Local tumor regrowth after clinical complete response following neoadjuvant therapy for rectal cancer: what happens when organ preservation falls short.

Organ preservation strategies, especially watch and wait, after neoadjuvant treatment in locally advanced rectal cancer, have become topics that generate significant interest, for both patients and clinicians. The obvious advantage of these strategies is the avoidance of surgery with its associated risks and functional consequences. Over time, it has become evident that these strategies offer acceptable safety in oncological terms and, in most patients, allows preservation of the rectum without harming patients in terms of distant metastasis or survival. However, there is a small group of patients in whom the tumor returns after an initially diagnosed clinical complete response; patients with local tumor regrowth. The main threat in these patients is not simply local disease, which can be successfully managed in most cases, but the possible effects it may have on distant metastases. The pathophysiology of the phenomenon of local tumor regrowth is not well known and, therefore, strategies to minimize possible impact on survival are not well defined. Our aim is to review key issues in this subgroup that pose a substantial threat to the safety and viability of organ-preserving and watch-and-wait strategies. We also explore possible pathophysiologic explanations and future directions and perspectives that may improve both local and systemic disease control.

Individual participant data pooled-analysis of risk factors for recurrence after neoadjuvant radiotherapy and transanal local excision of rectal cancer: the PARTTLE study.

BACKGROUND: An organ-preserving strategy may be a valid alternative in the treatment of selected patients with rectal cancer after neoadjuvant radiotherapy. Preoperative assessment of the risk for tumor recurrence is a key component of surgical planning. The aim of the present study was to increase the current knowledge on the risk factors for tumor recurrence. METHODS: The present study included individual participant data of published studies on rectal cancer surgery. The literature was reviewed according to according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Individual Participant Data checklist (PRISMA-IPD) guidelines. Series of patients, whose data were collected prospectively, having neoadjuvant radiotherapy followed by transanal local excision for rectal cancer were reviewed. Three independent series of univariate/multivariate binary logistic regression models were estimated for the risk of local, systemic and overall recurrence, respectively. RESULTS: We identified 15 studies, and 7 centers provided individual data on 517 patients. The multivariate analysis showed higher local and overall recurrences for ypT3 stage (OR 4.79; 95% CI 2.25-10.16 and OR 6.43 95% CI 3.33-12.42), tumor size after radiotherapy > 10 mm (OR 5.86 95% CI 2.33-14.74 and OR 3.14 95% CI 1.68-5.87), and lack of combined chemotherapy (OR 3.68 95% CI 1.78-7.62 and OR 2.09 95% CI 1.10-3.97), while ypT3 was the only factor correlated with systemic recurrence (OR 5.93). The analysis of survival curves shows that the overall survival is associated with ypT and not with cT. CONCLUSIONS: Local excision should be offered with caution after neoadjuvant chemoradiotherapy to selected patients with rectal cancers, who achieved a good response to neoadjuvant chemoradiotherapy.

