High-risk Rectal Cancer Patients Research Articles

INNOVA: Interval or neoadjuvant chemotherapy in rectal cancer—A phase II randomized study comparing interval versus neoadjuvant chemotherapy in magnetic resonance imaging-defined high-risk rectal cancer.

91 Background: Total neoadjuvant treatment is a promising option in rectal cancer. We aim to compare neoadjuvant versus interval chemotherapy in high risk rectal cancer to identify the optimal sequencing of treatment. Methods: Using a Simon two-stage design, newly diagnosed MRI defined high risk rectal cancer patients were randomly assigned in a 1:1 ratio to receive three 21 day cycles of chemotherapy with Capecitabine 1000 mg/m2 and Oxaliplatin 130 mg/m2 either before (Arm A-neoadjuvant) or after (Arm B-interval) chemoradiation followed by surgery. Primary end point was the pathological complete response (pCR) following surgery. A heirarchial model was used to assess the primary and secondary end points (toxicity and compliance) and compare the two regimens. (Clinical Trial Registry of India No. CTRI/2015/01/005385). Results: In this single centre study conducted between November 2015 and February 2020, 42 patients were randomised in the first stage. A pCR was seen in 4 patients in Arm A and 6 in Arm B. Hence another 52 patients were randomised in the second stage of which an additional 3 and 2 patients had a pCR leading to an overall pCR of 7 and 8 patients (15.5% vs 17% and 18.4% vs 19.5% in the intent-to-treat and per-protocol populations in Arm A and B respectively. This exceeded the minimum predetermined number of 5 pCR needed to qualify for further evaluation for each arm. Grade ≥3 toxicity was observed in 2.2% of 132 cycles and 4.6% of 129 cycles of chemotherapy delivered in 45 and 43 patients in Arm A and B respectively while 11/43 (25.5%) and 10/47 (21.2%) patients experienced grade ≥3 toxicity during chemoradiation. Treatment break of > 7 days was seen in 23.2% and 29.7% of patients in Arm A and B respectively while 93.3% in Arm A and 100% of patients in Arm B completed all 3 planned cycles of pre-operative chemotherapy. A non-significant trend towards greater pathological downstaging was seen in Arm B than in Arm A (ypT1-2 39% vs 26.3%; p = 0.1 and ypN0 68.3% vs 57.9%; p = 0.5 respectively). Conclusions: In this phase two study, both neoadjuvant and interval chemotherapy emerged eligible for further evaluation against the standard of care in a future phase III study. Although we could not pick one winner based on pCR, toxicity or compliance, the greater downstaging observed with interval chemotherapy suggests it could play a greater role in an organ preservation approach. Clinical trial information:CTRI/2015/01/005385, UTN no: U111111650578.

Results of laparoscopic resection in high-risk rectal cancer patients.

Obesity, neoadjuvant-radiotherapy, tumour proximity to the anal verge and previous abdominal surgery are factors that might increase the intra-operative difficulty of laparoscopic rectal cancer surgery. However, whether patients with these 'high-risk' characteristics are subject to worse short- or long-term outcomes is debated. The aim of this study is to examine the short- and long-term clinical and oncological outcomes of patients receiving laparoscopic rectal surgery with any of these high-risk characteristics and compare them with patients that do not possess any of these high-risk features. For the purpose of this study data from consecutive patients receiving laparoscopic rectal cancer resections between 2006 and 2016 from two centres were analysed. High-risk patients were defined as patients with either one of the following characteristics: BMI ≥ 30, neoadjuvant chemoradiotherapy, tumour < 8cm from the anal verge and previous abdominal surgery. A total of 313 patients were identified (227 high risk, 86 low risk). Short-term outcomes were similar between the two groups with the exception of blood loss and length of stay, which were higher in the high-risk group (10 vs 2.5ml, p = 0.045; 7 vs 5days, p = 0.001). There were no statistically significant differences in 5-year overall survival (79.7% vs 79.8%, p = 0.757), disease-free survival (76.8% vs 69.3%, p = 0.175), distant disease-free interval (84.8% vs 79.7%, p = 0.231) and local recurrence-free interval (100%, 97.4%, p = 0.162) between the two groups. Similar short- and long-term outcomes can be achieved in high-risk and low-risk patients receiving laparoscopic rectal surgery. The presented data support the suitability of laparoscopic surgery for this group of patients.

Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer – Results of the international randomized RAPIDO-trial

BackgroundPreoperative chemoradiotherapy (CRT) followed by total mesorectal excision is widely accepted as the standard of care for high-risk rectal cancer. Adjuvant chemotherapy is advised in several international guidelines, although the survival benefit remains unclear and compliance is poor. The current multidisciplinary approach has led to major improvements in local control, yet the occurrence of distant metastases has not decreased accordingly. The combination of short-course radiotherapy (SCRT) and chemotherapy in the waiting period before surgery might have several benefits, including higher compliance, downstaging and better effect of systemic therapy. MethodsThis is an investigator-initiated, international multicentre randomized phase III trial. High-risk rectal cancer patients were randomized to SCRT followed by chemotherapy (6 cycles CAPOX or alternatively 9 cycles FOLFOX4) and subsequent surgery, or long-course radiotherapy (25–28 × 2–1.8 Gy) with concomitant capecitabine followed by surgery and optional postoperative chemotherapy (8 cycles CAPOX or 12 cycles FOLFOX4) according to local institutions’ policy. The primary endpoint is time to disease-related treatment failure. Here, we report the compliance, toxicity and postoperative complications in both study groups. FindingsBetween June 2011 and June 2016, 920 patients were enrolled. Of these, 901 were evaluable (460 in the experimental arm and 441 in the standard arm). All patients in the experimental arm received 5 × 5 Gy radiotherapy, and 84% of all patients received at least 75% of the prescribed chemotherapy. In the standard arm, the compliance for CRT was 93% and 58% for postoperative chemotherapy. Toxicity ≥grade 3 occurred in 48% of patients in the experimental arm, compared to 25% of patients in the standard arm during preoperative treatment and 35% of patients during postoperative chemotherapy. No statistically significant differences in surgical procedures or postoperative complications were observed. InterpretationHigh compliance (84%) of preoperative systemic treatment could be achieved with the experimental approach. Although considerable toxicity was observed during preoperative therapy, this did not lead to differences in surgical procedures or postoperative complications. Longer follow-up time is needed to assess the primary endpoint and related outcomes.

Hospital variance in neoadjuvant rectal cancer treatment and the influence of a national guideline update: Results of a nationwide population-based study

IntroductionThe aim of this study was to examine the hospital variation in neoadjuvant treatment of rectal cancer according to the different risk groups (low-, intermediate- and high-risk) and evaluate the influence on survival. Materials and methodsPatients with non-metastasized rectal cancer diagnosed between 2009 and 2016 were selected from the Netherlands Cancer Registry. The observed and case-mix adjusted distribution of the different neoadjuvant treatment schemes (none, radiotherapy (RT), chemoradiotherapy (CRT)) by hospital of diagnosis were generated for each risk group in the cohorts before and after the national guideline update of 2014. ResultsA total of 25,306 patients were included and after case-mix adjustment, hospital of diagnosis was found to have a significant impact on neoadjuvant treatment administration in each of the three risk groups (p < 0.001). Overall survival was however not influenced, except for the high-risk group where hospitals with highest rates of CRT were associated with a better 5-years overall survival (HR 0.79; p = 0.03). After guideline revision, the rate of patients in the low-risk group who did not undergo RT increased from a median of 30.8% to 90.5% (p < 0.001). ConclusionAlthough a significant change in treatment was observed after revision of the national guidelines, a wide range of hospital variation still exists in administered neoadjuvant treatment in rectal cancer patients. High-risk rectal cancer patients had a better survival when treated in hospitals with the highest rates of CRT provided. In order to minimize treatment differences, further research into the causes of this variation and implementation of regionalized MDTs may be warranted.

Preoperative Oxaliplatin-based Chemoradiotherapy and Consolidation Chemotherapy Versus Fluorouracil-based Chemoradiotherapy for MRIdefined Intermediate and High-risk Rectal Cancer Patients

Preoperative Oxaliplatin-based Chemoradiotherapy and Consolidation Chemotherapy Versus Fluorouracil-based Chemoradiotherapy for MRIdefined Intermediate and High-risk Rectal Cancer Patients

Total neoadjuvant treatment of locally advanced rectal cancer with high risk factors in Slovenia.

