Prognostic impact of peritonealisation in rectal cancer treated with preoperative chemoradiotherapy: Extraperitoneal versus intraperitoneal rectal cancer

Background and purpose

The oncologic outcomes of extraperitoneal (EP) rectal cancer are known to differ from those of intraperitoneal (IP) rectal cancer; however, these differences have not been studied in rectal patients treated by preoperative chemoradiotherapy (CRT). The aim of this study is to evaluate the prognostic impact of peritonealisation in rectal patients treated by preoperative CRT.

Materials and methods

This study analyzed the data of 362 patients who received preoperative CRT and underwent curative surgery for locally advanced rectal cancer at 3-9 cm above the anal verge. Patients were categorised into EP and IP groups based on whether peritonealisation was present, according to pathology reports. The oncologic outcomes between the two groups were compared.

Results

Peritonealisation was absent in 330 patients and present in 32 patients. In univariate analysis, disease-free survival was significantly worse in the EP group than in the IP group (73.0% versus 93.5%, p = 0.035). Multivariate analysis revealed the following independent risk factors for recurrence: the absence of peritonealisation (p = 0.023), ypT stage (p = 0.015) and ypN stage (p < .0001).

Conclusions

Peritonealisation of rectal cancer may be a prognostic factor of disease-free survival in patients with rectal cancer treated by preoperative CRT and surgery.     

Tumour regression grading after chemoradiotherapy for locally advanced rectal cancer: A near pathologic complete response does not translate into good clinical outcome

Background

After preoperative chemoradiotherapy (CRT) for rectal cancer, clinically undetectable residual tumour deposits or pathologic lymph nodes may remain in the mesorectum.

Aim

The aim of this study was to report histopathological effects of CRT and factors affecting outcome in a uniformly treated series of locally advanced rectal cancer (LARC) patients.

Methods

Between 2004 and 2008, 107 patients with cT3 (threatening the mesorectal fascia or <5 cm from the anal verge), cT4 or cN2 rectal cancer were treated with preoperative CRT (25 × 2 Gy with capecitabine) and TME 6–8 weeks later. Central histopathological review followed. Tumour regression grade (TRG) was scored in pCR, near-pCR, response and no response. Cox regression was performed to identify prognosticators.

Results

The 3-year distant metastasis-free interval, disease-free rate and overall survival rate were 82%, 73% and 87% (median 44 months follow-up). TRG consisted of 20% pCR, 11% near-pCR, 55% response and 14% no response. 6/21 pCR patients harboured nodal metastases. 5/12 near-pCR had ypT3 disease, while 6 harboured node metastases. 5/12 near-PCR patients developed distant metastases. ypN and TRG were powerful outcome discriminators.

Conclusion

The high number of near-pCR with ypT3 or ypN1/2 and their poor outcome demonstrates that “watch-and-wait” in LARC patients should be applied with care.     

Lymph node ratio is an independent prognostic factor in patients with rectal cancer treated with preoperative chemoradiotherapy and curative resection

Purpose

To evaluate the prognostic effect of lymph node ratio (LNR) in patients with locally advanced rectal cancer who were treated with curative resection after preoperative chemoradiotherapy (CRT).

Methods

Between October 2001 and December 2007, 519 patients who had undergone curative resection of primary rectal cancer after preoperative CRT were enrolled. Of these, 154 patients were positive for lymph node (LN) metastasis and were divided into three groups according to the LNR (≤0.15 [n = 80], 0.16–0.3 [n = 44], >0.3 [n = 30]) to evaluate the prognostic effect on overall survival (OS) and disease-free survival (DFS).

Results

LNR (≤0.15, 0.16–0.3, and >0.3) was significantly associated with 5-year OS (90.3%, 75.1%, and 45.1%; p < 0.001) and DFS (66.7%, 55.8%, and 21.9%; p < 0.001) rates. In a multivariate analysis, LNR (≤0.15, 0.16–0.3, and >0.3) was a significant independent prognostic factor for OS (hazard ratios [HRs], 1, 3.609, and 8.197; p < 0.001) and DFS (HRs, 1, 1.699, and 3.960; p < 0.001). LNR had a prognostic impact on OS and DFS in patients with <12 harvested LNs, as well as in those with ≥12 harvested LNs (p < 0.05).

