Life after PROSPER. What do people do for external rectal prolapse?

AIM: A questionnaire completed by members of the ACPGBI in 1997 was a precursor to the PROSPER trial. It showed a significant variation in favoured practice for the surgical treatment of external rectal prolapse. We repeated the same questionnaire to assess how practice has changed since the completion of the trial and its publication. METHOD: An online survey was circulated to all members of the ACPGBI with identical questions to those used in the original in 1997. RESULTS: Similar numbers of recipients responded (122/791 [15.4%] in 2014;153/600 [25.5%] in 1997). The median number of operations per surgeon per year was unchanged (6 [0-30] vs 6 [0-25]). The percentage of surgeons who favoured an abdominal approach in fit patients in 1997 rose significantly from 63.5% to 81.7% in 2014 (P < 0.01). Delorme's remains the most popular perineal procedure (78.5% vs 93.3%), but the Altemeier procedure increased from 14.9% to 39.3%. Ventral rectopexy was the preferred abdominal approach in 2014 (48.6% vs 5.9% [P < 0.01]), with 96.3% of these being performed laparoscopically. The number of surgeons carrying out posterior rectopexy decreased from 92.6% to 45.9% (P < 0.01). Only 9.9% of surgeons still undertook resection rectopexy compared with 39.7% in 1997 (P < 0.01). The numbers of surgeons favouring a perineal approach decreased (18.3% vs 36.5%) although the use of a perineal procedure in elderly or unfit patients was unchanged (38.5% vs 37.9%). CONCLUSION: The surgical management of external rectal prolapse had changed. More surgeons favoured a laparoscopic abdominal approach in 2014 than in 1997 and the use of perineal approaches had decreased. Of these Delorme's operation remained the most popular but the incidence of the use of Altmeier's procedure had increased.

Extended lateral pelvic sidewall excision (ELSiE): an approach to optimize complete resection rates in locally advanced or recurrent anorectal cancer involving the pelvic sidewall.

BACKGROUND: Complete pathological resection of locally advanced or recurrent rectal and anal cancer is regarded as one of the most important determinants of oncological outcome. Disease in the lateral pelvic sidewall has been considered a contraindication for pelvic exenteration surgery owing to the significant likelihood of incomplete resection. METHODS: We describe a novel technique (ELSiE) to resect disease involving the lateral pelvic sidewall. Patient demographics, post-operative histology, length of hospital stay and complications were collected from prospectively maintained electronic patient database. RESULTS: During 2011-2013, six patients underwent pelvic exenteration surgery with the ELSiE approach. All patients had R0 resection. Three patients required sciatic nerve excision. Four patients developed post-operative complications although no major complications occurred. CONCLUSIONS: Patients with locally advanced and recurrent cancer involving the lateral pelvic sidewall may be rendered suitable for potentially curative radical resection with a modification in the approach to the lateral pelvic sidewall. Our pilot series seems to indicate that our novel technique (ELSiE) is feasible, safe and yields high rates of complete pathological resection.

Prognostic significance of extramural vascular invasion in T4 rectal cancer.

AIM: Extramural vascular invasion (EMVI) has been proposed as an adverse prognostic indicator in colorectal cancer, although its use remains both variable and controversial. This study aimed to determine the survival effect of EMVI in T4 rectal cancer. METHOD: Patients undergoing surgery with curative intent for primary T4 rectal cancer between 1971 and 2011 were included from two prospectively collected rectal cancer databases. The main end-point was 3-year survival. RESULTS: From 1142 patients undergoing resection of rectal cancer during the study period, 126 (11.0%) had T4 rectal cancer and were included in the study group. Sphincter preservation was performed in 61 (48%) and a pathologically negative resection margin (R0) was achieved in 104 patients (82.5%). EMVI was present in 51 patients (40.5%) and was an independent predictor of positive lymph node status (adjusted odds ratio 2.66, P = 0.013). Considering all patients, EMVI was associated with reduced overall survival (P = 0.007) and disease-free survival (P = 0.002), but not local recurrence-free survival (P = 0.198). In only those undergoing R0 resection, EMVI predicted reduced disease-free survival with positive nodal status (P = 0.021); it did not predict survival with negative nodal status. CONCLUSION: Overall, EMVI was a strong prognostic marker of survival. However, after complete surgical resection in patients with node-negative disease, EMVI did not predict local recurrence.

