Vimentin and tumor–stroma ratio for neoadjuvant chemoradiotherapy response prediction in locally advanced rectal cancer

Vimentin expression in tumor tissues and the tumor–stroma ratio (TSR) have been demonstrated as strong prognostic factors for cancer patients, but whether they are predictive markers of neoadjuvant chemoradiotherapy (nCRT) outcome in locally advanced rectal cancer (LARC) patients is poorly understood. This study aimed to explore the predictive significance of vimentin and TSR combined for nCRT response in LARC patients. Imaging mass cytometry (IMC) was performed to determine the association of vimentin and TSR with nCRT response in six LARC patients [three achieved pathological complete response (pCR), three did not]. Immunohistochemistry (IHC) for vimentin and TSR on biopsy tissues before nCRT and logistic regression analysis were performed to further evaluate their predictive value for treatment responses in a larger patient cohort. A trend of decreased vimentin expression and increased TSR in the pCR group was revealed by IMC. In the validation group, vimentin [odds ratio (OR) 0.260, 95% confidence interval (CI) 0.102–0.602, p = 0.002] and TSR (OR 4.971, 95% CI 1.933–15.431, p = 0.002) were associated with pCR by univariate analysis. Patients in the vimentin-low/TSR-low or vimentin-high/TSR-high (OR 5.211, 95% CI 1.248–35.582, p = 0.042) and vimentin-low/TSR-high groups (OR 11.846, 95% CI 3.197–77.079, p = 0.001) had significantly higher odds of pCR. By multivariate analysis, only the combination of vimentin and TSR was an independent predictor for nCRT response (OR 9.324, 95% CI 2.290–63.623, p = 0.006). Our study suggested that the combined assessment of vimentin and TSR can provide additive significance and may be a promising indicator of nCRT response in LARC patients.     

Gene Expression Profiles of Epidermal Growth Factor Receptor,Vascular Endothelial Growth Factor and Hypoxia-inducible Factor-1 with Special Reference to Local Responsiveness to Neoadjuvant Chemoradiotherapy and Disease Recurrence After Rectal Cancer Surgery

AimsTo establish a causal relationship between the gene expression profiles of angiogenetic molecular markers, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1), in rectal cancer and the local responsiveness to neoadjuvant chemoradiotherapy and subsequent disease recurrence.Materials and methodsWe examined the pre-treatment tumour biopsies (n = 40) obtained from patients with rectal adenocarcinoma (clinical International Union Against Cancer stage ll/III) who were scheduled to receive neoadjuvant 5-fluorouracil-based chemoradiotherapy for EGFR, VEGF and HIF-1 expression by quantitative real-time polymerase chain reaction.ResultsResponders (patients with significant tumour regression, i.e. pathological grades 2/3) showed significantly lower VEGF, HIF-1 and EGFR gene expression levels than the non-responders (patients with insignificant tumour regression, i.e. pathological grades 0/1) in the pre-treatment tumour biopsies. The elevated expression level of each gene could predict patients with a low response to chemoradiation. During the median follow-up of all patients (41 months; 95% confidence interval 28–60 months), 6/40 (15%) developed disease recurrence. Although local responsiveness to neoadjuvant chemoradiotherapy was associated with neither local nor systemic disease recurrence, lymph node metastasis and an elevated VEGF gene expression level were independent predictors of systemic disease recurrence. The 3-year disease-free survival rates of the patients with lower VEGF or EGFR expression levels were significantly lower than those of patients with higher VEGF or EGFR expression levels.ConclusionsAnalysing VEGF expression levels in rectal cancer may be of benefit in estimating the effects of neoadjuvant chemoradiotherapy and in predicting systemic recurrence after rectal cancer surgery.     

Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

BackgroundNeoadjuvant chemoradiotherapy (nCRT) is the standard of care for locally advanced adenocarcinoma of the rectum, but it is currently unknown which patients have disease that will respond. This study tested the correlation between response to nCRT and intratumoral heterogeneity using next-generation sequencing assays.Patients and MethodsDNA was extracted from formalin-fixed, paraffin-embedded biopsy samples from a cohort of patients with locally advanced rectal adenocarcinoma (T3/4 or N1/2 disease) who received nCRT. High read-depth sequencing of > 400 cancer-relevant genes was performed. Tumor mutations and variant allele frequencies were used to calculate mutant-allele tumor heterogeneity (MATH) scores as measures of intratumoral heterogeneity. Response to nCRT was pathologically scored after surgical resection.ResultsBiopsy samples from 21 patient tumors were analyzed. Eight patients had disease noted to have complete response, 2 moderate, 4 minimal, and 7 poor. Higher MATH scores correlated with poorer response to treatment, demonstrating significantly increased tumor heterogeneity compared to complete response (P = .039).ConclusionThe application of MATH scores as a measure of tumor heterogeneity may provide a useful biomarker for treatment response in locally advanced rectal cancer.     

The stromal part of adenocarcinomas of the oesophagus: Does it conceal targets for therapy?

ObjectiveTo evaluate the prognostic value of the tumour stroma ratio (TSR) in resected adenocarcinoma of the oesophagus.BackgroundIn the literature, a refinement of oesophageal cancer staging has been proposed. Recently, TSR has been identified as a histological characteristic of the tumour itself that proved to be a strong predictor for survival in colorectal cancer.MethodsIn our cancer registry database, we identified 93 consecutive patients who underwent resection for oesophageal adenocarcinoma between 1990 and 2004 in two hospitals in our region. Using a predefined histopathological protocol, TSR was determined on the original haematoxylin–eosin (H&E) tissue sections of oesophagectomy specimens by two independent investigators.ResultsWith a cut-off value of 50% tumour/stroma, patients were classified as TSR high (n = 60) or TSR low (n = 33). There were no significant differences in patient, tumour and treatment characteristics between the two groups, except for M status (M1a) and radicality of resection. The (disease-free) survival in the TSR high group was significantly better than in the TSR low group. By multivariate analysis, TSR was identified as a highly significant prognostic factor for overall survival (HR 2.0; P = 0.010), independent of depth of tumour invasion, nodal status, lymph node ratio, extracapsular involvement, TNM stage, histological grade and radicality of resection.ConclusionTSR is a new and practicable prognostic tumour characteristic for oesophageal adenocarcinoma that can discriminate patients with a poor outcome from those with a better outcome.     

Systematic review and meta-analysis of long-term oncological outcomes of lateral lymph node dissection for metastatic nodes after neoadjuvant chemoradiotherapy in rectal cancer

BackgroundStandard Western management of rectal cancers with pre-treatment metastatic lateral lymph nodes (LLNs) is neoadjuvant (chemo)radiotherapy (nCRT) followed by total mesorectal excision (TME). In recent years, there is growing interest in performing an additional lateral lymph node dissection (LLND). The aim of this systematic review and meta-analysis was to investigate long-term oncological outcomes of nCRT followed by TME with or without LLND in patients with pre-treatment metastatic LLNs.MethodsPubMed, Ovid MEDLINE, Embase, Cochrane Library and Clinicaltrials.gov were searched to identify comparative studies reporting long-term oncological outcomes in pre-treatment metastatic LLNs of nCRT followed by TME and LLND (LLND+) vs. nCRT followed by TME only (LLND-). Newcastle-Ottawa risk-of-bias scale was used. Outcomes of interest included local recurrence (LR), disease-free survival (DFS), and overall survival (OS). Summary meta-analysis of aggregate outcomes was performed.ResultsSeven studies, including 946 patients, were analysed. One (1/7) study was of good-quality after risk-of-bias analysis. Five-year LR rates after LLND+ were reduced (range 3–15%) compared to LLND- (11–27%; RR = 0.40, 95%CI [0.25–0.62], p < 0.0001). Five-year DFS was not significantly different after LLND+ (range 61–78% vs. 46–79% for LLND-; RR = 0.72, 95%CI [0.51–1.02], p = 0.143), and neither was five-year OS (range 69–91% vs. 72–80%; RR = 0.72, 95%CI [0.45–1.14], p = 0.163).ConclusionIn rectal cancers with pre-treatment metastatic LLNs, nCRT followed by an additional LLND during TME reduces local recurrence risk, but does not impact disease-free or overall survival. Due to the low quality of current data, large prospective studies will be required to further determine the value of LLND.     