Conclusion

LNR was a significant independent prognostic predictor for OS and DFS in patients with locally advanced rectal cancer who were treated with curative resection after preoperative CRT.     

Neorectal hyposensitivity after neoadjuvant therapy for rectal cancer

Background and purpose

Preoperative radiotherapy for rectal cancer has a detrimental effect on long-term anorectal function and quality of life, additional to that observed after rectal resection. The exact physiological mechanisms for the excess impairment remain unknown. We aimed to investigate neorectal and anal sphincter properties in patients treated with neoadjuvant therapy (NT) prior to total mesorectal excision (TME).

Material and methods

Sixteen patients (NT+ patients) were examined by multimodal neorectal stimulation and standard anorectal physiological testing. Data were compared to the results of 23 patients, who underwent TME without NT (NT− patients).

Results

NT+ patients had elevated sensory thresholds to heat (median temperature, 60 vs. 55 °C; p < 0.01) and mechanical distension (median tension, 2513 vs. 1521 mmHg mm; p = 0.05) in the fasting state, and altered perception of the sensory response to heat (p = 0.01) and cold (p = 0.01) compared to NT− patients. No differences in the biomechanical properties of the neorectal wall were detected. Anal resting pressure was lower in NT+ patients compared to NT− patients (median pressure, 31 vs. 45 cm H₂O; p = 0.05).

Conclusions

Pelvic radiotherapy causes neorectal hyposensitivity to mechanical and thermal stimuli in patients receiving NT prior to TME surgery for rectal cancer, possibly due to impaired afferent nerve function.     

Post-chemoradiation intraoperative electron-beam radiation therapy boost in resected locally advanced rectal cancer: Long-term results focused on topographic pattern of locoregional relapse

Background

Patients with locally advanced rectal cancer (LARC) have a dismal prognosis. We investigated outcomes and risk factors for locoregional recurrence (LRR) in patients treated with preoperative chemoradiotherapy (CRT), surgery and IOERT.

Methods

A total of 335 patients with LARC [?cT3 93% and/or cN+ 69%) were studied. In multivariate analyses, risk factors for LRR, IFLR and OFLR were assessed.

Results

Median follow-up was 72.6 months (range, 4–205). In multivariate analysis distal margin distance ?10 mm [HR 2.46, p = 0.03], R1 resection [HR 5.06, p = 0.02], tumor regression grade 1–2 [HR 2.63, p = 0.05] and tumor grade 3 [HR 7.79, p < 0.001] were associated with an increased risk of LRR. A risk model was generated to determine a prognostic index for individual patients with LARC.

Conclusions

Overall results after multimodality treatment of LARC are promising. Classification of risk factors for LRR has contributed to propose a prognostic index that could allow us to guide risk-adapted tailored treatment.     

The metabolic response using F-fluorodeoxyglucose-positron emission tomography/computed tomography and the change in the carcinoembryonic antigen level for predicting response to pre-operative chemoradiotherapy in patients with rectal cancer

Background and purpose

To predict tumor regression in pre-operative chemoradiotherapy (CRT) using ¹⁸F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) and serum carcinoembryonic antigen (CEA) in patients with rectal cancer.

Materials and methods

The metabolic response of the tumor was assessed by determining the maximal standardized uptake value (SUV_max), absolute difference (ΔSUV_max), and SUV reduction ratio (SRR) on pre- and post-CRT PET/CT scans. The serum CEA, absolute difference (ΔCEA), and the CEA reduction ratio (CRR) were also determined. A receiver-operating characteristic (ROC) curve was generated.

Results

Of all seventy two patients, mean pre- and post-CRT SUV_max was 14.9 and 5.8, respectively. The mean pre- and post-CRT CEA level was 15.5 ng/ml and 5.4 ng/ml, respectively. Forty-three patients (59.8%) were classified as responders (Dworak’s tumor regression grade 3-4) and 36 patients (50%) achieved tumor down-staging. ROC analysis showed that both post-CRT SUV_max and SRR were predictive factors for responders (p = 0.03 and p = 0.02, respectively). A threshold of post-CRT SUV_max was 5.4 and that of SRR was 53.1%. Pre-CRT SUV_max, ΔSUV_max, and all parameters in regard to CEA were not significant in ROC analysis.

