Major low anterior resection syndrome has equivalent health-related quality of life implications as having a permanent colostomy.

BACKGROUND: The literature is inconclusive when comparing health-related quality of life following restorative anterior resection (AR) compared with abdominoperineal resection (APR). Consideration of functional outcomes may explain this inconsistency. The aim of this study was to compare health-related quality of life in patients post-anterior resection, stratified by low anterior resection syndrome score, and post-abdominoperineal resection patients. METHODS: A cross-sectional study of consecutive patients post APR and AR for rectal or sigmoid adenocarcinoma at a tertiary centre in Sydney, Australia (Jan 2012- Dec 2021) was performed. HRQoL outcomes (SF36v2 physical [PCS] and mental component summary [MCS] scores) were compared between APR and AR patients, with subgroup analyses stratifying AR patients according to LARS score (no/minor/major). Age- and gender-adjusted comparisons were performed by linear regression. RESULTS: Overall, 248 post-AR patients (57.3% male, mean age 70.8 years, SD 11.6) and 64 post-APR patients (62.5% male, mean age 68.1 years, SD 13.1) participated. When stratified by LARS, 'major LARS' had a similar negative effect on age-and sex-adjusted PCS scores as APR. 'No LARS' (p < 0.001) and 'minor LARS' (p < 0.001) patients had higher PCS scores compared to post-APR patients. 'Major LARS' had a similarly negative effect on MCS scores compared with post-APR patients. MCS scores were higher in 'no LARS' (p = 0.006) compared with APR patients. CONCLUSIONS: Postoperative bowel dysfunction significantly impacts health-related quality of life. Patients with 'major LARS' have health-related quality of life as poor as those following APR. This requires consideration when counselling patients on postoperative health-related quality of life, especially where poor postoperative bowel function is anticipated following restorative surgery.

Relative effects of direct spread, lymph node metastasis and venous invasion in relation to blood borne distant metastasis present at the time of resection of colorectal cancer.

Conventionally, lymphatic spread is regarded as the principal mechanism by which haematogenous metastasis occurs in colorectal cancer. The aim of this cross sectional study was to determine the relative strengths of direct tumour spread, the presence of lymph node metastasis and histologically demonstrated venous invasion as drivers of haematogenous metastasis diagnosed at the time of resection of colorectal cancer. The data were drawn from a hospital database of consecutive bowel cancer resections between 1995 and 2017 inclusive. The presence of haematogenous metastasis was determined at the time of surgery by imaging or other investigations or operative findings. Where possible, histological confirmation was obtained. Specimen dissection and reporting followed a standardised procedure. Tumour staging was according to the 7th edition of the UICC/AJCC pTNM system. Analysis was by multivariable logistic regression. After exclusions 3133 patients remained, among whom 380 (12.1%) had one or more haematogenous metastases. In bivariate analyses, the frequency of haematogenous metastasis was directly associated with increasing T status (p<0.001), increasing N status (p<0.001) and increasing extent of venous invasion (p<0.001) and with some other patient and tumour features. In a multivariable model, after adjustment for other features, associations with the occurrence of haematogenous metastasis were as follows: T3 odds ratio (OR) 4.41 (95% confidence interval 2.40-8.10), p<0.001; T4a OR 6.29 (3.27-12.10), p<0.001; T4b OR 5.50 (2.71-11.15), p<0.001; N1 OR 3.39 (2.47-4.64), p<0.001; N2 OR 4.59 (3.21-6.54), p<0.001; mural venous invasion OR 2.18 (1.14-4.16), p=0.018; extramural venous invasion OR 2.91 (2.21-3.83), p<0.001. Only three other features had significant, though weak effects in the model. These results led to the conclusion that venous invasion, demonstrated histologically and also inferred independently by the extent of direct tumour spread, made a greater contribution to the occurrence of haematogenous metastasis than did spread through lymphatics. Our approach and findings may have implications for other cancer sites apart from colorectal cancer.

Competing risks analysis of the association between perioperative blood transfusion and long-term outcomes after resection of colorectal cancer.

