Session 2: Are we ready for primary chemotherapy in rectal cancer: who, when, why?

The potential of preoperative chemotherapy in rectal cancer is the subject of investigation in a number of global randomized trials. In this overview and expert discussion, Professor Cervantes summarizes the findings of numerous Phase II trials testing neoadjuvant chemotherapy. The crucial points in the next phase of trials include: patient selection, whether radiotherapy can be omitted altogether and whether chemotherapy can be used to augment the initial response to chemoradiotherapy. Finally, with the emergence of Magnetic Resonance Tumour Regression Grade a reliable method for assessing response after initial chemoradiotherapy, we ask if this can be used to drive the use of further sele…

KRAS and BRAF mutations in circulating tumour DNA from locally advanced rectal cancer

There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Digital droplet (dd)PCR was used to investigate KRAS/BRAF mutations in ctDNA from baseline blood samples of 97 LARC patients who were treated with CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in a randomised phase II trial. KRAS mutation in G12D, G12V or G13D was detected in the ctDNA of 43% and 35% of patients with tumours that were mutant and wild-type for these hotspot mutations, respectively, according to standard PCR-based analyses on tissue. The detection rate in the ctDNA of 10 patients with less common mutations was 50%. In 26 cases ctDNA…

Panex: A pooled analysis of EXPERT and EXPERT-C, two trials of neoadjuvant chemotherapy (NACT) and chemoradiotherapy (CRT) in high-risk locally advanced rectal cancer (LARC).

3575 Background: After the use of preoperative radiotherapy and TME, survival of LARC has reached a plateau. More effective therapies, predictive/prognostic factors for treatment selection and vali...

Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial

KRAS mutation has been reported as a marker of radio-resistance in rectal cancer and unfavourable outcome in both colon and rectal cancer. This study suggests that a single-nucleotide polymorphism of the KRAS gene (LCS-6 variant) may predict response to neoadjuvant treatment and mitigate the poor prognosis associated with KRAS mutation in locally advanced rectal cancer.

Analysis of KRAS , NRAS , BRAF , PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 21…

Corrigendum to "2nd St. Gallen EORTC Gastrointestinal Cancer Conference: Consensus recommendations on controversial issues in the primary treatment of rectal cancer" [Eur J Cancer 63 (August 2016) 11-24].

FcγRIIa and Fc γ RIIIa Polymorphisms and Cetuximab Benefit in the Microscopic Disease

Abstract Purpose: FcγR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX ± cetuximab in high-risk, locally advanced rectal cancer. Experimental Design: FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan–Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment…

Sequence variation in mature microRNA-608 and benefit from neo-adjuvant treatment in locally advanced rectal cancer patients

Summary Analysis of a polymorphism in mature microRNA-608 (rs4919510) in rectal cancer patients enrolled in a randomized phase II clinical trial identified patient subpopulations who might benefit from the use of an intensified neo-adjuvant treatment strategy with Cetuximab.

Second St. Gallen European Organisation for Research and Treatment of Cancer Gastrointestinal Cancer Conference: consensus recommendations on controversial issues in the primary treatment of rectal cancer

Contains fulltext : 171468pub.pdf (Publisher’s version ) (Open Access) Primary treatment of rectal cancer was the focus of the second St. Gallen European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Cancer Conference. In the context of the conference, a multidisciplinary international expert panel discussed and voted on controversial issues which could not be easily answered using published evidence. Main topics included optimal pretherapeutic imaging, indication and type of neoadjuvant treatment, and the treatment strategies in advanced tumours. Here we report the key recommendations and summarise the related evidence. The treatment strategy for localised rect…

Comparison between MRI and pathology in the assessment of tumour regression grade in rectal cancer

Background: Limited data exist regarding the correlation between MRI tumour regression grade (mrTRG) and pathological TRG (pTRG) in rectal cancer. Methods: mrTRG and pTRG were compared in rectal cancer patients from two phase II trials (EXPERT and EXPERT-C). The agreement between radiologist and pathologist was assessed with the weighted κ test while the Kaplan–Meier method was used to estimate survival outcomes. Results: One hundred ninety-one patients were included. Median time from completion of neoadjuvant treatment to pre-operative MRI and surgery was 4.1 weeks (interquartile range (IQR): 3.7–4.7) and 6.6 weeks (IQR: 5.9–7.6), respectively. Fair agreement was found between mrTRG and pT…

Multicenter Randomized Phase II Clinical Trial Comparing Neoadjuvant Oxaliplatin, Capecitabine, and Preoperative Radiotherapy With or Without Cetuximab Followed by Total Mesorectal Excision in Patients With High-Risk Rectal Cancer (EXPERT-C)

Purpose To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. Patients and Methods Patients with operable magnetic resonance imaging–defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), an…

FCγRIIa and FCγRIIIa polymorphisms (SNPs) and cetuximab (C) benefit in the EXPERT-C trial.

