Introduction

Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related mortality worldwide despite advances in systemic therapy.1 In selected patients with good performance status and high tumor burden, treatment intensification with triplet chemotherapy combined with bevacizumab has emerged as an effective first-line strategy to achieve rapid tumor shrinkage and improve survival outcomes.2 The Phase III TRIBE study demonstrated that FOLFOXIRI plus bevacizumab significantly improved PFS and OS compared with FOLFIRI plus bevacizumab, establishing triplet-based therapy as a standard option in fit patients.3 Subsequent evidence from TRIBE2 further supported an upfront triplet strategy with reintroduction after progression, while studies such as OLIVIA, STEAM, CHARTA, and Asian programs including QUATTRO and JACCRO have confirmed its efficacy and feasibility across different clinical settings.4–9 However, most evidence comes from Western populations or Japanese multicenter trials. Data from Vietnam and Southeast Asia are sparse, especially regarding OS and clinically relevant prognostic factors after first-line mFOLFOXIRI plus bevacizumab. In Vietnam, where access to intensive therapy is constrained by healthcare resources and reimbursement policies, treatment strategies often differ from those in clinical trials. In routine practice, sequential doublet chemotherapy is more commonly used than upfront triplet regimens, largely due to physician preference and concerns regarding toxicity. Consequently, available studies have mainly focused on response rates and PFS, with limited mature OS data, particularly in patients treated with modern triplet-based regimens such as mFOLFOXIRI plus bevacizumab.10,11 Although pembrolizumab has become the preferred first-line treatment for MSI-H/dMMR mCRC following KEYNOTE-177, these tumors represent only a small subset of patients. In addition, access to immunotherapy in Vietnam has remained limited because of financial and reimbursement barriers, resulting in substantial out-of-pocket costs for many patients. Therefore, chemotherapy-based regimens, including mFOLFOXIRI plus bevacizumab, continue to play an important role in routine clinical practice.12 Real-world validation of these strategies is particularly important in resource-constrained settings. Therefore, this study aimed to evaluate survival outcomes and to investigate factors associated with PFS and OS in Vietnamese patients with mCRC treated with first-line mFOLFOXIRI plus bevacizumab in routine clinical practice.

MethodsStudy Design and Patients

This retrospective real-world, single-center cohort study included patients with mCRC treated at Hanoi Medical University Hospital between January 2019 and December 2025. Eligible patients had histologically confirmed metastatic colorectal adenocarcinoma deemed unresectable at diagnosis and received at least four cycles of first-line mFOLFOXIRI plus bevacizumab. All patients had measurable disease according to RECIST 1.1, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate baseline hematologic, hepatic, and renal function. Patients were excluded if they had another active malignancy within the previous 5 years, prior oxaliplatin-based therapy within 2 years, uncontrolled hypertension or ongoing anticoagulation, brain or leptomeningeal metastases, pregnancy or breastfeeding, or had received local treatment for metastatic lesions (eg, radiofrequency ablation) prior to systemic therapy.

Data Collection and Treatment

All patients received first-line mFOLFOXIRI plus bevacizumab every 2 weeks. The regimen consisted of bevacizumab 5 mg/kg administered intravenously over 60 minutes on day 1, irinotecan 150 mg/m2 intravenously over 60 minutes on day 1, oxaliplatin 85 mg/m2 intravenously over 2 hours on day 1, and leucovorin (calcium folinate) 200 mg/m2 intravenously over 2 hours on day 1, followed by 5-fluorouracil (5-FU) 2400 mg/m2 administered as a continuous intravenous infusion over 46–48 hours. Dose modifications and treatment delays were permitted at the discretion of the treating physicians based on toxicity and patient tolerance. Baseline clinicopathological characteristics, molecular data and treatment information, including dose intensity, number of chemotherapy cycles, bevacizumab exposure, dose reduction, treatment delay, maintenance therapy and surgery/local treatment were extracted from medical records. Molecular profiling was performed as part of routine clinical practice using either validated PCR-based assays or targeted next-generation sequencing (NGS) panels. NGS analyses were conducted on Illumina sequencing platforms (NextSeq/Novaseq) and included clinically relevant colorectal cancer genes, such as KRAS, NRAS, BRAF, and PIK3CA. MSI/MMR status was assessed using either immunohistochemistry (IHC) or NGS, depending on test availability and institutional practice.