The use of personalized biomarkers and liquid biopsies to monitor treatment response and disease recurrence in locally advanced rectal cancer after neoadjuvant chemoradiation

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the mainstay treatment for locally advanced rectal cancer. Variable degrees of tumor regression are observed after nCRT and alternative treatment strategies, including close surveillance without immediate surgery, have been investigated to spare patients with complete tumor regression from potentially adverse outcomes of radical surgery. However, clinical and radiological assessment of response does not allow accurate identification of patients with complete response. In addition, surveillance for recurrence is similarly important for these patients, as early detection of recurrence allows salvage resections and adjuvant interventions. We report the use of liquid biopsies and personalized biomarkers for monitoring treatment response to nCRT and detecting residual disease and recurrence in patients with rectal cancer. We sequenced the whole-genome of four rectal tumors to identify patient-specific chromosomal rearrangements that were used to monitor circulating tumor DNA (ctDNA) in liquid biopsies collected at diagnosis and during nCRT and follow-up. We compared ctDNA levels to clinical, radiological and pathological response to nCRT. Our results indicate that personalized biomarkers and liquid biopsies may not be sensitive for the detection of microscopic residual disease. However, it can be efficiently used to monitor treatment response to nCRT and detect disease recurrence, preceding increases in CEA levels and radiological diagnosis. Similar good results were observed when assessing tumor response to systemic therapy and disease progression. Our study supports the use of personalized biomarkers and liquid biopsies to tailor the management of rectal cancer patients, however, replication in a larger cohort is necessary to introduce this strategy into clinical practice.     

Oncologic impact of lateral lymph node metastasis at the distal lateral compartment in locally advanced low rectal cancer after neoadjuvant (chemo)radiotherapy

IntroductionThe frequency and oncologic outcomes of lateral lymph node (LLN) metastasis at the most distal lateral compartment (DLC) among clinical stage II-III low rectal cancer patients treated with neoadjuvant (chemo)radiotherapy (nCRT) are poorly understood. The aim was to investigate the oncologic impact of LLN metastasis in the DLC versus the proximal lateral compartment (PLC).Materials and methodsConsecutive patients with low rectal cancer treated with nCRT followed by total mesorectal excision and selective LLN dissection including the DLC were analyzed retrospectively. DLC was defined as the area distal to the infra–piriformis foramen on axial MRI images. Size and location of LLN metastasis on MRI, and survival were retrospectively assessed.ResultsOf the 718 patients, 72 (10.0%) had pathological LLN metastasis. Thirty-two (44.4%) had metastasis in the DLC (DLC group), while 40 (55.6%) had metastasis in the PLC without metastasis in the DLC (PLC group). The proportion of ypN2 category tended to be lower in the DLC group (15.6% vs 35.0%, P = 0.105). The median number of metastatic LLN was similar (1 vs. 1, P = 0.691). The median short-axis size of metastatic LLN was smaller in the DLC group than in the PLC group on pre-treatment (P < 0.001) and re-staging (P = 0.004) MRI. By multivariable analysis, LLN metastasis in the DLC was predictive of better disease-free survival (HR, 0.412; 95% CI, 0.159–0.958, P = 0.039).ConclusionLLN metastasis in the DLC is frequent and has favorable oncologic outcomes after surgical dissection with nCRT.     

Global DNA methylation is altered by neoadjuvant chemoradiotherapy in rectal cancer and may predict response to treatment – A pilot study

Aim

In rectal cancer, not all tumours display a response to neoadjuvant treatment. An accurate predictor of response does not exist to guide patient-specific treatment. DNA methylation is a distinctive molecular pathway in colorectal carcinogenesis. Whether DNA methylation is altered by neoadjuvant treatment and a potential response predictor is unknown. We aimed to determine whether DNA methylation is altered by neoadjuvant chemoradiotherapy (CRT) and to determine its role in predicting response to treatment.