AIM: Despite numerous reports over three decades, the association between perioperative blood transfusion and long-term outcomes after resection of colorectal cancer remains controversial. This cohort study used competing risks statistical methods to examine the association between transfusion and recurrence and colorectal cancer-specific death after potentially curative and noncurative resection. METHOD: A hospital database provided prospectively recorded clinical, operative and follow-up information. All surviving patients were followed for at least 5 years. Data were analysed by multivariable competing risks regression. RESULTS: From 2575 patients in the period 1995-2010 inclusive, after exclusions, 2334 remained for analysis. Among 1941 who had a potentially curative resection and 393 who had a noncurative resection the transfusion rates were 24.9% and 33.6%, respectively. After potentially curative resection there was no significant bivariate association between transfusion and recurrence (HR 0.93, CI 0.74-1.16, P = 0.499) or between transfusion and colorectal cancer-specific death (HR 1.04, CI 0.82-1.33, P = 0.753). After noncurative resection there was no significant association between transfusion and cancer-specific death (HR 0.93, CI 0.73-1.19, P = 0.560). Multivariable models showed no material effect of potential confounder variables on these results. CONCLUSION: The competing risks findings in this study showed no significant association between perioperative transfusion and recurrence or colorectal cancer-specific death.

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.

Competing risks analysis of microsatellite instability as a prognostic factor in colorectal cancer.

BACKGROUND: Despite an extensive literature suggesting that high microsatellite instability (MSI-H) enhances survival and protects against recurrence after colorectal cancer resection, such effects remain controversial as many studies show only a weak bivariate association or no multivariable association with outcome. This study examined the relationship between MSI status and colorectal cancer outcomes with adjustment for death from other causes as a competing risk. METHODS: A hospital database of patients following colorectal cancer resection was interrogated for clinical, operative, pathology, adjuvant therapy and follow-up information. MSI-H status was determined by immunohistochemistry for mismatch repair protein deficiency. The cumulative incidence of recurrence and colorectal cancer-specific death was evaluated by competing risks methods. RESULTS: Among 1009 patients who had a resection between August 2002 and December 2008, and were followed to at least December 2013, there were 114 (11·3 per cent) with MSI-H (72·8 per cent aged at least 70 years; 63·2 per cent women). After potentially curative resection, with adjustment for non-colorectal cancer death as a competing risk and adjustment for 22 clinical, operative and pathological variables, there was no association between MSI-H and recurrence (hazard ratio (HR) 0·81, 95 per cent c.i. 0·42 to 1·57) or colorectal cancer-specific death (HR 0·73, 0·39 to 1·35) in this patient population. For palliative resections, there was no association between MSI-H and colorectal cancer-specific death (HR 0·65, 0·21 to 2·04). MSI-H was associated with non-colorectal cancer death after both curative (HR 1·55, 1·04 to 2·30) and palliative (HR 3·80, 1·32 to 11·00) resections. CONCLUSION: Microsatellite instability status was not an independent prognostic variable in these patients.

Rectal mobilization: the place of Denonvilliers' fascia and inconsistencies in the literature.

Confusion remains as to what is meant by Denonvilliers' fascia. This review searched the literature on pelvic surgical anatomy to determine whether there is agreement with Denonvilliers' original description and its implication in defining the correct anterior plane of dissection when mobilizing the rectum. The original French description of the fascia was translated into English and then compared both with French and with English studies identified by searching PubMed, Medline and Scopus from 1836 to June 2015. Special emphasis was given to the years between 1980 and 2015 in order to capture the literature pertinent to, and following on from, the description of total mesorectal excision for rectal cancer. The final literature search revealed 16 studies from the original 2150 citations. Much of the debate was concerned with the origin and development of the fascia, arising from either the 'fusion' or the 'condensation' of local primitive tissue into a mature 'multilayered' structure. Controversy regarding the correct plane of rectal mobilization occurs as a result of different interpretations by surgeons, anatomists and radiologists and bears little resemblance to Denonvilliers' original description. This may reflect wide anatomical variability in the adult pelvis or a form of dissection artefact. Further study is required to investigate this. Logically, for both men and women, the plane of rectal mobilization should be behind Denonvilliers' fascia and between it and the fascia propria of the rectum.

Long-term results following an anatomically based surgical technique for resection of colon cancer: a comparison with results from complete mesocolic excision.