Outcomes and Definitions

The primary endpoints were PFS and OS. Secondary endpoints included ORR, DCR, ETS, and DpR. PFS was defined as the time from treatment initiation to radiologic or clinical progression or death, whichever occurred first. OS was defined as the time from treatment initiation to death from any cause. Patients without an event were censored at the last known follow-up. Tumor response was assessed according to RECIST1.1 by institutional investigators. ETS was defined as ≥20% reduction in the sum of target lesion diameters at first radiological evaluation (8 weeks). DpR was defined as maximum percentage reduction in tumor burden from baseline to nadir; DpR ≥ 40% was used as an exploratory binary marker.

Statistical Analysis

Continuous variables are summarized as median and interquartile range (IQR); categorical variables are summarized as number and percentage. PFS and OS were estimated using the Kaplan-Meier method and displayed with numbers at risk at predefined time points. Univariate survival analyses were performed using the Kaplan–Meier method, with comparisons between groups conducted using the Log rank test. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Variables with a P value <0.10 in univariate analysis or those considered clinically relevant were entered into the multivariable Cox regression model. Due to the strong correlation and conceptual overlap between ETS and DpR, only ETS was retained in the multivariable analysis to avoid multicollinearity. Analyses involving molecular variables were performed on available cases only; patients with missing molecular data were excluded from the respective analyses, and no imputation was performed. Given the limited number of events, the multivariable analysis was restricted and should be interpreted as exploratory. Two-sided P values <0.05 were considered statistically significant.

ResultsPatient Characteristics

A total of 76 patients were included in the analysis and their characteristics are summarized in Table 1. The median age was 59.5 years (range, 19–76), with 14.5% aged <40 years and 30.3% aged ≥65 years. The majority of patients were male (61.8%), and most had a good performance status, with 61.8% having an ECOG PS of 0. Left-sided primary tumors were more common than right-sided tumors (65.8% vs 34.2%). Liver metastasis was the predominant metastatic site (75%), followed by peritoneal (42.1%) and lung metastases (25%), while abdominal lymph-node involvement was observed in 19.7% of patients. Nearly half of the cohort (46.1%) had metastases in two or more organs, and 65.8% presented with more than five metastatic lesions, indicating a high tumor burden. Molecular characteristics were assessed in 73 patients and showed that RAS mutations were present in 49.3% of evaluable patients, while BRAF V600E and PIK3CA mutations were relatively uncommon (5.5% and 9.6%, respectively). MSI-H/dMMR status was identified in 3.4% of tested cases (58 patients). Elevated baseline tumor markers were frequently observed, with 72.4% of patients having CEA ≥5 ng/mL and 53.9% having CA19-9 ≥37 U/mL.

Table 1 Baseline Characteristics

Treatment Exposure and Tumor Response

Treatment exposure and tumor response are presented in Table 2. The median number of total treatment cycles was 12.0 (IQR 10.0–12.0), and the median number of bevacizumab-containing cycles was 11.0 (IQR 9.0–12.0). Treatment with mFOLFOXIRI plus bevacizumab demonstrated a high level of antitumor activity. The ORR was 73.7%, and the DCR reached 97.4%. ETS was observed in 56.6% of patients. The mDpR was 40.0% (IQR, 18.5–54.3), with 51.3% and 36.8% of patients achieving DpR ≥40% and ≥50%, respectively. The median time to DpR was 4.9 months (IQR, 2.4–7.0). Regarding treatment exposure, primary tumor resection was performed in 63.2% of patients, and 78.9% received maintenance therapy with capecitabine with or without bevacizumab. Among 56 patients with first disease progression, 73.2% received second-line therapy. Among 48 patients with second disease progression or death, 27.1% received third-line therapy or beyond.