BackgroundIn the light of a high rate of distant recurrence and poor compliance of adjuvant chemotherapy in high risk rectal cancer patients the total neoadjuvant treatment was logical approach to gaining acceptance. We aimed to evaluate toxicity and efficiency of this treatment in patients with rectal cancer and high risk factors for local or distant recurrence.Patients and methodsPatients with rectal cancer stage II and III and with at least one high risk factor: T4, presence of extramural vein invasion (EMVI), positive extramesorectal lymph nodes or mesorectal fascia (MRF) involvement were treated with four cycles of induction CAPOX/FOLFOX, followed by capecitabine-based radiochemotherapy (CRT) and two consolidation cycles of CAPOX/FOLFOX before the operation. Surgery was scheduled 8–10 weeks after completition of CRT.ResultsFrom November 2016 to July 2018 66 patients were evaluable. All patients had stage III disease, 24 (36.4%) had T4 tumors, in 46 (69.7%) EMVI was present and in 47 (71.2%) MRF was involved. After induction chemotherapy, which was completed by 61 (92.4%) of patients, radiologic downstaging of T, N, stage, absence of EMVI or MRF involvement was observed in 42.4%, 62.1%, 36.4%, 69.7% and 68.2%, respectively. All patients completed radiation and 54 (81.8%) patients received both cycles of consolidation chemotherapy. Grade 3 adverse events of neoadjuvant treatment was observed in 4 (6%) patients. Five patients rejected surgery, 3 of them with radiologic complete clinical remissions. One patient did not have definitive surgery of primary tumor due to unexpected cardiac arrest few days after sigmoid colostomy formation. Among 60 operated patients pathological complete response rate was 23.3%, the rate of near complete response was 20% and in 96.7% radical resection was achieved. Pathological T, N and stage downstaging was 65%, 96.7% and 83.4%, respectively. Grade ≥ 3 perioperative complications were anastomotic leakage in 3, pelvic abscess in 1 and paralytic ileus in 2 patients. The rate of pathologic complete response (pCR) in patients irradiated with 3D conformal technique was 12.1% while with IMRT and VMAT it was 37% (p < 0.05). Hypofractionation with larger dose per fraction and simultaneous integrated boost used in the latest two was the only factor associated with pCR.ConclusionsTotal neoadjuvant treatment of high risk rectal cancer is well tolerated and highly effective with excellent tumor and node regression rate and with low toxicity rate. Longer follow up will show if this strategy will improve distant disease control and survival.

Phospho-ERK levels as predictors for chemotherapy of rectal carcinoma.

Treatment of rectal cancer has been vastly improved by advances in surgery and radiochemotherapy but remains an important cause of morbidity and mortality worldwide. A particular problem is the lack of predictive markers that can help to individualize treatment. The growth- and apoptosis-regulating signaling molecules ERK 1 and 2 are important to cancer growth and progression. They are activated through phosphorylation, which is initiated by a cascade involving the EGF receptor and RAS as upstream regulators. Moreover, in vitro studies indicate that phospho-ERKs interfere with 5-fluorouracil-based chemotherapy. Recently, we showed that high levels of phospho-ERKs in rectal cancer cells predict poor responses to neoadjuvant (preoperative) radiochemotherapy. We now report that preoperative phospho-ERK levels also can subdivide high-risk rectal cancer patients into a favorable and a poor prognostic group with respect to recurrence-free survival. Importantly, phospho-ERK levels were of predictive significance only in high-risk patients, who received adjuvant (postoperative) chemotherapy, but not in high-risk patients not receiving such therapy. Our results suggest that high cancer cell levels of phospho-ERK predict poor responsiveness to both preoperative and postoperative chemotherapy of rectal cancer.

Diagnostic value of 3.0-tesla high-resolution magnetic resonance imaging for invasion depth of rectal cancer