PROSPER: a randomised comparison of surgical treatments for rectal prolapse.

AIM: Rectal prolapse is a profoundly disabling condition, occurring mainly in elderly and parous women. There is no accepted standard surgical treatment, with previous studies limited in methodological quality and size. PROSPER aimed to address these deficiencies by comparing the relative merits of different procedures. METHOD: In a pragmatic, factorial (2 × 2) design trial, patients could be randomised between abdominal and perineal surgery (i), and suture vs resection rectopexy for those receiving an abdominal procedure (ii) or Altemeier's vs Delorme's for those receiving a perineal procedure (iii). Primary outcome measures were recurrence of the prolapse, incontinence, bowel function and quality of life scores (Vaizey, bowel thermometer and EQ-5D) measured up to 3 years. RESULTS: Two hundred and ninety-three patients were recruited: 49 were randomised between surgical approaches (i); 78 between abdominal procedures (ii); and 213 between perineal procedures (iii). Recurrence rates were higher than anticipated, but not significantly different in any comparison: Altemeier's vs Delorme's 24/102 (24%) and 31/99 (31%) [hazard ratio (HR) 0.81; 95% CI 0.47, 1.38; P = 0.4]; resection vs suture rectopexy 4/32 (13%) and 9/35 (26%) (HR 0.45; 95% CI 0.14, 1.46; P = 0.2); perineal vs abdominal 5/25 (20%) and 5/19 (26%) (HR 0.83; 95% CI 0.24, 2.86; P = 0.8). Vaizey, bowel thermometer and EQ-5D scores were not significantly different in any of the comparisons. CONCLUSION: No significant differences were seen in any of the randomised comparisons, although substantial improvements from baseline in quality of life were noted following all procedures.

Human papillomavirus infection and anal dysplasia in renal transplant recipients.

BACKGROUND: Immunosuppression is a known risk factor for anal human papillomavirus (HPV) disease, including anal squamous cell carcinoma. Additional risk factors for HPV-related disease have not been studied in the renal transplant population. The demographics of anal HPV and associated risk factors were investigated in this population. METHODS: Anal cytology and polymerase chain reaction were used to assess anal HPV disease in a cohort of transplant recipients at the Royal London Hospital. Risk factors associated with increased immunosuppression and HPV exposure were collated to determine any association with anal disease. RESULTS: Anal dysplasia was associated with anal oncogenic HPV infection (P < 0.001), duration of immunosuppression (P = 0.050), previous genital warts (P = 0.018) and receptive anal intercourse (P = 0.013). CONCLUSION: Anal dysplasia was related to immunosuppression and patient factors in this cohort.

Outcomes following repair of traumatic cloacal deformities.

BACKGROUND: Severe obstetric injury can result in a defect similar to a congenital cloacal deformity, with associated faecal incontinence and sexual dysfunction. The aim of this study was to assess the efficacy of surgical repair of such injuries. METHODS: Patients were identified retrospectively from hospital records. Long-term follow-up data were collected by telephone interview. RESULTS: Outcomes in 31 consecutive patients seen over a 14-year period were reviewed. An overlapping external sphincter repair, with repair of the anorectum and vagina, was performed in 29 patients. Detailed long-term follow-up data were available for 20 patients at a median of 5 years after surgery. Three patients had a stoma at presentation. Surgical repair reduced incontinence to solid stool from seven of 17 to none of 20 patients, to liquid stool from 14 of 17 to ten of 20, and to flatus from 17 of 17 to 12 of 20. Nine patients reported improvement in sexual function. CONCLUSION: Surgical repair of a cloacal injury is associated with significant improvements in faecal incontinence and sexual function. Outcomes are similar to those seen with repair of less severe injuries, and may be maintained in the long term.

