Research ArticleClinical Studies

The Predictive Role of Primary Tumour Sidedness in Metastatic Colorectal Cancer Treated With Targeted Agents

ONDREJ FIALA, PAVEL OSTASOV, PETR HOSEK, ONDREJ SOREJS, VACLAV LISKA, TOMAS BUCHLER, ALEXANDR POPRACH, RADEK KUCERA, ONDREJ TOPOLCAN, JAN SUSTR, MONIKA SEDIVCOVA and JINDRICH FINEK
Anticancer Research October 2019, 39 (10) 5645-5652; DOI: https://doi.org/10.21873/anticanres.13761

Abstract

Background/Aim: The aim of our study was to assess the predictive role of primary tumour sidedness (PTS) in patients with metastatic colorectal cancer (mCRC) harbouring wild-type RAS and treated with targeted agents. Patients and Methods: The cohort included 178 patients treated with first-line chemotherapy plus cetuximab, panitumumab or bevacizumab. Results: We observed longer progression-free survival (PFS) and overall survival (OS) in patients with left-sided (L-CRC) compared to right-sided tumours (R-CRC) treated with anti-EGFR mAbs (p=0.0033 and p=0.0037), while there was no difference in patients treated with bevacizumab (p=0.076 and p=0.56). Finally, we observed longer PFS and OS in patients with L-CRC treated with anti-EGFR mAbs and those with R-CRC treated with bevacizumab compared to the reverse combination (p=0.0002 and p=0.011). Conclusion: PTS is a predictive factor for anti-EGFR mAbs, not for bevacizumab. Superior survival was observed when anti-EGFR mAbs were used for L-CRC and bevacizumab for R-CRC.

Colorectal cancer (CRC) is the second most commonly diagnosed malignancy and the leading cause of cancer-related death in Europe (1). Considerable progress in the treatment of metastatic CRC (mCRC) has been reached in recent years and several novel active agents have been approved for the systemic therapy of mCRC patients. The monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) bevacizumab and mAbs cetuximab and panitumumab against epidermal growth factor receptor (EGFR) are widely used in the treatment of metastatic CRC (mCRC). Anti-EGFR mAbs are used for patients with tumours harbouring the wild-type RAS gene, which is a well-established predictive biomarker (2-11). However, optimal selection of targeted agents for use in the first-line treatment of wild-type RAS mCRC patients is still not fully resolved. Recently, several retrospective analyses have shown an association between the primary tumour location and the efficacy of different targeted agents (12-19).

The aim of our study was to assess the predictive role of primary tumour sidedness (PTS) in patients with wild-type RAS mCRC treated with first-line anti-EGFR mAbs or bevacizumab in combination with standard chemotherapy, and to compare two different therapy approaches: anti-EGFR mAbs for left-sided CRC (L-CRC) with bevacizumab for right-sided CRC (R-CRC) vs. anti-EGFR mAbs for R-CRC with bevacizumab for L-CRC.

Patients and Methods

Patients and treatment. Clinical data of 178 adult patients with histologically confirmed mCRC harbouring the wild-type RAS gene (KRAS and NRAS) who underwent a first-line treatment consisting of a combination of standard chemotherapy with cetuximab, panitumumab or bevacizumab between the years 2009 and 2018 at the Department of Oncology and Radiotherapy, Medical School and University Hospital Pilsen, Czech Republic were analyzed retrospectively. Baseline characteristics of patient group are described in Table I.

Cetuximab (Erbitux, Merck & Co., Kenilworth, NJ, USA) was used in combination with chemotherapy or as a single agent in a standard approved dose (initial dose 400 mg/m2 and next doses 250 mg/m2 every 7 days). Panitumumab (Vectibix, Amgen Inc., Thousand Oaks, CA, USA) was used in combination with chemotherapy or as a single agent in a standard approved dose (6.0 mg/kg every 14 days). Bevacizumab (Avastin, F. Hoffman-La Roche Ltd., Basel, Switzerland) was used in combination with chemotherapy or as a single agent in standard approved doses (5.0 mg/kg every 14 days or 7.5 mg every 21 days). The chemotherapy consisted of the following schedules: fluorouracil and leucovorin in combination with irinotecan (FOLFIRI) or with oxaliplatin (FOLFOX). The participating patients had not received targeted therapies in the past.