To evaluate the accuracy of 3.0T high-resolution magnetic resonance imaging(MRI) in definition of tumor invasion depth staging (T staging) before operation. Clinical and radiographic data of 49 rectal cancer patients who underwent radical resection within two weeks after 3.0 T high-resolution MRI examination without preoperative neoadjuvant chemotherapy in Peking University People's Hospital between February 2015 and November 2015 were retrospectively collected. Two radiologists reviewed the MRI imagines and evaluated the location and T staging of rectal cancer independently(radiologist A and B). The kappa statistics was used to evaluate the interobserver agreement, and kappa value greater than 0.81 indicated excellent agreement. The accuracy, sensitivity and specificity of high-resolution MRI in definition of rectal cancer T staging were assessed with pathological result as golden standard. According to pathological result of 49 rectal cancer patients, 3 were pT1, 17 were pT2, 22 were pT3, and 7 were pT4a. In 2 cases of mucinous adenocarcinoma, MRI T2WI showed focal or diffuse significantly higher signal close to perirectal fat. And in other 47 patients of non-mucinous adenocarcinoma, MRI T2WI showed equal or higher signal compared with pelvic muscle. Interobserver agreement was excellent in diagnosis of T staging of rectal cancer with 3.0T high-resolution MRI(Kappa=0.87). The accuracy, sensitivity and specificity of both radiologists for T1 staging was 95.9%(47/49), 1/3 and 100%(46/46) respectively, besides, 1 case was both diagnosed correctly and 2 cases were overstaged. For 2 radiologists, the accuracy of T2 staging was 87.8%(43/49) and 91.8%(45/49) respectively, the sensitivity was both 88.2%(15/17), and the specificity was 87.5%(28/32) and 93.5%(30/32) respectively, besides, 15 cases were both diagnosed correctly and 2 cases were overstaged. The accuracy for T3 staging was 89.8%(44/49) and 93.9%(46/49) respectively, the sensitivity was 86.4%(19/22) and 95.5%(21/22) respectively, and the specificity was both 92.6%(25/27). Radiologist A made correct diagnosis for 19 cases, understaged 2 cases and overstaged 1 case. Radiologist B made correct diagnosis for 21 cases and only overstaged 1 case. The accuracy, sensitivity and specificity of both radiologists for T4a staging was 98.0%(48/49), 7/7 and 97.6%(41/42) respectively, besides, 7 cases were both diagnosed correctly. The overall accuracy of T staging was 85.7%(42/49) and 89.8%(44/49) by two radiologists respectively. The accuracy for differentiating T1/T2 from T3/T4 was 91.8%(45/49) and 95.9%(47/49) by two radiologists respectively. Radiologist A overstaged 2 cases and understaged 2 cases, and radiologist B overstaged 2 cases. High-resolution MRI can accurately evaluate preoperative T staging of rectal cancer and help select the high-risk rectal cancer patients with over T3 to receive neoadjuvant treatment.

Tumor budding in colorectal cancer—ready for diagnostic practice?

Tumor budding is an important additional prognostic factor for patients with colorectal cancer (CRC). Defined as the presence of single tumor cells or small clusters of up to 5 cells in the tumor stroma, tumor budding has been likened to an epithelial-mesenchymal transition. Based on well-designed retrospective studies, tumor budding is linked to adverse outcome of CRC patients in 3 clinical scenarios: (1) in malignant polyps, detection of tumor buds is a risk factor for lymph node metastasis indicating the need for colorectal surgery; (2) tumor budding in stage II CRC is a highly adverse prognostic indicator and may aid patient selection for adjuvant therapy; (3) in the preoperative setting, presence of tumor budding in biopsy material may help to identify high-risk rectal cancer patients for neoadjuvant therapy. However, lack of consensus guidelines for standardized assessment still limits reporting in daily diagnostic practice. This article provides a practical and comprehensive overview on tumor budding aimed at the practicing pathologist. First, we review the prognostic value of tumor budding for the management of colon and rectal cancer patients. Second, we outline a practical, evidence-based proposal for the assessment of tumor budding in the daily sign-out. Last, we summarize the current knowledge of the molecular characteristics of high-grade budding tumors in the context of personalized treatment approaches and biomarker discovery.

Chronomodulated Capecitabine and Adjuvant Radiation in Intermediate-risk to High-risk Rectal Cancer

The aim of this study was to evaluate the feasibility and tolerability of capecitabine administration according to a specific time schedule, combined with adjuvant radiation therapy, in intermediate-risk to high-risk rectal cancer patients treated with an upfront surgery. The primary endpoint was the rate of grade 3 to 4 diarrhea during chemoradiation (CRT). Stage II and III rectal cancer patients received, after total mesorectal excision, 2 cycles of XELOX regimen (oxaliplatin 130 mg/m(2) on day 1; capecitabine 1000 mg/m(2) bid on day 1 to 14, q21), followed by capecitabine (800 mg/m(2) bid daily; 20% dose at 12:00 AM and 80% dose at 12:00 PM) administered continuously during pelvic radiation (total 50.4 Gy in 28 fractions, 1.8 Gy daily dose between 2:00 and 4:00 PM). Four additional cycles of XELOX were administered after chemoradiotherapy. Fifty-one radically resected rectal cancer patients were enrolled. All, but one, cases were evaluated for safety of CRT. We reported a grade 3 and 4 diarrhea rate of 14% (7 of 50 patients), whereas no grade 3 and 4 leukopenia was observed. Grade 1 and 2 proctitis was observed in 26 (52%) cases, whereas grade 1 and 2 cystitis in 5 (10%) patients. Only 2 cases of grade 3 proctitis and cystitis were reported, respectively. The CRT phase was feasible and was completed by 43 (84%) patients. Three patients developed actinic enteritis 60 days after the end of the radiotherapy program. Capecitabine timetable administration combined with adjuvant radiation therapy of rectal cancer is well tolerated and feasible. Further investigation of this chronomodulated schedule in terms of efficacy is warranted in neoadjuvant setting.