Hypoxia-inducible factor-1alpha and -2alpha are expressed in most rectal cancers but only hypoxia-inducible factor-1alpha is associated with prognosis.

The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-2alpha protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1alpha and HIF-2alpha expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1alpha and HIF-2alpha, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1alpha and -2alpha were expressed in >50% of rectal cancers (HIF-1alpha, 54%, 48/90; HIF-2alpha, 64%, 58/90). HIF-1alpha positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were demonstrated [corrected] between HIF-2alpha [corrected] and any pathological features or [corrected] outcome. The study showed an independent association between HIF-1alpha expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1alpha, but not HIF-2alpha, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management.

Assessment of microvessel density and carbonic anhydrase-9 (CA-9) expression in rectal cancer.

AIM: The mechanism by which neoplasias respond to hypoxia determines their biological behavior and prognosis. Understanding the biology of tumors under hypoxic conditions is crucial for the development of anti-angiogenic therapy. Using the largest cohort of rectal adenocarcinomas to date, this study aimed to assess microvessel density (MVD) and carbonic anhydrase-9 (CA-9) expression and to correlate the results with recurrence and cancer-specific survival. MATERIALS AND METHODS: Patients (n=101) who underwent surgery for rectal adenocarcinoma without previous neoadjuvant therapy or metastatic disease were selected. MVD and CA-9 expression were assessed immunohistologically by using the CD34 antibody and the MN/CA9 M75 antibody, respectively. In a multifactorial analysis, the results were correlated with tumor stage, recurrence rate, and long-term survival. RESULTS: MVD was higher with increased T- and N-stages (p<0.01) and associated positively with poor survival (hazard ratio (HR) 1.3 per 10 vessel increase, p<0.01). CA-9 was expressed in 73% of cancers. Negative lymph node status correlated with CA-9 positivity (p<0.05), reflected in a higher rate of CA-9 positivity in earlier Dukes' stages (p<0.05). CA-9 positivity across tumor node metastasis (TNM) stages approached significance (Stage I/II: 80% CA-9 positive vs. 20% CA-9 negative; Stage III: 63% CA-9 positive vs. 37% negative, p=0.051). A trend was seen towards better cancer-specific survival in patients with CA-9 positive carcinomas (HR 0.51, p=0.07) on univariate analysis. DISCUSSION: MVD was higher in more advanced T- and N-stages and may be used as a determinant of survival in patients with rectal adenocarcinomas. CA-9 expression was seen more often in earlier Dukes' stages, possibly representing an early tumor hypoxic response. CA-9 expression by adenocarcinoma cells may confer long-term survival advantage in surgically treated rectal cancer.

No socioeconomic inequalities in colorectal cancer survival within a randomised clinical trial.

There is strong evidence that colorectal cancer survival differs between socioeconomic groups. We analysed data on 2481 patients diagnosed during 1989-1997 and recruited to a randomised controlled clinical trial (AXIS, ISRCTN32414363) of chemotherapy and radiotherapy for colorectal cancer. Crude and relative survival at 1 and 5 years was estimated in five categories of socioeconomic deprivation. Multiple imputation was used to account for missing data on tumour stage. A multivariable fractional polynomial model was fitted to estimate the excess hazard of death in each deprivation category, adjusting for the confounding effects of age, stage, cancer site (colon, rectum) and sex, using generalised linear models. Relative survival in the trial patients was higher than in the general population of England and Wales. The socioeconomic gradient in survival was much smaller than that seen for colorectal cancer patients in the general population, both at 1 year -3.2% (95% CI -7.3 to 1.0%, P=0.14) and at 5 years -1.7% (95% CI -8.3 to 4.9%, P=0.61). Given equal treatment, colorectal cancer survival in England and Wales does not appear to depend on socioeconomic status, suggesting that the socioeconomic gradient in survival in the general population could well be due to health-care system factors.

