Neoadjuvant Chemotherapy without Radiation in Colorectal Cancer.

In colon cancer, primary surgery followed by postoperative chemotherapy represents the standard of care. In rectal cancer, the standard of care is preoperative radiotherapy or chemoradiation, which significantly reduces local recurrence but has no impact on subsequent metastatic disease or overall survival. The administration of neoadjuvant chemotherapy (NACT) before surgery can increase the chance of a curative resection and improves long-term outcomes in patients with liver metastases. Hence, NACT is being explored in both primary rectal and colon cancers as an alternative strategy to shrink the tumor, facilitate a curative resection, and simultaneously counter the risk of metastases. Yet, this lack of clarity regarding the precise aims of NACT (downstaging, maximizing response, or improving survival) is hindering progress. The appropriate cytotoxic agents, the optimal regimen, the number of cycles, or duration of NACT prior to surgery or in the postoperative setting remains undefined. Several potential strategies for integrating NACT are discussed with their advantages and disadvantages.

Development and external validation of a nomogram and online tool to predict bowel dysfunction following restorative rectal cancer resection: the POLARS score.

OBJECTIVE: Bowel dysfunction is common following a restorative rectal cancer resection, but symptom severity and the degree of quality of life impairment is highly variable. An internationally validated patient-reported outcome measure, Low Anterior Resection Syndrome (LARS) score, now enables these symptoms to be measured. The study purpose was: (1) to develop a model that predicts postoperative bowel function; (2) externally validate the model and (3) incorporate these findings into a nomogram and online tool in order to individualise patient counselling and aid preoperative consent. DESIGN: Patients more than 1 year after curative restorative anterior resection (UK, median 54 months; Denmark (DK), 56 months since surgery) were invited to complete The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 version3 (EORTC QLQ-C30 v3), LARS and Wexner incontinence scores. Demographics, tumour characteristics, preoperative/postoperative treatment and surgical procedures were recorded. Using transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, risk factors for bowel dysfunction were independently assessed by advanced linear regression shrinkage techniques for each dataset (UK:DK). RESULTS: Patients in the development (UK, n=463) and validation (DK, n=938) datasets reported mean (SD) LARS scores of 26 (11) and 24 (11), respectively. Key predictive factors for LARS were: age (at surgery); tumour height, total versus partial mesorectal excision, stoma and preoperative radiotherapy, with satisfactory model calibration and a Mallow's Cp of 7.5 and 5.5, respectively. CONCLUSIONS: The Pre-Operative LARS score (POLARS) is the first nomogram and online tool to predict bowel dysfunction severity prior to anterior resection. Colorectal surgeons, gastroenterologist and nurse specialists may use POLARS to help patients understand their risk of bowel dysfunction and to preoperatively highlight patients who may require additional postoperative support.

Late gastrointestinal toxicity after radiotherapy for anal cancer: a systematic literature review.

INTRODUCTION: There is a paucity of data on incidence and mechanisms of long-term gastrointestinal consequences after chemoradiotherapy for anal cancer. Most of the adverse effects reported were based on traditional external beam radiotherapy whilst only short-term follow-ups have been available for intensity-modulated radiotherapy, and there is lack of knowledge about consequences of dose-escalation radiotherapy. METHOD: A systematic literature review. RESULTS: Two thousand nine hundred and eighty-five titles (excluding duplicates) were identified through the search; 130 articles were included in this review. The overall incidence of late gastrointestinal toxicity was reported to be 7-64.5%, with Grade 3 and above (classified as severe) up to 33.3%. The most commonly reported late toxicities were fecal incontinence (up to 44%), diarrhea (up to 26.7%), and ulceration (up to 22.6%). Diarrhea, fecal incontinence and buttock pain were associated with lower scores in radiotherapy specific quality of life scales (QLQ-CR29, QLQ-C30, and QLQ-CR38) compared to healthy controls. Intensity-modulated radiation therapy appears to reduce late toxicity. CONCLUSION: Late gastrointestinal toxicities are common with severe toxicity seen in one-third of the patients. These symptoms significantly impact on patients' quality of life. Prospective studies with control groups are needed to elucidate long-term toxicity.

Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer.