Conclusions

The post-CRT SUV_max and SRR are potential factors for predicting tumor response in pre-operative CRT. The patients with lower post-CRT SUV_max and higher SRR could be expected to achieve maximum tumor regression after pre-operative CRT in this study.     

Impact of planning target volume margins and rectal distention on biochemical failure in image-guided radiotherapy of prostate cancer

Background and purpose

A previous study in our department demonstrated the negative impact on freedom from biochemical failure (FFBF) of using too narrow planning target volume (PTV) margins during prostate image-guided radiotherapy (IGRT). Here, we investigated the impact of appropriate PTV margins and rectal distention on FFBF.

Methods and materials

A total of 50 T1-T3N0M0 prostate cancer patients were treated with daily IGRT by implanted markers. In the first 25 patients, PTV margins were 3 mm laterolateral, 5 mm anterioposterior and 4 mm craniocaudal. The subsequent 25 patients were treated with isotropic margins of 6 mm. The rectal cross-sectional area (CSA) was determined on the planning CT. Median follow-up was 61 months.

Results

The overall 5-year FFBF was 83%. A 6 mm PTV margin was related to increased 5-year FFBF on univariate analysis (96% vs 74% with the tighter PTV margins, p = 0.04). The 5-year FFBF of patients with a rectal distention on the planning CT was worse compared to those with limited rectal filling (75% for CSA ? 9 cm² vs 89% for CSA < 9 cm², p = 0.02), which remained significant on multivariate analysis (p = 0.04).

Conclusion

This retrospective study illustrated the positive impact of PTV margin adaptation and addressed the importance of avoiding rectal distention at time of the planning CT.     

Prediction of rectal lymph node metastasis by pelvic computed tomography measurement

Aim

Rectal cancer staging represents a crucial step to select the best treatment for this tumour. Particularly after neo-adjuvant chemoradiotherapy (CRT), it may influence the surgical procedure (e.g. radical resection vs. local excision). The aim of this study was to determine the best lymph node size cut-off at computed tomography (CT) to predict nodal metastasis in rectal cancer patients with and without preoperative CRT.

Methods

A consecutive series of patients operated on for primary mid–low rectal adenocarcinoma, all staged with pelvic CT scan, were subdivided as follows: those who underwent surgery alone treatment without CRT (Group A) and those who underwent preoperative CRT (Group B). All CT scans were re-viewed by a single radiologist and, based on the lymph node size, findings were compared with pathologic lymph node status (pN). At each lymph node size cut-off value, the following were calculated: accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). The best cut-off value was defined as having an accuracy ≥70% with the highest NPV.

Results

The study population consisted of 162 patients: Group A (n = 52) and Group B (n = 110). Patients classified as pN-positive (n = 45) had a higher number of and larger sized lymph nodes by CT scan than patients classified as pN-negative (n = 117). The cut-off values with an accuracy ≥70% ranged between 7 and 11 mm in Group A and between 9 and 14 mm in Group B. The cut-off with the best NPV was 7 mm for Group A and 10 mm for Group B.

Conclusions

Acknowledging the limitations of the dimensional criterion, lymph node size cut-off values found in our study may be useful for planning rectal cancer treatment using CT scan.     

Results in the elderly with locally advanced rectal cancer from the ACCOR12/PRODIGE 2 phase III trial: Tolerance and efficacy

Background

Rectal cancer predominantly affects the elderly. Unfortunately, this age category is under-represented in clinical trials because clinicians are loath to include patients with a high risk of comorbidity.

Patients and methods

An exploratory analysis of the ACCORD12/PRODIGE 2 phase III trial was carried out to retrospectively compare the benefit of neoadjuvant chemotherapy between the elderly (?70 years; n = 142) and younger patients (<70 years; n = 442), this analysis was not preplanned in the study protocol. Patients with histologically confirmed resectable stage T3 or T4 rectal adenocarcinoma were eligible with an age limit of 80 years.

