Colorectal cancer: new developments after the 2013 ECCO/ESMO congress.

In 2013, at the congress of the European CanCer Organization and the European Society for Medical Oncology, colorectal cancer was the subject of various oral presentations and posters. In this article, we have selected the most innovative studies that are likely to change our daily practice.

The congress of the European Society of Medical Oncology (ESMO) is the main multidisciplinary congress that takes place in Europe in the field of medical oncology. In 2013, ESMO was organized through a partnership with the European CanCer Organisation (ECCO), the European Society of Radiotherapy and Oncology (ESTRO), the European Society of Surgical Oncology (ESSO), the European Association of Cancer Research (EACR), the European Oncology Nursing Society (EONS), and the European Society of Paediatric Oncology (SIOPE).

This 17th ECCO–38th ESMO–32nd ESTRO congress took place in Amsterdam between September 27 and October 1, 2013, with 38% increase in the number of oral presentations and posters in comparison to the Stockholm Congress 2 years ago. Colorectal cancer was the subject of various oral presentations and posters that will play a pivotal role in establishing future treatment standards for colorectal cancer in Europe.

Metastatic Colorectal Cancer

What is the preferred targeted agent that should be added to first-line chemotherapy for metastatic colorectal cancer (mCRC)?

FIRE 3, which is the first head-to-head comparison between two biological agents for the treatment of metastatic colorectal cancer, has been designed to answer this question[1]. This study compared FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab (BEV) in the first-line setting for patients with KRAS wild type mCRC. The results were first reported at the 2013 American Society of Clinical Oncology (ASCO) congress. The primary endpoint of this study, the overall response rate (ORR), was not met (62% for FOLFIRI-cetuximab vs. 58% for FOLFIRI-BEV, P = 0.18). No difference in progression-free survival (PFS) was observed (10.5 months in the FOLFIRI-cetuximab arm compared with 10.4 months in the FOLFIRI-BEV arm, P = 0.627); however, a significant difference in overall survival (OS) was observed, with 28.7 months in the FOLFIRI-cetuximab group versus 25.0 months in the FOLFIRI-BEV group (P = 0.017).

In a preliminary analysis, the effects of mutations in KRAS [exon 3 (codon 59/61), exon 4 (codon 117/146)], NRAS [exon 2 (codon 12/13), exon 3 (codon 59/61), exon 4 (codon 117/146)], and BRAF (V600E) on ORR, PFS, and OS were evaluated[1]. Patients with wild-type RAS had a median OS of 33.1 months with FOLFIRI-cetuximab versus 25.6 months with FOLFIRI-BEV [hazard ratio (HR) = 0.70; 95% confidence interval (CI), 0.53-0.92; P = 0.011]. However, in patients with mutant RAS, this difference between the regimens was not observed (median OS, 16.4 months vs. 20.6 months, HR = 1.20, P = 0.57).

Based on these results, a complete determination of RAS status may be necessary before prescribing epidermal growth factor receptor (EGFR) inhibitors in first-line treatment of mCRC, and the prescription of cetuximab may be restricted to patients with wild-type RAS. Thus far, the factors that contribute to the difference in OS are unclear. Current clinical practice, which includes the use of cetuximab or BEV, should not be changed.

Is there any role for maintenance treatment with capecitabine/BEV in mCRC?

The CAIRO 3 trial (CApecitabine, IRinotecan, and Oxaliplatin in advanced colorectal cancer 3) was the first study to investigate the role of maintenance treatment with low-dose capecitabine (CAPE) plus BEV in patients with non-progressive, advanced colorectal cancer after 6 cycles of CAPE-BEV[2]. A total of 558 patients with non-progressive mCRC who were not eligible for metastasectomy were randomized into observation and maintenance groups with 12-hour continuous administration of CAPE (625 mg/m2) and intravenous administration of BEV (7.5 mg/kg) every 3 weeks. Upon first progression (PFS1), patients in both arms were treated with CAPE-BEV until second progression (PFS2, primary endpoint). For those who were not able to receive CAPE-BEV regimen upon PFS1, PFS2 was considered to be equal to PFS1.