For patients with high-risk stage II or stage III colon cancer, adjuvant chemotherapy with fluoropyrimidine monotherapy reduces the risk of recurrence and death by approximately 20-30%. Additional improvements have been reported in three phase 3 colon cancer trials when oxaliplatin was added to fluoropyrimidines, although the effect was mainly on disease-free survival. However, patients with rectal cancer were specifically excluded from these landmark studies because of potential toxicity and the confounding impact of radiotherapy and chemoradiation. Hence, despite evidence from smaller individual postoperative adjuvant phase 3 trials, meta-analyses, retrospective analyses, reviews, and population studies, the precise benefit of adjuvant chemotherapy for patients with rectal cancer following radiotherapy or chemoradiation remains unclear. Consequently, clinical guidelines offer inconsistent recommendations for the management of this patient population. In this Review, we suggest that the available data do not robustly support the routine use of postoperative adjuvant chemotherapy for patients with rectal cancer treated with preoperative chemoradiation. We discuss sources of bias and offer potential reasons to explain this observation, as well as propose a recommended schema for a randomised phase 3 trial that might potentially answer this question definitively.

Streamlining staging of lung and colorectal cancer with whole body MRI; study protocols for two multicentre, non-randomised, single-arm, prospective diagnostic accuracy studies (Streamline C and Streamline L).

BACKGROUND AND AIMS: Rapid and accurate cancer staging following diagnosis underpins patient management, in particular the identification of distant metastatic disease. Current staging guidelines recommend sequential deployment of various imaging platforms such as computerised tomography (CT) and positron emission tomography (PET) which can be time and resource intensive and onerous for patients. Recent studies demonstrate that whole body magnetic resonance Imaging (WB-MRI) may stage cancer efficiently in a single visit, with potentially greater accuracy than current staging investigations. The Streamline trials aim to evaluate whether WB-MRI increases per patient detection of metastases in non-small cell lung and colorectal cancer compared to standard staging pathways. METHODS: The Streamline trials are multicentre, non-randomised, single-arm, prospective diagnostic accuracy studies with a novel design to capture patient management decisions during staging pathways. The two trials recruit adult patients with proven or highly suspected new diagnosis of primary colorectal (Streamline C) or non-small cell lung cancer (Streamline L) referred for staging. Patients undergo WB-MRI in addition to standard staging investigations. Strict blinding protocols are enforced for those interpreting the imaging. A first major treatment decision is made by the multi-disciplinary team prior to WB-MRI revelation based on standard staging investigations only, then based on the WB-MRI and any additional tests precipitated by WB-MRI, and finally based on all available test results. The reference standard is derived by a multidisciplinary consensus panel who assess 12 months of follow-up data to adjudicate on the TNM stage at diagnosis. Health psychology assessment of patients' experiences of the cancer staging pathway will be undertaken via interviews and questionnaires. A cost (effectiveness) analysis of WB-MRI compared to standard staging pathways will be performed. DISCUSSION: We describe a novel approach to radiologist and clinician blinding to ascertain the 'true' diagnostic accuracy of differing imaging pathways and discuss our approach to assessing the impact of WB-MRI on clinical decision making in real-time. The Streamline trials will compare WB-MRI and standard imaging pathways in the same patients, thereby informing the most accurate and efficient approach to staging. TRIAL REGISTRATION: Streamline C ISRCTN43958015 (registered 25/7/2012). Streamline L ISRCTN50436483 (registered 31/7/2012).

Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.

BACKGROUND: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. METHODS: Patients were randomised (2 : 1) to IMM-101 (10 mg ml(-l) intradermally)+GEM (1000 mg m(-2) intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. RESULTS: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44-1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33-0.87, P=0.01). CONCLUSIONS: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer. METHODS: We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomised, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. FINDINGS: We analysed data from four eligible trials, including data from 1196 patients with (y)pTNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumour located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0.97, 95% CI 0.81-1.17; p=0.775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0.91, 95% CI 0.77-1.07; p=0.230) or distant recurrences (0.94, 0.78-1.14; p=0.523) compared with observation. However, in subgroup analyses, patients with a tumour 10-15 cm from the anal verge had improved disease-free survival (0.59, 0.40-0.85; p=0.005, p(interaction)=0.107) and fewer distant recurrences (0.61, 0.40-0.94; p=0.025, p(interaction)=0.126) when treated with adjuvant chemotherapy compared with patients undergoing observation. INTERPRETATION: Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumour 10-15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted. FUNDING: None.