AIM: Complete mesocolic excision (CME) has been advocated as likely to improve the long-term oncological outcome of colon cancer resection, although there is a paucity of long-term results in the literature. The aim of this study was to supplement our previously published results on colon cancer resection based on a standardized technique of precise dissection along anatomical planes with high vascular ligation and to compare our long-term results with those of recent European studies of CME. METHOD: Data were drawn from a prospective hospital registry of consecutive resections for colon cancer between 1996 and 2007, including follow-up to the end of 2012. The principal outcomes from potentially curative resections were 5-year Kaplan-Meier rates of local recurrence, systemic recurrence, overall survival and cancer-specific survival. Secondary outcomes for all resections were postoperative complications, number of lymph nodes retrieved and R0 status. RESULTS: For 779 potentially curative resections the local recurrence rate was 2.1% (95% CI 1.3-3.4), the systemic recurrence rate was 10.2% (95% CI 8.1-12.7), the 5-year overall survival rate was 76.2% (95% CI 73.0-79.0) and the cancer-specific survival rate was 89.8% (95% CI 87.3-91.9). For all 905 resections, rates of 14 surgical complications were low and not dissimilar to those in a comparable study. The median lymph node count was 15 (range 0-113). R0 status was confirmed in 883/905 patients (97.6%; 95% CI 96.4-98.5). CONCLUSION: For colon cancer, meticulous dissection along anatomical planes together with high vascular ligation results in few complications, a high R0 rate, low recurrence and high survival.

Impact of obesity on complications after resection for rectal cancer.

AIM: The prevalence of obesity in Australia is high and increasing, with associated serious negative effects on health. The technical complexity of rectal cancer surgery is exacerbated in obese patients, which may compromise outcomes. The aim of this study was to examine the association between obesity and complications after resection of rectal cancer. METHOD: Data were drawn from a comprehensive prospective registry of rectal cancer resections performed from 2007 to 2011 by members of the colorectal surgical unit in a tertiary referral hospital and in a single private hospital with which they were affiliated. RESULTS: Of 255 patients who had a resection for rectal cancer during the study period, 95 (37%) were classified as obese on the basis of a body mass index (BMI) ≥ 30 kg/m(2) . Among 24 postoperative complications the only significant differences for obese patients were higher rates of wound complications (16% vs 8%, P = 0.038), small bowel obstruction (4% vs 0%, P = 0.019) and prolonged ileus (18% vs 8%, P = 0.011). The total number of complications did not differ significantly between obese and nonobese patients, and there was no difference between obese and nonobese patients in the rates of reoperation and postoperative death. CONCLUSION: This study did not support an association between obesity and early postoperative complications after resection of rectal cancer.

A comparison of published rates of resection margin involvement and intra-operative perforation between standard and 'cylindrical' abdominoperineal excision for low rectal cancer.

AIM: The study aimed to compare recent reports on standard and alternative methods of abdominoperineal excision for low rectal cancer regarding the rates of circumferential resection margin involvement and intra-operative bowel perforation. METHOD: Data on rates of margin involvement and perforation were obtained from eight recently published reports and also from a prospective registry of resections at Concord Hospital. Rates of these outcomes and their 95% confidence intervals were evaluated. RESULTS: There was no evidence that extralevator abdominoperineal excision yielded significantly lower rates of resection margin involvement or intra-operative bowel perforation compared with standard abdominoperineal excision in six independent hospital- and population-based patient series. Abdominosacral resection of the rectum, on the other hand, did show significantly lower rates of these endpoints, albeit in selected patients. CONCLUSION: The role of extralevator abdominoperineal excision and abdominosacral resection of the rectum should be investigated further in randomized controlled trials.

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.

Magnetic resonance imaging cannot predict histological tumour involvement of a circumferential surgical margin in rectal cancer.

AIM: Several recent studies have attempted to evaluate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting the likelihood of tumour involvement of the postoperative circumferential resection margin (CRM) in rectal cancer with the intention of selecting patients who might benefit from neoadjuvant therapy and as a guide to surgery. The aim of this study was to assess whether such studies can provide a valid answer as to whether preoperative MRI can accurately predict CRM involvement by tumour. METHOD: The study design and methodology of studies on this topic were critically examined. RESULTS: Features identified as affecting the efficacy of these studies were: representativeness of patients, definition of the margin assessed by MRI and by histology, lack of blinding of surgeons and pathologists to MRI results, effect of neoadjuvant treatment, and number of patients studied. CONCLUSION: Because of methodological inadequacies in studies completed to date, there is insufficient evidence of the ability of a positive MRI result to predict an involved CRM. Although MRI may be able to identify a tumour that has extended to the mesorectal fascia and/or intersphincteric plane, logically, it cannot indicate where the surgical boundary of the resection will ultimately lie, and therefore cannot validly predict an involved CRM and should not be relied upon for this purpose.

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.

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.

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.