The investigators concluded that maintenance therapy significantly prolonged PFS2 (11.8 months vs. 10.5 months, P = 0.003) and adjusted OS (21.7 months vs. 18.2 months, P = 0.035). In terms of quality of life, there was a significant difference in favor of the therapeutic pause (P = 0.004), with a small difference in the quality of life score that was not clinically relevant. Thus, maintenance CAPE-BEV therapy may be a treatment option for the extension of OS and PFS in these patients.

Does therapeutic intensification improve the resection rate and long-term outcome of unresectable liver metastases?

An update on the results of the OLIVIA study was communicated at the 2013 ESMO/ECCO congress. OLIVIA is a phase II trial evalua-ting the possibilities of improving resection rate and outcome after treatment intensification in patients receiving first-line treatment for mCRC which has been judged as unresectable[3]. Thus, 80 patients with unresectable CRC and liver-only metastases were randomized to receive BEV plus mFOLFOX6 (modified fluorouracil, folinic acid, and oxaliplatin) or BEV plus FOLFOXIRI (fluorouracil, folinic acid, oxaliplatin, and irinotecan) every 2 weeks. The results suggest that FOLFOXIRI-BEV improves resection rate and median PFS as compared with mFOLFOX6-BEV (80.5% vs. 61.5%; 21 months vs. 11.6 months). However, grade≥3 adverse events occurred in 95% and 84% of patients receiving FOLFOXIRI-BEV and mFOLFOX6-BEV, respectively. As was clearly mentioned in the presentation and discussion of this study at the congress, these data are interesting but are derived from an exploratory analysis. Therefore, further studies are needed to clarify the role of FOLFOXIRI-BEV in patients with mCRC limited to the liver.

In the same context, the TRIBE trial, which was presented at the 2013 ASCO Annual Meeting, demonstrated that FOLFOXIRI-BEV significantly increased PFS and response rate compared to FOLFIRI-BEV (median PFS of 11.9 vs. 9.5 months, P = 0.001; response rate of 64% vs. 53%, P = 0.015). Results of early tumor shrinkage and depth of response were presented at the 2013 ESMO/ECCO congress. Depth of response was defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline. Early tumor shrinkage (at 8 weeks) and depth of response were significantly higher in the intensified arm (64% vs. 51% tumor shrinkage, P = 0.006; 48.1% vs. 32.9% depth of response, P = 0.003)[4]. Unfortunately, the FOLFOXIRI-BEV arm has severe adverse events and deploys all effective therapies in the first-line setting, leaving few new choices for second-line treatment. However, the use of this treatment for 12 cycles (6 months) followed by 5-fluorouracil (5-FU) plus BEV until progression may allow the reintroduction of irinotecan and oxaliplatin in the second-line setting.

Furthermore, another study evaluated the data from published studies to assess whether the addition of cetuximab to first-line chemotherapy increased the conversion rate of liver-limited metastatic disease from initially unresectable to resectable in patients with KRAS wild type tumors[5]. In this review, the authors concluded that data from randomized trials (CRYSTAL OPUS, NCTC 01564910, and COIN) confirmed that the addition of cetuximab improved the R0 resection rate of initially unresectable, liver-limited, KRAS wild type mCRC when compared with the corresponding chemotherapy regimen alone.

In this setting, we can conclude that the addition of a biological agent (cetuximab or panitumumab for individuals with KRAS wild type tumors) to a chemotherapy backbone containing oxaliplatin or irinotecan may increase the number of patients potentially eligible for resection and improve outcomes.

Which EGFR inhibitor should be used in chemorefractory KRAS wild type tumors?

The ASPECCT (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab) trial is an open-labeled, randomized, phase 3 non-inferiority trial designed to compare the effects of intravenous infusion of panitumumab (6 mg/kg every 14 days) and cetuximab (400 mg/m2 followed by 250 mg/m2 every 7 days) for monotherapy of chemorefractory mCRC patients with KRAS wild type tumors[6]. The primary endpoint was OS. The ORR was 22% for the panitumumab arm compared to 19.8% for the cetuximab arm [odds ratio (OR) = 1.15]. The PFS was 4.1 months in patients treated with panitumumab versus 4.4 months in patients treated with cetuximab (HR = 1.00). The study met its primary endpoint, demonstrating that panitumumab was non-inferior to cetuximab for OS (10.4 months vs. 10 months). Therefore, based on these results and those from other previous trials, there is no therapeutic preference in clinical practice for using cetuximab versus panitumumab either as monotherapy or in combination with chemotherapy in naïve or chemorefractory mCRC.

