2.0 (95% confidence interval 1.1-3.6)). CONCLUSIONS: Sporadic MSI-L and MSS CRCs have comparable clinicopathological features. Further studies are required to assess the impact of MSI-L on prognosis.

What pathologic features influence survival in patients with local residual tumor after resection of colorectal cancer?

BACKGROUND: Local residual tumor predicts poor patient survival after resection for colorectal cancer. The aim of this study was to determine the prevalence of residual tumor in a line of resection in a large prospective series and to identify other pathology variables that may influence survival in the absence of distant metastases in such patients. STUDY DESIGN: This study was based on all patients who had a resection for colorectal cancer at Concord Hospital between 1971 and 2001. Patients were followed up annually until death or December 2002. Survival analysis used the Kaplan-Meier method and log rank test. Proportional hazards regression was used in multivariate modeling. RESULTS: The overall prevalence of residual tumor in a line of resection was 5.9%. Of 12 pathology variables examined, only high grade and apical node metastasis were independently associated with survival in the subset of 120 patients with residual tumor in a line of resection but without distant metastases. The 2-year survival rate for patients with neither of these adverse features was 46.4% (95% CI, 31.7% to 59.9%) as compared with only 7.7% (CI, 0.5% to 29.2%) in those who had both. CONCLUSIONS: These results show that presence of local residual tumor after colorectal cancer resection does not carry a universally poor prognosis. Two specific histopathologic features independently associated with diminished survival were identified.