Patients and methods

Fifty-three (n = 53) patients with locally advanced rectal cancers treated with neoadjuvant CRT followed by surgery were identified from the pathology databases of 2 tertiary referral centres over a 4-year period. Immunohistochemical staining of treatment specimens was carried out using the 5-Methylcytidine (Eurogentec, Seraing, Belgium) antibody. Quantitative analysis of staining was performed using an automated image analysis platform. The modified tumour regression grading system was used to assess tumour response to neoadjuvant therapy.

Results

Seven (13%) patients showed complete pathological response while 46 (87%) patients were partial responders to neoadjuvant treatment. In 38 (72%) patients, significant reduction in methylation was observed in post-treatment resection specimens compared to pre-treatment specimens (171.5 vs 152.7, p = 0.01); in 15 (28%) patients, methylation was increased. Pre-treatment methylation correlated significantly with tumour regression (p < 0.001), T-stage (p = 0.005), and was able to predict complete and partial pathological responders (p = 0.01).

Conclusion

Neoadjuvant CRT appears to alter the rectal cancer epigenome. The significant correlation between pre-treatment DNA methylation with tumour response suggests a potential role for methylation as a biomarker of response.     

Human epidermal growth factor receptor‐2 expression in locally advanced rectal cancer: Association with response to neoadjuvant therapy and prognosis

The aim of this study was to determine whether pretreatment status of human epidermal growth factor receptor‐2 (HER‐2) could predict pathologic response to neoadjuvant chemoradiotherapy (nCRT) and outcomes for patients with locally advanced rectal cancer (LARC). A total of 119 patients diagnosed with LARC received standardized multimodal treatment. Their HER‐2 status was determined in pretreatment biopsies by immunohistochemistry (IHC) and FISH. Tumor response was assessed in resected regimens using the tumor regression grade system and TNM staging system. Twenty‐two cases in 119 patients assessed as IHC3+ or IHC2+ plus gene‐amplified were determined as HER‐2 positive. Positive HER‐2 status was not associated with any pretreatment clinicopathologic parameters (P > 0.05). HER‐2 status could not predict pathologic response to nCRT based on downstaging (P = 0.210) and tumor regression grade (P = 0.085) but it provides us with a trend that HER‐2‐positive tumors may be resistant to nCRT. Positive HER‐2 status was significantly associated with poor 5‐year disease‐free survival (P = 0.015) and 5‐year overall survival (P = 0.026). It can act as a worse prognostic factor for LARC patients.     

ctDNA on liquid biopsy for predicting response and prognosis in locally advanced rectal cancer: A systematic review

BackgroundThe management of locally advanced rectal cancer (LARC) requires a multidisciplinary approach, with an increasing interest for non-operative strategies. Liquid biopsy for obtaining circulating tumor DNA (ctDNA) can provide information on neoadjuvant chemoradiotherapy (nCRT) pathological response and cancer-specific prognosis, and therefore might be a promising guide for these treatments.MethodsA systematic review of the studies available in literature has been performed to assess the role of ctDNA as a predictive and prognostic biomarker in LARC patients.ResultsWe retrieved 21 publications, of which 17 full-text articles and 4 abstracts. Results have been labelled into two groups: predictive and prognostic. Data about the usefulness of liquid biopsy in this setting is still inconclusive. However, baseline higher levels of longer fragments of cell-free DNA and integrity index, tumor-specific mutations and certain methylated genes could predict non-responders. Also, undetectable baseline ctDNA and decrease of common rectal cancer mutations throughout treatment (dynamic monitoring) were predictive factors of pathological complete response. The continuous detection of ctDNA in different timepoints of treatment (minimal residual disease) was consistently associated with worse prognosis.ConclusionsctDNA is a promising biomarker that could assist predicting treatment response to nCRT and prognosis in patients with LARC. The ideal methods and timings for the liquid biopsy still have to be defined.     