Results

Overall, the two age categories did not statistically differ in terms of patient’s clinical and tumor baseline characteristics. Preoperative chemoradiotherapy leads to more severe grade 3/4 toxicities (25.6% vs. 15.8%, p = 0.01) and more permanent stomas (33.3% vs. 22.8%, p = 0.014) in elderly patients who were less often operated on than younger patients (95.8% vs. 99.0%, p = 0.008). The relative number of interventions per surgery type (p = 0.18), treatment efficacy in terms of R0 resection rate (88.6% vs. 90.6%; p = 0.54) and complete pathological response (14.7% vs. 16.9%; p = 0.55) were nearly identical between the two categories.

Conclusion

Altogether these results warrant the development of specific optimal therapeutic strategies for the elderly.     

Local recurrence in rectal cancer can be predicted by histopathological factors

Aim

The main cause of local recurrence (LR) in rectal cancer is involvement of the circumferential resection margin (CRM). However, patients with a negative CRM can also develop LR, suggesting that additional factors are important for LR. The aim of this study was to identify histopathological factors predictive for the development of LR after primary rectal cancer treatment.

Methods

T × N × M0 patients treated for locally recurrent rectal cancer at the Catharina hospital from 1994 to 2006 (n = 92) were matched with a control group of patients who did not develop LR after primary rectal cancer treatment for at least 2 years (n = 185) based on the type of neoadjuvant treatment in a 1:2 ratio. The pathology of all primary rectal cancers was reviewed. Patient, treatment and histopathological characteristics were studied in relation to the development of LR with logistic regression.

Results

Logistic regression indicated the presence of lymphovascular invasion (LVI, OR 4.66, P < 0.001), extramural venous invasion (EMVI, OR 4.54, P < 0.001), positive CRM (OR 2.56, P = 0.032), serosal involvement (OR 6.74, P = 0.035) and poor differentiation (OR 2.59, P = 0.012) as factors with an increased risk to develop LR. Older age was a protective factor (OR 0.95, CI 0.93–0.98, P = 0.001).

Conclusion

Apart from a positive CRM and serosal involvement, LVI, EMVI and poor differentiation are important independent predictive factors for the development of LR. Adjuvant therapy may be considered in the presence of these features in order to decrease the risk of a local recurrence.     

Prognostic factors after preoperative irradiation and surgery for locally advanced rectal cancer

Aims

The experience of preoperative irradiation in clinically locally advanced rectal cancer for the period 1991–2003 is reported. Prognostic factors for survival and recurrence, and parameters for obtaining a free circumferential margin were evaluated.

Methods

A prospective cohort study of 204 M0 patients given >45 Gy preoperatively (median age 66 years; 29% women; tumour level <16 cm from the anal verge).

Results

Multivisceral and/or pelvic wall resections were performed in 61% of the patients. R0, R1 and R2 resections were achieved in 74%, 21% and 5%. Five-year survival was 52% for all patients, 60% for R0 resections, 31% for R1 and 0% for R2. The calculated 5-year recurrence rates were 13% for R0 resections and 24% for R1 resections (p < 0.035). R-stage, N-stage, age, type of rectal resection and pelvic wall resection remained significant in Cox multivariate analysis for survival. Regarding local recurrence, the following parameters were independent: N-stage, carcinoembryonic antigen (CEA) response and pelvic wall resection. Medium high tumour level and reduced histopathological differentiation are important individual factors that seem to predict increased risk for not obtaining a R0 resection.

Conclusions

After preoperative irradiation and surgery, about 50% of the patients with locally advanced rectal cancer without overt metastases (M0) can be cured.     

Improving staging accuracy in colon and rectal cancer by sentinel lymph node mapping: A comparative study

Aim

To compare the predictive value of sentinel lymph node (SN) mapping between patients with colon and rectal cancer.

Patients and methods

An ex vivo SN procedure was performed in 100 patients with colon and 32 patients with rectal cancer. If the sentinel node was negative, immunohistochemical analyses using two different antibodies against cytokeratins (Cam5.2 and CK 20) and one antibody against BerEp-4 were performed to detect occult tumour cells. Isolated tumour cells (<0.2 mm) were discriminated from micrometastases (0.2–2 mm).

