Clinicians’ Attitude to Doublet Plus Anti-EGFR Versus Triplet Plus Bevacizumab as First-line Treatment in Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Patients: A Multicenter, “Real-Life”, Case-Control Study

Parisi, Alessandro; Porzio, Giampiero; Cannita, Katia; Venditti, Olga; Avallone, Antonio; Filippi, Roberto; Salvatore, Lisa; Ribelli, Marta; Nigro, Olga; Gelsomino, Fabio; Spallanzani, Andrea; Zurlo, Valeria; Leo, Silvana; Dell’Aquila, Emanuela; Claudia, Fulgenzi; Lombardi, Pasquale; Keränen, S. Roselló; Aimar, Giacomo; Depetris, Ilaria; Morelli, Cristina; Tursi, Michele De; Tinari, Nicola; Pietro, Francesca Di; Galitiis, Federica De; Zanaletti, N.; Troiani, Teresa; Vitale, Pasquale; Garajová, Ingrid; Ghidini, Michele; Spinelli, Gian Paolo; Zoratto, Federica; Roberto, Michela; Ierinò, Debora; Petrillo, Angelica; D’Orazio, C.; Ficorella, Corrado; Cortellini, Alessio

doi:10.1016/j.clcc.2021.07.003

Cited by 9 publications

(3 citation statements)

References 27 publications

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“…According to major guidelines, the preferred option as first-line treatment for patients with unresectable left-sided RAS and BRAF wild-type metastatic colorectal cancer (mCRC) is represented by a cytotoxic fluoropyrimidine-based doublet (FOLFOX or FOLFIRI) in association with an Anti-epidermal growth factor receptor monoclonal antibody (i.e., EGFRi, cetuximab, or panitumumab) [ 3 , 4 ]. In this regard, a landmark retrospective pooled analysis of six randomized phase III trials showed a significant survival benefit for doublet plus EGFRi compared to doublet plus bevacizumab in RAS wild-type tumors originating from the left side of the colon, and this trend has been confirmed in real-life settings [ 5 , 6 ]. Although systemic treatment remains the cornerstone of metastatic disease management, with different emerging strategies after induction treatment in the never-resectable disease [ 7 ], surgical resection has progressively gained interest in the scientific community.…”

Section: Introductionmentioning

confidence: 99%

Conversion Strategy in Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer Patients with Unresectable Liver-Limited Disease: A Multicenter Cohort Study

Granieri

Cotsoglou

Bonomi

et al. 2022

Cancers

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Colorectal cancer (CRC) patients frequently develop liver metastases. Different treatment strategies are available according to the timing of appearance, the burden of metastatic disease, and the performance status of the patient. Systemic treatment (ST) represents the cornerstone of metastatic disease management. However, in select cases, combined ST and surgical resection can lead to remarkable survival outcomes. In the present multicentric cohort study, we explored the efficacy of a conversion strategy in a selected population of left-sided RAS/BRAF wild-type CRC patients with liver-limited metastatic disease. Methods: The primary endpoint was to compare survival outcomes of patients undergoing ST not leading to surgery, liver resection after conversion ST, and hepatic resection with perioperative ST. Furthermore, we explored survival outcomes depending on whether the case was discussed within a multidisciplinary team. Results: Between 2012 and 2020, data from 690 patients respecting the inclusion criteria were collected. Among these, 272 patients were deemed eligible for the analysis. The conversion rate was 24.1% of cases. Fifty-six (20.6%) patients undergoing surgical resection after induction treatment (i.e., ultimately resectable) had a significant survival advantage compared to those receiving systemic treatment not leading to surgery (176 pts, 64.7%) (5-year OS 60.8% and 11.7%, respectively, Log Rank test p < 0.001; HR = 0.273; 95% CI: 0.16–0.46; p < 0.001; 5-year PFS 22.2% and 6.3%, respectively, Log Rank test p < 0.001; HR = 0.447; 95% CI: 0.32–0.63; p < 0.001). There was no difference in survival between ultimately resectable patients and those who had liver resection with perioperative systemic treatment (potentially resectable—40 pts) (5-year OS 71.1%, Log Rank test p = 0.311. HR = 0.671; 95% CI: 0.31–1.46; p = 0.314; 5-year PFS 25.7%, Log Rank test p = 0.305. HR = 0.782; 95% CI: 0.49–1.25; p = 0.306). Conclusions: In our selected population of left-sided RAS/BRAF wild-type colorectal cancer patients with liver-limited disease, a conversion strategy was confirmed to provide a survival benefit. Patients not deemed surgical candidates at the time of diagnosis and patients judged resectable with perioperative systemic treatment have similar survival outcomes.