A prognostic model comprising pT stage, N status, and the chemokine receptors CXCR4 and CXCR7 powerfully predicts outcome in neoadjuvant resistant rectal cancer patients

Despite the optimization of the local treatment of advanced rectal cancer (LARC), combination of preoperative chemoradiotherapy (CRT) and surgery, approximately one third of patients will develop distant metastases. Since the chemokine receptor CXCR4 has been implicated in metastasis development and prognosis in colorectal cancer, the role of the entire axis CXCR4-CXCL12-CXCR7 was evaluated to identify high relapse risk rectal cancer patients. Tumor specimens of 68 LARC patients undergoing surgery after neoadjuvant-CRT were evaluated for CXCR4, CXCR7, and CXCL12 expression through immunohistochemistry. Multivariable prognostic model was developed using classical prognostic factors along with chemokine receptor expression profiles. High CXCR4 correlated with a shorter relapse-free survival (RFS) (p = 0.0006) and cancer specific survival (CSS) (p = 0.0004). Concomitant high CXCR4-negative/low CXCR7 or high CXCR4-negative/low CXCL12 significantly impaired RFS (p = 0.0003 and p = 0.0043) and CSS (p = 0.0485 and p = 0.0026). High CXCR4/N+ identified the worst prognostic category for RFS (p < 0.0001) and CSS (p = 0.0003). The optimal multivariable predictive model for RFS was a five-variable model consisting of gender, pT stage, N status, CXCR4, and CXCR7 (AUC = 0.92, 95% CI = 0.77-0.98). The model is informative and supportive for adjuvant treatment and identifies CXCR4 as a new therapeutic target in rectal cancer.

HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab

BackgroundHER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. Patients and methodsEligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0–3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. ResultsOf 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. ConclusionsBased on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation.Trial registration: ISRCTN Register: 99828560.

HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

e14616 Background: HER-2 is a well established therapeutic target in breast and gastric cancer. The role of HER-2 in rectal cancer is unclear, as conflicting data on prevalence of HER-2 expression have been reported. Preclinical data indicate a potential role of HER-2 in mediating resistance of rectal cancer to chemoradiotherapy and cetuximab. This analysis evaluates the prevalence of HER-2 and its impact on the outcome of high risk rectal cancer patients treated with neoadjuvant CAPOX and CRT ± cetuximab in EXPERT-C. Methods: Eligible patients with available tumour tissue for HER-2 analysis were included. HER-2 expression was determined by immunohistochemistry (IHC) in biopsy and/or surgical specimens (score 0 to 3+). Tumours with equivocal IHC result (2+) were tested for HER-2 amplification by B-DISH. Tumours with IHC 3+ or B-DISH ratio ≥2.0 were classified as HER-2 positive. The impact of HER-2 on primary (CR) and secondary endpoints (RR, PFS, OS) of the study was analyzed. Results: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3/104 (2.9%) and 3/114 (2.6%) were HER-2 positive, respectively. In 77 patients with paired specimens, concordance for HER-2 status was found in 74 (96%). Overall 141 patients were assessable for HER-2; 6/141 (4.3%) had a HER-2 positive tumour in at least 1 specimen. The median follow-up was 58.7 months. HER-2 expression or amplification was not associated with a difference in outcome for any of the study endpoints, including in the subset of 90 KRAS/BRAF wild type patients treated ± cetuximab. In an exploratory analysis, 44 IHC 0/1+ random specimens were tested by B-DISH and HER-2 amplification was found in 3/38 (7.9%, insufficient material in 6 cases). Conclusions: Based on the low prevalence of expression (according to the classical criteria for defining HER-2 positivity) as recorded in EXPERT-C, HER-2 does not appear to represent a useful therapeutic target for high risk rectal cancer. We did not confirm the role of HER-2 as prognostic factor or potential predictive biomarker for cetuximab-based treatment.