Effect of Akt activation and experimental pharmacological inhibition on responses to neoadjuvant chemoradiotherapy in rectal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) is one of the preferred initial treatment strategies for locally advanced rectal cancer. Responses are variable, and most patients still require surgery. The aim of this study was to identify molecular mechanisms determining poor response to CRT. METHODS: Global gene expression and pathway enrichment were assessed in pretreatment biopsies from patients with non-metastatic cT2-4 N0-2 rectal cancer within 7 cm of the anal verge. Downstream Akt activation was assessed in an independent set of pretreatment biopsies and in colorectal cancer cell lines using immunohistochemistry and western blot respectively. The radiosensitizing effects of the Akt inhibitor MK2206 were assessed using clonogenic assays and xenografts in immunodeficient mice. RESULTS: A total of 350 differentially expressed genes were identified, of which 123 were upregulated and 199 downregulated in tumours from poor responders. Mitochondrial oxidative phosphorylation (P < 0·001) and phosphatidylinositol signalling pathways (P < 0·050) were identified as significantly enriched pathways among the set of differentially expressed genes. Deregulation of both pathways is known to result in Akt activation, and high immunoexpression of phosphorylated Akt S473 was observed among patients with a poor histological response (tumour regression grade 0-2) to CRT (75 per cent versus 48 per cent in those with a good or complete response; P = 0·016). Akt activation was also confirmed in the radioresistant cell line SW480, and a 50 per cent improvement in sensitivity to CRT was observed in vitro and in vivo when SW480 cells were exposed to the Akt inhibitor MK2206 in combination with radiation and 5-fluorouracil. CONCLUSION: Akt activation is a key event in the response to CRT. Pharmacological inhibition of Akt activation may enhance the effects of CRT. Surgical relevance Organ preservation is an attractive alternative in rectal cancer management following neoadjuvant chemoradiotherapy (CRT) to avoid the morbidity of radical surgery. Molecular steps associated with tumour response to CRT may provide a useful tool for the identification of patients who are candidates for no immediate surgery. In this study, tumours resistant to CRT were more likely to have activation of specific genetic pathways that result in phosphorylated Akt (pAkt) activation. Pretreatment biopsy tissues with high immunoexpression of pAkt were more likely to exhibit a poor histological response to CRT. In addition, the introduction of a pAkt inhibitor to cancer cell lines in vitro and in vivo led to a significant improvement in sensitivity to CRT. Identification of pAkt-activated tumours may thus allow the identification of poor responders to CRT. In addition, the concomitant use of pAkt inhibitors to increase sensitivity to CRT in patients with rectal cancer may constitute an interesting strategy for increasing the chance of a complete response to treatment and organ preservation.

Putting down the scalpel in rectal cancer management - a historical perspective.

The surgical management of rectal cancer has evolved from a disease without any possibility of cure in the early 1700s where surgical management consisted of the palliative drainage of disease related abscesses to the present day where surgical cure is not only possible but also possible with sphincter or even organ preservation. Prof Habr-Gama's lecture describes the evolution of the surgical management of rectal cancer and the current focus on organ preservation.

Magnetic resonance imaging following neoadjuvant chemoradiation and transanal endoscopic microsurgery for rectal cancer.

AIM: Full-thickness local excision after neoadjuvant chemoradiotherapy (CRT) for patients with rectal cancer and incomplete clinical response has been a treatment strategy for organ preservation. Follow-up of these patients is challenging since anatomic distortion and postoperative changes may be clinically indistinguishable from tumour recurrence. MRI may have a role in detecting recurrence. The aim of this study was to describe the MRI findings during follow-up in patients having local excision following CRT with and without local recurrence. METHOD: The data were collected retrospectively from a single centre. Fifty-three patients with rectal cancer who had full-thickness local excision after neoadjuvant CRT and near-complete response were eligible for the study. Patients with local recurrence were treated by radical salvage surgery. The main outcome was local MRI assessment findings during follow-up. RESULTS: Fifteen patients (five who developed local recurrence and 10 with no evidence of local recurrence) had MR images available for review and were included in the study. High signal intensity and thickening of the rectal wall were present in all patients with recurrent disease within the rectal wall. Overall, 80% of the patients with recurrence showed diffusion restriction. MRI mesorectal fascia status and circumferential resection margin showed agreement in all cases. A low signal intensity scar was seen in all patients without recurrent disease. CONCLUSION: MRI shows high signal intensity and thickening of the rectal wall in recurrent disease in comparison to a low signal intensity fibrotic scar in non-recurrent disease. These findings may be useful in surveillance of these patients.

Predicting complete response to neoadjuvant CRT for distal rectal cancer using sequential PET/CT imaging.