直肠癌新辅助治疗中盆腔骨髓保护调强放疗与病理反应的相关性北大核心

目的:探讨直肠癌新辅助治疗中盆腔骨髓保护调强放疗与病理反应的相关性。方法:回顾性分析2017年01月至2020年12月于我院接受新辅助放化疗及根治性手术的192例Ⅱ、Ⅲ期直肠癌患者的临床病理资料,其中95例为接受盆腔骨髓保护调强放疗的患者(淋巴细胞保护组),余97例患者来源于本单位回顾性数据库(对照组)。比较两组患者淋巴细胞绝对计数最低值、淋巴细胞下降程度及肿瘤病理反应率差异,分析直肠癌新辅助治疗中盆腔骨髓保护调强放疗与病理反应的相关性。结果:淋巴细胞保护组患者放化疗期间最低淋巴细胞计数、放化疗后淋巴细胞计数及病理反应率均高于对照组,差异有统计学意义。淋巴细胞保护组3-4级淋巴细胞减少症发生率为38.9%,低于对照组的56.8%(P=0.034)。多因素Logistic回归分析结果显示3-4级淋巴细胞减少症、淋巴细胞保护、临床分期及等待手术期间化疗是肿瘤病理反应状态的独立影响因素。结论:直肠癌患者新辅助放化疗期间3-4级淋巴细胞减少症与治疗后肿瘤病理反应状态密切相关,通过盆腔骨髓保护调强放疗可有效保护患者的淋巴细胞,减轻3-4级淋巴细胞减少症发生率,提高肿瘤病理反应。     

Local recurrences in western low rectal cancer patients treated with or without lateral lymph node dissection after neoadjuvant (chemo)radiotherapy: An international multi-centre comparative study

BackgroundIn the West, low rectal cancer patients with abnormal lateral lymph nodes (LLNs) are commonly treated with neoadjuvant (chemo)radiotherapy (nCRT) followed by total mesorectal excision (TME). Additionally, some perform a lateral lymph node dissection (LLND). To date, no comparative data (nCRT vs. nCRT + LLND) are available in Western patients.MethodsAn international multi-centre cohort study was conducted at six centres from the Netherlands, US and Australia. Patients with low rectal cancers from the Netherlands and Australia with abnormal LLNs (≥5 mm short-axis in the obturator, internal iliac, external iliac and/or common iliac basin) who underwent nCRT and TME (LLND-group) were compared to similarly staged patients from the US who underwent a LLND in addition to nCRT and TME (LLND + group).ResultsLLND + patients (n = 44) were younger with higher ASA-classifications and ypN-stages compared to LLND-patients (n = 115). LLND + patients had larger median LLNs short-axes and received more adjuvant chemotherapy (100 vs. 30%; p < 0.0001). Between groups, the local recurrence rate (LRR) was 3% for LLND + vs. 11% for LLND- (p = 0.13). Disease-free survival (DFS, p = 0.94) and overall survival (OS, p = 0.42) were similar. On multivariable analysis, LLND was an independent significant factor for local recurrences (p = 0.01). Sub-analysis of patients who underwent long-course nCRT and had adjuvant chemotherapy (LLND-n = 30, LLND + n = 44) demonstrated a lower LRR for LLND + patients (3% vs. 16% for LLND-; p = 0.04). DFS (p = 0.10) and OS (p = 0.11) were similar between groups.ConclusionA LLND in addition to nCRT may improve loco-regional control in Western patients with low rectal cancer and abnormal LLNs. Larger studies in Western patients are required to evaluate its contribution.     