The genetic assessment including KRAS and NRAS gene status was done at the time of diagnosis of metastatic disease. The sample analysis was performed using direct sequencing, real-time PCR (2008-2010) and reverse hybridization (StripAssay) (since 2010) as it is standard practice in the Czech Republic. To assure long-term quality, the methods were certified by the Czech Accreditation Institute (ČIA) or intended for use in clinical laboratories (CE-IVD).

The protocol of the study and the form of Informed consent for participants were approved by the Ethical Committee of the Medical School and University Hospital in Pilsen on 12th May 2016 and complied with the International Ethical Guidelines for Biomedical Research, the Declaration of Helsinki, and local laws. The Informed consent with subsequent analysis of the follow-up data was obtained from all the participants.

Study design. R-CRC was defined as tumour localized in the caecum or in the colon ascending up to the flexura hepatica. L-CRC was defined as tumour localized in the flexura splenica and distal parts including rectum. Patients with CRC localized in the transverse colon were not included. The outcome of patients including progression-free survival (PFS) and overall survival (OS) was compared between groups with L-CRC and with R-CRC treated with either bevacizumab or anti-EGFR mAbs. Finally, PFS and OS were compared for two different therapy approaches: anti-EGFR mAbs for L-CRC with bevacizumab for R-CRC vs. anti-EGFR mAbs for R-CRC with bevacizumab for L-CRC. The results were tested in a Cox multivariate model.

Clinical monitoring. The follow-up controls including a physical examination and routine laboratory tests were performed every two weeks and restaging using radiological imaging techniques including computed tomography (CT) or positron emission tomography - (PET)-CT was performed every three months during the time of treatment or in case of clinical suspicion of progression. The objective tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) (20). The clinical data were obtained retrospectively from the hospital information system.

View this table:
Table I.

Baseline patient's characteristics according to the first-line targeted treatment.

Statistical analysis. Descriptive statistics and standard frequency tables were used to characterize the sample data set. PFS was determined from the date of treatment initiation until the date of first documented progression or death. OS was determined from the date of treatment initiation until the date of death. PFS and OS were estimated using the Kaplan–Meier method and all point estimates were accompanied by two-sided 95% confidence intervals. The statistical analysis was performed using R (version 3.5.1) (Foundation for Statistical Computing, Vienna, Austria) and packages survival (version 2.46) and survminer (0.4.3) for survival analysis and visualisation (21, 22). The Gehan-Breslow-Wilcoxon test was used for assessment of statistical significance of the differences in survival according to treatment and the primary tumour sidedness. A multivariable Cox proportional hazards model was used to evaluate the effect of all potential prognostic factors on the survival indicators. The Wald test was used for assessment of statistical significance of hazard ratios. The level of statistical significance was set at α=0.05 and all reported p-values are two-tailed.

Figure 1.
Figure 1.

Comparison of progression-free (PFS) and overall survival (OS) between patients with L-CRC and R-CRC treated with bevacizumab (A, B) and between patients with L-CRC and R-CRC treated with anti-EGFR mAbs (A, B). Our data clearly demonstrate that patients with L-CRC had significantly greater survival benefit from anti-EGFR treatment (A, B). This effect was not visible for R-CRC when isolated results of bevacizumab are presented (C, D).

Results

The median PFS and OS for patients with L-CRC treated with anti-EGFR mAbs was 11.93 and 33.22 months compared to 5.45 and 17.97 months for those with R-CRC treated with anti-EGFR mAbs (p=0.0033 and p=0.0037, respectively) (Figure 1). The median PFS and OS for patients with L-CRC treated with bevacizumab was 8.05 and 27.83 months compared to 14.46 and 26.15 months for those with R-CRC treated with bevacizumab (p=0.076 and p=0.56, respectively) (Figure 1). The median PFS and OS for patients with L-CRC treated with anti-EGFR mAbs and those with R-CRC treated with bevacizumab was 12.16 and 33.15 months compared to 7.92 and 23.59 months for patients with R-CRC treated with anti-EGFR mAbs and those with L-CRC treated with bevacizumab (p=0.0002 and p=0.011, respectively) (Figure 2). Survival data are summarized in Table II. In the Cox multivariable analysis, anti-EGFR mAbs for L-CRC and bevacizumab for R-CRC remains a significant factor for PFS (HR=0.6286, p=0.0096), but not for OS (HR=0.6973, p=0.0612) (Table III).