Results

An SN was identified in 117 patients (89%), and accurately predicted nodal status in 106 patients (accuracy 91%). Both sensitivity and negative predictive value were higher in colon carcinomas than in rectal carcinomas (83% versus 57%, p = 0.06 and 93% versus 65%, p = 0.002 respectively). In patients with extensive lymph node metastases the SN procedures were less successful. Eleven of the 13 unsuccessful SN procedures were performed in patients with rectal cancer who had pre-operative radiotherapy. After immunohistochemical analysis 21 of the 73 N0 patients had occult tumour cells in their SN; eight patients had micrometastases and 13 patients had isolated tumour cells.

Conclusion

SN mapping accurately predicts nodal status in patients with colonic cancer. Immunohistochemical analysis demonstrates micrometastatic disease in eight out of 73 N0 patients, with a true upstaging rate of 11%. SN mapping is less reliable in patients with rectal cancer after pre-operative radiotherapy.     

Oncologic outcomes of laparoscopic surgery for rectal cancer: A systematic review and meta-analysis of the literature

Aim

To review and compare the oncologic outcomes in patients with rectal cancer undergoing laparoscopic vs. open rectal surgery.

Methods

An electronic literature search was performed for trials reporting oncologic outcomes for laparoscopic rectal resections. Variables of interest were survival, recurrence rates, margin status and nodal retrieval. Trials were excluded if variables were not specifically analysed for rectal resections. A meta-analysis was performed to assess the difference in oncologic outcomes between the two treatment approaches.

Results

Data on a total of 1403 laparoscopic (LG) and 1755 open (OG) rectal resections were gathered from 24 publications. Overall survival at 3 years (LG = 76%, OG = 69%) was not statistically different between the two treatment groups. The mean local recurrence rates were 7% for laparoscopic and 8% for open procedures (NS). There was no difference in radial margin positivity, 5% of patients undergoing laparoscopic surgery compared to 8% for open surgery. Laparoscopic procedures harvested a mean of 10 nodes as compared to 12 for open procedures, p = 0.001.

Conclusions

Data gathered in this meta-analysis indicate that there are no oncologic differences between laparoscopic and open resections for treatment of primary rectal cancer.     

Development and external validation of a predictive model for pathological complete response of rectal cancer patients including sequential PET-CT imaging

Purpose

To develop and validate an accurate predictive model and a nomogram for pathologic complete response (pCR) after chemoradiotherapy (CRT) for rectal cancer based on clinical and sequential PET-CT data. Accurate prediction could enable more individualised surgical approaches, including less extensive resection or even a wait-and-see policy.

Methods and materials

Population based databases from 953 patients were collected from four different institutes and divided into three groups: clinical factors (training: 677 patients, validation: 85 patients), pre-CRT PET-CT (training: 114 patients, validation: 37 patients) and post-CRT PET-CT (training: 107 patients, validation: 55 patients). A pCR was defined as ypT0N0 reported by pathology after surgery. The data were analysed using a linear multivariate classification model (support vector machine), and the model’s performance was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve.

Results

The occurrence rate of pCR in the datasets was between 15% and 31%. The model based on clinical variables (AUC_train = 0.61 ± 0.03, AUC_validation = 0.69 ± 0.08) resulted in the following predictors: cT- and cN-stage and tumour length. Addition of pre-CRT PET data did not result in a significantly higher performance (AUC_train = 0.68 ± 0.08, AUC_validation = 0.68 ± 0.10) and revealed maximal radioactive isotope uptake (SUV_max) and tumour location as extra predictors. The best model achieved was based on the addition of post-CRT PET-data (AUC_train = 0.83 ± 0.05, AUC_validation = 0.86 ± 0.05) and included the following predictors: tumour length, post-CRT SUV_max and relative change of SUV_max. This model performed significantly better than the clinical model (p_train < 0.001, p_validation = 0.056).

Conclusions

The model and the nomogram developed based on clinical and sequential PET-CT data can accurately predict pCR, and can be used as a decision support tool for surgery after prospective validation.     

Long-term quality-of-life after neoadjuvant short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer

Purpose

To evaluate long-term quality-of-life (QoL) after neoadjuvant short-course radiotherapy (SC-RT) and long-course radiochemotherapy (LC-RCHT) for locally advanced rectal cancer.