Individualizing surgical treatment based on tumour response following neoadjuvant therapy in T4 primary rectal cancer

BackgroundRectal cancer involving at least one adjacent organ (mrT4b) requires multi-visceral resection to achieve clear resection margin (R0). Performing pelvic compartment preservation according to the tumour response has not been considered. This study assesses the impact of changing the surgical strategy according to tumour response in rectal cancer mrT4b.MethodsPatients with non-metastatic T4b rectal cancer at two tertiary referral centres between 2008 and 2013 were grouped as “Responders” ypT0-3abNx versus “Non-responders” ypT3cd-4Nx and divided into three surgical procedures: total mesorectal excision (TME), extended-TME (eTME) and beyond-TME (b-TME). End-points were circumferential resection margin, postoperative morbidity, definitive stoma formation, 3-years local recurrence (3y-LR) and 3-years disease-free survival (3y-DFS) according to both tumours' response and surgical procedures.ResultsAmong 883 patients with rectal cancer, 101 were included. Responders had a higher rate of induction chemotherapy (59.7% vs. 38.2%; p = 0.04). Morbidity and definitive stoma formation were significantly higher in Non-responders. R0 was not impacted by either the tumour response or the surgical procedures. The 3y-LR was lower in Responders (14%) compared to Non Responders (32%) (HR 1.6; 95% CI: 1.02–2.59; p = 0.041), and was two-fold higher in e-TME compared to b-TME in Non-responders, whereas no difference was found in Responders. The 3y-DFS was higher in Responders irrespective to the surgery (71% vs. 47%; p = 0.07).ConclusionIn Responders, TME or e-TME are technically and oncollogically feasible and should be considered in preferrence to b-TME. In Non-responders, allowing for high rates of morbidity and local recurrence in patients with e-TME, b-TME procedures should be preferred.     

Laparoscopic resection for rectal adenocarcinoma

Aims

Laparoscopic surgery for rectal cancer is still under discussion, but there is evidence that minimal access surgery can be feasible and safe also in this field. The aim of this study was to confirm that laparoscopic resection for rectal cancer can afford good results in terms of recurrence rate and survival.

Patients and methods

Since June 1998 through December 2007 as many as 252 patients underwent laparoscopic resection for rectal cancer. Laparoscopic anterior resection (LAR) was performed in 209 and laparoscopic abdominoperineal resection (LAPR) in 43. Neoadjuvant radiochemotherapy (nCRT) was administered in 48 patients with mid-low rectal cancer stage II and III with evidence of nodal involvement in preoperative work up.

Results

Patients who received nCRT showed a significant longer duration of surgery compared to patients who did not (p = 0.004). Conversion to laparotomy was needed in 24 cases, (21 LAR and three LAPR) but no patient receiving nCRT needed conversion. Postoperative surgical complications occurred in 38 patients, 20 of which were represented by anastomotic leak after LAR. Six patients died postoperatively, in half the cases for surgery related causes. Downstaging after nCRT was seen in 40 patients, and complete histological response was observed in six cases. The mean number of lymph nodes harvested was 12, also in patients receiving nCRT. The mean follow-up was 48 ± 33 months (range 0.1–120.4), and 10 patients experienced local recurrence. Cumulative 5 year survival was 73.7%.

Conclusion

Laparoscopic resection for rectal cancer is feasible and safe, with morbidity and long-term results quite acceptable also in patients receiving neoadjuvant treatment.     

Establishing and validating predictive nomograms for lateral pelvic lymph node metastasis in patients with rectal cancer based on radiologic factors and clinicopathologic characteristics

IntroductionIt is critical to accurately predict the occurrence of lateral pelvic lymph node (LPN) metastasis. Currently, verified predictive tools are unavailable. This study aims to establish nomograms for predicting LPN metastasis in patients with rectal cancer who received or did not receive neoadjuvant chemoradiotherapy (nCRT).Materials and methodsWe carried out a retrospective study of patients with rectal cancer and clinical LPN metastasis who underwent total mesorectal excision (TME) and LPN dissection (LPND) from January 2012 to December 2019 at 3 institutions. We collected and evaluated their clinicopathologic and radiologic features, and constructed nomograms based on the multivariable logistic regression models.ResultsA total of 472 eligible patients were enrolled into the non-nCRT cohort (n = 312) and the nCRT cohort (n = 160). We established nomograms using variables from the multivariable logistic regression models in both cohorts. In the non-nCRT cohort, the variables included LPN short diameter, cT stage, cN stage, histologic grade, and malignant features, and the C-index was 0.930 in the training cohort and 0.913 in the validation cohort. In the nCRT cohort, the variables included post-nCRT LPN short diameter, ycT stage, ycN stage, histologic grade, and post-nCRT malignant features, and the C-index was 0.836 in the training dataset and 0.827 in the validation dataset. The nomograms in both cohorts were moderately calibrated and well-validated.ConclusionsWe established nomograms for patients with rectal cancer that accurately predict LPN metastasis. The performance of the nomograms in both cohorts was high and well-validated.     