Adjuvant chemotherapy in rectal cancer: defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients.

Recent literature suggests that the benefit of adjuvant chemotherapy (aCT) for rectal cancer patients might depend on the response to neoadjuvant chemoradiation (CRT). Aim was to evaluate whether the effect of aCT in rectal cancer is modified by response to CRT and to identify which patients benefit from aCT after CRT, by means of a pooled analysis of individual patient data from 13 datasets. Patients were categorized into three groups: pCR (ypT0N0), ypT1-2 tumour and ypT3-4 tumour. Hazard ratios (HR) for the effect of aCT were derived from multivariable Cox regression analyses. Primary outcome measure was recurrence-free survival (RFS). One thousand seven hundred and twenty three (1723) (52%) of 3,313 included patients received aCT. Eight hundred and ninety eight (898) patients had a pCR, 966 had a ypT1-2 tumour and 1,302 had a ypT3-4 tumour. For 122 patients response, category was missing and 25 patients had ypT0N+. Median follow-up for all patients was 51 (0-219) months. HR for RFS with 95% CI for patients treated with aCT were 1.25(0.68-2.29), 0.58(0.37-0.89) and 0.83(0.66-1.10) for patients with pCR, ypT1-2 and ypT3-4 tumours, respectively. The effect of aCT in rectal cancer patients treated with CRT differs between subgroups. Patients with a pCR after CRT may not benefit from aCT, whereas patients with residual tumour had superior outcomes when aCT was administered. The test for interaction did not reach statistical significance, but the results support further investigation of a more individualized approach to administer aCT after CRT and surgery based on pathologic staging.

Guidance on the management of diarrhoea during cancer chemotherapy.

Diarrhoea induced by chemotherapy in cancer patients is common, causes notable morbidity and mortality, and is managed inconsistently. Previous management guidelines were based on poor evidence and neglect physiological causes of chemotherapy-induced diarrhoea. In the absence of level 1 evidence from randomised controlled trials, we developed practical guidance for clinicians based on a literature review by a multidisciplinary team of clinical oncologists, dietitians, gastroenterologists, medical oncologists, nurses, pharmacist, and a surgeon. Education of patients and their carers about the risks associated with, and management of, chemotherapy-induced diarrhoea is the foundation for optimum treatment of toxic effects. Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step. Use of octreotide and seeking specialist advice early for patients who do not respond to treatment will reduce morbidity and mortality. In view of the burden of chemotherapy-induced diarrhoea, appropriate multidisciplinary research to assess meaningful endpoints is urgently required.

Do t3 rectal cancers always need radiochemotherapy?

The limitation of the traditional method of stratifying patients with rectal cancer for prognosis using magnetic resonance imaging (MRI) and computerised tomography (CT)-TNM staging-is that cT3 tumors comprise the vast majority of rectal cancers. There is a wide variability in outcomes for cT3. Despite this observation, many still advocate routine short course preoperative radiotherapy (SCPRT) or chemoradiation (CRT) for all patients staged as cT3N0 regardless of tumour location, proximity to other structures or extent, despite the fact that advances in imaging with MRI now offer the ability to predict potential outcomes in terms of the risk of local and metastatic recurrence for the individual. Preoperative CRT is designed to reduce local recurrence. The majority of local recurrences historically reflected inadequate quality of the mesorectal resection. Currently, optimal quality-controlled surgery in terms of total mesorectal excision (TME) in the trial setting can be associated with much lower local recurrence rates of less than 10 % whether patients receive radiotherapy or not. Because of the high risk of metastatic disease in selected patients, integrating more active chemotherapy is now attractive. Chemoradiotherapy (CRT) achieves shrinkage and sometimes eradication of tumour-i.e. a pathological complete response (pCR), and reduces local recurrence, but has no impact on overall survival. CRT also increases surgical morbidity and impacts on anorectal, urinary and sexual function with an increased risk of second malignancies. Hence, the predominant aims of CRT have been to shrink/downstage a tumour to allow an R0 resection to be performed, or to increase the chances of performing sphincter-sparing surgery. However, it remains unclear why shrinkage/downstaging is meaningful to a patient unless the tumour is initially borderline resectable or unresectable (i.e. the CRM is threatened) or the aim is to perform a lesser operation (i.e. sphincter-sparing or local excision) or for organ-sparing, i.e. to avoid surgery altogether. If it is important to shrink the cancer-ie there is a predicted threat to the CRM, then CRT is currently the treatment of choice. If the cancer is resectable and the aim is simply to lower the risk of local recurrence and preoperative CRT does not impact on survival, can CRT be omitted in selected cases? The answer is yes-with the proviso that we are using good quality MRI and the surgeon is performing good quality TME surgery within the mesorectal plane.