Can depth of tumour invasion predict lymph node positivity in patients undergoing resection for early rectal cancer? A comparative study between T1 and T2 cancers.

OBJECTIVE: The present study investigated the risk of lymph node metastasis according to the depth of tumour invasion in patients undergoing resection for rectal cancer. METHOD: The histology of patients undergoing oncological resection with regional lymphadenectomy for rectal cancer at St Marks Hospital from 1971 to 1996 was reviewed. Of the total number of 1549 patients, 303 patients with T(1) or T(2) rectal cancers were selected. The tumour type, grade, evidence of vascular invasion, depth of submucosal invasion (classed into 'sm1-3') were evaluated as potential predictors of lymph node positivity using univariate and multi-level logistic regression analysis. RESULTS: Tumour stage was classified as T(1) in 55 (18.2%) and T(2) in 248 (81.2%) patients. The incidence of lymph node metastasis in the T(1) group was 12.7% (7/55), compared to 19% (47/247) in the T(2) group. The node positive and negative groups were similar with regard to patient demographics, although the former contained a significantly higher number of poorly differentiated (P = 0.001) and extramural vascular invasion tumours (P = 0.002). There was no significant difference in the number of patients with sm1-3, or T(2) tumour depths within the lymph node positive and negative groups. On multivariate analysis the presence of extramural vascular invasion (odds ratio = 10.0) and tumour grade (odds ratio for poorly vs well-differentiated = 11.7) were independent predictors of lymph node metastasis. CONCLUSION: Whilst the degree of vascular invasion and poor differentiation of rectal tumours were significant risk factors for lymph node metastasis, depth of submucosal invasion was not. This has important implications for patients with superficial early rectal cancers in whom local excision is being considered.

The impact of surgically induced ischaemia on protein levels in patients undergoing rectal cancer surgery.

The goal of targeted therapy has driven a search for markers of prognosis and response to adjuvant therapy. The surgical resection of a solid tumour induces tissue ischaemia and acidosis, both potent mediators of gene expression. This study investigated the impact of colorectal cancer (CRC) surgery on prognostic and predictive marker levels. Tumour expression of thymidylate synthase, thymidine phosphorylase, cyclin A, vascular endothelial growth factor (VEGF), carbonic anhydrase-9, hypoxia inducible factor-1alpha, and glucose transporter-1 (GLUT-1) proteins was determined before and after rectal cancer surgery. Spectral imaging of tissue sections stained by immunohistochemistry provided quantitative data. Surgery altered thymidylate synthase protein expression (P=0.02), and this correlated with the change in the proliferation marker cyclin A. The expression of hypoxia inducible factor-1alpha, VEGF, and GLUT-1 proteins was also different following surgery. Colorectal cancer surgery significantly impacts on intratumoral gene expression, suggesting archival specimens may not accurately reflect in situ marker levels. Although rectal cancer was the studied model, the results may be applicable to any solid tumour undergoing extirpation in which molecular markers have been proposed to guide patient therapy.

Can pathological complete response in the primary tumour following pre-operative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for sterilisation of pelvic lymph nodes, a low risk of local recurrence and the appropriateness of local excision?