Methods

Between 1999 and 2008, 225 patients were treated with curative intent for locally advanced rectal cancer using neoadjuvant SC-RT (n = 108) or LC-RCHT (n = 117). SC-RT delivered 10 × 2.9 Gy twice daily with immediate surgery. LC-RCHT delivered 28 × 1.8 Gy concomitant with 5-FU based chemotherapy and delayed surgery. A cross-sectional QoL analysis was performed in disease-free patients using the EORTC-QLQ-C30 and EORTC-QLQ-CR29 questionnaires.

Results

After a median follow-up of 67 months, 133 patients were disease-free of which 120 (90%) returned the QoL questionnaires. Patients in the LC-RCHT cohort had a higher rate of uT4, uN+ and low tumor location. No difference in QoL was observed between SC-RT and LC-RCHT except an improved physical functioning in the LC-RCHT group (p = 0.04). Comparing our total patient cohort with the general German population showed no difference in global health status but decreased QoL in several functional and bowel symptom scores.

Conclusions

The finding of comparable long-term QoL after SC-RT and LC-RCHT adds to our knowledge of equivalent oncological outcome and may be useful in the decision making process between the two neoadjuvant approaches.     

Curative rectal cancer surgery in a low-volume hospital: A quality assessment

Aims

Hospital volume or caseload is often used as a surrogate measure for quality of care in rectal cancer treatment. The aim of this study was to assess outcome in a low-volume hospital and secondly to examine the impact of surgeon volume on the results.

Methods

A retrospective review of 131 patients' charts identified 102 patients receiving apparently curative resections for rectal cancer in the period 1993–2002. Our study population did not differ significantly from the national average except for shift towards more advanced Dukes stage (p = 0.00) and a higher rate of node positive patients at time of diagnosis (p = 0.00).

Results

There were no significant differences from the national outcome results, neither in perioperative mortality or complications, nor 5-year survival or local recurrences. Thirteen different on-staff surgeons performed rectal cancer surgery in our hospital in the decade, and median annual caseload was four. We detect a difference in 5-year survival when grouping the surgeons by annual caseload, but the significance is inconclusive. It is, however, interesting that in 85% of the resections, two or more certified gastrointestinal surgeons with specific training were involved. A relatively high number (9%) of discrepancies between the Norwegian Rectal Cancer Registry (NRCR) database and the local hospital database were identified.

Conclusion

Adequate results for surgical outcome can be achieved in a low-volume hospital. Surgeon volume showed inconclusive impact for our results of outcome. A local quality initiative is justified in addition to national registries.     

Tumour regression grading in patients with residual rectal cancer after preoperative chemoradiation

Background and purpose

To explore the utility of tumour regression grading (TRG, the amount of residual tumour cells in relation to extension of fibrosis) after chemoradiation of rectal cancer.

Materials and methods

Of 131 patients who received preoperative chemoradiation in the frame of the randomized trial, pathological complete response (pCR, TRG0), good regression (TRG1), moderate regression (TRG2), and poor regression (TRG3) were recorded in 17%, 31%, 31%, and 22% of patients, respectively.

Results

The rates of ypN-positive category for TRG0, TRG1, TRG2, and TRG3 groups were 5%, 23%, 45%, and 46%, respectively, p = 0.001. When ypT-category and TRG were evaluated by the logistic regression analysis, only ypT-category remained significant for independent prediction of the risk for mesorectal nodal metastases, p = 0.006. The 4-year (median follow-up) disease-free survival (DFS) for TRG0, TRG1, TRG2, and TRG3 groups were 91%, 67%, 54%, and 47%. When patients with persistent disease (TRG1 vs. TRG2 vs. TRG3) were analyzed separately, TRG had no prognostic value for DFS, p = 0.402.

Conclusions

TRG in patients with residual cancer had no prognostic value for the incidence of nodal disease and for DFS. Our findings and literature data question the need for the inclusion of TRG assessment into a routine pathological report.     

Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer

Background and purpose

Rectal bleeding can occur following radiotherapy for prostate cancer and negatively impacts quality of life for cancer survivors. Treatment and clinical factors do not fully predict rectal bleeding, and genetic factors may be important.