Squamous cell carcinoma antigen: a potentially useful prognostic marker in squamous cell carcinoma of the anal canal and margin.

BACKGROUND: The objective of this retrospective study was to investigate the predictive value of pretreatment serum squamous cell carcinoma antigen (SCCAg) levels in 174 patients with squamous cell carcinoma of the anus who received concurrent chemoradiation between 1997 and 2010. METHODS: Pretreatment serum SCCAg measurements in patients with histologically diagnosed squamous cell carcinoma of the anal canal and margin who received chemoradiation were compared with clinical tumor classification and lymph node status for prognostic/predictive ability, including 1) tumor response after the completion of chemoradiation treatment, 2) disease recurrence, and 3) overall survival. Clinical measurements and scores were compared using Spearman rank tests, and survival was assessed in both univariate and multivariate survival analyses. RESULTS: The median pretreatment levels of SCCAg according to clinical tumor classification and clinical lymph node status were 0.8 µg/L in T1 tumors, 1.90 µg/L in T2 tumors, 2.5 µg/L in T3 tumors, 3.8 µg/L in T4 tumors, 1.35 µg/L in patients with N0 status, and 3.05 µg/L in patients with N0+ status (correlation coefficient: T-classification, 0.43; lymph node status, 0.38; both P < .00001). Of the patients who had normal SCCAg levels, 95% achieved a complete response after initial treatment; and, of those who had elevated SCCAg levels, 86% achieved a complete response (P = .05). Overall survival (hazard ratio, 2.5; P = .007) and disease-free survival (hazard ratio, 2.2; P = .058) were worse for those who had elevated pretreatment serum SCCAg concentrations. CONCLUSIONS: Pretreatment SCCAg levels in patients with squamous cell carcinoma of the anal canal and margin were correlated with clinical tumor classification and clinical lymph node status. Elevated levels of SCCAg were associated with a reduced chance of achieving a complete response and an increased chance of recurrence and death. The authors recommend further studies to determine the prognostic value of SCCAg in anal squamous cell carcinoma and suggest the potential use of SCCAg as a stratification factor in future trials.

Using whole disease modeling to inform resource allocation decisions: economic evaluation of a clinical guideline for colorectal cancer using a single model.

OBJECTIVE: To assess the feasibility and value of simulating whole disease and treatment pathways within a single model to provide a common economic basis for informing resource allocation decisions. METHODS: A patient-level simulation model was developed with the intention of being capable of evaluating multiple topics within National Institute for Health and Clinical Excellence's colorectal cancer clinical guideline. The model simulates disease and treatment pathways from preclinical disease through to detection, diagnosis, adjuvant/neoadjuvant treatments, follow-up, curative/palliative treatments for metastases, supportive care, and eventual death. The model parameters were informed by meta-analyses, randomized trials, observational studies, health utility studies, audit data, costing sources, and expert opinion. Unobservable natural history parameters were calibrated against external data using Bayesian Markov chain Monte Carlo methods. Economic analysis was undertaken using conventional cost-utility decision rules within each guideline topic and constrained maximization rules across multiple topics. RESULTS: Under usual processes for guideline development, piecewise economic modeling would have been used to evaluate between one and three topics. The Whole Disease Model was capable of evaluating 11 of 15 guideline topics, ranging from alternative diagnostic technologies through to treatments for metastatic disease. The constrained maximization analysis identified a configuration of colorectal services that is expected to maximize quality-adjusted life-year gains without exceeding current expenditure levels. CONCLUSIONS: This study indicates that Whole Disease Model development is feasible and can allow for the economic analysis of most interventions across a disease service within a consistent conceptual and mathematical infrastructure. This disease-level modeling approach may be of particular value in providing an economic basis to support other clinical guidelines.