BACKGROUND: Molecular imaging using positron emission tomography/computerized tomography (PET/CT) may add relevant incremental diagnostic information to standard structural cross-sectional imaging. Such information may allow identification of patients with rectal cancer that are more likely to develop complete tumor regression after neoadjuvant chemoradiation therapy (CRT). The objective of this report was to identify PET/CT features that are associated with a complete response after CRT. METHODS: 99 cT2-4N0-2M0 distal rectal cancer patients (≤7 cm from anal verge) were included in this prospective single center trial (NCT 00254683). Patients underwent baseline PET/CT followed by 54 Gy and 5-fluorouracil-based neoadjuvant CRT. After completion of therapy, patients underwent 6- and 12-week PET/CT. Clinical assessment of tumor response was performed at 12 weeks and was blinded to radiological information. Patients were treated according to clinical assessment. RESULTS: There were seven patients with a complete pathological response (pCR) and 16 with a complete clinical response (cCR) (23 complete responders). Comparison of pCR exclusively and non-pCR revealed that only baseline primary tumor standard uptake value (SUV) was a significant predictor of response. Comparison of complete responders (pCR or cCR) and non-complete responders showed that depth of rectal wall uptake at baseline PET/CT (p = 0.002) and variation between baseline and 12-week maximum standard uptake value (SUVmax) of primary tumor (p = 0.001) were independent predictors for complete response at multivariate analysis. A decrease >67 % between baseline and 6-week or 76 % between baseline and 12-week SUVmax were associated with complete response (pCR or cCR; p = 0.02 and p < 0.001, respectively). CONCLUSIONS: Positron emission tomography/computerized tomography at baseline, 6 and 12 weeks, may provide information regarding patients with a higher likelihood of developing complete tumor regression following neoadjuvant CRT.

Clinical relevance of positron emission tomography/computed tomography-positive inguinal nodes in rectal cancer after neoadjuvant chemoradiation.

AIM: Inguinal nodes may be a possible route for lymphatic spread in patients with distal rectal cancer. The outcome was examined for patients with distal rectal cancer undergoing neoadjuvant chemoradiation (CRT) and having 2-fluorine-18-fluoro-2-deoxy-d-glucose (FDG)-avid inguinal nodes using positron emission tomography/computed tomography (PET/CT) imaging. METHOD: Ninety-nine consecutive patients with cT2-4N0-2M0 distal rectal adenocarcinoma were enrolled in a clinical trial (NCT00254683) and underwent baseline PET/CT followed by 54 Gy and 5-fluorouracil-based CRT. After CRT, patients underwent 6- and 12-week PET/CT. Patients with positive inguinal node uptake were compared with patients with negative uptake. The inguinal region was not included in the field of radiation therapy. RESULTS: Seventeen (17%) patients had baseline positive inguinal node FDG uptake. They were more likely to have the tumour closer to the anal verge (2.0 vs 4.2 cm; P = 0.001). Of these, eight (47%) demonstrated a positive inguinal uptake at PET/CT after 12 weeks from CRT. Patients with inguinal node FDG uptake after CRT (positive PET at baseline and 12 weeks) had a significantly worse 3-year overall and disease-free survival (P = 0.02 and P = 0.03). After a median follow-up period of 22 months, none of these patients had developed inguinal recurrence. CONCLUSION: Uptake of inguinal nodes at PET/CT may be present in up to 17% of patients with distal rectal cancer, particularly with ultra-low tumours. Nearly half of these nodes no longer show uptake after CRT despite the groin area not being included in the radiation field. Persistence of inguinal node uptake 12 weeks after CRT completion may be a marker for worse oncological outcome.

Role of biopsies in patients with residual rectal cancer following neoadjuvant chemoradiation after downsizing: can they rule out persisting cancer?