HER-2 in high risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

420 Background: HER-2 is a well established therapeutic target in breast and gastric cancer. The role of HER-2 in rectal cancer is unclear, as conflicting data on prevalence of HER-2 expression in this disease have been reported. This analysis evaluates the prevalence of HER-2 and its impact on the outcome of high risk rectal cancer patients treated with neoadjuvant CAPOX and CRT ± cetuximab in the EXPERT-C trial. Methods: Eligible patients with available tumour tissue for HER-2 analysis were included. HER-2 expression was determined by immunohistochemistry (IHC) in biopsy and/or surgical specimens (score 0 to 3+). Tumours with equivocal IHC result (2+) were tested for HER-2 amplification by B-DISH. Tumours with IHC 3+ or B-DISH ratio ≥2.0 were classified as HER-2 positive. The impact of HER-2 on primary (CR) and secondary endpoints (RR, PFS, OS) of the study was analyzed. Results: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3/104 (2.9%) and 3/114 (2.6%) were HER-2 positive, respectively. In 77 patients with paired specimens, concordance for HER-2 status was found in 74 (96%), with 3 patients with discordant results (1 patient with HER-2 negative biopsy/positive surgical specimen, 2 patients with HER-2 positive biopsy/negative surgical specimen). Overall 141 patients were assessable for HER-2; 6/141 (4.3%) had a HER-2 positive tumour in at least 1 specimen. The median follow-up was 58.7 months. HER-2 expression or amplification was not associated with a difference in outcome for any of the study endpoints, including in the subset of 90 KRAS/BRAF wild type patients treated ± cetuximab. Conclusions: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER-2 does not appear to represent a useful therapeutic target for high-risk rectal cancer. However, the role of HER-2 as prognostic factor and potential predictive biomarker for cetuximab-based treatment in rectal cancer warrants further investigation. A more comprehensive B-DISH analysis in IHC 0/1+ tumours is currently ongoing and data will be presented at the meeting.

P-0296 Could Pre-Treatment Cea be an Effective Predictor of Relapse in High Risk Rectal Cancer?

ABSTRACT Introduction Over 14,000 cases of rectal cancer occur per year in the UK. Radical surgery with total mesorectal excision (TME) is the main curative treatment for disease localised to the pelvis. Some cases are judged on pelvic MRI to be at high risk of positive margins from surgery alone. They are offered pre-operative chemo-radiotherapy (CRT) before surgery with TME. This hopes to downsize and downstage tumors to provide clear circumferential resection margins and reduce the likelihood of relapse. Good pathological responses to CRT are associated with improved cancer outcomes. We investigated whether carcinoembryonic antigen (CEA) levels at presentation could act as a simple predictor of relapse when using CRT followed by TME for patients with high-risk rectal cancers. Methods Retrospective data was collected on high-risk rectal cancer patients treated radically with pre-op CRT and TME surgery at Ipswich Hospital between March 2005 and Jan 2012. All received at least 45 Gy in 25 fractions of radiotherapy using a three-field CT plan and 5 weeks of oral capecitabine chemotherapy. CEA levels were obtained prior to radiotherapy. Following surgery, rectal specimens were assessed by our pathologists to evaluate response to treatment and whether complete pathological response (pCR) was achieved. Follow-up was by our oncology department and colorectal surgeons with annual CT scanning, 1-3 yearly colonoscopies and clinical surveillance for 5 years. Results 56 patients met inclusion criteria. Male to female ratio: 1.8:1. 96% (n=54) patients received pre-op chemotherapy alongside radiotherapy: 2 patients were considered too high-risk for this component of treatment. Mean follow-up from commencing radiotherapy was 33 months (range 7-69). Mean time from last dose of radiotherapy to surgery was 11 weeks (range 5-18). 93% (n=52) had (R0) resection margins following surgery. 7.1% (n=4) had (R1) incomplete resection margins following surgery; 2 of these 4 suffered local relapse in the pelvis. 30% (n=17) achieved a pCR following CRT, none of the patients who achieved a pCR have relapsed. 77% (n=43) presented with a normal CEA (≤5, range 5, range 6-54). Normal CEA group: 35%, (n=15) achieved pCR following CRT and 14% (n=6) relapsed. High CEA group: 15% (n=2) achieved pCR following CRT and 46%, (n=6) relapsed. There was a significant between group difference in relapse (Fisher's exact test p=0.02). Further survival analysis for relapse revealed a statistically significant hazard ratio of 4.5 (95% CI 1.04 to 19.4). Conclusion 1. High CEA on presentation was associated with an estimated relative risk of relapse 4.5 times greater than presenting with a normal CEA. 2. Therefore high CEA at presentation could be a useful biomarker to identify patients with the highest risk of relapse who may benefit from more intensive treatment. 3. Our high rates of R0 resection margin (93%) and pCR (30%) could be due to a relatively prolonged time from radiotherapy to surgery in our cohort.