Regorafenib improves OS over placebo, but does it alter the quality of life?

The CORRECT trial was conducted to evaluate regorafenib in patients with mCRC which had progressed after all approved standard therapies[7]. In a previous presentation of the study, treatment with regorafenib led to significant improvements in OS and PFS over placebo as well as comparable efficacy benefits across all patient subgroups analyzed. At the 2013 ESMO/ECCO congress, the investigators presented results regarding quality of life in patients receiving this treatment. The questionnaires used were the EORTC QLQ-C30 and EQ-5D. In the overall analysis from 2 questionnaires, no significant difference in quality of life was observed between patients treated with regorafenib versus those treated with placebo. Taking into account the non-exhaustive nature of the analysis of the entire study, the proper management of adverse events by the different teams, and the impact of treatment response on the perception of adverse events by the patient are the main possible explanations for these results.

Localized CRC

At the 2013 ESMO/ECCO congress, results were reported from only a few trials that examined localized CRC, and most of the trials were focused on preoperative chemoradiation in rectal cancer.

The Pan European Trials for Adjuvant Colon Cancer 6 (PETACC-6) investigated whether the addition of oxaliplatin to preoperative oral fluoropyrimidine-based chemoradiation can improve disease-free survival in locally advanced rectal cancer[8]. A total of 1,094 patients with rectal cancer (T3/4 and/or node-positive) with no evidence of metastatic disease were randomly assigned to receive 5 weeks of preoperative chemoradiotherapy (45 Gy in 25 fractions) with capecitabine (825 mg/m2 twice daily), followed by 6 cycles of adjuvant chemotherapy with capecitabine (1,000 mg/m2 twice daily on days 1-15 and repeated every 3 weeks) (arm 1) or to receive the same regimen with the addition of oxaliplatin before (50 mg/m2 on days 1, 8, 15, 22, and 29) and after surgery (130 mg/m2 on day 1 every 3 weeks) (arm 2). The R0 resection rate was 92.0% in arm 1 and 86.3% in arm 2. The pathologic complete response rate (ypT0N0) was similar in both arms (11.3% vs. 13.3%, P = 0.31). The anal sphincter was preserved in 70% versus 65% (P = 0.09) of patients in arm 1 and arm 2, respectively. Postoperative complications did not differ between arms (38% vs. 41%; 5 vs. 4 patients died following surgery). This study concluded that the addition of oxaliplatin to preoperative fluoropyrimidine-based chemoradiotherapy led to decreased treatment compliance and increased toxicity but did not improve surgical outcome.

In another study, the EXPERT-C trial, the predictive nature of a mutation in p53 (exons 4-9) was examined[9]. This trial assessed the value of combining cetuximab with CAPE-L-OHP (oxaliplatin) regimen as a neoadjuvant and adjuvant therapy for locally advanced rectal cancer with chemoradiation followed by surgery. The benefit of cetuximab appeared only in patients with tumors lacking a p53 mutation, suggesting that p53 status may predict cetuximab treatment efficacy. This effect appeared to be relatively important in this study and was independent of RAS and BRAF. These data should be validated using additional staff and patients who were not treated with radiochemotherapy.

In a retrospective cohort of 896 patients from the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial[10], the authors evaluated the predictive nature of a mutation in the phosphatidylinositol 3-kinase catalytic alpha isoform (PIK3CA) in rofecoxib and aspirin treatment after primary treatment. The authors found no benefit from rofecoxib treatment in patients with PIK3CA mutations compared with those with wild-type PIK3CA. Nevertheless, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (P = 0.036) but not in patients lacking a PIK3CA mutation in tumors. These retrospective observational data support adjuvant aspirin use in PIK3CA-mutant CRC. However, we are still awaiting the results of the prospective randomized clinical trial.

Conclusions

The 2013 ESMO/ECCO congress was rich in presentations regarding CRC. The concept of personalized treatment has been confirmed with the arrival of new targeted therapies and the identification of new biomarkers. Taken together, these trials will certainly play a pivotal role in establishing standards for future CRC treatments in Europe.