Figure 2.
Figure 2.

Comparison of progression-free (PFS) and overall survival (OS) between anti-EGFR mAbs for L-CRC and bevacizumab for R-CRC vs. anti-EGFR mAbs for R-CRC and bevacizumab for L-CRC. Our results suggest anti-EGFR mAbs for L-CRC and bevacizumab for R-CRC as an optimal treatment strategy. We found significantly longer PFS and OS for patients with L-CRC treated with anti-EGFR mAbs and with R-CRC treated with bevacizumab. The multivariate Cox proportional hazards model confirmed that anti-EGFR mAbs for L-CRC and bevacizumab for R-CRC approach is significantly associated with longer PFS.

Discussion

The results of our study suggest that PTS is a predictive factor feasible for the selection of the optimal first-line targeted therapy for mCRC patients with tumours harbouring wild-type RAS gene and that the use of anti-EGFR mAbs for L-CRC and bevacizumab for R-CRC is a promising treatment approach.

CRC is a heterogeneous disease with differing outcomes and clinical responses to systemic therapies. Proximal and distal parts of the colon differ in embryologic origins; R-CRC arises from midgut and L-CRC from hindgut. According to PTS, CRCs can be grouped into R-CRCs and L-CRCs. R-CRCs are located within the caecum and colon ascendens through the transverse colon, excluding the appendix. L-CRCs are located within the flexura splenica, colon descendens, colon sigmoideum and rectum (23). For clarity, we excluded patients with primary tumour in the transverse colon from our study. There has been growing evidence showing that R-CRCs and L-CRCs are distinct biological and clinical entities. Various characteristics associated with primary tumour location have been described including epidemiology, pathogenesis, morphology, pathophysiology, and genetic and epigenetic alterations (24-35). The prognostic and possible predictive role of location of the primary tumour, in terms of right and left sided origin, has been recently investigated. R-CRCs are frequently characterized by several adverse prognostic factors, including mucinous histology, hypermutation, microsatellite instability and BRAF gene mutation positivity (36-38). Different molecular characteristics translate into different clinical outcomes. In general, R-CRCs are associated with a markedly worse prognosis (39). Moreover, several retrospective analyses have suggested that PTS may also be a predictive marker of the efficacy of targeted therapies with anti-VEGF and anti-EGFR mAbs directed agents (12-19).

View this table:
Table II.

Comparison of progression-free survival (PFS) and overall survival (OS) in selected groups in months.

View this table:
Table III.

Multivariable Cox-proportional hazards model for progression-free survival (PFS) and overall survival (OS).

To evaluate the predictive role of PTS with regard to the efficacy of anti-EGFR mAbs, data from randomised clinical trials evaluating anti-EGFR mAbs were studied. These retrospectively analysed clinical trials include CRYSTAL, PRIME, NCIC CO.17 and study 20050181. It has been reported that for RAS wild-type cases, the efficacy of anti-EGFR mAbs was greater in L-CRC compared to R-CRC (12-15). On the other hand, the response to either of the standard chemotherapy targeted agents is generally poor in R-CRC. The data from the randomised clinical trials including AGITG MAX, NO16966, AVF2107g, as well as the data from the Australian registry evaluating the predictive role of PTS for anti-VEGF treatment suggest that treatment effects of bevacizumab are independent of the primary tumour location (17-19). Thus, PTS seems to be to be a predictive factor for the efficacy of anti-EGFR mAbs in the first- or second-line setting. By contrast, it seems that it has no predictive role for bevacizumab. This is in agreement with our study. In patients treated with anti-EGFR mAbs we found significantly longer PFS and OS for those with L-CRC compared to R-CRC. On the other hand, in patients treated with bevacizumab we did not find any significant difference in PFS or OS between the PTS groups.