3573 Background: FCγRIIa-H131R and FCγRIIIa-V158F SNPs have been reported to enhance the immune-mediated effects of monoclonal antibodies including cetuximab (C) in metastatic colorectal cancer (CR...

Definition of the Rectum An International, Expert-based Delphi Consensus

Mini: A radiological, anatomic distinction between the rectum and sigmoid colon was agreed by consensus of international experts in rectal cancer using the Delphi Technique. Use of this landmark, “the sigmoid take-off,” may harmonize efforts in research and clinical practice to improve patient outcomes. Background: The wide global variation in the definition of the rectum has led to significant inconsistencies in trial recruitment, clinical management, and outcomes. Surgical technique and use of preoperative treatment for a cancer of the rectum and sigmoid colon are radically different and dependent on the local definitions employed by the clinical team. A consensus definition of the rectum…

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 fol…

EURECCA colorectal: multidisciplinary management: European consensus conference colon & rectum.

Contains fulltext : 137861.pdf (Publisher’s version ) (Closed access) BACKGROUND: Care for patients with colon and rectal cancer has improved in the last 20years; however considerable variation still exists in cancer management and outcome between European countries. Large variation is also apparent between national guidelines and patterns of cancer care in Europe. Therefore, EURECCA, which is the acronym of European Registration of Cancer Care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012, the first multidisciplinary consensus conference about…

KRAS and BRAF mutations in circulating tumour DNA from locally advanced rectal cancer.

Abstract There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Digital droplet (dd)PCR was used to investigate KRAS/BRAF mutations in ctDNA from baseline blood samples of 97 LARC patients who were treated with CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in a randomised phase II trial. KRAS mutation in G12D, G12V or G13D was detected in the ctDNA of 43% and 35% of patients with tumours that were mutant and wild-type for these hotspot mutations, respectively, according to standard PCR-based analyses on tissue. The detection rate in the ctDNA of 10 patients with less common mutations was 50%. In 26 ca…

PAN-EX: a pooled analysis of two trials of neoadjuvant chemotherapy followed by chemoradiotherapy in MRI-defined, locally advanced rectal cancer

This analysis confirms that administering neoadjuvant chemotherapy (NACT) before chemoradiotherapy (CRT) could be a potential option for high-risk, locally advanced rectal cancer. In this setting, MRI tumour regression grade is an independent prognostic factor and, when assessed after NACT, may predict the probability and magnitude of incremental benefit from sequential CRT.EXPERT and EXPERT-C were phase II clinical trials of neoadjuvant chemotherapy (NACT) followed by chemoradiotherapy (CRT) in high-risk, locally advanced rectal cancer (LARC). We pooled individual patient data from these trials. The primary objective was overall survival (OS) in the intention-to-treat (ITT) population. Pro…

RAS mutations and cetuximab in locally advanced rectal cancer: Results of the EXPERT-C trial

Background: RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial. Methods: Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-di…

Short- and Long-Term Quality of Life and Bowel Function in Patients With MRI-Defined, High-Risk, Locally Advanced Rectal Cancer Treated With an Intensified Neoadjuvant Strategy in the Randomized Phase 2 EXPERT-C Trial

Objective Intensified preoperative treatments have been increasingly investigated in locally advanced rectal cancer (LARC), but limited data are available for the impact of these regimens on quality of life (QoL) and bowel function (BF). We assessed these outcome measures in EXPERT-C, a randomized phase 2 trial of neoadjuvant capecitabine combined with oxaliplatin (CAPOX), followed by chemoradiation therapy (CRT), total mesorectal excision, and adjuvant CAPOX with or without cetuximab in magnetic resonance imaging-defined, high-risk LARC. Methods and Materials QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29 questionnaires. Bowel inc…