Table 2 Treatment Exposure and Tumor Response

Survival Outcomes

In the full cohort of 76 patients, the median follow-up time was 18.2 months (range, 5.6–61.9 months), 56 progression/death events were observed for PFS. Median PFS was 14.9 months (95% CI, 10.3–19.4), and the 12-month PFS rate was 62.2%. For OS, 35 deaths were recorded. Median OS was 27.0 months (95% CI, 12.4–41.7), with 12- and 24-month OS rates of 81.8% and 56.3%, respectively. Estimated PFS and OS are shown in Figure 1A and B, respectively.

Figure 1 Kaplan–Meier curves for survival outcomes in the study population. (A) Progression-free survival. (B) Overall survival. Tick marks indicate censored observations. Numbers at risk are presented below the x-axis.

Abbreviations: CI, confidence interval; OS, overall survival; PFS, progression-free survival.

Exploratory Factors Associated with Survival

In exploratory analyses, ETS was the most consistent predictor of survival outcomes. Patients achieving ETS or DpR ≥40% had significantly improved PFS and OS. Patients achieving ETS had longer median PFS (20.3 vs 9.3 months; HR 0.44, 95% CI 0.26–0.75; P = 0.003) and OS (42.7 vs 20.4 months; HR 0.28, 95% CI 0.13–0.59; P = 0.001). Similarly, DpR ≥40% (mDPR of the cohort) was associated with improved PFS (20.3 vs 10.5 months; HR 0.52, 95% CI 0.30–0.89; P = 0.016) and OS (42.7 vs 21.8 months; HR 0.32, 95% CI 0.15–0.66; P = 0.002). Primary tumor resection and age ≥65 years were also associated with favorable outcomes, while a higher tumor burden (≥2 metastatic organs) was associated with shorter PFS and showed a trend toward worse OS. Among molecular factors, BRAF mutation was the strongest adverse prognostic factor, with markedly shorter survival (PFS 5.8 vs 16.8 months; OS 10.8 vs 39.4 months; both P < 0.01). Elevated baseline CA19-9 was also associated with inferior OS (21.8 vs 43.0 months; P = 0.005). Other clinicopathological variables, including tumor sidedness, ECOG performance status, RAS and PIK3CA mutation status, and baseline CEA levels, were not significantly associated with survival outcomes. Exploratory factors associated with PFS and OS are shown in Figure 2A and B, respectively.

Figure 2 (A) Forest plot of factors associated with PFS. HRs and 95% CIs were estimated using univariable Cox regression. (B) Forest plot of factors associated with OS. HRs and 95% CIs were estimated using univariable Cox regression.

Abbreviations: ETS, early tumor shrinkage; DpR, depth of response; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; NR, not reached.

Note: Bold p-values indicate statistical significance (p < 0.05).

In multivariable Cox regression analysis (Figure 3A and B), ETS was independently associated with improved outcomes. ETS was significantly associated with both PFS (HR 0.36, 95% CI 0.19–0.67; P = 0.001) and OS (HR 0.25, 95% CI 0.11–0.61; P = 0.002). A higher tumor burden, defined as ≥2 metastatic organs, was independently associated with shorter PFS (HR 2.11, 95% CI 1.13–3.95; P = 0.019) and showed a borderline association with worse OS (HR 2.24, 95% CI 1.00–5.00; P = 0.050). Age ≥65 years was associated with improved PFS (HR 0.39, 95% CI 0.20–0.78; P = 0.008), although its association with OS did not reach statistical significance (HR 0.48, 95% CI 0.20–1.15; P = 0.100). Elevated baseline CA19-9 (≥37 U/mL) was independently associated with inferior OS (HR 3.12, 95% CI 1.41–6.89; P = 0.005), but not with PFS. Other variables, including BRAF mutation and primary tumor resection, were not independently associated with PFS or OS after adjustment.

Figure 3 Multivariable Cox regression analyses for survival outcomes. (A) Progression-free survival. (B) Overall survival. Forest plots show hazard ratios (HRs) and 95% confidence intervals (CIs) for factors included in the multivariable models. Bold p-values indicate statistical significance (p < 0.05).

Abbreviations: ETS, early tumor shrinkage; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; BRAF, v-Raf murine sarcoma viral oncogene homolog B; CA19-9, carbohydrate antigen 19–9.