Anal cancer: are we making progress?

Anal cancer is an uncommon malignancy. There have been some intriguing developments in the past 3 years, in terms of our understanding of the molecular biology and processes that lead to anal cancer. There have also been some notable successes in prevention, imaging and treatment. Nonsurgical treatment is highly effective. The primary aim of such treatment is to achieve loco-regional control with chemoradiation (CRT), and preserve anal function without a colostomy. Randomised phase III trials presented or published over the past 3 years have explored novel strategies of neoadjuvant chemotherapy, maintenance chemotherapy, radiotherapy dose escalation and replacement of mitomycln C (MMC) with cisplatin in CRT. All have failed to improve on the current standard of care; i.e. MMC/ 5 fluorouracil (5FU) chemoradiation. However, more conformal strategies such as intensity modulated radiotherapy (IMRT) appear feasible to deliver with reduced toxicity, and may offer an opportunity to dose-escalate both to gross tumour and areas of potential nodal spread. Preliminary outcome data suggest no loss of efficacy. We evaluate the relevant recent literature published over the past 2 years, and summarize interesting and important new findings, with the aim of bringing the reader up-to-date on anal cancer.

Neoadjuvant therapy before surgical treatment.

Neoadjuvant treatment in terms of preoperative radiotherapy reduces local recurrence in rectal cancer, but this improvement has little if any impact on overall survival. Currently performed optimal quality-controlled total mesorectal excision (TME) surgery for patients in the trial setting can be associated with very low local recurrence rates of less than 10% whether the patients receive radiotherapy or not. Hence metastatic disease is now the predominant issue. The concept of neoadjuvant chemotherapy (NACT) is a potentially attractive additional or alternative strategy to radiotherapy to deal with metastases. However, randomised phase III trials, evaluating the addition of oxaliplatin at low doses plus preoperative fluoropyrimidine-based chemoradiotherapy (CRT), have in the main failed to show a significant improvement on early pathological response, with the exception of the German CAO/ARO/AIO-04 study. The integration of biologically targeted agents into preoperative CRT has also not fulfilled expectations. The addition of cetuximab appears to achieve relatively low rates of pathological complete responses, and the addition of bevacizumab has raised concerns for excess surgical morbidity. As an alternative to concurrent chemoradiation (which delivers only 5-6 weeks of chemotherapy), potential options include an induction component of 6-12 weeks of NACT prior to radiotherapy or chemoradiation, or the addition of chemotherapy after short-course preoperative radiotherapy (SCPRT) or chemoradiation (defined as consolidation chemotherapy) which utilises the "dead space" of the interval between the end of chemoradiation and surgery, or delivering chemotherapy alone without any radiotherapy.

International Validation of the EORTC QLQ-ANL27, a Field Study to Test the Anal Cancer-Specific Health-Related Quality-of-Life Questionnaire.

PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) health-related quality of life questionnaire for anal cancer (QLQ-ANL27) supplements the EORTC cancer generic measure (QLQ-C30) to measure concerns specific to people with anal cancer treated with chemoradiotherapy. This study tested the psychometric properties and acceptability of the QLQ-ANL27. METHODS AND MATERIALS: People with anal cancer were recruited from 15 countries to complete the QLQ-C30 and QLQ-ANL27 and provide feedback on the QLQ-ANL27. Item responses, scale structure (multitrait scaling, factor analysis), reliability (internal consistency and reproducibility) and sensitivity (known group comparisons and responsiveness to change) of the QLQ-ANL27 were evaluated. RESULTS: Data from 382 people were included in the analyses. The EORTC QLQ-ANL27 was acceptable, comprehensive, and easy to complete, taking an average 8 minutes to complete. Psychometric analyses supported the EORTC QLQ-ANL27 items and reliability (Cronbach's α ranging from 0.71-0.93 and test-retest coefficients above 0.7) and validity of the scales (particularly nonstoma bowel symptoms and pain/discomfort). Most scales distinguished people according to treatment phase and performance status. Bowel (nonstoma), pain/discomfort, and vaginal symptoms were sensitive to deteriorations over time. The stoma-related scales remained untested because of low numbers of people with a stoma. Revisions to the scoring and question ordering of the sexual items were proposed. CONCLUSIONS: The QLQ-ANL27 has good psychometric properties and is available in 16 languages for people treated with chemoradiotherapy for anal cancer. It is used in clinical trials and has a potential role in clinical practice.