Materials and methods

A genome-wide association study (GWAS) was performed to identify SNPs associated with the development of late rectal bleeding following radiotherapy for prostate cancer. Logistic regression was used to test the association between 614,453 SNPs and rectal bleeding in a discovery cohort (79 cases, 289 controls), and top-ranking SNPs were tested in a replication cohort (108 cases, 673 controls) from four independent sites.

Results

rs7120482 and rs17630638, which tag a single locus on chromosome 11q14.3, reached genome-wide significance for association with rectal bleeding (combined p-values 5.4 × 10⁻⁸ and 6.9 × 10⁻⁷ respectively). Several other SNPs had p-values trending toward genome-wide significance, and a polygenic risk score including these SNPs shows a strong rank-correlation with rectal bleeding (Sommers’ d = 5.0 × 10⁻¹² in the replication cohort).

Conclusions

This GWAS identified novel genetic markers of rectal bleeding following prostate radiotherapy. These findings could lead to the development of a predictive assay to identify patients at risk for this adverse treatment outcome so that dose or treatment modality could be modified.     

Identification of a microRNA expression signature for chemoradiosensitivity of colorectal cancer cells,involving miRNAs-320a, -224, -132 and let7g

Background and purpose

Preoperative chemoradiotherapy (CRT) represents the standard treatment for locally advanced rectal cancer. Tumor response and progression vary considerably. MicroRNAs represent master regulators of gene expression, and may therefore contribute to this diversity.

Material and methods

Genome-wide microRNA (miRNA) profiling was performed for 12 colorectal cancer (CRC) cell lines and an individual in vitro signature of chemoradiosensitivity was established. Functional relevance of selected miRNAs was established by transfecting miRNA-mimics into SW480 and SW837 cells. The prognostic value of selected miRNAs was assessed in 128 pretherapeutic patient biopsies.

Results

Thirty-six miRNAs were identified to significantly correlate with sensitivity to CRT (Q < 0.05) including miR-320a and other miRNAs involved in the MAPK-, TGF- and Wnt-pathway. Transfection of selected miRNAs (let-7g, miR-132, miR-224, miR-320a) each induced a shift of sensitivity. High expression of let-7g was associated with a good prognosis in rectal cancer patients (P = 0.03).

Conclusions

This is the first report of a miRNA expression signature for in vitro chemoradiosensitivity of CRC cell lines. Many of the identified miRNAs have not been linked to the response to CRT and may represent potential molecular targets to sensitize resistant cancers. If further validated, let7g expression may serve as predictive biomarker.     

Diffusion-weighted magnetic resonance for prediction of response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: Preliminary results of a monoinstitutional prospective study

Purpose

To evaluate diffusion-weighted imaging (DWI) for assessment of treatment response in locally advanced rectal cancer (LARC) 8 weeks after neoadjuvant chemoradiotherapy (CRT).

Methods and materials

A total of 28 patients with LARC underwent magnetic resonance imaging (MRI) prior to and 8 weeks after CRT. Tumor volume (TV) was calculated on T2-weighted MRI scans as well as the apparent diffusion coefficient (ADC) was calculated using Echo-planar DWI-sequences. All data were correlated to surgical results and histopathologic tumor regression grade (TRG), according to Mandard's classification. Post-treatment difference ADC (%ΔADC) and TV (%ΔTV) changes at 8 weeks were compared complete response (CR; TRG1) and non-complete response tumors (non-CR; TRG2–5).

Results

The mean % ADC increase of CR group was significantly higher compared to non-CR group (77.2 ± 54.63% vs. 36.0 ± 29.44%; p = 0.05). Conversely, the mean % TV reduction did not significantly differ in CR group from non-CR group (73.7% vs. 63.77%; p = 0.21). Accordingly, the diagnostic accuracy of the mean % ADC increase to discriminate CR from non-CR group was significantly higher than that of the mean % TV reduction (0.913 vs. 0.658; p = 0.022). No correlation was found between mean % TV reduction and TRG (rho = 0.22; p = 0.3037), whereas a negative correlation between mean % ADC increase and TRG was recorded (r = −0.69; p = 0.006).

Conclusion

The mean % ADC increase appears to be a reliable tool to differentiate CR from non-CR after CRT in patients with LARC.