Clinical and biochemical predictors of tumor response after neoadjuvant therapy in rectal cancer

Background

Patients who have a good clinical and/or pathologic response to neoadjuvant chemoradiotherapy (nCRT) for rectal cancer have better long-term outcomes and can potentially be spared morbid surgery. This study aimed to identify pretreatment clinical and biochemical predictors of response to neoadjuvant treatment for rectal cancer.

Methods

Patients undergoing neoadjuvant therapy for rectal cancer between 2007 and 2022 were retrospectively included. Those patients who achieved a complete clinical response were offered a nonoperative management strategy and the remaining patients underwent surgical resection. The primary endpoint was tumor regression grade (TRG) based on radiological imaging (mrTRG) or pathology (pTRG). Patient response was classified as good (mrTRG 1–2 or pTRG 0–1) versus poor (mrTRG 3–4 or pTRG 2–3). Logistic regression was performed to determine predictors of TRG.

Results

A total of 984 patients with rectal cancer were identified of which 274 met the inclusion criteria. Of 274 patients, 228 (83%) underwent surgical resection. A good TRG response was observed in 119 (41%) patients, and a complete response was achieved in 53 (17%) patients. On univariable and multivariable logistic regression, clinical T2 stage and body mass index of ≥25 kg/m² were significant predictors of a good TRG. Clinical T2 stage and a personalised total neoadjuvant therapy regimen were significant predictors of complete response.

Conclusion

Clinical T2 stage and a BMI≥25 kg/m² were predictors of good response to neoadjuvant therapy for rectal cancer. Future prospective studies are required to confirm these findings and evaluate their potential use in better targeting of nCRT.     

Changes in body composition during neoadjuvant therapy can affect prognosis in rectal cancer patients: An exploratory study

Aim: To establish the correlation between changes in body composition after neoadjuvant chemoradiotherapy (nCRT) and postoperative outcomes, in patients with advanced low rectal cancer. Methods: Patients with clinical stage T≥3 or N+ rectal cancer who underwent nCRT and surgical resection were studied. Skeletal muscle, visceral, and subcutaneous fat cross-sectional area were measured by computed tomography before and after nCRT. Postoperative morbidity, pathologic response to nCRT, overall and disease-free survival was assessed. Results: Fifty-two patients, median age 62 (range 32-79) were studied. A skeletal muscle loss >2% significantly correlated with a shorter disease-free survival both in the overall population (P = 0.048) and in the subgroup of N0 patients (P = 0.048). A subcutaneous fat loss >5% was also associated with a shorter disease-free survival (P = 0.012) in the whole population. Conclusions: Skeletal muscle loss, after neoadjuvant chemoradiotherapy, negatively impacts on disease-free survival in surgically treated rectal cancer patients.     

The role of local excision in rectal cancer after complete response to neoadjuvant treatment