INTRODUCTION: Local excision is considered inappropriate treatment for T3-T4 rectal adenocarcinomas, as it cannot provide prognostic information regarding lymph node involvement and has a high risk of pelvic recurrence. Preoperative chemoradiation (CRT) studies in rectal cancer suggest that a pathological complete response (pCR) in the primary tumour provides an excellent long-term outcome. If downstaging to stage pT0 predicts a tumour response within the perirectal and pelvic lymph nodes, this may allow local excision to be performed without increased risk of pelvic recurrence. This retrospective study aimed to determine the incidence of involved lymph nodes following pCR (ypT0) after preoperative CRT and total mesorectal excision. METHOD: The outcome and treatment details of 211 patients undergoing preoperative CRT for clinically staged T3-T4 unresectable rectal adenocarcinomas between 1993 and 2003 at Mount Vernon Hospital were reviewed. RESULTS: Data were recorded from the 143 patients who completed treatment with a median follow-up of 25 months. Twenty-three patients (18%) were found to have had a pCR. Four out of 23 patients (17%) had involved lymph nodes. No pelvic recurrences developed after a ypCR. Overall survival was similar for patients with ypT0 or residual tumour. CONCLUSION: Pathological complete response in the primary tumour failed to predict a response in the perirectal lymph nodes (p=0.08). The degree of response predicted a lymph node response (p=0.02). The detection of ypCR identified patients with a low rate of pelvic recurrence. This may in the future allow selection of patients for whom local excision can be performed without a higher risk of local relapse.

Randomized clinical trial of adjuvant radiotherapy and 5-fluorouracil infusion in colorectal cancer (AXIS).

BACKGROUND: Postoperative portal vein infusion (PVI) of 5-fluorouracil (5-FU) is a well tolerated and widely applicable treatment for colorectal cancer that might have an enormous public health impact, even if it produced survival benefits of just a few per cent. Very large trials are required to detect such differences, and the Adjuvant X-ray and 5-FU Infusion Study (AXIS) is the largest such trial yet reported. METHODS: Consenting patients with presumed colorectal cancer were randomized to surgery with or without 7 days of PVI (1 g 5-FU plus 5000 units heparin in 1 litre 5 per cent dextrose infused over each 24-h period). In addition, patients with rectal cancer could be randomized to radiotherapy or no radiotherapy to be given either before or after surgery. RESULTS: Between November 1989 and December 1997, 3583 patients were randomized with respect to PVI. The survival hazard ratios (95 per cent confidence interval (c.i.)) in all patients randomized and in the curatively resected subgroup (71.2 per cent of patients) were 1.00 (0.92 to 1.11) and 0.94 (0.83 to 1.06) respectively. Tests for heterogeneity suggested a greater treatment benefit for patients with colonic cancer than for patients with rectal cancer with respect to disease-free survival (hazard ratio 0.79 versus 1.03; P = 0.07), and there was a non-significant trend with respect to overall survival (hazard ratio 0.87 versus 1.03; P = 0.17). No survival benefit was seen in the 761 patients randomized with respect to radiotherapy; although not statistically significant, the impact on local recurrence rates was similar to that reported in the literature. CONCLUSION: No overall benefit of PVI was established in AXIS when colonic and rectal cancers were considered together, but the evidence suggesting a differential treatment effect according to site of cancer in AXIS was strongly supported by a meta-analysis incorporating the previous trials. Combining the data gave hazard ratios of 0.82 and 1.00 for colonic and rectal tumours respectively (test for interaction, P = 0.024), equating to an absolute survival benefit for patients with colonic cancer of 5.8 (95 per cent c.i. 2.8 to 8.5) per cent, a level close to that seen for prolonged systemic therapy.

Pathological staging of epidermoid anal carcinoma for the new era.

Chemoradiotherapy is the standard treatment for most patients with epidermoid anal cancer. Pre-treatment staging is based on size for T1-T3 lesions and clinical and radiological assessment of adjacent organ invasion for T4 lesions. For patients with residual or recurrent carcinoma, anorectal excision offers the best chance of oncological salvage. Pathological staging systems for anorectal excision specimens were validated at the time when surgical treatment was first line therapy. A validated staging system is necessary for salvage surgical excision specimens following an attempt to cure by radiotherapy and chemotherapy for the purpose of prognosis and further treatment planning.