AIM: The study aimed to determine the value of postchemoradiation biopsies, performed after significant tumour downsizing following neoadjuvant therapy, in predicting complete tumour regression in patients with distal rectal cancer. METHOD: A retrospective comparative study was performed in patients with rectal cancer who achieved an incomplete clinical response after neoadjuvant chemoradiotherapy. Patients with significant tumour downsizing (> 30% of the initial tumour size) were compared with controls (< 30% reduction of the initial tumour size). During flexible proctoscopy carried out postchemoradiation, biopsies were performed using 3-mm biopsy forceps. The biopsy results were compared with the histopathological findings of the resected specimen. UICC (Union for International Cancer Control) ypTNM classification, tumour differentiation and regression grade were evaluated. The main outcome measures were sensitivity and specificity, negative and positive predictive values, and accuracy of a simple forceps biopsy for predicting pathological response after neoadjuvant chemoradiotherapy. RESULTS: Of the 172 patients, 112 were considered to have had an incomplete clinical response and were included in the study. Thirty-nine patients achieved significant tumour downsizing and underwent postchemoradiation biopsies. Overall, 53 biopsies were carried out. Of the 39 patients who achieved significant tumour downsizing, the biopsy result was positive in 25 and negative in 14. Only three of the patients with a negative biopsy result were found to have had a complete pathological response (giving a negative predictive value of 21%). Considering all biopsies performed, only three of 28 negative biopsies were true negatives, giving a negative predictive value of 11%. CONCLUSION: In patients with distal rectal cancer undergoing neoadjuvant chemoradiation, post-treatment biopsies are of limited clinical value in ruling out persisting cancer. A negative biopsy result after a near-complete clinical response should not be considered sufficient for avoiding a radical resection.

Bioinformatics construction of the human cell surfaceome.

Cell surface proteins are excellent targets for diagnostic and therapeutic interventions. By using bioinformatics tools, we generated a catalog of 3,702 transmembrane proteins located at the surface of human cells (human cell surfaceome). We explored the genetic diversity of the human cell surfaceome at different levels, including the distribution of polymorphisms, conservation among eukaryotic species, and patterns of gene expression. By integrating expression information from a variety of sources, we were able to identify surfaceome genes with a restricted expression in normal tissues and/or differential expression in tumors, important characteristics for putative tumor targets. A high-throughput and efficient quantitative real-time PCR approach was used to validate 593 surfaceome genes selected on the basis of their expression pattern in normal and tumor samples. A number of candidates were identified as potential diagnostic and therapeutic targets for colorectal tumors and glioblastoma. Several candidate genes were also identified as coding for cell surface cancer/testis antigens. The human cell surfaceome will serve as a reference for further studies aimed at characterizing tumor targets at the surface of human cells.

Factors affecting management decisions in rectal cancer in clinical practice: results from a national survey.

BACKGROUND: Management of rectal cancer has become increasingly complex and a multidisciplinary approach is considered of key importance for improving outcomes. A national survey among specialists involved in this multidisciplinary setting was performed. METHODS: A web-based survey containing 11 questions regarding rectal cancer management was sent to surgeons and medical oncologists registered by their corresponding societies as members. Statistical analysis was performed using the chi-square and Fisher's exact tests for all categorical variables according to response to individual questions. Multivariate analysis was performed using Cox's logistic regression. RESULTS: Overall, 418 email recipients responded the survey. Local staging was performed without either magnetic resonance imaging or endorectal ultrasound by 64% of responders. Seventy-two percent considered that final management decision should be made after neoadjuvant chemoradiation therapy. Additionally, 46% considered that an alternative procedure (local excision or observation) was appropriate in a patient with a complete clinical response. Colorectal surgeons were more frequently in favor of longer intervals after completion of chemoradiation therapy (P = 0.001) and of alternative management procedures after a complete clinical response (P = 0.02). After multivariate analysis, the choice of a watch and wait approach after a complete clinical response following neoadjuvant chemoradiation therapy was significantly more frequent among surgeons (OR 3.5, 95% CI 1.8-7.1). CONCLUSIONS: Surgeons seem to be more in favor of tailoring management of rectal cancer according to tumor response after neoadjuvant chemoradiation therapy, with longer intervals after chemoradiation therapy, decisions about treatment strategy being made after chemoradiation therapy instead of before, and the use of alternative surgical procedures after a complete clinical response following neoadjuvant therapy.

Evaluation of molecular markers in hepatic metastasis of colorectal adenocarcinoma.