Currently, data on direct comparisons of the first-line anti-EGFR mAbs and bevacizumab with regard to PTS are limited to retrospective analyses of several randomised clinical trials and meta-analyses of their results. These include data from two randomised phase III trials (FIRE-3/AIO KRK0306 and CALGB/SWOG 80405) and one phase II trial (PEAK) directly comparing anti-EGFR mAbs and bevacizumab in combination with standard chemotherapy (FOLFOX, FOLFIRI) in the first-line treatment of wild-type RAS mCRC patients (12, 13, 16). The relevance of PTS has recently been investigated in a meta-analysis of first-line clinical trials by Holch et al. (40). A meta-analysis of FIRE-3/AIO KRK0306, CALGB/SWOG 80405 and PEAK trials showed that patients with L-CRC had greater survival benefit from anti-EGFR mAbs compared to bevacizumab in combination with standard chemotherapy regimens (HR=0.71; 95%CI=0.58-0.85; p=0.0003). On the other hand, in patients with R-CRC, the benefit from standard chemotherapy was poor and a combination with bevacizumab was associated with significantly longer survival (HR=1.3; 95%CI=0.97-1.74; p=0.081) (40). Overall, these results suggest anti-EGFR mAbs for L-CRC and bevacizumab for R-CRC as an optimal treatment strategy. In our study, we compared PFS and OS of patients treated with two different treatment approaches, anti-EGFR mAbs for L-CRC with bevacizumab for R-CRC vs. anti-EGFR mAbs for R-CRC with bevacizumab for L-CRC. We found significantly longer PFS and OS for patients with L-CRC treated with anti-EGFR mAbs and with R-CRC treated with bevacizumab. The multivariate Cox proportional hazards model confirmed that the anti-EGFR mAbs for L-CRC and bevacizumab for R-CRC approach is significantly associated with longer PFS, but not OS. Even though the OS results from the multivariate Cox model were not significant, there was a visible trend and the results could have been influenced by the subsequent cross-over use of targeted agents in the second or third-line settings. In conclusion, the results of the presented retrospective study suggest that PTS is a predictive factor for anti-EGFR mAbs, but not for bevacizumab in the first-line treatment of patients with wild-type RAS mCRC. Moreover, the results show superior PFS and OS for anti-EGFR mAbs for L-CRC and bevacizumab for R-CRC as compared to anti-EGFR mAbs for R-CRC and bevacizumab for L-CRC. The treatment approach was revealed to be an independent factor for PFS. Prospective studies on the predictive role of PTS and also providing elucidation of the molecular background responsible for such effects are urgently needed.

Acknowledgements

The Authors would like to thank all patients voluntarily taking part in the study. This study was supported by the project “Centrum of clinical and experimental liver surgery”, UNCE/MED/006, by the National Sustainability Program I (NPU I) Nr. LO1503 provided by the Ministry of Education Youth and Sports of the Czech Republic and by the Charles University Research Fund (Progres Q39) and by the European Regional Development Fund-Project “Application of Modern Technologies in Medicine and Industry” (No.CZ.02.1.01/0.0/0.0/17_048/0007280) and by Ministry of Health, Czech Republic - conceptual development of research organization (University Hospital in Pilsen - FNPl, 00669806).

Footnotes

  • Authors' Contributions

    OF designed the study and wrote the manuscript with support from VL, TB, AP, RK, OT and JF. OS, JS and MS collected clinical data. PO and PH performed statistical analyses.

  • Conflicts of Interest

    OF received honoraria from Roche, GSK and Pfizer for consultations and lectures unrelated to this project. TB and AP received lecture honoraria from Novartis, Pfizer, Bayer-Schering and Roche. TB also received research support from Roche and Novartis. JF has received honoraria from Astra Zeneca, Roche and Novartis for consultations and lectures unrelated to this project. PO, PH, OS, VL, RK, OT, JS and MS declare that they have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence this work.

  • Received August 1, 2019.
  • Revision received August 11, 2019.
  • Accepted August 14, 2019.

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The Predictive Role of Primary Tumour Sidedness in Metastatic Colorectal Cancer Treated With Targeted Agents
ONDREJ FIALA, PAVEL OSTASOV, PETR HOSEK, ONDREJ SOREJS, VACLAV LISKA, TOMAS BUCHLER, ALEXANDR POPRACH, RADEK KUCERA, ONDREJ TOPOLCAN, JAN SUSTR, MONIKA SEDIVCOVA, JINDRICH FINEK
Anticancer Research Oct 2019, 39 (10) 5645-5652; DOI: 10.21873/anticanres.13761
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