Discussion

In this retrospective real-world Vietnamese cohort of 76 patients with mCRC treated with first-line mFOLFOXIRI plus bevacizumab, the ORR was 73.7%, with a mPFS of 14.9 months and a mOS of 27.0 months. Although median OS was reached, the relatively short follow-up duration and limited number of death events suggest that the OS estimates should be interpreted with caution. These outcomes are clinically meaningful, particularly given the high disease burden, with a substantial proportion of patients presenting with ≥2 metastatic organs (46.1%), more than five metastatic lesions (65.8%), liver metastases (75.0%), and peritoneal metastases (42.1%). These findings should be interpreted in the context of Vietnam as a lower-middle-income country with constrained healthcare resources. According to the World Bank, the GDP per capita in 2024 of Vietnam was approximately 4700 USD.13 In routine practice, chemotherapy is largely reimbursed, whereas targeted agents such as bevacizumab and cetuximab are only partially covered (~50%), and most newer targeted therapies remain out-of-pocket. Notably, bevacizumab represents one of the most accessible targeted agents in Vietnam, particularly with the availability of biosimilars. However, mFOLFOXIRI plus bevacizumab still imposes a substantial financial burden, with an estimated monthly out-of-pocket cost of approximately 500–1000 USD depending on the product (originator or biosimilar), even after insurance reimbursement, representing a considerable proportion of the average annual income. Overall, the favorable survival outcomes observed in this study suggest that treatment intensification is feasible and clinically beneficial in carefully selected patients, even within a resource-limited setting.

The efficacy observed in our cohort is consistent with pivotal trials of triplet chemotherapy plus bevacizumab. In the TRIBE study, FOLFOXIRI plus bevacizumab improved outcomes compared with FOLFIRI plus bevacizumab, with a median PFS of 12.1 vs 9.7 months and median OS of 29.8 vs 25.8 months.3,14 TRIBE2 further supported an upfront triplet strategy, reporting a median PFS of approximately 12.0 months and OS of 27.4 months with a triplet-based sequence.4 The OLIVIA study provides additional context in patients with liver metastases, where FOLFOXIRI plus bevacizumab improved PFS (18.6 vs 11.5 months) and resection rates compared with mFOLFOX6 plus bevacizumab. Although our cohort was not restricted to liver-only disease, the high response rate and its association with survival support the role of intensive therapy when tumor shrinkage is a key treatment goal.5

Asian studies further support the feasibility of triplet–bevacizumab therapy, while emphasizing the need for dose adaptation. In the QUATTRO study, FOLFOXIRI plus bevacizumab achieved an ORR of approximately 72%, a median PFS of 13.3 months.9 Similarly, the JACCRO CC-11 study of modified FOLFOXIRI plus bevacizumab in RAS-mutant mCRC reported an ORR of 75.8% and a median PFS of 11.5 months, although OS data were not mature.8 The FORBES Phase II study by Shen reported that mFOLFOXIRI + bevacizumab achieved an ORR of 75.8% and a conversion resection rate of 40.7% in patients with initially unresectable colorectal liver metastases, with manageable toxicity.15 Dose modification in Asian populations is primarily driven by toxicity concerns. Japanese studies have consistently reported higher rates of hematologic toxicity with standard FOLFOXIRI dosing, particularly grade ≥3 neutropenia (up to ~70–80%) and febrile neutropenia (~10–20%), which are generally higher than those observed in Western trials such as TRIBE.14 These findings support the use of modified FOLFOXIRI regimens and proactive supportive care in Asian practice. This is directly relevant to Vietnam, where treatment intensity is frequently individualized. The outcomes observed in our cohort (ORR 73.7%, median PFS 14.9 months, median OS 27.0 months) are comparable to these Asian data, supporting the feasibility of mFOLFOXIRI plus bevacizumab in selected patients within routine practice.