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Section: Introductionmentioning

confidence: 99%

Conversion Strategy in Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer Patients with Unresectable Liver-Limited Disease: A Multicenter Cohort Study

Granieri

Cotsoglou

Bonomi

et al. 2022

Cancers

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“…cetuximab, panitumumab) in combination with chemotherapy in the metastatic disease ( 10 , 11 ). Therefore, the assessment of RAS and BRAF mutational status is a main step in the diagnostic and therapeutic algorithm of CRC, both for predictive and prognostic aims, particularly in the metastatic disease setting, in order to support physicians in properly choosing the best treatment strategy as first and subsequent lines of treatment both in left- and right-sided tumors ( 12 – 16 ).…”

Section: Introductionmentioning

confidence: 99%

Concurrent RAS and RAS/BRAF V600E Variants in Colorectal Cancer: More Frequent Than Expected? A Case Report

et al. 2022

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The assessment of RAS and BRAF mutational status is one of the main steps in the diagnostic and therapeutic algorithm of metastatic colorectal cancer (mCRC). Multiple mutations in the BRAF and RAS pathway are described as a rare event, with concurrent variants in KRAS and BRAF genes observed in approximately 0.05% of mCRC cases. Here, we report data from a case series affected by high-risk stage III and stage IV CRC and tested for RAS and BRAF mutation, treated at our Medical Oncology Unit. The analysis of KRAS, NRAS (codons 12, 13, 59, 61, 117, 146), and BRAF (codon 600) hotspot variants was performed in 161 CRC tumors from August 2018 to September 2021 and revealed three (1.8%) patients showing mutations in both KRAS and BRAF (V600E), including two cases with earlier CRC and one with metastatic disease. We also identified one patient (0.6%) with a mutation in both KRAS and NRAS genes and another one (0.6%) with a double KRAS mutation. Notably, the latter was characterized by aggressive behavior and poor clinical outcome. The mutational status, pathological features, and clinical history of these five CRC cases are described. Overall, this study case series adds evidence to the limited available literature concerning both the epidemiological and clinical aspects of CRC cases characterized by the presence of concurrent RAS/BRAF variants. Future multicentric studies will be required to increase the sample size and provide additional value to results observed so far in order to improve clinical management of this subgroup of CRC patients.

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“…An anti-epidermal growth factor receptor (EGFR) agent (i.e., cetuximab or panitumumab) added to doublet chemotherapy is currently recommended as the first-line treatment option, particularly in left-sided RAS/BRAF wild-type mCRC (6)(7)(8). However, only few phase 2 studies investigating the role of maintenance (9)(10)(11)(12) or intermittent (13,14) strategies following anti-EGFR-based induction are available.…”

Section: Introductionmentioning

confidence: 99%

Post-Induction Management in Patients With Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR-Based Doublet Regimens: A Multicentre Study

et al. 2021

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BackgroundFew data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available.MethodsThis multicenter, retrospective study aimed at evaluating clinicians’ attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR).ResultsAt the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9–35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3–17.7, 86 events), 13.0 (95%CI = 11.4–14.5, 56 events), 14.0 (95%CI = 8.1–20.0, 8 events), and 10.1 months (95%CI = 9.0–11.2, 136 events), respectively (p < 0.001). The median OS values were 39.6 (95%CI = 31.5–47.7, 43 events), 36.1 (95%CI = 31.6–40.7, 36 events), 39.5 (95%CI = 28.2–50.8, 4 events), and 25.1 months (95%CI = 22.6–27.6, 99 events), respectively (p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44–0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51–0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38–0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51–0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts.ConclusionAmong the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a “real-life” setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.

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Clinicians’ Attitude to Doublet Plus Anti-EGFR Versus Triplet Plus Bevacizumab as First-line Treatment in Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Patients: A Multicenter, “Real-Life”, Case-Control Study

Cited by 9 publications

References 27 publications

Conversion Strategy in Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer Patients with Unresectable Liver-Limited Disease: A Multicenter Cohort Study

Conversion Strategy in Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer Patients with Unresectable Liver-Limited Disease: A Multicenter Cohort Study

Concurrent RAS and RAS/BRAF V600E Variants in Colorectal Cancer: More Frequent Than Expected? A Case Report

Post-Induction Management in Patients With Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR-Based Doublet Regimens: A Multicentre Study

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