The impact of TP53 mutation on high-risk rectal cancer patients treated within the EXPERT-C trial, a randomized phase II study of neoadjuvant oxaliplatin/capecitabine (CAPOX) and chemoradiation (CRT) with or without cetuximab.

e14088 Background: The EXPERT-C trial randomised 165 patients into neoadjuvant CAPOX and CRT ± cetuximab and demonstrated a significant increase in radiological response (RR) and overall survival (OS) with cetuximab in KRAS/BRAF wild type (WT) rectal cancer (Dewdney et al JCO in press). TP53 mutation has been associated with worse CRT response and survival in rectal cancer and could lead to stimulation of PI3K signalling pathway, thus potential resistance to cetuximab. This analysis evaluates the impact of TP53 mutation in the EXPERT-C trial. Methods: FFPE tissue from biopsy (n=102) and resection specimens (n=99) were analysed for TP53 mutations (exons 5-8) using a multiplex PCR method followed by direct sequencing. If discordant results were encountered on paired biopsy and resection samples, analyses were repeated. Results: 53/102 (52%) biopsy and 24/99 (24%) resection samples harboured TP53 mutation, most commonly missense in exons 5 and 7. The vast majority had single TP53 mutations, only 4/53 biopsy and 1/24 resection samples had 2 mutations. 21/55 (38%) paired samples demonstrated discordant TP53 mutation status. In both all-treated and KRAS WT populations, presence of TP53 mutation had no impact on RR to neoadjuvant chemotherapy or CRT, regardless of treatment arm. A trend towards worse progression-free (PFS) (HR: 2.68; 95% CI: 0.85 - 8.43; p=0.08) and OS (HR: 4.04; 95% CI: 0.86 - 19.11; p=0.056) was observed in patients with TP53 mutation when treated with cetuximab, independent of the KRAS status. Conclusions: TP53 mutations were common in high-risk rectal cancer patients, the lower mutation rate in the resection samples was potentially due to lower tumour volume post CRT. The presence of a TP53 mutation at baseline had no impact on RR to treatment, however a trend towards worse PFS and OS was observed with the addition of cetuximab, consistent with the perceived biology.

T3 Subdivision Correlation with Nodal or Distant Metastasis in Colorectal Cancer; Is It Practically Useful?

See Article on Page 160-164 The pathological staging system has been regarded as a guideline for predicting the prognosis of patients and for deciding on the need for further adjuvant treatment. In this issue, the Yoo et al. [1] analyzed 555 colorectal cancer patients who underwent curative surgery, especially for pT3 cancer subdivided according to the depth of tumor infiltration beyond the muscle proper layer: 15 mm. These 4 types of pT3 subdivisions were shown to be deeply correlated to the known prognostic histopathologic factors. One thing they did not analyze was the relation between T3 subdivision and the 5-year disease-free survival rate. They only compared pT3 subdivision with nodal and distant metastasis; furthermore, their multivariate analysis revealed that pT3 subtype might be an independent prognostic factor in colorectal cancer. Some studies regarding the relevant risk factors for regional lymph node metastasis in submucosal adenocarcinomas have been performed, and some of those measured not only the submucosal depth of invasion but also tumor budding, lymphatic invasion, vascular invasion, etc. In rectal cancer, the circumferential resection margin (CRM) and tumor deposit also have been reported as important risk factors for predicting patient prognosis, but none of those are recognized as definite prognostic factors in the current American Joint Committee on Cancer (AJCC) staging system. However, several reports have already demonstrated extramural invasion depth to be related with nodal metastasis and distant metastasis in colorectal cancer. Interestingly, pT3 subdivision has been analyzed and has been reported as a prognostic factor in rectal cancer patients not colon cancer patients. Miyoshi et al. [2] analyzed pT3 rectal cancer patients according to a 6-mm cutoff value for the extent of mesorectal invasion, and there were definite differences in the overall 5-year survival rates between the two groups of patients. Kim et al. [3] reported an interesting study regarding how to select high-risk rectal cancer patients based on preoperative local staging using rectal magnetic resonance imaging (MRI). He compared the extent of mesorectal invasion between whole mounted rectal cancer histopathology and MRI using a 5-mm cutoff value to evaluate its value as a prognostic indicator. The overall accuracy of preoperative MRI was 88%, which means MRI can be used to select patient who show T3 with 5-mm infiltration beyond the muscle layer. Those patients could be candidates for preoperative chemoradiation. Unfortunately, T3 pathological subdivision is not accepted as a prognostic factor in the new AJCC tumor-node-metastasis staging system, Furthermore, cutoff points for the penetration depth of cancer invasion beyond the muscle proper layer have not been determined. Currently, most pathologists do not report T3 subdivision, and as far as I can determine, they seem in Korea to be reluctant to measure the distance of tumor infiltration beyond the muscle proper layer. If pT3 subdivision might be a clinically significant prognostic factor, two issues still remain to be solved. One is the lack of a consensus about cutoff points, which should be studied more based on a large patient cohort; the other involves the support and cooperation of pathologists. Based on personal experiences concerning pathological descriptions of the CRM, we have had long discussions and cooperative conferences with pathologists. Currently, CRM status documentation is mandatory in pathological reports submitted in Korea. I think this study showed us an important message about the heterogeneity of the prognoses for the pT3 group of patients. Conventionally, we have not paid attention to the prognoses of colorectal cancer patients in the same category of pT3 patients. Important feedback to the multidisciplinary team conference can allow patients with high risk of nodal and distant recurrence after curative surgery to be identified. Therefore, the strategy for treating patients with high risk may be changed based on preoperative modern imaging. Currently, some evidence exists that preoperative chemotherapy or chemoradiotherapy may have oncological benefits compared surgery first [4, 5]. A couple of well-known high-risk factors are CRM status, tumor deposit, vascular encasement of nodes, etc., and patients with such factors should be candidates for preoperative treatment. Hopefully, pT3 subdivision may be a candidate for use as another high-risk factor, but it seems to have a long way to go.