Data from Vietnam and Southeast Asia remain limited, particularly regarding mature OS after first-line triplet–bevacizumab therapy. Earlier Vietnamese studies mainly evaluated triplet chemotherapy without routine biologic agents. Trinh Le Huy reported an ORR of 79.4% after six cycles of first-line FOLFOXIRI, with a mean PFS of 13.4 months and 12- and 24-month OS rates of 90% and 76%, respectively; importantly, targeted or biologic therapy was not incorporated.10 Similarly, Vuong Dinh Thy Hao evaluated FOLFOXIRI alone in a conversion-intent cohort of patients with synchronous colorectal liver metastases, reporting a median PFS of 13 months and median OS of 21 months in the overall population, with 12- and 24-month OS rates of 80% and 37%, respectively.11 These findings support the potential value of adding bevacizumab to triplet chemotherapy and provide practical local evidence for treatment counseling and shared decision-making in Vietnamese routine practice.

Prognostic Factors

One of the most consistent findings in our study was the strong prognostic value of ETS. As ETS is assessed after treatment initiation, the observed association between ETS and survival outcomes may be partly influenced by immortal time bias and should therefore be interpreted cautiously. ETS was achieved in 56.6% of patients and DpR ≥40% in 51.3%, both of which were significantly associated with improved outcomes. Patients achieving ETS had markedly prolonged PFS (20.3 vs 9.3 months; HR 0.36, p=0.001) and OS (42.7 vs 20.4 months; HR 0.25, p=0.002), and ETS remained independently associated with both endpoints in multivariable analysis. These findings indicate that early radiologic response is not merely descriptive but reflects clinically meaningful treatment sensitivity. This observation is consistent with prior studies. Volker Heinemann demonstrated that ETS (typically defined as ≥20% tumor reduction at first assessment) was associated with improved survival across multiple first-line regimens in mCRC, supporting its role as an early marker of treatment activity.16 Similarly, Hiroaki Nozawa showed that greater DpR was significantly correlated with longer post-progression survival, highlighting the prognostic relevance of response depth beyond conventional RECIST categories.17 The DEEPER trial further reinforced the clinical importance of DpR. In RAS wild-type mCRC, DEEPER reported significantly deeper tumor shrinkage with cetuximab-based therapy (median DpR ~57%) compared with bevacizumab-based therapy (~46%), although ETS rates were similar between arms. While differences in biologic agents and molecular selection limit direct comparison with our cohort, these data support a consistent framework: depth of response provides additional prognostic discrimination beyond early response alone.18 In our cohort, ETS remained independently associated with both PFS and OS after multivariable adjustment. However, as ETS is a post-baseline variable, the observational design and potential immortal time bias preclude causal interpretation. Therefore, ETS should be considered an exploratory prognostic marker rather than a direct determinant of survival. The observed association may reflect underlying tumor chemosensitivity and more effective disease control among patients who achieve an early response to treatment.

BRAF mutation was among the strongest adverse prognostic factors in our exploratory analyses, associated with markedly shorter PFS and OS. This is consistent with the established biology of BRAF V600E-mutant mCRC, which is characterized by aggressive clinical behavior, poor response to standard chemotherapy, and inferior survival, as highlighted in studies.19,20 However, interpretation in our cohort should be cautious given the small number of BRAF-mutant cases, resulting in wide confidence intervals and loss of independent significance in multivariable analysis. Therefore, while our findings are directionally consistent with global evidence, the magnitude of effect should not be overinterpreted and requires validation in larger regional cohorts. These findings highlight the persistent unmet need for more effective targeted strategies in this molecular subgroup. RAS mutation was not significantly associated with PFS or OS in our cohort. This is clinically plausible in a bevacizumab-based regimen, where RAS status primarily guides anti-EGFR selection rather than prognosis. Similarly, tumor sidedness was not associated with survival. While sidedness is a strong predictive and prognostic factor in anti-EGFR-treated RAS wild-type mCRC, its impact appears attenuated in bevacizumab-based therapy, as suggested by trials such as FIRE-3 trial, CALGB/SWOG 80405 trial, and PARADIGM trial.21,22 PIK3CA mutation was infrequent and not associated with outcomes; given the small number of cases, this finding should be considered exploratory. Tumor burden was a clinically relevant prognostic factor in our cohort. Patients with ≥2 metastatic organs had significantly shorter PFS and a trend toward worse OS, consistent with findings from the TRIBE study.14 In addition, multiple studies have shown that greater disease extent, including the number of metastatic sites, is independently associated with inferior survival in mCRC.23 In contrast, individual metastatic sites were not independently associated with outcomes, suggesting that overall disease extent may be more informative than single-site involvement under intensive systemic therapy.