Correlation between pathological response of primary tumour and mesorectal lymph node involvement was prospectively evaluated to assess the role of local excision (LE) in rectal cancer after complete response to neoadjuvant treatment. A series of 272 consecutive rectal cancer, submitted to neoadjuvant radiochemotherapy (RCT) and surgery with total mesorectal excision (TME) were analysed. Tumour downstaging (pT) and tumour regression grade (TRG) together with sex, age, location of the tumour, pre-treatment clinical stage, type of chemoradiation and operation performed entered in an univariate and multivariate analysis. Pathological complete response on primary tumour was found in 56 patients (20.6%). Lymph node metastases were found in 72 patients (26.5%). The rate of positive nodes was 1.8% for pT0 and TRG1 cases, respectively, to go up to 6.3% for pT1 and 24.1% for TRG 2 cases, respectively. At the univariate analysis, factors with a statistically significant correlation with the risk of lymph node metastasis were: clinical pre-treatment N stage (p<0.05), pT stage (p<0.001) and TRG (p<0.001). At the multivariate analysis, the best predictors of pathologic lymph node involvement were pT stage (p=0.0013 ) and TRG (p=0.0011). Because LE is an adequate technique to assess the tumour pathological response and nodal involvement in pT0 or TRG1 cases seems extremely infrequent, radical resection is probably not justified after pathological complete response. Prospective randomized trials are necessary to establish if, in these cases, LE can guarantee the same oncologic results offered by the currently adopted protocols of RCT followed by radical resections.     

Pathological complete response may underestimate distant metastasis in locally advanced rectal cancer following neoadjuvant chemoradiotherapy and radical surgery: Incidence,metastatic pattern,and risk factors

AimTo evaluate the pattern of tumor relapse of pathological complete response (pCR) patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME), and to identify predictive factors of distant metastasis in pCR patients after nCRT.MethodThis was a retrospective analysis of 118 LARC patients who achieved a pCR following nCRT and TME from 2008 to 2015. Clinicopathological and therapeutic parameters were evaluated as possible predictors of distant metastasis-free survival (DMFS), and COX regression analysis was performed.ResultsAfter a median follow-up of 57 months, the 5-year overall and disease-free survival rates were 94.7% and 88.1%, respectively. Overall, 6 patients (5.1%) died, no local recurrence occurred, 13 patients (11%) developed distant metastases, including lung (n = 5), liver (n = 2), bone (n = 3), lung and brain (n = 1), peritoneal (n = 1), and spleen (n = 1) metastasis. On univariate analysis, tumor distance from the anal verge (HR = 0.706, P = 0.039), acellular mucin pools (HR = 6.687, P = 0.002), and MUC1 expression (HR = 8.280, P < 0.001) were independently associated with DMFS. COX regression demonstrated that MUC1 expression (HR = 3.812, P = 0.041) remained to be an independent predictor of DMFS in pCR patients.ConclusionDistant metastasis still remained a major concern in pCR patients following nCRT and TME. Tumor distance from the anal verge, acellular mucin pools, and MUC1 expression were associated with distant metastasis in patients with pCR. MUC1 staining remained to be an independent risk factor for DMFS. Such information could facilitate treatment decision in these patients, such as adjuvant chemotherapy and follow-up.     

Regression of Rectal Cancer with Radiotherapy with or without Concurrent Capecitabine — Optimising the Timing of Surgical Resection

AimsTo determine tumour regression (volume-halving time) obtained after chemo/radiotherapy, and thereby the ideal interval between the start of treatment and surgery in order to obtain a high rate of complete response.Materials and methodsIn total, 106 patients with cT3,4 rectal cancer who received preoperative radiotherapy alone or concurrently with capecitabine chemotherapy at Nottingham City Hospital, UK were studied. The rectal tumour volume visible on the computed tomography planning scan was compared with the residual pathological volume and the tumour volume-halving time calculated. The radiotherapy response was graded according to the Mandard system.ResultsFifty-three patients had radiotherapy alone, with 53 patients having concurrent chemoradiotherapy. The median tumour volume-halving time was found to be 14 days and not influenced by the addition of chemotherapy. The Mandard score, the interval from the start of treatment to surgery and the tumour volume-halving time were statistically associated with tumour regression. The median tumour volume in our series of 54 cm³ would require an interval of 20 weeks after the start of treatment to surgery to regress to <0.1 cm³ (10 volume-halving times; 140 days).ConclusionsThe initial tumour volume and median volume-halving time provide the best estimates for determining the optimum length of interval between the completion of preoperative chemo/radiotherapy and surgery in locally advanced rectal cancer.