BACKGROUND/AIMS: There were 49 patients studied, coming from The Liver Unit at the "Hospital das Clinicas da Faculdade de Medicina da USP (N=41) and from "Prof. Dr. Angelita Habr-Gama and Joaquim Gama-Rodrigues Surgery Institute", SP (N=8); all of which had hepatic metastasis of colorectal adenocarcinoma, with no evidence of concurrent metastasis in any other organs and were submitted to surgical treatment, during the period of 1992 to 2002, with the aim of analyzing the immunoexpression of the p53, ki-67, p16 and molecular markers in order to relate the disease-free period with the prognosis. METHODOLOGY: The patient's clinical data were analyzed retrospectively for verification of information such as age, gender, size of the hepatic metastasis and/or the largest lesion, number of satellite nodules resected and compromised, margin of resection free from neoplasia. RESULTS: The immunoexpression of the p53 was associated with the shortest period of life free from disease (p = 0.04). The proliferation marker ki-67 was not associated with the reduction of the disease-free interval and survival; the immunoexpression of the proliferation marker p16 was not associated with the reduction of disease-free period and survival, however, it was associated with hepatic metastasis synchronism. In patients who received postoperative systemic chemotherapy with 5-FU and leucovorin, the immunoexpression on the hepatic metastasis was not associated with a longer disease-free interval. CONCLUSIONS: Molcular markers may be useful to evaluate hepatic metastasis of colorectal Adenocarcinoma.

Diet and colorectal cancer: current evidence for etiology and prevention.

The etiology of colorectal cancer (CRC) involves the interaction of cell molecular changes and environmental factors, with a great emphasis on diet components. But the paths connecting lifestyle characteristicas and the colorectal carcinogenesis remain unclear. Several risk factors are commonly found in western diets, such as high concentrations of fat and animal protein, as well as low amounts of fiber, fruits and vegetables. A large number of experimental studies have found a counteractive effect of fiber on neoplasia induction, especially in relation to fermentable fiber (wheat bran and cellulose). Epidemiological correlation studies have also indicated that a greater ingestion of vegetables, fruit, cereal and seeds is associated to a lower risk for colorectal neoplasia. Moreover, beneficial properties of fiber (especially from vegetable sources) were documented in more than half of case-control studies. Nevertheless, recent epidemiological data from longitudinal and randomized trials tended not to support this influence. Future research should evaluate what sources of fiber provide effective anti-neoplasic protection, carrying out interventional studies with specific fibers for longer periods. Red meat, processed meats, and perhaps refines carbohydrates are also implicated in CRC risk. Recommendantions to decrease red meat intake are well accepted, although the total amount and composition of specific fatty acids may have distinct roles in this setting. Current evidence favors the substitution of long and medium-chain fatty acids and arachidonic acid for short-chain fatty acids and eicosapentaenoic acid. Excess boy weight and excess energy intake inducing hyperinsulinemia have been also associated to CRC, as well as personal habits such as physical inactivy, high alcohol consumption, smoking and low consumption of folate and methionine. Thus, current recommendations for decreasing the risk of CRC include dietary measures such as increased plant food intake; the consumption of whole grains, vegetables and fruits; and reduced red meat intake.

Clinical applications and techniques of cinedefecography.

BACKGROUND: Cinedefecography is of value in routine examination of functional disorders of the pelvic floor. Interest in this technique has rapidly expanded owing to the increased availability of colorectal physiologic testing and better understanding of the multifactorial pathophysiology involving evacuation disorders. METHODS: A summary of the available techniques, methodology, and indications for cinedefecography was undertaken. In addition, information was provided on interpretation of these images particularly in the context of anatomic abnormalities and clinical applications. RESULTS: Cinedefecography can be rapidly and easily performed using standard radiographic equipment. Effective radiation dose is significantly lower than for other intestinal contrast studies. The technique has been found most useful for measurements of perineal descent, puborectalis length, and ascertaining the function of the puborectalis muscle and pelvic floor. Common diagnoses that can be made by this test include nonrelaxing puborectalis syndrome, perineal descent, rectocele, enterocele, sigmoidocele, and rectoanal intussusception. CONCLUSION: Cinedefecography provides a wide range of information to assist the surgeon with the evaluation and management of patients with evacuatory and other associated pelvic floor disorders.

Preoperative assessment in cases of adult megacolon suffering from moderate malnutrition.