Primary tumor resection was associated with improved PFS and OS in univariate analyses but was not independently significant after adjustment, likely reflecting selection bias in this retrospective cohort. Patients undergoing resection generally have more favorable baseline characteristics, including better performance status, lower disease burden, and improved treatment response. The role of primary tumor resection in asymptomatic unresectable mCRC remains controversial. While retrospective studies and meta-analyses suggest a survival association, randomized evidence, including the JCOG1007 iPACS trial, has not demonstrated a clear OS benefit.24,25 Therefore, primary tumor resection in our study should be interpreted as a marker of favorable prognosis rather than an independent therapeutic factor. Age ≥65 years was associated with improved PFS and a favorable trend for OS in our cohort. This seemingly counterintuitive finding likely reflects selection bias, as older patients receiving triplet therapy are typically highly selected and clinically fit. Conversely, younger patients may present with more aggressive disease biology or higher tumor burden, particularly in early-onset mCRC.26 Elevated baseline CA19-9 was independently associated with inferior OS in our cohort, whereas CEA was not. This suggests that CA19-9 may capture a distinct aspect of tumor biology beyond conventional markers. Prior studies have similarly reported that elevated CA19-9 is associated with adverse outcomes in advanced colorectal cancer.27 However, given its limited specificity and susceptibility to non-malignant influences (eg, biliary obstruction), CA19-9 should be interpreted as a complementary rather than standalone prognostic marker.

Limitations

This study has several limitations. Its retrospective, single-center design and modest sample size may limit the generalizability and robustness of the findings. Molecular data and several potentially relevant biological and clinical prognostic variables (eg, hemoglobin level, absolute neutrophil count, and other laboratory parameters) were not consistently available for all patients. In addition, the absence of a comparator group precludes direct comparisons with alternative treatment strategies. Treatment-related safety outcomes were beyond the scope of the current manuscript and were therefore not analyzed in detail. Therefore, the findings should be considered exploratory and require validation in larger prospective studies.

Conclusion

In this Vietnamese retrospective real-world cohort, first-line mFOLFOXIRI plus bevacizumab achieved clinically meaningful response and survival outcomes, with results generally consistent with those reported in previous triplet-bevacizumab studies. ETS was associated with improved survival outcomes, while metastatic burden was associated with poorer prognosis. These findings provide real-world evidence supporting treatment intensification in selected patients with mCRC.

Abbreviations

mCRC, Metastatic colorectal cancer; PFS, Progression-free survival; OS, Overall survival; ORR, Objective response rate; DCR, Disease control rate; ETS, Early tumor shrinkage; DpR, Depth of response; CI, Confidence interval; HR, Hazard ratio; ECOG PS, Eastern Cooperative Oncology Group performance status; RECIST, Response Evaluation Criteria in Solid Tumors; IQR, Interquartile range; CEA, Carcinoembryonic antigen; CA19-9, Carbohydrate antigen 19-9; MSI, Microsatellite instability; MSI-H, Microsatellite instability-high; dMMR, Deficient mismatch repair; NGS, Next-generation sequencing; PCR, Polymerase chain reaction; CR, Complete response; PR, Partial response; SD, Stable disease; 5-FU, 5-fluorouracil.

Data Sharing Statement

The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy restrictions but may be available from the corresponding author upon reasonable request and with institutional approval. The datasets used and/or analyzed during the current study are available from Ngan Thi Kim Mai, the corresponding author, upon reasonable request.

Ethics Approval and Consent to Participate

This study was conducted in accordance with the Declaration of Helsinki. This retrospective study was approved by the Ethics Committee of Hanoi Medical University (approval number: HMUIRB1099). The requirement for informed consent was waived due to the retrospective nature of the study, in accordance with local regulations. All patient data were anonymized prior to analysis.

Acknowledgments

The authors would like to thank the medical and nursing staff of the Oncology Center, Hanoi Medical University Hospital, for their support in patient care and data collection. We also acknowledge all patients and their families for their contribution to this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Disclosure

The authors declare that they have no competing interests.

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