Long-term Anorectal Function after Postoperative Chemoradiotherapy in High-Risk Rectal Cancer Patients

After sphincter-preserving surgery for rectal cancer and postoperative radiochemotherapy, many patients have unsatisfactory anorectal functional results which are not considered by the most common toxicity scales. The aim of the present study was to retrospectively assess the long-term incidence of impaired anorectal function in rectal cancer patients who underwent anterior resection and postoperative radiochemotherapy. Ninety-nine patients who underwent sphincter-saving surgery and postoperative radiochemotherapy for stage II-III rectal cancer from July 1991 to January 2002 were given a questionnaire on anorectal function. Postoperative incontinence was evaluated according to a scale proposed by Jorge and Wexner. Factors influencing anorectal function were examined. The median follow-up from surgery was 10 years. Ten (10.1%) patients reported >or= 5 bowel movements per day and 26 (26.3%) experienced clustering. The median frequency of bowel movements per 24 h was 2 (range, 1-10). Stool fragmentation was recorded in 56 (56.6%) cases, and 36 (36.4%) patients experienced urgency to defecate with inability to delay defecation for more than 15 min. The mean continence score was 4.91 (median 1, range 0-18). Incontinence to flatus, liquid and solid stools was reported at least once a week in 24 (24.2%), 11 (11.1%) and 5 (5.1%) patients, respectively. According to the study criteria, 61% of patients had good functional results. None of the variables analyzed showed a significant correlation with functional outcome. Although retrospective, the present study included a large selected series that had undergone uniform adjuvant treatment and was followed for a median of 10 years. Our data demonstrated that 39% of patients did not have good functional results and suffered some degree of urgency, increased frequency and occasional incontinence even many years after the surgery. Anorectal function assessment should enter routinely in clinical practice and should have importance in the therapeutic decisions.

Circulating endothelial cells and acute toxicity in rectal cancer patients receiving postoperative radiotherapy with concurrent UFT administration

15102 Background: Concurrent chemoradiation (CCRT) is now a standard postoperative adjuvant treatment for high-risk rectal cancer patients. However, no surrogate marker for optimization of adjuvant...

Postoperative irradiation combined with chemotherapy for high-risk rectal cancer patients

In a prospective open-study we evaluated the combination of radiation therapy and adjuvant 5-FU plus levamisole in controlling Modified Astler-Coller (MAC) B2 or C rectal cancer following a curative-intended surgery. Sixty-four consecutive rectal cancer patients were treated by adjuvant radiation therapy (Linac 8 MV, 50-50.4 Gy to an isocentric pelvis brick volume in 5 fractions per week each of 1.8-2 Gy), and 12 monthly courses of 5-fluorouracil (375 mg/m(2)/day for 5 consecutive days) plus levamisole (50 mg t.i.d. for 3 days). Within a median follow-up period of 36 months, 19 patients (29.6%) experienced relapses. The 3-year-DFS of MAC B2 patients was 82%, compared with 60% in MAC C. Early radiation treatment was not associated with a higher proportion of relapses, while late radiation therapy initiation was associated with a significantly higher proportion of relapses. Early radiation therapy, not later than following the 2nd to 4th course of chemotherapy, is associated with the more acceptable proportion of relapses.