Acquired megacolon is a chronic disease associated with constipation and malnutrition. Surgical treatment may be required for the alleviation of the intestinal symptoms, emphasizing the interest of nutritional assessment in this population. In a prospective study of 33 patients suffering from acquired megacolon and requiring either anterior resection or pull-through operation, standard anthropometric and biochemical measurements as well as the PNI of Buzby and Mullen were preoperatively assessed. Mean age of the population was 49 +/- 13 y, with 17 males and 16 females. The combined nutritional score indicated 63.6% of the population were malnourished (21/33) of the patients, whereas the Prognostic nutritional index (PNI) revealed 3 high-risk cases (9.1%), 9 with moderate risk (27.3%), and reduced risk for all others. Indeed, 39.4% (13/33) of the patients displayed surgical or septic problems. Chi-square analysis confirmed that both studied criteria were significantly associated with complications (p < 0.05), as morbidity was restricted predominantly to cases with unfavorable Prognostic nutritional index (PNI) results or clear signs of nutritional deficit. Both PNI and conventinoal nutritional assessment are valuable tools for the screening of these surgical candidates. Artificial alimentation was not used in this experience, but deserves consideration in selected patients. Nutritional status improved in the late postoperative period, with normalization of bowel function.

Steroid receptors in Brazilian patients with large bowel cancer.

1. Twenty-two colorectal carcinomas were examined for the presence of estrogen (ER), progesterone (PR), androgen (AR) and glucocorticoid receptors (GR) by a charcoal dextran assay. 2. ER was detected in 4/13 (31%) and 5/9 (56%) of the rectum and colon carcinomas analyzed, and density values ranged from 10 to 14 and from 10 to 27 fm/mg protein, respectively. Normal distal or adjacent mucosa presented similar incidence and ER density values within the tumor ranges. 3. The incidence of PR-positive samples was also higher in colon than in rectal carcinomas (44% vs 23%). Normal mucosa displayed significantly higher PR titers than the corresponding tumor tissue. It seems reasonable to assume that normal colorectal mucosa may be one of the target tissues of progesterone activity. Most tumor biopsies and normal mucosa were completely AR negative, whilst GR was present in a larger fraction (63%) of tumoral specimens, occurring more commonly in colon than in rectum carcinomas. GR incidence tended to be higher in neoplasms than in normal mucosa (54% vs 38% in rectum and 78% vs 56% in colon), suggesting that glucocorticoids may be involved in the control of tumor-cell proliferation. 4. Our findings which indicate low densities of ER, PR, and absence of AR in some large bowel cancers, suggest sex hormone and endocrine independence for those cancers. The role of glucocorticoid receptors in those forms of cancer remains to be elucidated.

Pharmacological nutrition in inflammatory bowel diseases.

Inflammatory Bowel Diseases--ulcerative colitis and Crohn's disease--are chronic gastrointestinal inflammatory diseases of unknown etiology. Decreased oral intake, malabsorption, accelerated nutrient losses, increased requirements, and drug-nutrient interactions cause nutritional and functional deficiencies that require proper correction by nutritional therapy. The goals of the different forms of nutritional therapy are to correct nutritional disturbances and to modulate inflammatory response, thus influencing disease activity. Nutritional intervention may improve outcome in certain individuals; however, because of the costs and complications of such therapy, careful selection is warranted. Total parenteral nutrition has been used to correct and prevent nutritional disturbances and to promote bowel rest during active disease, mainly in cases of digestive fistulae with a high output. Its use should be reserved for patients who cannot tolerate enteral nutrition. Enteral nutrition is effective in inducing clinical remission of disease in adults and promoting growth in children. Recent research has focused on the use of specific nutrients as primary treatment agents. Although some reports have indicated that glutamine, short-chain fatty acids, antioxidants and immunonutrition with omega-3 fatty acids are an important therapeutic alternative in the management of inflammatory bowel diseases, the beneficial reported effects have yet to be translated into the clinical practice. The real efficacy of these nutrients still need further evaluation through prospective and randomized trials.