Reproducibility of 2D and 3D fractal analysis techniques for the assessment of spatial heterogeneity of regional blood flow in rectal cancer.

PURPOSE: To characterize the two-dimensional (2D) and three-dimensional (3D) fractal properties of rectal cancer regional blood flow assessed by using volumetric helical perfusion computed tomography (CT) and to determine its reproducibility. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Ten prospective patients (eight men, two women; mean age, 72.3 years) with rectal adenocarcinoma underwent two repeated volumetric helical perfusion CT studies (four-dimensional adaptive spiral mode, 11.4-cm z-axis coverage) without intervening treatment within 24 hours, with regional blood flow derived by using deconvolution analysis. Two-dimensional and 3D fractal analyses of the rectal tumor were performed, after segmentation from surrounding structures by using thresholding, to derive fractal dimension and fractal abundance. Reproducibility was quantitatively assessed by using Bland-Altman statistics. Two-dimensional and 3D lacunarity plots were also generated, allowing qualitative assessment of reproducibility. Statistical significance was at 5%. RESULTS: Mean blood flow was 63.50 mL/min/100 mL ± 8.95 (standard deviation). Good agreement was noted between the repeated studies for fractal dimension; mean difference was -0.024 (95% limits of agreement: -0.212, 0.372) for 2D fractal analysis and -0.024 (95% limits of agreement: -0.307, 0.355) for 3D fractal analysis. Mean difference for fractal abundance was -0.355 (95% limits of agreement: -0.869, 1.579) for 2D fractal analysis and -0.043 (95% limits of agreement: -1.154, 1.239) for 3D fractal analysis. The 95% limits of agreement were narrower for 3D than 2D analysis. Lacunarity plots also visually confirmed close agreement between repeat studies. CONCLUSION: Regional blood flow in rectal cancer exhibits fractal properties. Good reproducibility was achieved between repeated studies with 2D and 3D fractal analysis.

Neoadjuvant treatment in rectal cancer: do we always need radiotherapy-or can we risk assess locally advanced rectal cancer better?

There is good quality evidence that preoperative radiotherapy reduces local recurrence but there is little impact on overall survival. This is not completely unexpected as radiotherapy is a localised treatment and local control may not prevent systemic failure. Optimal quality-controlled surgery for patients with operable rectal cancer in the trial setting can be associated with local recurrence rates of less than 10 % whether patients receive radiotherapy or not (Quirke et al. 2009). However, despite the reassuring results of randomised trials, concerns remain that radiotherapy increases surgical morbidity (Horisberger et al. 2008; Stelzmueller et al. 2009; Swellengrebel et al. 2011), which can compromise the delivery of postoperative adjuvant chemotherapy. There are also significant late effects from pelvic radiotherapy (Peeters et al. 2005; Lange et al. 2007) and a risk of second malignancies (Birgisson et al. 2005; van Gijn et al. 2011). If preoperative radiotherapy does not impact on survival, can it be omitted in selected cases? The answer is yes-with the proviso that we are using good quality magnetic resonance imaging and good quality TME surgery within the mesorectal plane and the predicted risk of subsequent metastatic disease justifies its use. In this case, the concept of neoadjuvant chemotherapy (NACT) is a potentially attractive alternative strategy which might have less early and long-term side effects compared to preoperative radiotherapy-particularly where the MRI predicts a high risk of metastatic disease in the context of a modest risk of local recurrence. This chapter discusses a more precise method of risk categorisation for locally advanced rectal cancer, and discusses possible options for neoadjuvant chemotherapy (NACT).