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.

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.

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.

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.

Management of distal rectal cancer: results from a national survey.

Owing to the complexity of distal rectal cancer its management requires a multidisciplinary approach. The diagnosis and the response after neoadjuvant chemoradiotherapy are not easy to assess and therefore the surgical approach is heterogeneous. The purpose of this survey is to evaluate the experiences of members of the Italian Society of Surgery in diagnosis and treatment strategies for rectal cancer and compare it with international practice. A questionnaire was devised comprising 18 questions with 11 sub-items making a total of 29 questions and submitted online to all the 2,500 members of the SIC starting from July 2010. The survey was completed in June 2011. The overall response rate was 17.8 % (444). The majority of the Italian surgeons' responses were in line with the international consensus reflecting the complex management of distal rectal cancer. Other opinions, especially those on staging, diverge from the common view of MRI being the gold standard in the assessment of loco-regional diffusion of the disease and on the superiority of FDG PET-CT versus CT for systemic staging. The timing for the re-staging and for surgery following neoadjuvant chemoradiotherapy does not reflect the international opinion. Italian surgeons are also exposed to the common difficulties encountered internationally in the management of distal rectal cancer. Probably, the implementation of an Italian rectal cancer registry and of many national and international multicentre studies may improve the management of rectal cancer in Italy.

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.

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.

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.

Distribution of lymph nodes in the mesorectum: how deep is TME necessary?

BACKGROUND: Standardization of total mesorectal excision (TME) had a great impact on decreasing local recurrence rates for the treatment of rectal cancer. However, exact numbers and distribution of lymph nodes (LN) along the mesorectum remains controversial with some studies suggesting that few LNs are present in the distal third of the mesorectum. METHODS: Eighteen fresh cadavers without a history of rectal cancer were studied. The rectum was removed by TME and then was divided into right lateral, posterior and left lateral sides, which were further subdivided into 3 levels (upper, middle and lower). A pathologist determined the number and sizes of the LNs in each of the nine areas, b linded to their anatomical origin. RESULTS: Overall, the mesorectum had a mean of 5.7 LNs (SD=3.7) and on average each LN had a maximum diameter of 3.0 mm (SD=2.7). There was no association between the mean number or size of LNs with gender, BMI, or age. There was a significantly higher prevalence of LNs in the posterior location (2.8 per mesorectum) than in the two lateral locations (0.8 and 1.2 per mesorectum; p=0.02). The distribution of LNs in the three levels of the rectum was not significant. CONCLUSIONS: The distribution of LNs reinforces the fact that TME should always include the distal third of the mesorectum. Care must be taken to not violate the posterior aspect of the mesorectum.